Bupleurum and Saiboku-To

Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

References

Abe H, Sakaguchi M, Yamada M, Arichi S, Odashima S. Pharmacological actions of saikosaponins isolated from Bupleurum falcatum. 1. Effects of saikosaponins on liver function. Planta Med. 1980 Dec;40(4):366-372.

Bensky D, Barolet R. Chinese Herbal Medicine: Formulas and Strategies. Seattle WA: Eastland Press, 1997.

Bermejo Benito P, Abad Martinez MJ, Silvan Sen AM, Sanz Gomez A, Fernandez Matellano L, Sanchez Contreras S, Diaz Lanza AM. In vivo and in vitro antiinflammatory activity of saikosaponins. Life Sci 1998;63(13):1147-56 Related Articles
Abstract: Buddlejasaponin I and saikosaponin 1 and 2, biologically active compounds from Scrophularia scorodonia and Bupleurum rigidum respectively, exert potent in vivo antiinflammatory effects on mouse ear edema induced by phorbol myristate acetate (PMA). The effects of these compounds on swelling and other inflammatory parameters are described. In screening for in vitro effects of saikosaponins on cellular systems generating cyclooxygenase (COX) and lipoxygenase (LOX) metabolites, we observed that most saikosaponins showed a significant effect. The action is more marked on LOX metabolite LTC4. Our data support the inhibition of arachidonic acid metabolism as one of the biochemical mechanisms that might be the rationale for the putative antiphlogistic activity of these saikosaponins.

Chang WC, Hsu FL. Inhibition of platelet activation and endothelial cell injury by flavan-3-ol and saikosaponin compounds. Prostaglandins Leukot Essent Fatty Acids. 1991 Sep;44(1):51-56.
Abstract: The effects of flavan-3-ol and saikosaponin compounds on platelet aggregation, platelet thromboxane biosynthesis and H2O2-induced endothelial cell injury were studied. Seven flavan-3-ol compounds isolated from Camellia sinensis L. var sinensis O. Kuntze (Theaceae) and three saikosaponin compounds isolated from Bupleurum falcatum L. (Umbelliferae) were used. Among the 10 compounds tested, only epigallocatechin and saikosaponin a significantly inhibited human platelet aggregation induced by ADP, and the potency of inhibition was comparable with aspirin. Both of epigallocatechin and saikosaponin a dose-dependently inhibited the platelet thromboxane formation from exogenous and endogenous arachidonic acid. In the prevention of H2O2-induced endothelial cell injury in culture, only gallocatechin-3-0-gallate and epicatechin-3-0-gallate were effective. The inhibitory effect of epigallocatechin and saikosaponin a on platelet activation and the cytoprotective effect of gallocatechin-3-0-gallate and epicatechin-3-0-gallate on H2O2-induced endothelial cell injury could give evidence of explaining the possible role of flavan-3-ol and saikosaponin compounds in maintaining vascular homeostasis.

Chiu HF, Lin CC, Yang CC, Yang F. The pharmacological and pathological studies on several hepatic protective crude drugs from Taiwan (I). Am J Chin Med. 1988;16(3-4):127-137.
Abstract: This study is to investigate the hepatic protective effect of several Taiwan crude drug extractions on the carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. The pharmacological and pathological effects of Bupleurum chinense, Phellodendron wilsonii, Clematis chinensis and Hedyotis corymbosa were analyzed by liver enzyme function test and pathological studies. However, the results of amine transferase SGOT and SGPT have shown a significant hepatic protective effect after treatment with Bupleurum chinense (P less than 0.005), Phellodendron wilsonii (P less than 0.001), Clematis chinensis (P less than 0.005) and Hedyotis corymbosa (P less than 0.005, SGPT only). The fatty degeneration around the central vein area and necrosis of the central lobule can be significantly improved by P. wilsonii and moderately changed by B. chinense or C. chinensis. Although fatty metamorphosis has been affected by H. corymbosa, various inflammatory cell infiltrations in the cytoplasm were noted.

