Canna~Fangled Abstracts

Chemical constituents of industrial hemp roots and their anti-inflammatory activities

By January 19, 2023No Comments

 2023; 5: 1.
Published online 2023 Jan 16. doi: 10.1186/s42238-022-00168-3
PMCID: PMC9841654
PMID: 36642726
Shijie Huang,#1 Huifang Li,#2 Jun Xu,1 Huihao Zhou,1 Navindra P. Seeram,2 Hang Ma,corresponding author2 and Qiong Gucorresponding author1
Author information Article notes Copyright and License information Disclaimer

Abstract

Objective

Although the chemical constituents of the aerial parts of Cannabis have been extensively studied, phytochemicals of Cannabis roots are not well characterized. Herein, we investigated the chemical constituents of industrial hemp (Cannabis sativa L.) roots and evaluated the anti-inflammatory activities of phytochemicals isolated from the hemp roots extract.

Methods

An ethyl acetate extract of hemp roots was subjected to a combination of chromatographic columns to isolate phytochemicals. The chemical structures of the isolates were elucidated based on spectroscopic analyses (by nuclear magnetic resonance and mass spectrometry). The anti-inflammatory effects of phytochemicals from hemp roots were evaluated in an anti-inflammasome assay using human monocyte THP-1 cells.

Results

Phytochemical investigation of hemp roots extract led to the identification of 32 structurally diverse compounds including six cannabinoids (1–6), three phytosterols (26–28), four triterpenoids (22–25), five lignans (17–21), and 10 hydroxyl contained compounds (7–16), three fatty acids (29–31), and an unsaturated chain hydrocarbon (32). Compounds 14–21, 23, 27, and 32 were identified from the Cannabis species for the first time. Cannabinoids (1–5) reduced the level of cytokine tumor necrosis-alpha (by 38.2, 58.4, 47.7, 52.2, and 56.1%, respectively) and 2 and 5 also decreased the interleukin-1β production (by 42.2 and 92.4%, respectively) in a cell-based inflammasome model. In addition, non-cannabinoids including 11, 13, 20, 25, 29, and 32 also showed selective inhibition of interleukin-1β production (by 23.7, 22.5, 25.6, 78.0, 24.1, 46.6, and 25.4%, respectively) in THP-1 cells.

Conclusion

The phytochemical constituent of a hemp roots extract was characterized and compounds from hemp roots exerted promising anti-inflammatory effects.

Supplementary Information

The online version contains supplementary material available at 10.1186/s42238-022-00168-3.

Keywords: Hemp, Cannabis sp. phytochemicals, Cannabinoids, Inflammasome

Introduction

The medicinal uses of Cannabis roots for a variety of maladies are supported by empirical practice and emerging scientific evidence. The ancient Chinese herbology Compendium of Materia Medica (“Bencao Gangmu” in Chinese or Great Pharmacopoeia) was one of the earliest books that documented the use of hemp (Cannabis sativa L.) roots as a folk medicine to soothe the pain. The traditional Chinese medicine system also uses hemp roots as a common practice to treat Reqi (“hot air” or heatiness)-related symptoms (e.g., mouth ulcers) by indigenous people from Southwest China regions. Modern scientific studies provide more rigorous evidence of the biological activities of cannabis roots. Several pre-clinical studies reported that cannabis root extracts exert various pharmacological effects including anti-inflammatory, estrogenic, liver protective, and anti-cancer activities (Elhendawy et al., ; Kornpointner et al. ; Lima, et al., ; Ryz et al., ). Notably, there are fewer reported studies on cannabis roots as compared to the plant’s aerial parts including the inflorescences and leaves. This is possibly due to the lower density of glandular trichomes in cannabis roots, which leads to a lower level of cannabinoids biosynthesis (Stout et al., ). Moreover, the mechanisms of actions of enzymes that contribute to the biosynthesis of phytochemicals in the roots of cannabis are not fully elucidated (Sirikantaramas and Taura ). Nevertheless, several studies on hemp roots have reported the isolation and identification of several phytochemicals including cannabinoid-type of compounds, such as cannabidiol (CBD), tetrahydrocannabinol (THC), cannabichromene, cannabigerol, and cannabigerolic acid, as well as non-cannabinoid-type of compounds including flavonoids, triterpenes, polyphenols, and alkaloids (Stout et al., ). In addition, a study characterized the cannabinoids content (ranging between 0.001 and 0.004%) in three chemovars, which was lower than the other chemotypes of compounds such as sterols (0.06–0.09%) and triterpenoids (0.13–0.24%) (Jin et al. ). Notably, some unique compounds have been isolated from cannabis roots. For instance, a phenolic amide, namely, N-trans-coumaroyltyramine, was isolated from the roots of a Cannabis sp. grown in Mississippi, USA (Pollastro et al., ). In addition, several arylnapthalene-type of compounds including cannabisins B and G were only found in fruits and roots of cannabis (Sakakibara et al., ). However, to date, the phytochemical constituents of hemp roots and their biological activities are not been fully investigated. Our group has initiated a program to systematically investigate the biological activities of non-psychedelic cannabinoids (Liu et al., , , ; Ma, Li, et al., ; Ma, Xu, et al., ; Puopolo et al., ). During this course, we revealed that the anti-inflammatory activity of CBD is associated with its inhibitory effect on the activation of NLR-family-pyrin-domain-containing 3 (NLR3) inflammasome, which is a vital molecular target for the production of pro-inflammatory cytokine (i.e., interleukin 1 beta; IL-1β) (Liu et al. ). However, the phytochemical constituents of hemp roots from the region of Southwest China (i.e., Yunnan Province) and the inhibitory effects of cannabinoids from hemp roots are still not clear. Herein, we report the isolation and identification of phytochemicals of hemp roots as well as the biological evaluation of isolated phytochemicals from hemp roots using a cell-based inflammasome model.

