Research Progress on Chemical Constituents and Pharmacological Effects of Laportea bulbifera

Ao XIE Yongjing SU Gan LUO Qi WU Haicheng WEN

Abstract Laportea bulbifera (Sieb. et Zucc.) Wedd. is a perennial herb of Laportea in Urticaceae. At present, more than 90 compounds have been isolated from L. bulbifera, mainly including flavonoids, coumarins, phenolic acids, esters, ketones, phenylpropanoids and steroids, which have anti-inflammatory and analgesic, immunosuppressive, anti-oxidant, hypoglycemic and lipid-lowering pharmacological effects. This article summarized the research progress of the pharmacological effects and the chemical constituents of L. bulbifera in recent years, hoping to provide references for its further research and development.

Key words Laportea bulbifera; Chemical composition; Pharmacological effects

Received: March 5, 2021  Accepted: May 6, 2021

Supported by Research Fund of Guangxi Colleges and Universities (YB2014192); Guangxi Key R&D Program (GK AB19110027); High-level Innovation Team and Outstanding Scholars Project of Guangxi Colleges and Universities: Zhuang Medical Foundation and Clinical Innovation Team (GJR［2014］07).

Ao XIE (1999-), female, P. R. China, master, devoted to research about development, identification and quality evaluation of traditional Chinese medicine and ethnic medicine.

*Corresponding author.

Laportea bulbifera (Sieb. et Zucc.) Wedd. is a perennial herb of Laportea in Urticaceae, also known as Honghema, Honghuoma, Ruidagun or Wadou, also known as Mafengcao in Fuchuan, Guangxi. The whole herb or roots are used as a medicine. The whole herb tastes pungent and warm in nature. It is a Zhuang medicine for clearing the Gudao, which has the effects of clearing the Gudao and tonifying the spleen and removing food retention. It is often used by Zhuang doctors in the treatment of infantile malnutrition (chancre) and urinary tract stones. The roots of L. bulbifera are pungent in taste and warm in nature, and have the effects of clearing the Longlu and Huolu, dispelling wind and dampness, and promoting blood circulation and relieving pain. Zhuang doctors use the roots to treat rheumatic arthralgia, numbness, bruises and other diseases［1-7］. Since 2003［8］, many scholars have carried out chemical and pharmacological research on the L. bulbifera, and extracted and isolated flavonoids from its medicinal parts, such as coumarins, phenolic acids, esters, ketones, phenylpropanoids and sterides. The pharmacological effects of anti-inflammatory and analgesic, immunosuppressive, anti-oxidant, sugar-reducing and lipid-lowering have also been studied［9］, but the research content is less and not comprehensive. In this study, the development status of L. bulbifera was summarized, aiming to provide reference for further research and development of its application.

Study on the Chemical Constituents of L. bulbifera

At present, more than 90 components have been isolated from L. bulbifera, including flavonoids, coumarins, phenolic acids, esters, phenylpropanoids, ketones and steroids, etc., among which coumarins and flavonoids are the main chemical components of L. bulbifera.

Flavonoids

Flavonoids are the earliest separated and reported components of L. bulbifera and one of the main chemical components of L. bulbifera. At present, there are 30 kinds of flavonoids isolated from L. bulbifera, mainly including three categories, i.e., flavonoids, flavonols, and isoflavones. Flavonoids in L. bulbifera have strong antioxidant activity［9-15］.

Coumarins

At this stage, there have been many studies on the coumarins of L. bulbifera, which have good anti-inflammatory and analgesic and immunosuppressive activity. The simple coumarins in L. bulbifera include coumarin, 7-methoxychromen-2-one, scoparone and scopoletin, and other coumarins include 4-hydroxy-6-methoxychromen-2-one, 3,6-dihydroxy-coumarin, 6,6,7,7-tetramethoxyl-8,8-biscoumarin 7,7-dihydroxy-6,6-dimethoxy-8,8-biscoumarin and 7,7-dimethoxy-6,6-biscoumarin［15-17］.

Phenolic acids

Phenolic acids such as vanillic acid, gallocatechin, epigallocatechin, catechin, epicatechin, chlorogenic acid, 4-O-trans-caffeoylquini acid, neochlorogenic acid, 5-hydroxymethyl-2-furancarboxaldehyde, C-veratroylglycol and 4-hydroxy-5-methoxy-benzoic acid have been isolated from L. bulbifera ［10,13-14,17-19］.