Ebata N, Nakajima K, Hayashi K, Okada M, Maruno M. Saponins from the root of Bupleurum falcatum. Phytochemistry. 1996 Feb;41(3):895-901.
Abstract: Three new saponins and nine known saponins were isolated from the dried roots of Bupleurum falcatum. On the basis of chemical and spectral analyses, the structures of new compounds, named 4''-O-acetylsaikosaponin d and hydroxysaikosaponins a and c, were established. In aqueous acidic conditions, saikosaponins a and d were converted into not only known compounds, saikosaponins b1 and b2, but also hydroxysaikosaponins a and d, respectively. Furthermore, quantitative analysis of the decoction of Bupleuri Radix itself by HPLC exhibited that it contained saikosaponins a, c and d, and hydroxysaikosaponins a, c and d.

Homma M, Oka K, Niitsuma T, Itoh H. A novel 11 beta-hydroxysteroid dehydrogenase inhibitor contained in saiboku-to, a herbal remedy for steroid-dependent bronchial asthma. J Pharm Pharmacol 1994 Apr;46(4):305-309.
Abstract: To identify the inhibitor of prednisolone metabolism contained in Saiboku-To, we conducted in-vitro experiments of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), using rat liver homogenate and cortisol as a typical substrate. We studied the effects of ten herbal constituents on 11 beta-HSD. Five herbal extracts showed inhibitory activity with Glycyrrhiza glabra > Perillae frutescens > Zizyphus vulgaris > Magnolia officinalis > Scutellaria baicalensis. This suggests that unknown 11 beta-HSD inhibitors are contained in four herbs other than G. glabra which contains a known inhibitor, glycyrrhizin (and glycyrrhetinic acid). Seven chemical constituents which have been identified as the major urinary products of Saiboku-To in healthy and asthmatic subjects were studied; magnolol derived from M. officinalis showed the most potent inhibition of the enzyme (IC50, 1.8 x 10(-4) M). Although this activity was less than that of glycyrrhizin, the inhibition mechanism (non-competitive) was different from a known competitive mechanism. These results suggest that magnolol might contribute to the inhibitory effects of Saiboku-To on prednisolone metabolism through inhibition of 11 beta-HSD.

Imi N, Fujimoto H, Shibata S. The chemical studies on oriental plant drugs. 18. The constituents of Bupleurum spp. (3). Saikogenins E and G. Chem Pharm Bull (Tokyo). 1968 Apr;16(4):641-646.

Ishizaki T, Sasaki F, Ameshima S, Shiozaki K, Takahashi H, Abe Y, Ito S, Kuriyama M, Nakai T, Kitagawa M. Pneumonitis during interferon and/or herbal drug therapy in patients with chronic active hepatitis. Eur Respir J 1996 Dec;9(12):2691-2696.
Abstract: We report four cases of acute pneumonitis due either to interferon, or a herbal drug, "Sho-saiko-to", or both in combination, in patients with chronic active hepatitis, focusing on its pathogenesis and response to prednisolone therapy. These cases shared common clinical features: fever, dry cough, dyspnoea, hypoxaemia, diffuse infiltrates both on chest radiography and chest computed tomography, restrictive pulmonary functional impairment, and alveolitis on examination of transbronchial lung biopsy, all of which suggest acute interstitial pneumonia. Furthermore, lymphocytosis was observed in association with the dominant CD8+ T-cell subset in bronchoalveolar lavage fluid. A lymphocyte stimulation test using peripheral blood was positive to interferon in one case and to Sho-saiko-to in another. All patients responded to oral prednisolone therapy. Peripheral soluble interleukin-2 receptor levels decreased in parallel with improvement in the clinical course. All patients were free of symptoms with a follow-up of 1-3 yrs. We conclude that interferon- and/or Sho-saiko-to-induced acute pneumonitis may be due to allergic-immunological mechanisms rather than toxicity, and that peripheral levels of soluble interleukin-2 receptor appear to be good markers of disease activity.

Izumi S, Ohno N, Kawakita T, Nomoto K, Yadomae T. Wide range of molecular weight distribution of mitogenic substance(s) in the hot water extract of a Chinese herbal medicine, Bupleurum chinense. Biol Pharm Bull. 1997 Jul;20(7):759-764.
Abstract: In this study, we examined the contribution of lignin-like materials in lower molecular weight (MW) fractions from the hot water extract of Bupleuri Radix (Bupleurum chinense) (HWE-BR) for their immunopharmacological activities. Mitogenic activity was detected in all the fractions of MW ranges: lower than 1.0 kDa, 1.0-3.5 kDa, 3.5-10 kDa, and 10-50 kDa. After NaClO2 treatment of these subfractions, UV spectra, ESR spectra, mitogenic activities on murine B-cells, and the activity of inducing nitric oxide in RAW 264.7 cells were significantly reduced, suggesting that lignin-like polyphenolic substance(s) of various MW might take part in these activities. The intensity of ESR spectra and mitogenic activities were stronger in higher MW subfractions, thus the content of stable radical species and/or the degrees of polymerization would be important for their immunopharmacological activities.