Materials and methods

Chemical reagents

The roots of industrial hemp were provided by Mawang Shenzhen Co. Ltd. (Shenzhen, China) and a voucher sample (No. MG20191230) is deposited in the School of Pharmaceutical Sciences of Sun Yat-Sen University. Lipopolysaccharides (LPS), nigericin, phorbol 12-myristate 13-acetate (PMA), and phosphate-buffered saline were purchased from Sigma-Aldridge Chemical Co (St. Louis, MO, USA).

Extraction and isolation

Dried hemp roots (20 kg) were pulverized and extracted with 95% EtOH (3 × 150 L) for 48 h at room temperature. The solvent was evaporated in vacuo, and the dried ethyl acetate extract (732 g) was suspended in water and partitioned with ethyl acetate 3 times to obtain an ethyl acetate extract (350 g). This extract was chromatographed over a combination of columns (silica gel, Sephadex LH-20, thin-layer chromatography, and semi-preparative HPLC) using various eluting solvents to obtain following purified compounds (see detailed separation and purification in the Supplementary Data): compounds 1 (4 mg, 0.00002%), 2 (31 mg, 0.000155%), 3 (12 mg, 0.00006%), 4 (7 mg, 0.000035%), 5 (9 mg, 0.000045%), 6 (6 mg, 0.00003%), 7 (12 mg, 0.00006%), 8 (90 mg, 0.00045%), 9 (48 mg, 0.00024%), 10 (22 mg, 0.00011%), 11 (125 mg, 0.000625%), 12 (8 mg, 0.00004%), 13 (9 mg, 0.000045%), 14 (11 mg, 0.000055%) 15 (30 mg, 0.00015%), 16 (6 mg, 0.00003%), 17 (43 mg, 0.000215%), 18 (89 mg, 0.000445%), 19 (8 mg, 0.00004%), 20 (67 mg, 0.000335%), 21 (314 mg, 0.00157%), 22 (28 mg, 0.00014%), 23 (17 mg, 0.000085%), 24 (239 mg, 0.001195%), 25 (1.3 g, 0.0065%), 26 (15 mg, 0.000075%), 27 (14 mg, 0.00007%), 28 (18 mg, 0.00009%), 29 (31 mg, 0.000155%), 30 (51 mg, 0.000255%), 31 (25 mg, 0.000125%), and 32 (14 mg, 0.00007%).

Cell culture

Human monocyte THP-1 cells were purchased from the American Type Culture Collection (ATCC, Rockville, MD, USA) and cultured in the Roswell Park Memorial Institute 1640 medium supplemented with 10% fetal bovine serum (Gibco, Life Technologies, Gaithersburg, MD, USA).

Inflammasome inhibition assay

The anti-inflammasome effects of cannabinoids isolated from hemp root were evaluated by measuring the production of lipopolysaccharide (LPS)- and nigericin-induced secretion of pro-inflammatory cytokines including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) using a previously reported method (Liu et al. ). Briefly, THP-1 cells were seeded at a density of 5 × 104 cells per well in a 48-well plate and differentiated with phorbol 12-myristate 13-acetate (PMA) (25 nM) for 48 h. Then, culture medium was removed and replaced with PMA-free medium for 24 h. Next, LPS (100 ng/mL) was added and incubated for 4 h, followed by adding hemp root samples (compounds 1–5; 50 µM) and further incubated for 1 h. Then, nigericin (10 µM) was added and incubated with the cells for 4 h. The cell culture supernatant was collected to measure the levels of IL-1β and TNF-α using the ELISA kits (BioLegend, San Diego, CA, USA).

Statistical analysis

Data are presented as mean ± standard deviation of values from three replicated experiments. Statistical analysis was performed using the GraphPad Prism9 software (GraphPad, La Jolla, CA, USA) with a one-way analysis of variance with multiple comparisons. The significance was noted as p < 0.05 (*), p < 0.01 (**), p < 0.001 (***), and p < 0.0001 (****).