Esters

Wang［19］ separated and identified 8 esters from the L. bulbifera, including methyl hexadecanoate, methylhexadec-9-enoate, and ethyl hexadecanoate, 8,11-octadecadienoic acid methyl ester, methyloleate, methyl stearate, ethyl linoleate, and ethyl oleate.

Phenylpropanoids

The simple phenylpropanoids in L. bulbifera mainly include (1-p-hydroxy-cis-cinnamoyl) cinnamic acid, 12-hydroxypentanoic acid methyl ester, trans-cinnamic acid, p-coumaric acid, cis-4-coumaric acid, caffeic acid docosanoyl ester, isomerizing and caffeic acid［13-15］.

Ketones

Lu et al.［20］ found 4-(3-α-hydroxy-1-butenyl)-3,5,5-trimethyl-2-cyclohexen-1-one, 4-(3- β-hydroxy-1-butenyl)-3,5,5-trimethyl-2-cyclohexen-1-one, 3-(3-hydroxy-1-butenyl)-2,4,4 -trimethyl-2-cyclohexen-1-one, 2-(2-pentenyl-3-methyl)-4-hydroxy-2-cyclopenten-1-one, 4-(3-hydroxy-1-butyl)-3,5,5-trimethyl-2-cyclohexenone and other ketone compounds.

Sterides

Xu［21］ isolated compounds such as ergosta-4,6,8(14),22-tetraen-3-one, sitostenone, stigmast-4-ene-3,6-dione and stigmast-4,22-diene-3,6-dione from L. bulbifera.

Other components

Furthermore, 2,2-oxybis(1-phenylethanol), 1-(2-phenylcarbonyloxy acetyl)benzene, 1H-indole-2-carbaldehyde, betulaprenol 8, betulaprenol 9, linoleic acid, Z-10-eicosenoic acid, hexadec-(4Z)-enoic acid and 9(Z)-octadecenamide were also isolated from L. bulbifera［13,16,21-22］.

Study on the Pharmacological Effects of L. bulbifera

Immunosuppressive effect

Immune response is the result of the interaction of various immune cell components under antigen stimulation, which is manifested in the formation of antibodies, or the production of specific immunologically active cells, or the release of various allergic mediators. Therefore, suppression of immune response can be achieved by eliminating antigens or suppressing antibodies, or by suppressing the production of immunocompetent cells［23］.

Yu et al.［25］ used a mouse allogeneic skin transplantation model to study the survival time of skin grafts, the recipients spleen lymphocyte proliferation test, the determination of cytokine secretion levels, and the analysis of CD4~+CD25~+T cell subsets. The results showed that the effective part of L. bulbifera could stimulate the distribution of CD4~+CD25~+ on the surface of lymphocytes, regulate the synthesis of cytokines such as IL-2, IL-10 and IFN-γ, inhibit the transformation function of T lymphocytes, and induce host cell immune tolerance, thereby effectively inhibiting skin graft rejection.

The study by Wang et al.［24］ showed that the ethyl acetate part of L. bulbifera could inhibit the expression of bone marrow-derived DC MHc II and the co-stimulatory molecule CD86 and the secretion of IL-12p70 in the supernatant. When drug-treated DC and T cells of the same species were mixed and cultured in different ratios, the ability to stimulate the proliferation of T cells of the same species was significantly reduced, indicating that the ethyl acetate part of L. bulbifera had immunosuppressive activity.

Su et al.［26-27］ used T lymphocyte proliferation experiments and applied enzyme-linked immunoassay (ELISA) to determine the contents of IFN-γ, IL-2 and IL-4 in the supernatant of spleen cells. The results showed that the ethyl acetate part of the ethanol extract of L. bulbifera could inhibit the proliferation of splenic T lymphocytes in a dose-dependent manner in vitro, with an inhibition rate of 35%, and inhibit the secretion of IL-2 and IFN-γ in the supernatant of T cell culture. The ethyl acetate part of the ethanol extract of L. bulbifera had a certain immunosuppressive effect.