Jin RL, Shi L, Kuang Y. [Comparative studies on the roots of wild and cultured Bupleurum chinense DC]. Chung Yao Tung Pao. 1988 Apr;13(4):11-3, 61. [Article in Chinese]

Kakumu S, et al. Effects of TJ-9 Sho-saiko-to (kampo medicine) on interferon gamma and antibody production specific for hepatitis B virus antigen in patients with type B chronic hepatitis. Int J Immunopharmacol. 1991; 13(2-3): 141-146.
Abstract: To examine whether Sho-saiko-to (kampo medicine) could modulate the immune response of immunocompetent cells to hepatitis B virus (HBV)-associated antigens, we investigated in vitro interferon gamma (IFN-gamma) and antibody (antibody to HB core and e antigens; anti-HBc and anti-HBe) production by peripheral blood mononuclear cells (PBMC) from eight patients with chronic active hepatitis (CAH) (four with HBeAg and four with anti-HBe) in the presence of recombinant HBcAg and purified HBeAg. IFN-gamma and antibody production were measured using ELISA and RIA, respectively. PBMC from both HBeAg and anti-HBe positive patients generated significantly increased IFN-gamma and antibody (anti-HBc and anti-HBe) production in the culture containing Sho-saiko-to (TJ-9) in a dose-dependent manner in comparison with those of medium alone culture. Similarly, when various concentrations of TJ-9 were added to the HBV antigen-stimulated cultures, TJ-9 was found to enhance both IFN-gamma and antibody production dose-dependently. These results indicate that TJ-9 is able to modulate both cellular and humoral immune responses specific for HBV-associated antigens. These findings also may account for, at least in part, the efficacy of TJ-9 treatment for type B chronic hepatitis.

Kato M, Pu MY, Isobe K, Iwamoto T, Nagase F, Lwin T, Zhang YH, Hattori T, Yanagita N, Nakashima I. Characterization of the immunoregulatory action of saikosaponin-d. Cell Immunol. 1994 Nov;159(1):15-25.
Abstract: The immunoregulatory action of saikosaponin-d (SSd), which was isolated from the root of Bupleurum falcatum L. and has a steroid-like structure, was examined on splenic T lymphocytes of C57BL/6 mice. SSd displayed a definite action in vitro to bidirectionally control the growth response of T lymphocytes stimulated by concanavalin A, anti-CD3 monoclonal antibody, and calcium ionophore A23187 plus phorbol 12-myristate 13-acetate. Low concentrations (1-3 micrograms/ml) of SSd upregulated the responses to suboptimum stimuli of agonists, particularly during the relatively late stage of the responses, whereas it downregulated the responses to supraoptimal stimuli. Under appropriate experimental conditions, SSd promoted interleukin-2 (IL-2) production and IL-2 receptor expression. It also accelerated c-fos gene transcription, but it did not modulate the level of tyrosine phosphorylation of cellular proteins. We concluded from these results that SSd uniquely modulates T lymphocyte function and that at least one target of the action of SSd is located at or before the step of c-fos gene transcription and after T-cell receptor/CD3-mediated protein tyrosine kinase activation.