Results and discussion

Isolation and identification of phytochemicals isolated from hemp roots

Thirty-two phytochemicals (1–32) were isolated from the hemp roots extract, and their chemical structures (Fig. 1) were elucidated on the basis of spectroscopic analysis (by NMR and MS) and comparisons of the literature reported values as follows: cannabinol (1) (Wang et al., ); (9R,10 S)-6,6,9-trimethyl-3-pentyl-7,8,9,10-tetrahydro-6 H-benzo[c]chromene-1,9,10-triol (2) (Li et al., ); (-)-7R-cannabicoumarononic acid A (3) (Radwan et al., ); (9R,10 S)-6,6,9-trimethyl-3-propyl-7,8,9,10-tetrahydro-6 H-benzo[c]chromene-1,9,10-triol (4) (Li et al., ); cannabivarin (5) (Wang et al., ); cannabidiol (6) (Marchetti et al. ); 4-hydroxy-3-methoxybenzaldehyde (7) (Ito et al., ); 4-hydroxybenzaldehyde (8) (Bouaicha et al., ); 4-hydroxy-3,5-dimethoxybenzaldehyde (9) (Xue et al., ); syringic acid (10) (Queirós et al., ); vanillic acid (11) (Xu et al. ); 2,6-dimethoxyphenol (12) (Goda et al., ); (2E)-3-(4-hydroxyphenyl)-2-propenoic acid (13) (Seal, ); (3 S)-3-hydroxy-β-ionone (14) (DellaGreca et al., ); (-)-dihydrovomifoliol (15) (Bennett et al., ); 1 H-indole-3-carboxaldehyde (16) (Wang et al., ); 3-(4-hydroxyphenyl)-2-propenoic acid ethyl ester (17) (Pizzolatti et al., ); 4-hydroxyphenethyl trans-ferulate (18) (Fujita et al., ); 1,2-diguaiacyl-1-ethoxy-3-propanol (19) (Mohammed et al., ); (+)-4-ketopinoresinol (20) (Chen et al., ); dadahol A (21) (Devanathan and Stalin ); (+)-oleanolic acid (22) (He et al., ), epipseudotaraxastanediol (23) (Hinge et al., ); 3-epifriedelinol (24) (Sousa et al., ); 9,12-octadecadienoic acid (9Z,​12Z)​-​friedelin (25) (Zhou & Guo, ); β-sitosterol (26) (Kadowaki et al., ); 5α,8α-epidioxy-(22E,24R)-ergosta-6,22-dien-3β-ol (27) (Gao et al., ); stigmast-​4-​en-3-one (28) (Smania et al., ); 9,​12-​octadecadienoic acid (9Z,​12Z)​-​methyl ester (29) (Huh et al., ); α-linolenic acid (30) (Kishino et al., ); linoleic acid (31) (Yoon et al., ); and dotriacont-1-ene (32) (Chen et al., ). The isolated phytochemicals can be divided into two classes, the cannabinoid-type (1–6) and the non-cannabinoid-type (7–32). Among the cannabinoids, compound 1 (cannabinol) is a derivative of tetrahydrocannabinol, which is the major psychedelic (hallucinogenic substance triggering non-ordinary states of consciousness, also referred to as psychoactive or psychotropic) cannabinoid found in cannabis (Sampson, ). In contrast to tetrahydrocannabinol, cannabinol only shows mild psychedelic effects (Rhee et al., ). Other cannabinoid-type compounds isolated from the hemp roots were non-psychedelic (Fig. 1).

An external file that holds a picture, illustration, etc. Object name is 42238_2022_168_Fig1_HTML.jpg

Chemical structures of compounds 1–32 including cannabinoids (1–6) and non-cannabinoids (7–32) isolated from hemp roots

Apart from cannabinoid-type compounds (1–6), several non-cannabinoid compounds were identified from hemp roots. These phytochemicals included three phytosterols (26–28), four triterpenoids (22–25), and five lignans (17–21). Several compounds were isolated and identified from Cannabis sp. for the first time as follows. Compounds 20, 21, 23, and 27 were reported from the Cannabis species for the first time. Additionally, 10 hydroxyl-contained compounds (7–16) were isolated from the hemp roots. Among these, compounds 14–19 were identified from Cannabis for the first time. Moreover, three fatty acids (29–31) and an unsaturated hydrocarbon (32) were identified in Cannabis for the first time.