Wang［28］ found that the total coumarins of L. bulbifera had a significant inhibitory effect on the proliferation of splenic lymphocytes in vitro, and a significant therapeutic effect on CIA-induced arthritis and autoimmune diseases induced by type II collagen.

Scholars such as Lu et al.［29］ reported that the total coumarins of L. bulbifera could effectively improve the weight loss of mice with colitis, reduce the serum IL-6 and IFN-γ levels, increase the inhibitory cytokines IL-10 and TGF- β1 level, and reduce colon tissue damage and the expression level of TLR4 and NF-κB in colon tissue.

Zhang et al.［30］ found that various concentrations of total coumarin extract from L. bulbifera could inhibit the proliferation of T lymphocytes and B lymphocytes. Meanwhile, in vitro experiments showed that the inhibitory effect of total coumarins from L. bulbifera on the cellular immunity mediated by T lymphocytes was stronger than that on humoral immunity mediated by B lymphocytes. In vivo experiments showed that the total coumarin extract could inhibit the immune activity of immunized mice. The study showed that the total coumarin extract of L. bulbifera had an inhibitory effect on the cellular and humoral immunity of mice both in vivo and in vitro.

Xiang［31］ found that 6,6,7,7-tetramethoxyl-8,8-biscoumarin, a compound isolated from L. bulbifera, could specifically promote the differentiation of T cells into Treg cells, inhibit the expression of T-bet transcription factors in dendritic cells (DC), and induce the generation of immature DC.

Anti-inflammatory and analgesic effects

Yao［32］ showed through a xylene-induced ear swelling experiment that the ethyl acetate part of L. bulbifera had a significant inhibitory effect on inflammation, and the pain could be obviously relieved by intragastric administration of the ethyl acetate part of L. bulbifera.

Lu［29］ found that the total coumarins of L. bulbifera had a significant therapeutic effect on arthritis in Balb/c mice induced by type II collagen, and its mechanism was related to the induction of immune tolerance.

Xiang［33］ discussed the immunosuppressive effect of LBW-6 (mainly containing flavonoids), an effective part of L. bulbifera, which had a strong anti-inflammatory and analgesic effect, on CIA and its effects on key transcription factors of DC. A model of arthritis caused by type II collagen was established in BAIB/c mice. The effects of LWB-6 on the onset of arthritis and joint damage were observed by intragastric administration every other day; and determination was performed through DC phenotype and the transcription level of DCT-bet gene mRNA. The results showed that LWB-6 decreased the incidence of CIA arthritis in a dose-dependent manner, which was significantly different from that of the blank control group. In HE staining of foot joint synovial tissue, no inflammatory cell infiltration was observed, and the joint space was intact. 20 mg/L LWB-6 significantly down-regulated the transcription level of DCT-bet mRNA from bone marrow of BALB/c mice. FACS analysis showed that this part had no significant effect on the expression of MHC-II and CD86 on the surface of CD11c DC. The preventive administration of LWB-6 had a significant intervention effect on CIA arthritis, which was related to the negative regulation of DCTbet expression.

The research results of Han et al.［13］ showed that the P-coumaric acid and caffeic acid in the national medicine L. bulbifera had anti-inflammatory activity and could enter the blood. They are likely to be the anti-inflammatory active ingredients of the national medicine L. bulbifera.

Zou［35］ used ELISA to measure the secretion and expression of tumor necrosis factor (TN1F-a) in macrophages, and obtained the average activation inhibition rate of each polar part. The result was: petroleum ether part (15.38%)>ethyl acetate part (7.91%)>water part (2.60%). And combined with SPSS software for variance analysis, the petroleum ether part was screened out as the anti-inflammatory active part of L. bulbifera.

Chen et al.［36］ showed that petroleum ether extract had good anti-inflammatory activity.

Ma et al.［37］ observed the analgesic effect of 70% ethanol extract of L. bulbifera and of the water-soluble part of the 70% ethanol extract by the hot plate method and the acetic acid writhing method, and found that the two had a certain analgesic effect, and the analgesic effect in the acetic acid writhing method was more effective, suggesting that the effect is similar to non-steroidal anti-inflammatory drugs.