Kawakita T, Nakai S, Kumazawa Y, Miura O, Yumioka E, Nomoto K. Induction of interferon after administration of a traditional Chinese medicine, xiao-chai-hu-tang (shosaiko-to). Int J Immunopharmacol 1990;12(5):515-521.
Abstract: We examined the ability of a traditional chinese herbal medicine, xiao-chai-hu-tang (Japanese name: shosaiko-to) to induce IFN in mice. A maximum activity (105 units/ml) of interferon (IFN) appeared in the serum of mice 16 h after intraperitoneal (i.p.) treatment with 250 mg/kg of shosaiko-to. Addition of polymyxin B did not abrogate the ability of shosaiko-to to induced serum IFN. The IFN was identified as IFN-alpha/beta by neutralizing test using anti-IFN alpha/beta antibodies. Pretreatment of mice with carrageenan suppressed the IFN induction by shosaiko-to, whereas the IFN induction by shosaiko-to was impaired neither in mice treated with anti-asialo-GM1 antibody nor in T-cell-deficient athymic nude mice. IFN was produced in vitro by spleen cells obtained from shosaiko-to treated mice. Moreover, spleen cells from untreated mice could also produce IFN when they were cultured with shosaiko-to. Additionally, serum IFN was also induced by the adoptive transfer of spleen cells from shosaiko-to treated mice to normal mice. On the other hand, peroral administration of shosaiko-to also induced IFN-alpha/beta in the serum. While IFN activity induced by i.p. administration of shosaiko-to declined after repeated treatments, the activity induced by its peroral administration did not decline during a long term treatment. These results showed that shosaiko-to is an IFN-alpha/beta inducer capable of repeated peroral administration.

Li XZ. [Research on the pharmacology of Bupleurum chinensis]. Chung Yao Tung Pao. 1983 Mar;8(2):39-42.[Article in Chinese]

Lin CC, Chiu HF, Yen MH, Wu CC, Chen MF. The pharmacological and pathological studies on Taiwan folk medicine (III): The effects of bupleurum kaoi and cultivated bupleurum falcatum var. komarowi. Am J Chin Med. 1990;18(3-4):105-112.
Abstract: The protective effects of water extract from roots of Bupleurum kaoi Liu, Chao et Chuang and Bupleurum flacatum L. var. Komarowi Koso-Polj on CCl4-induced hepatoxicity have been investigated. Both B. kaoi (p less than 0.05) and B. falcatum var. komarowi (p less than 0.01) possessed more marked anti-hepatotoxic pharmacological effects than Bupleurum chinense DC., the typical strain widely used in Taiwan. The pathological improvement from treatment by means of the three drugs to alleviate CCl4-induced hepatic toxicity was estimated using morphological changes of hepatocytes, reduction of inflammatory cells infiltration and liver function tests.

Matsumoto T, Hirano M, Kiyohara H, Yamada H. Characterisation of the endo-polygalacturonase-resistant region of the pectin from Bupleurum falcatum L.--a polysaccharide with an active function in clearance of immune complexes. Carbohydr Res. 1995 Apr 30;270(2):221-229.

Matsumoto T, Cyong JC, Kiyohara H, Matsui H, Abe A, Hirano M, Danbara H, Yamada H. The pectic polysaccharide from Bupleurum falcatum L. enhances immune-complexes binding to peritoneal macrophages through Fc receptor expression. Int J Immunopharmacol. 1993 Aug;15(6):683-693.
Abstract: Binding of glucose oxidase-anti-glucose oxidase complexes (GAG), a model of immune complexes, to macrophages was enhanced by treatment with an acidic pectic polysaccharide, bupleuran 2IIb, from Bupleurum falcatum L. GAG binding to macrophages by bupleuran 2IIb increased in a dose-dependent fashion, and was abolished when the Pronase-treated macrophages were incubated with bupleuran 2IIb. The GAG binding enhancing activity of bupleuran 2IIb was reduced by periodate oxidation but not Pronase digestion of bupleuran 2IIb. When bupleuran 2IIb was digested with endo-polygalacturonase, the resulting enzyme resistant carbohydrate portion showed potent activity. Scatchard analysis indicated enhanced expression of the Fc receptor (FcR) on the surface by the action of bupleuran 2IIb. The enhancement of GAG binding by bupleuran 2IIb was inhibited by the presence of actinomycin D or cycloheximide. Bupleuran-2IIb-stimulated cells showed enhanced expression of both FcRI and FcRII mRNA, which were measured as PCR products. These results suggested that the endo-polygalacturonase resistant carbohydrate portion of bupleuran 2IIb is important for the expression of the activity, and that the activity of bupleuran 2IIb on GAG binding was mediated by receptors for polysaccharide on the cells. The up-regulation of the Fc receptor by bupleuran 2IIb was also suggested to mediate by de novo synthesis of the receptor protein.