Anti-inflammatory effects of phytochemicals isolated from hemp roots

Our group has previously reported that CBD, the major non-psychedelic cannabinoid in cannabis, confers the anti-inflammatory effect via a specific mechanism, namely, inhibition of inflammasome activation (Liu et al. ). However, it is not clear whether other cannabinoids from the hemp roots are inflammasome inhibitors. Thus, an inflammasome inhibition assay was performed to evaluate the anti-inflammatory effects of cannabinoids isolated from hemp roots. The production of IL-1β and TNF-α in inflammasome inducers (LPS and nigericin) stimulated THP-1 cells were significantly increased as compared to the control group (6.1 vs. 1211.6 and 13.0 vs. 102.6 pg/mL, respectively), suggesting that inflammasome in THP-1 cells was activated by the stimulation with LPS and nigericin. Compounds 2 and 5 (50 µM) counteracted LPS-nigericin-induced production of IL-1β by 42.2% and 92.4%, respectively (Fig. 2A). Cannabinoids (1–5) reduced the level of TNF-α by 38.2%, 58.4%, 47.7%, 52.2%, and 56.1%, respectively (Fig. 2B). To confirm whether the anti-inflammatory of these cannabinoids were selective inhibitors of the inflammasome, we used a small molecule with known a selective inflammasome inhibitor effect (Wu et al., ), namely, MCC950, as a positive control. MCC950 (10 µM) showed a specific inhibitory effect against the activation of the inflammasome by reducing the level of IL-1β (by 95.8%) without decreasing the level of TNF-α. Additionally, a small molecule with inhibitory effects on the production of TNF-α (DaSilva et al., ; Xu et al., ), namely, urolithin A, was included as a positive control (as a TNF-α inhibitor) to validate the anti-inflammatory assay. Urolithin A reduced the level of TNF-α by 51.7% as compared to the model group. With these validated bioassays, we were able to evaluate the selective anti-inflammasome activity of the isolates. Although our previously reported study showed that CBD is a specific inflammasome inhibitor (Liu et al. ), cannabinoids isolated from hemp roots extract exerted general anti-inflammatory effects rather than specific inhibition of inflammasome activation. The inhibitory effects of cannabinoids from hemp roots on the secretion of pro-inflammatory cytokine (TNF-α) may be accounted for the overall anti-inflammatory activities of Cannabis roots extracts in previously reported studies (Lima, et al., ; Ryz et al., ). However, several factors that may influence the anti-inflammatory effects of tested cannabinoids should be examined. For instance, the cytotoxicity of these cannabinoids in THP-1 cells may be accounted for the reduction of the pro-inflammatory cytokines. Thus, we assessed the viability of THP-1 cells treated with cannabinoids. Compounds 1–4 showed no significant cytotoxic effect (viability > 95%) at the concentration used for the anti-inflammasome assay (50 µM) whilst cannabivarin (5) reduced the cell viability by 54.7%, which possibly contributed to its suppressive effect on the production of IL-1β and TNF-α (see cell viability data in the Supplementary Data Figure S1). Therefore, further mechanistic investigation on the anti-inflammatory effects of cannabinoids from hemp roots should be conducted at non-cytotoxic concentrations. Nevertheless, this is the first study on the specific anti-inflammasome activity of cannabinoids isolated from hemp roots.

An external file that holds a picture, illustration, etc. Object name is 42238_2022_168_Fig2_HTML.jpg

Anti-inflammatory effects of cannabinoids (1–5) isolated from hemp roots. Inflammasome activation in THP-cells was induced by the stimulation with LPS-nigericin. Effects of 1–5 (at 50 µM) on the production of pro-inflammatory cytokines including IL-1β (A) and TNF-α (B). Data are presented as means ± standard deviation from samples with three replicated experiments (n = 3). Statistical analysis was performed with a one-way analysis of variance with multiple comparisons and the significance was noted as: ***p < 0.001, ****p < 0.0001 vs. the model (LPS-nigericin stimulated) group and ####p < 0.0001 vs. the control group

As none of the cannabinoids showed a selective inhibitory effect on inflammasome, we expanded the test samples for the anti-inflammation assay and further evaluated the suppressive effects of other isolates (7–32) on the production of IL-1β (Figure S2). At a concentration of 50 µM, compounds 11, 13, 19, 20, 25, 29, and 32 reduced the production of IL-1β by 23.7, 22.5, 25.6, 78.0, 24.1, 46.6, and 25.4%, respectively (Fig. 3A). These active compounds belong to different chemotypes including simple phenolics (11 and 13), lignans (19 and 20), triterpenoid (25), and unsaturated fatty acids (29 and 32). These active compounds were further assayed in the TNF-α inhibition assay, which showed that, apart from 19, they were inactive in reducing TNF-α production (Fig. 3B). Thus, compounds 11, 13, 20, 25, 29, and 32 showed an inhibitory effect on the activation of the inflammasome and they may contribute to the overall anti-inflammatory activity of cannabis (Lima, et al., ; Ryz et al., ). The selective inhibitory effects of compounds 11, 13, 20, 25, 29, and 32 on TNF-α production were in agreement with previously reported studies showing that these types of compounds were inflammasome inhibitors (Guo et al., ; L’homme et al., ; Ma, Huang, et al., ; Villar-Lorenzo et al., ). Further mechanistic studies are warranted to elucidate whether other pathways (e.g., via the antagonistic effect against the P2 × 7 receptor (Liu et al. )) were involved in the anti-inflammasome effects of these compounds from Cannabis roots.

An external file that holds a picture, illustration, etc. Object name is 42238_2022_168_Fig3_HTML.jpg

Anti-inflammatory effects of non-cannabinoids isolated from hemp roots (11, 13, 19, 20, 25, 29, and 32). Inflammasome activation in THP-cells was induced by the stimulation with LPS-nigericin. Effects of 11, 13, 19, 20, 25, 29, and 32 (at 50 µM) on the production of pro-inflammatory cytokines including IL-1β (A) and TNF-α (B). Data are presented as means ± standard deviation from samples with three replicated experiments (n = 3). Statistical analysis was performed with a one-way analysis of variance with multiple comparisons and the significance was noted as: *p < 0.005, ****p < 0.0001 vs. the model (LPS-nigericin stimulated) group and ####p < 0.0001 vs. the control group

In summary, a phytochemical investigation of a hemp roots extract led to the identification of 32 compounds including six cannabinoids (1–6) and 26 non-cannabinoid compounds. Isolates 14–21, 23, 27, and 32 were reported from Cannabis for the first time. Cannabinoids from the hemp roots extract exerted anti-inflammatory effects by reducing pro-inflammatory cytokines in an inflammasome model with THP-1 cells. Cannabinoids 2 and 5 reduced LPS-nigericin-induced production of cytokines IL-1β (by 42.2% and 92.4%, respectively) and TNF-α (by 58.4% and 56.1%, respectively). In addition, non-cannabinoids type compounds including 11, 13, 19,20, 25, 29, and 32 also showed promising anti-inflammatory effects. Findings from the current study expanded the understanding of the phytochemical constituents of cannabis roots and their anti-inflammatory effects, which may provide useful information for the utilization of cannabis roots as bioactive natural products.