Anti-oxidation

Free radicals are chemically active and destructive unpaired electronic groups, which participate in many life activities in the body, including nerve conduction, cell proliferation, differentiation, apoptosis, muscle contraction, etc., while the damage of active oxygen free radicals to the human body is actually an oxidation process. According to the results of current research, the oxidative damage caused by free radicals is closely related to many diseases of the human body such as cardiovascular and cerebrovascular diseases, diabetes, hypertension, coronary heart disease and aging［38］.

Zou［35］ used the DPPH free radical scavenging method to determine the average scavenging rate of each polar part. The results were: ethyl acetate part (87.6%)> water part (63.3%)> petroleum ether part (36.8%). And combined with SPSS software for variance analysis, the petroleum ether part was screened out as the antioxidant active part of L. bulbifera.

Yang［8］ and other studies have shown that flavonoids in L. bulbifera had a certain antioxidant effect. Chen et al.［36］ found that the ethyl acetate extract had good antioxidant activity.

Lowering blood sugar and blood lipids

Zhao［39］ found that the total flavonoids of L. bulbifera could reduce blood sugar and lipids by up-regulating insulin receptor levels and increasing insulin sensitivity, instead of affecting traditional free radical pathways, and it had the potential to treat type 2 diabetes.

Shi［16］ found that the 30% ethanol part and 70% ethanol part of L. bulbifera could regulate the blood lipid metabolism of experimental hypercholesterolemia mice, and could significantly reduce their blood lipid levels. The main components of the effective parts of L. bulbifera for lowering blood lipids included 6 kinds of oligopeptides, 11 kinds of coumarins and 24 kinds of fatty acid derivatives. The blood lipid-lowering effect of L. bulbifera mainly involves its regulation of lipids, carbohydrates, vitamins, and amino acids in the body.

Ao XIE et al. Research Progress on Chemical Constituents and Pharmacological Effects of Laportea bulbifera

Conclusions

L. bulbifera is a herbaceous plant belonging to Laportea of Urticaceae. It is a traditional medicine and is often used in ethnic minority areas. With the increasing research on Zhuang medicine, the research on L. bulbifera, a traditional medicine of the Zhuang nationality, has also been intensified. At present, flavonoids, coumarins, phenolic acids, esters, ketones, phenylpropanoids, steroids and other chemical components have been extracted and isolated from its medicinal parts. Modern pharmacological research on L. bulbifera mainly focuses on its anti-inflammatory and analgesic and immunosuppressive effects and mechanisms. In addition, studies have shown that it also has certain anti-oxidation, hypoglycemic and lipid-lowering effects.

However, the current research on the medicinal material basis of L. bulbifera mainly focuses on coumarins and flavonoids, and most of the research on the pharmacological activity rests on the basis of the extract, while few researches have been conducted on the specific pharmacodynamic material basis. Zhuang doctors believe that the whole herb of L. bulbifera has the effects of strengthening the spleen and promoting digestion. In addition, there are certain differences in the efficacy of the whole plant and roots of L. bulbifera, and the differences in the types and contents of their chemical components have not been studied. The pharmacological effects of L. bulbifera are extensive, the medicinal effect is remarkable, and it is widely used in Zhuang areas. More in-depth research on its chemical components and pharmacological effects is needed to further clarify its mechanism of action and the material basis of its medicinal effects, so as to provide a scientific basis for the clinical application of this traditional Zhuang medicine.

References

［1］ FANG D, SHA WL. Guangxi medicinal plants directory［M］. Nanning: Guangxi Peoples Publishing House, 1986.

［2］ Medica Editorial Board of National Institute of Chinese Medicine. Chinese materia medica［M］. Shanghai: Shanghai Scientific & Technical Publishers, 1999. (in Chinese)

［3］ Editorial Committee of Flora of China. Flora Reipublicae Popularis Sinicae［M］. Beijing: SciencePress, 1995.