Matsushima T. [Drug-induced pneumonitis and related diseases]. Nippon Naika Gakkai Zasshi 1997 Mar 10;86(3):457-462. (Review) [Article in Japanese]

Matsuura K, Kawakita T, Nakai S, Saito Y, Suzuki A, Nomoto K. Role of B-lymphocytes in the immunopharmacological effects of a traditional Chinese medicine, xiao-chai-hu-tang (shosaiko-to). Int J Immunopharmacol 1993 Feb;15(2):237-243.
Abstract: We previously reported that a traditional Chinese medicine, Xiao-chai-hu-tang (Japanese name: Shosaiko-to), induced interferon (IFN) activity in the serum of mice after intraperitoneal (i.p.) administration. In the present study in which murine spleen cells were cultured in vitro with Shosaiko-to, B-cells isolated by anti-immunoglobulin-coated plates were confirmed to generate IFN in response to Shosaiko-to stimulation. IFN activity was induced in the serum after i.p. administration of Glycyrrhizae radix, Scutellariae radix, Bupleuri radix and Pinelliae tuber which are included in Shosaiko-to as its constituent. Such an IFN-inducing activity was confirmed to exist in methanol-insoluble fractions of these extracts derived from Shosaiko-to and these constituents but not in methanol-soluble fractions. These four extracts as well as Shosaiko-to, induced interleukin 6 (IL-6) in the serum after the administration. In in vitro stimulation of spleen cells, Shosaiko-to and extracts of Glycyrrhizae radix, Bupleuri radix and Pinelliae tuber showed mitogenic activity, but an extract of Scutellariae radix with in vivo IFN-inducing activity did not. B-cells appear to participate in the immunopharmacological effects of Shosaiko-to through mitogenic activity, IFN induction and the effect of IL-6.

Murakami K, Okajima K, Sakata K, Takatsuki K. [A possible mechanism of interstitial pneumonia during interferon therapy with sho-saiko-to]. Nihon Kyobu Shikkan Gakkai Zasshi 1995 Apr;33(4):389-394. [Article in Japanese]
Abstract: Interstitial pneumonia has been reported to be a side effect of treatment with interferon, and Sho-saiko-to (Xiao-Chai-Hu-Tang) may enhance this side effect. It is well known that activated neutrophils are important mediators of pulmonary fibrosis, so we studied the effects of interferon and Sho-saiko-to on neutrophil activation. Homogenized lung myeloperoxidase (MPO) activity was assayed after intraperitoneal injection of interferon with or without pretreatment with Sho-saiko-to. Although Sho-saiko-to alone did not change the lung MPO content, MPO in the lung was significantly increased by interferon administration. The increase was enhanced further by pretreatment with Sho-saiko-to. When the accumulated neutrophils are activated by some cytokines, such as TNF alpha or IL-1 beta from monocytes/macrophages, they may damage lung tissue. We therefore studied the effects of Sho-saiko-to and interferon on TNF alpha production in freshly isolated human monocytes. Sho-saiko-to increased the production of TNF alpha, but interferon did not. In addition, Sho-saiko-to significantly increased the production of TNF alpha by monocytes stimulated by lipopolysaccharide. Taken together, these data indicate that interferon causes neutrophils to accumulate in the lung. Sho-saiko-to alone may not injure lung tissue, but it increases the effect of interferon. When stimulated by some antigen, Sho-saiko-to may overstimulate the neutrophils. Granulocytes elastase and oxygen radicals released from activated neutrophils may damage lung tissue. The fibroblasts that repair the damaged tissue may increase the risk of pulmonary fibrosis.

Nakagawa A, Yamaguchi T, Takao T, Amano H. [Five cases of drug-induced pneumonitis due to Sho-saiko-to or interferon-alpha or both]. Nihon Kyobu Shikkan Gakkai Zasshi 1995 Dec;33(12):1361-1366. [Article in Japanese]
Abstract: We encountered five cases of drug-induced pneumonitis due to Sho-saiko-to or interferon-alpha or both. In all 5 cases the underlying disease was chronic hepatitis or liver cirrhosis caused by hepatitis C virus. Interferon-alpha alone was administered in one case, Sho-saiko-to alone was administered in two cases, and both were administered in two cases. Bronchoalveolar lavage was done in 4 cases. In three cases, lymphocytosis and abnormally low CD4/8 ratios were found on examination of bronchoalveolar lavage fluid. In the only case in which interferon-alpha alone was given the percentage of neutrophils in bronchoalveolar lavage fluid was abnormally high, and the adult respiratory distress syndrome developed. Lymphocyte stimulation tests were done in four cases, and in all four cases the only positive results were against Sho-saiko-to or against interferon-alpha. The frequency of drug-induced pneumonitis among patients with chronic hepatitis or liver cirrhosis was 0.7% in those given only Sho-saiko-to, 0.5% in those given only interferon-alpha, and 4.0% in those given both interferon-alpha and Sho-saiko-to. Therefore, pneumonitis due to Sho-saiko-to and to interferon-alpha is more likely to occur if these two drugs are given simultaneously.