Supplementary Information

 

Acknowledgements

Spectroscopic instruments used for the completion of the biological evaluations in this study were located in the RI-INBRE core facility supported by Grant # P20GM103430 from the National Institute of General Medical Sciences of the National Institutes of Health.

Abbreviations

CBD Cannabidiol
HPLC High-performance liquid chromatography
IL–1β Interleukin 1 beta
LPS Lipopolysaccharides
MS Mass spectrometry
NLR3 NLR family pyrin domain containing 3
NMR Nuclear magnetic resonance
PMA Phorbol 12-myristate 13-acetate
THC Tetrahydrocannabinol
TNF-α Tumor necrosis factor-α

Authors’ contributions

HM and QG conceived and designed the overall project; SH conducted the phytochemical isolation and identification; HL conducted the biological evaluations; JX, HZ, and NPS supervised the study; SH and HL wrote the manuscript; HM and QG extensively edited the manuscript. The author(s) read and approved the final manuscript.

Authors’ information

Not applicable.

Funding

The phytochemical investigation including the isolation and identification of compounds in the hemp root extract was supported by a research contract between Mawang Shenzhen Co. Ltd and Sun Yat-sen University (HT-99982019-0530).

Availability of data and materials

The data used for this study are available from the corresponding authors with a reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable. No human subjects involved in this study.

Consent for publication

Not applicable. No human subjects involved in this study.

Competing interests

J.X. received funding from a research contract between Mawang Shenzhen Co. Ltd and Sun Yat-sen University (HT-99982019-0530). Mawang Shenzhen provided the materials of hemp roots but did not involve in the design, investigation, and presentation of this study. Other authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

 

Shijie Huang and Huifang Li contributed equally to this work.

 

Contributor Information

Hang Ma, ude.iru@am_gnah.

Qiong Gu, nc.ude.usys.liam@gnoiqug.