［4］ WAN DR, CHEN JC, YU HH. Records of Hubei medicinal materials (Hubei Yaocaizhi)［M］. Wuhan: Hubei Science & Technology Press, 2002: 24-28.(in Chinese)

［5］ Chemical Plant of Northwestern Institute of Botany. Qinling flora［M］. Beijing: Science Press, 1974. (in Chinese)

［6］ LYU HZ, YU LY. General situation of Zhuang medicine plant resources in Guangxi［J］. China Journal of Chinese Materia Medica, 1999, 5(41): 354.(in Chinese)

［7］ LIN CY, LUO P, SU JL, et al. Preliminary test on chemical constituents of Zhuang medicine Laportea bulbifera (Sieb.et Zucc.) Wedd［J］. Journal of Medicine and Pharmacy of Chinese Minorities,2018(11):52-55. (in Chinese)

［8］ YANG MC, CHOI SZ, LEE SO, et al. Flavonoid constituents and their antioxidant activity of Laportea bulbifera Weddell［J］. Saengyak Hakhoechi, 2003.

［9］ CHEN YR, XU WF, MA ML, et al. Research progress of Laportea bulbifera［J］. Chinese Journal of Experimental Traditional Medical Formulae, 2019(18):214-220. (in Chinese)

［10］ TANG J, WU D, CHEN SY, et al. Identification of chemical compositions in Laportea bulbifera by UPLC-ESI-Q-TOF-MS［J］. Chinese Journal of Experimental Traditional Medical Formulae, 2018, 242467-242472.(in Chinese)

［11］ LI B, LU X, FENG BM, et al. Flavonoids in Laportea bulbifera［C］//Proceedings of the 11th National Conference on Natural Organic Chemistry of the Chinese Chemical Society, Volume 3, 2016. Chinese Chemical Society: China Academic Journals (CD Edition) Electronic Publishing House, 2016: 38.(in Chinese)

［12］ ZHANG Y, LU X, LI B, et al. Flavonoids from Laportea bulbifera and their anti-N1 neuraminidase activities［J］. Journal of Shenyang Pharmaceutical University, 2018, 35(11): 931-935, 942. (in Chinese)

［13］ HAN HY. Preliminary study on anti-inflammatory material basis and in vivo metabolism of national medicine Laportea bulbifera［D］. Beijing: Beijing University of Chinese Medicine, 2018. (in Chinese)

［14］ HAN HY, SUO YR, LIU X, et al. Screening of active components of Urtica dentata hand by RAW264.7 anti-inflammatory cell model and chemical constituents［J］. Global Traditional Chinese Medicine, 2018, 11(5): 651-655. (in Chinese)

［15］ WANG YM, WEN HC, DU DQ. Chemical constituents from Laportea bulbifera, a Zhuang Medicine［J］. Chinese Pharmaceutical Journal, 2019, 54(10): 773-776. (in Chinese)

［16］ SHI QX. Study on the mechanism of anti-hyperlipidmia effects and its pharmacodynamics substantial foundation of Laportea bulbifera［D］. Wuhan: Hubei University Of Traditional Chinese Medicine, 2018. (in Chinese)

［17］ SU ZQ. Study on the immunosuppressive components of Laportea bulbifera［J］. Chinese Pharmacological Bulletin, 2009, 25(10): 121. (in Chinese)

［18］ WANG SL, LIU JH, GUAN HY, et al. Study on chemical constituents of Laportea bulbifera［J］. Natural Product Research and Development, 2014, 26(suppl1): 25-27. (in Chinese)

［19］ WANG SL. Material basis for the anti-inflammatory and analgesic effects of Laportea bulbifera and its quality control［D］. Guiyang: Guizhou Medical University, 2015. (in Chinese)

［20］ LU X, ZHANG Y, FENG BM, et al. Study on the chemical constituents of Laportea bulbifera［C］// Abstracts of the 30th Annual Conference of the Chinese Chemical Society, 2016 Volume. Chinese Chemical Society: China Academic Journals (CD Edition) Electronic Publishing House, 2016: 304.