Natori S, Yoshihira K, Satake M, Yokoyama A, Kuroyanagi M. [Imported Bupleurum contaminated with Aconite]. Eisei Shikenjo Hokoku. 1974;49(92):102-103. [Article in Japanese]

Nose M, Amagaya S, Ogihara Y. Corticosterone secretion-inducing activity of saikosaponin metabolites formed in the alimentary tract. Chem Pharm Bull (Tokyo). 1989 Oct;37(10):2736-2740.
Abstract: The corticosterone secretion-inducing activities of saikosaponin a, saikosaponin c and saikosaponin d, isolated from the root of Bupleurum falcatum L., and 27 metabolites formed in the murine alimentary tract were studied in mice. Serum corticosterone was determined by high-performance liquid chromatography (HPLC). Intraperitoneal administration of saikosaponin a and its intestinal metabolite, prosaikogenin F, showed corticosterone secretion-inducing activity at a dose of 0.1 mmol/kg, and maximally increased it at a dose of 0.4 mmol/kg. On the other hand, the genuine sapogenin, saikogenin F, was inactive. Saikosaponin b1 and saikosaponin g, gastric metabolites of saikosaponin a, and their intestinal metabolites, prosaikogenin A, prosaikogenin H, saikogenin A and saikogenin H, were also inactive. Serum corticosterone was increased by the administration of saikosaponin d and its intestinal metabolite, prosaikogenin G, at a dose of 0.04 mmol/kg, and it reached the maximal level at the dose of 0.1 mmol/kg. Saikogenin G also showed a slight activity. A gastric metabolite of saikosaponin d, saikosaponin b2, and its intestinal metabolites, prosaikogenin D and saikogenin D, were inactive. In the experiments on saikosaponin c and its metabolites, saikosaponin c was inactive but its intestinal metabolites, especially prosaikogenin E-2, showed activity almost equal to that of saikosaponin a. Saikosaponin h and saikosaponin i, gastric metabolites of saikosaponin c, were also inactive, but their prosaikogenins showed slight activities. When these compounds were orally administered, their corticosterone secretion-inducing activities were similar to those obtained in the intraperitoneal experiment. These results suggest that a proper polar balance between the sugar moiety and the aglycone is important for the corticosterone secretion-inducing activity of saikosaponins and their metabolites.

Ono M, Yoshida A, Ito Y, Nohara T. Phenethyl alcohol glycosides and isopentenol glycoside from fruit of Bupleurum falcatum. Phytochemistry. 1999 Jul;51(6):819-823.
Abstract: Investigation on the constituents of the fruit of Bupleurum falcatum L. resulted in the isolation of the three new glycosides, phenethyl alcohol 8-O-beta-D-glucopyranosyl-(1-->2)-O-beta-D-apiofuranosyl-(1-->6)-b eta-D- glucopyranoside, phenethyl alcohol 8-O-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranoside and isopentenol 1-O-beta-D-apiofuranosyl-(1-->6)-beta-D-glucopyranoside along with five known glycosides, icariside D1, icariside F2, saikosaponin a, saikosaponin c and saikosaponin d. The structures of these compounds were elucidated on the basis of interpretation of chemical and spectral data.