References

  • Bennett RD, Norman SM, Maier VP. Intermediate steps in the biosynthesis of abscisic acid from farnesyl pyrophosphate in Cercospora rosicola. Phytochemistry. 1990;29(11):3473–7. doi: 10.1016/0031-9422(90)85260-M. [CrossRef] []
  • Bouaicha N, Amade P, Puel D, Roussakis C. Zarzissine, a new cytotoxic guanidine alkaloid from the Mediterranean sponge Anchinoe paupertas. J Nat Prod. 1994;57(10):1455–7. doi: 10.1021/NP50112A019. [PubMed] [CrossRef] []
  • Chen JJ, Lin WJ, Shieh PC, Chen IS, Peng CF, Sung PJ. A New Long-Chain Alkene and Antituberculosis Constituents from the Leaves of Pourthiaea lucida. Chem Biodivers. 2010;7(3):717–21. doi: 10.1002/CBDV.200900198. [PubMed] [CrossRef] []
  • Chen HH, Chen YT, Huang YW, Tsai HJ, Kuo CC. 4-Ketopinoresinol, a novel naturally occurring ARE activator, induces the Nrf2/HO-1 axis and protects against oxidative stress-induced cell injury via activation of PI3K/AKT signaling. Free Radic Biol Med. 2012;52(6):1054–66. doi: 10.1016/J.FREERADBIOMED.2011.12.012. [PubMed] [CrossRef] []
  • DaSilva NA, Nahar PP, Ma H, Eid A, Wei Z, Meschwitz S, Zawia NH, Slitt AL, Seeram NP. Pomegranate ellagitannin-gut microbial-derived metabolites, urolithins, inhibit neuroinflammation in vitro. Nutr Neurosci. 2019;22(3):185–95. doi: 10.1080/1028415X.2017.1360558. [PubMed] [CrossRef] []
  • DellaGreca M, di Marino C, Zarrelli A, D’Abrosca B. Isolation and phytotoxicity of apocarotenoids from Chenopodium album. J Nat Prod. 2004;67(9):1492–5. doi: 10.1021/NP049857Q. [PubMed] [CrossRef] []
  • Devanathan K, Stalin AN. Artocarpus heterophyllus Lam (Moraceae) 2020. pp. 1–11. []
  • Elhendawy MA, Wanas AS, Radwan MM, Azzaz NA, Toson ES, Elsohly MA. Chemical and biological studies of cannabis sativa roots. Med Cannabis Cannabinoids. 2019;1(2):104–11. doi: 10.1159/000495582. [PMC free article] [PubMed] [CrossRef] []
  • Fujita T, Kadoya Y, Aota H, Nakayama M. A new phenylpropanoid glucoside and other constituents of Oenanthe javanica. Bioscience Biotechnol Biochem. 1995;59(3):526–8. doi: 10.1271/BBB.59.526. [PubMed] [CrossRef] []
  • Gao JM, Wang M, Liu LP, Wei GH, Zhang AL, Draghici C, Konishi Y. Ergosterol peroxides as phospholipase A2 inhibitors from the fungus Lactarius hatsudake. Phytomedicine. 2007;14(12):821–4. doi: 10.1016/J.PHYMED.2006.12.006. [PubMed] [CrossRef] []
  • Goda Y, Shibuya M, Sankawa U. Inhibitors of prostaglandin biosynthesis from Mucuna birdwoodiana. Chem Pharm Bull. 1987;35(7):2675–7. doi: 10.1248/CPB.35.2675. [PubMed] [CrossRef] []
  • Guo M, An F, Yu H, Wei X, Hong M, Lu Y. Comparative effects of schisandrin A, B, and C on Propionibacterium acnes-induced, NLRP3 inflammasome activation-mediated IL-1β secretion and pyroptosis. Biomed Pharmacother. 2017;96:129–36. doi: 10.1016/J.BIOPHA.2017.09.097. [PubMed] [CrossRef] []
  • He H, Li H, Akanji T, Niu S, Luo Z, Li D, Seeram NP, Wu P, Ma H. Synthesis and biological evaluations of oleanolic acid indole derivatives as hyaluronidase inhibitors with enhanced skin permeability. J Enzyme Inhib Med Chem. 2021;36(1):1665–78. doi: 10.1080/14756366.2021.1956487. [PMC free article] [PubMed] [CrossRef] []
  • Hinge VK, Paknikar SK, Das KG, Bose AK, Bhattacharyya SC. Terpenoids-LXXXVI. Structure of epi-ψ-taraxastanonol and epi-ψ-taraxastanediol. Tetrahedron. 1966;22(8):2861–8. doi: 10.1016/S0040-4020(01)99077-5. [CrossRef] []
  • Huh S, Kim YS, Jung E, Lim J, Jung KS, Kim MO, Lee J, Park D. Melanogenesis inhibitory effect of fatty acid alkyl esters isolated from Oxalis triangularis. Biol Pharm Bull. 2010;33(7):1242–5. doi: 10.1248/BPB.33.1242. [PubMed] [CrossRef] []
  • Ito J, Chang FR, Wang HK, Park YK, Ikegaki M, Kilgore N, Lee KH. Anti-AIDS agents. 48.(1) Anti-HIV activity of moronic acid derivatives and the new melliferone-related triterpenoid isolated from Brazilian propolis. J Nat Prod. 2001;64(10):1278–81. doi: 10.1021/NP010211X. [PubMed] [CrossRef] []
  • Jin D, Dai K, Chen J. Secondary metabolites profiled in cannabis inflorescences, leaves, stem barks, and roots for medicinal purposes. Sci Rep. 2020;10(1):1–14. [PMC free article] [PubMed] []
  • Kadowaki E, Yoshida Y, Baba N, Nakajima S. Feeding stimulative activity of steroidal and secoiridoid glucosides and their hydrolysed derivatives toward the olive weevil (Dyscerus perforatus) Z Fur Naturforschung – Sect C J Biosci. 2003;58(5–6):441–5. doi: 10.1515/ZNC-2003-5-625/HTML. [PubMed] [CrossRef] []
  • Kishino S, Ogawa J, Ando A, Shimizu S. Conjugated α-linolenic acid production from α-linolenic acid by Lactobacillus plantarum AKU 1009a. Eur J Lipid Sci Technol. 2003;105(10):572–7. doi: 10.1002/EJLT.200300806. [CrossRef] []