［21］ XU LJ. Study on chemical constituents and bioactivities of two national medicinal plants［D］. Shanghai: China State Institute of Pharmaceutical Industry, 2018. (in Chinese)

［22］ ZHU Z, MA L, ZHU HY, et al. Studies oil the chemical constituents of Laportea bulbifera［J］. Journal of Chinese Medicinal Materials, 2011(342): 223-225.(in Chinese)

［23］ ZHANG XY, GAO YX. Research progress on immunosuppressive effects of traditional Chinese medicine［J］. Pharmacy and Clinics of Chinese Materia Medica, 2016, 7(1): 59-61. (in Chinese)

［24］ WANG X, ZOU XL, SU ZQ, et al. Effects of the immune-inhibitory active component of traditional Chinese medicine on murine BMDCs［J］. Chinese Journal of Experimental Surgery, 2007, 24(11): 1414-1416. (in Chinese)

［25］ YU MS, XIANG M, HUANG K, et al. Anti-rejection effects of the active component from Honghuoma on skin transplantation model［J］. Chinese Journal of Experimental Surgery, 2008(7): 940-942. (in Chinese)

［26］ SU ZQ, ZHAO ZY, YAO Y, et al. Study on the extraction and activity of the effective parts of Laportea bulbifera for analgesia, anti-inflammation and immunosuppression［C］//The Proceedings of The 9th National Member Congress of the Chinese Pharmacological Society and the National Academic Conference on Pharmacology. Chinese Pharmacological Society: Chinese Pharmacological Society, 2007: 1. (in Chinese)

［27］ SU ZQ, ZHAO ZY, XIE SN, et al. Effects of analgesia, anti-inflammation and immunosuppression of acetic ether extract of Chinese medicine Honghuoma［J］. Chinese Pharmacological Bulletin, 2009, 25(4): 559-560. (in Chinese)

［28］ WANG HC. Study on the pharmacological activity of the effective fractions of total coumarin in Laportea bulbifera［J］. Jiankang Bidu, 2010(8): 26. (in Chinese)

［29］ LU JL, LI WJ, HOU WR, et al. Study on effect of total coumarins from Urtica dentata on dextran sulfate sodium-induced colitis in mice［J］. China Journal of Chinese Materia Medica, 2012, 37(21): 3316-3320. (in Chinese)

［30］ ZHANG SS, ZHOU H, LI LL, et al. Study on the preparation process of total coumarin from Laportea bulbifera［J］. Journal of Chinese Medicinal Materials, 2013, 36(4): 636-639. (in Chinese)

［31］ XIANG M. Novel immunosuppressant extracted from Laportea bulbifera and its extraction method and application［D］. Wuhan: Huazhong University of Science and Technology, 2014. (in Chinese)

［32］ YAO Y. Study on the therapeutic effect and mechanism of the effective parts of Laportea bulbifera on rheumatoid arthritis［D］. Wuhan: Huazhong University of Science and Technology, 2008. (in Chinese)

［33］ XIANG M, TAO E, CHU T, et al. Preliminary study on preventing effects of the active component of honghuoma on cia model ［J］. Chinese Journal of Hospital Pharmacy, 2006(10): 1201-1205. (in Chinese)

［34］ LUO X. Study on the anti-rheumatoid arthritis effect of 6,6,7,7-tetramethoxyl-8,8-biscoumarin and the mechanism of inducing immune tolerance［D］. Wuhan: Huazhong University of Science and Technology, 2010. (in Chinese)

［35］ ZOU SH. Preliminary study on the quality control and the anti-oxidation and anti-inflammatory spectrum-activity relationship of Miao medicine Laportea bulbifera［D］. Guiyang: Guizhou University of Traditional Chinese Medicine, 2017. (in Chinese)

［36］ CHEN YR, ZOU SH, XU WF, et al. Spectrum-effect relationship of antioxidant and anti-inflammatory activities of Laportea bulbifera based on multivariate statistical analysis［J］. Biomedical chromatography: BMC, 2020, 34(2): 4734.

［37］ MA L, LIANG B, ZHU Z, et al. Study on the analgesic pharmacological action of the ethanol extract from the national medicine Laportea bulbifera［J］. Journal of Guiyang College of Traditional Chinese Medicine, 2012, 34(1): 24-26. (in Chinese)

［38］ GAI XH, LIU SX, REN T, et al. Research progress on the chemical constituents and pharmacological effects of Coptis chinensis［J］. Chinese Traditional and Herbal Drugs, 2018, 49(20): 4919-4927. (in Chinese)

［39］ ZHAO ZY. Study on the preparation of total flavonoids of Laportea bulbifera and its prevention and treatment of T2DM［D］. Wuhan: Hubei University of Traditional Chinese Medicine, 2009. (in Chinese)