  • Kornpointner C, Sainz Martinez A, Marinovic S, Haselmair-Gosch C, Jamnik P, Schröder K, Löfke C, Halbwirth H. (2021). Chemical composition and antioxidant potential of Cannabis sativa L. roots.Industr Crops Prod.165.10.1016/j.indcrop.2021.113422.
  • L’homme L, Esser N, Riva L, Scheen A, Paquot N, Piette J, Legrand-Poels S. Unsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages. J Lipid Res. 2013;54(11):2998–3008. doi: 10.1194/jlr.M037861. [PMC free article] [PubMed] [CrossRef] []
  • Li J, Wang G, Qin Y, Zhang X, Wang HF, Liu HW, Zhu LJ, Yao XS. Neuroprotective constituents from the aerial parts of Cannabis sativa L. subsp. sativa. RSC Adv. 2020;10(53):32043–9. doi: 10.1039/D0RA04565A. [PMC free article] [PubMed] [CrossRef] []
  • Lima KSB, da Cruz Silva MEG, de Lima Araújo TC, da Fonseca Silva CP, Santos BL, de Araújo Ribeiro LA, Menezes PMN, Silva MG, Lavor ÉM, Silva FS, Nunes XP. Cannabis roots: Pharmacological and toxicological studies in mice. J Ethnopharmacol. 2021;271(10):113868. doi: 10.1016/j.jep.2021.113868. [PubMed] [CrossRef] []
  • Liu C, Cai A, Li H, Deng N, Cho BP, Seeram NP, Ma H. Characterization of molecular interactions between cannabidiol and human plasma proteins (serum albumin and γ-globulin) by surface plasmon resonance, microcalorimetry, and molecular docking. J Pharm Biomed Anal. 2022;214:114750. doi: 10.1016/J.JPBA.2022.114750. [PubMed] [CrossRef] []
  • Liu C, Li H, Xu F, Jiang X, Ma H, Seeram N. (2021). Cannabidiol protects human skin keratinocytes from hydrogen-peroxide-induced oxidative stress via modulation of the caspase-1–IL-1β axis. J Nat Prod, 84(5), 1563–1572. 10.1021/acs.jnatprod.1c00083. [PubMed]
  • Liu C, Ma H, Slitt L, A., & Seeram P, N. (2020). Inhibitory effect of cannabidiol on the activation of NLRP3 inflammasome is associated with its modulation of the P2X7 receptor in human monocytes. J Nat Prod, 0(0). 10.1021/acs.jnatprod.0c00138. [PubMed]
  • Ma H, Li H, Liu C, Seeram NP. Evaluation of cannabidiol’s inhibitory effect on alpha-glucosidase and its stability in simulated gastric and intestinal fluids. J Cannabis Res. 2021;3(1):20. doi: 10.1186/S42238-021-00077-X. [PMC free article] [PubMed] [CrossRef] []
  • Ma H, Xu F, Liu C, Seeram NP. A network pharmacology approach to identify potential molecular targets for cannabidiol’s anti-inflammatory activity. Cannabis Cannabinoid Res. 2021;6(4):288–99. doi: 10.1089/CAN.2020.0025/SUPPL_FILE/SUPPL_FIGS5.PDF. [PMC free article] [PubMed] [CrossRef] []
  • Ma Z, Huang Z, Zhang L, Li X, Xu B, Xiao Y, Shi X, Zhang H, Liao T, Wang P. Vanillic acid reduces pain-related behavior in knee osteoarthritis rats through the inhibition of NLRP3 inflammasome-related synovitis. Front Pharmacol. 2021;11:2445. doi: 10.3389/FPHAR.2020.599022/XML/NLM. [PMC free article] [PubMed] [CrossRef] []
  • Marchetti L, Brighenti V, Rossi MC, Sperlea J, Pellati F, Bertelli D (2019). Use of 13C-qNMR spectroscopy for the analysis of non-psychoactive cannabinoids in fibre-type Cannabis sativa L. (Hemp). Molecules, 24(6). 10.3390/MOLECULES24061138. [PMC free article] [PubMed]
  • Mohammed F, Sibley P, Guillaume D, Abdulwali N. Chemical composition and mineralogical residence of maple syrup: a comprehensive review. Food Chem. 2022;374:131817. doi: 10.1016/J.FOODCHEM.2021.131817. [PubMed] [CrossRef] []
  • Pizzolatti MG, Verdi LG, Brighente IMC, Neiva TDJC, Schripsema J, Filho RB. Anticoagulant effect and constituents of Baccharis illinita. Nat Prod Commun. 2006;1(1):37–42. doi: 10.1177/1934578X0600100107. [CrossRef] []
  • Pollastro F, Minassi A, Fresu LG. Cannabis phenolics and their bioactivities. Curr Med Chem. 2018;25(10):1160–85. doi: 10.2174/0929867324666170810164636. [PubMed] [CrossRef] []
  • Puopolo T, Liu C, Ma H, Seeram NP. Inhibitory effects of cannabinoids on acetylcholinesterase and butyrylcholinesterase enzyme activities. Med Cannabis Cannabinoids. 2022;5(1):85–94. doi: 10.1159/000524086. [PMC free article] [PubMed] [CrossRef] []
  • Queirós CSGP, Cardoso S, Ferreira J, Miranda I, Lourenço MJv, Pereira H. Characterization of Hakea sericea fruits regarding chemical composition and extract properties. Waste Biomass Valoriz. 2020;11(9):4859–70. doi: 10.1007/S12649-019-00818-3. [CrossRef] []
  • Radwan MM, ElSohly MA, Slade D, Ahmed SA, Khan IA, Ross SA. Biologically active cannabinoids from high-potency Cannabis sativa. J Nat Prod. 2009;72(5):906–11. doi: 10.1021/NP900067K. [PMC free article] [PubMed] [CrossRef] []
  • Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanuš L, Breuer A, Mechoulam R. Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase. J Med Chem. 1997;40(20):3228–33. doi: 10.1021/JM970126F. [PubMed] [CrossRef] []
  • Ryz NR, Remillard DJ, Russo EB. Cannabis roots: a traditional therapy with future potential for treating inflammation and pain. Cannabis Cannabinoid Res. 2017;2(1):210–6. doi: 10.1089/can.2017.0028. [PMC free article] [PubMed] [CrossRef] []
  • Sakakibara I, Ikeya Y, Hayashi K, Okada M, Maruno M. Three acyclic bis-phenylpropane lignanamides from fruits of Cannabis sativa. Phytochemistry. 1995;38(4):1003–7. doi: 10.1016/0031-9422(94)00773-M. [PubMed] [CrossRef] []
  • Sampson PB. Phytocannabinoid pharmacology: medicinal properties of Cannabis sativa constituents aside from the “Big Two” J Nat Prod. 2021;84(1):142–60. doi: 10.1021/ACS.JNATPROD.0C00965. [PubMed] [CrossRef] []
  • Seal T. Antioxidant and Antiinflammatory Activities of Different Solvent Extracts and Isolated Compounds of Ipomoea pes-caprae (L) Sweet of Sunderban Mangrove Eco-complex. Asian J Chem. 2013;25(9):4997–5000. doi: 10.14233/ajchem.2013.14226. [CrossRef] []
  • Sirikantaramas S, Taura F. (2017). Cannabinoids: biosynthesis and biotechnological applications. Cannabis Sativa L – Bot Biotechnol. 183–206. 10.1007/978-3-319-54564-6_8/FIGURES/10.
  • Smania EFA, Monache D, Smania F, Yunes A, Cuneo RS. Antifungal activity of sterols and triterpenes isolated from Ganoderma annulare. Fitoterapia. 2003;74(4):375–7. doi: 10.1016/S0367-326X(03)00064-9. [PubMed] [CrossRef] []
  • Sousa GF, Ferreira FL, Duarte LP, Silva GDF, Messias MCTB, Vieira Filho SA. Structural determination of 3β,11β-dihydroxyfriedelane from Maytenus robusta (Celastraceae) by 1D and 2D NMR. J Chem Res. 2012;36(4):203–5. doi: 10.3184/174751912X13318236224684. [CrossRef] []
  • Stout JM, Boubakir Z, Ambrose SJ, Purves RW, Page JE. The hexanoyl-CoA precursor for cannabinoid biosynthesis is formed by an acyl-activating enzyme in Cannabis sativa trichomes. Plant J. 2012;71(3):353–65. doi: 10.1111/j.1365-313X.2012.04949.x. [PubMed] [CrossRef] []
  • Villar-Lorenzo A, Ardiles AE, Arroba AI, Hernández-Jiménez E, Pardo V, López-Collazo E, Jiménez IA, Bazzocchi IL, González-Rodríguez Á, Valverde ÁM. Friedelane-type triterpenoids as selective anti-inflammatory agents by regulation of differential signaling pathways in LPS-stimulated macrophages. Toxicol Appl Pharmcol. 2016;313:57–67. doi: 10.1016/J.TAAP.2016.10.004. [PubMed] [CrossRef] []
  • Wang RP, Lin HW, Li LZ, Gao PY, Xu Y, Song SJ. Monoindole alkaloids from a marine sponge Mycale fibrexilis. Biochem Syst Ecol. 2012;43:210–3. doi: 10.1016/J.BSE.2012.03.016. [CrossRef] []
  • Wang G, Zhu L, Zhao Y, Gao S, Sun D, Yuan J, Huang Y, Zhang X, Yao X. A natural product from Cannabis sativa subsp. sativa inhibits homeodomain-interacting protein kinase 2 (HIPK2), attenuating MPP +-induced apoptosis in human neuroblastoma SH-SY5Y cells. Bioorg Chem. 2017;72:64–73. doi: 10.1016/J.BIOORG.2017.03.011. [PubMed] [CrossRef] []
  • Wu D, Chen Y, Sun Y, Gao Q, Li H, Yang Z, Wang Y, Jiang X, Yu B. Target of MCC950 in Inhibition of NLRP3 inflammasome activation: a literature review. Inflammation. 2020;43(1):17–23. doi: 10.1007/S10753-019-01098-8. [PubMed] [CrossRef] []
  • Xu J, Yuan C, Wang G, Luo J, Ma H, Xu L, Mu Y, Li Y, Seeram NP, Huang X, Li L. Urolithins Attenuate LPS-Induced Neuroinflammation in BV2Microglia via MAPK, Akt, and NF-κB Signaling Pathways. J Agric Food Chem. 2018;66(3):571–80. doi: 10.1021/ACS.JAFC.7B03285. [PubMed] [CrossRef] []
  • Xu Z, Wang C, Yan H, Zhao Z, You L, Ho CT. (2022). Influence of phenolic acids/aldehydes on color intensification of cyanidin-3-O-glucoside, the main anthocyanin in sugarcane (Saccharum officinarum L.). Food Chem. 373(Pt A) 10.1016/J.FOODCHEM.2021.131396. [PubMed]
  • Xue Y, Yao G, Hu Z, Luo Z, Wang Y, Zhang Y. Chemical constituents from the leaves of Premna microphylla Turcz. Researchgate Net. 2013;6(3):4. doi: 10.5246/jcps.2013.05.063. [CrossRef] []
  • Yoon JY, Kim JH, Baek KS, Kim GS, Lee SE, Lee DY, Choi JH, Kim SY, Park HB, Sung GH, Lee KR, Cho JY, Noh HJ. A direct protein kinase B-targeted anti-inflammatory activity of cordycepin from artificially cultured fruit body of Cordyceps militaris. Pharmacogn Mag. 2015;11(43):477–85. doi: 10.4103/0973-1296.160454. [PMC free article] [PubMed] [CrossRef] []
  • Zhou W, Guo S. Components of the sclerotia of Polyporus umbellatus. Chem Nat Compd. 2009;45(1):124–5. doi: 10.1007/S10600-009-9229-X. [CrossRef] []
Articles from Journal of Cannabis Research are provided here courtesy of BioMed Central

Leave a Reply