Sakurai MH, Matsumoto T, Kiyohara H, Yamada H. B-cell proliferation activity of pectic polysaccharide from a medicinal herb, the roots of Bupleurum falcatum L. and its structural requirement. Immunology. 1999 Jul;97(3):540-547.
Abstract: Pectic polysaccharide fraction (BR-2) containing pharmacologically active pectic polysaccharide, bupleuran 2IIc, which was prepared from a medicinal herb, the roots of Bupleurum falcatum L., was administered orally to C3H/HeJ mice for 7 consecutive days. Proliferative responses of spleen cells were enhanced in the presence of the purified pectic polysaccharide, bupleuran 2IIc, but another B-cell mitogen, lipopolysaccharide (LPS) did not give a similar effect. In vitro studies using spleen cells showed that bupleuran 2IIc also stimulated lymphocytes, depleted of adherent cells or T cells. Bupleuran 2IIc treatment increased subpopulation of CD25+ and surface immunoglobulin M-positive (sIgM+) lymphocytes. Non-specific immunoglobulin secretion of spleen cells treated with bupleuran 2IIc was increased according to the culture time, and coexistence of interleukin-6 (IL-6) enhanced the secretion more than that of bupleuran 2IIc alone. These results suggest that bupleuran 2IIc proliferates B cells in the absence of macrophages, and the resulting activated B cells are then induced into antibody-forming cells in the presence of IL-6. Among the structural region of bupleuran 2IIc, ramified region (PG-1), which consists of rhamnogalacturonan core rich in neutral sugar chain, showed the potent mitogenic activity suggesting it to be an active site. Mitogenic activity of bupleuran 2IIc was reduced in the presence of antipolysaccharide antibody (antibupleuran 2IIc/PG-1-IgG), which recognizes the ramified region of bupleuran 2IIc as the antigenic epitope. Mitogenic activity of bupleuran 2IIc was also reduced by the addition of beta-d-GlcpA-(1-->6)-beta-d-Galp-(1-->6)-d-Galp or beta-d-GlcpA-(1-->6)-d-Galp, which are a part of the epitopes of antibupleuran 2IIc/PG-1-IgG. These results suggest that the epitopes in bupleuran 2IIc act as active sites of the polysaccharide during mitogenic activity.

Sakurai MH, Kiyohara H, Matsumoto T, Tsumuraya Y, Hashimoto Y, Yamada H. Characterization of antigenic epitopes in anti-ulcer pectic polysaccharides from Bupleurum falcatum L. using several carbohydrases. Carbohydr Res. 1998 Oct;311(4):219-229.
Abstract: A polyclonal antibody (anti-bupleuran 2IIc/PG-1-IgG) against the "ramified" region (PG-1) of an anti-ulcer pectic polysaccharide was prepared and its antigenic epitopes were analyzed by using several carbohydrases. Enzymatic removal of arabinosyl residues from PG-1 by endo-(1-->5)-alpha-L-arabinanase (from Aspergillus niger) did not reduce the binding ability of anti-bupleuran 2IIc/PG-1-IgG to PG-1. When the endo-(1-->5)-alpha-L-arabinanase-resistant fraction (EA-1) was digested with rhamnogalacturonase A (rRGase A from A. aculeatus), a high-molecular-mass fragment fraction (RA-1) and an oligosaccharide fraction (RA-3) were obtained. RA-3 contained at least four kinds of oligosaccharides liberated from the rhamnogalacturonan core. This partial removal of the rhamnogalacturonan core in EA-1 also did not reduce the binding of the antibody to the polysaccharide. Further digestion of RA-1 with exo-(1-->3)-beta-D-galactanase (from Irpex lacteus), gave a high-molecular-mass fragment (EXG-1) and a trace of oligosaccharides (EXG-3). Methylation and FABMS analyses indicated that EXG-3 contained mono- and di-galactosyl oligosaccharides possessing terminal GlcA or GlcA4Me. Removal of the EXG-3 fraction from RA-1 by exo-(1-->3)-beta-D-galactanase significantly reduced the ability of the binding of the antibody to the polysaccharide. When PG-1 was digested with endo-(1-->6)-beta-D-galactanase (from Trichoderma viride) or beta-D-glucuronidase (from A. niger), the reactivities of both enzyme-resistant fractions to the antibody were decreased in comparison with that of PG-1. Both radish arabinogalactan (containing GlcA4Me) and beta-D-GlcpA-(1-->6)-beta-D-Galp-(1-->6)-D-Galp were shown to inhibit the reactivity of PG-1 to the antibody by competitive ELISA. These results suggest that 6-linked galactosyl chains containing terminal GlcA or GlcA4Me attached to (1-->3)-beta-D-galactosyl chains, are important sugar residues in the antigenic epitopes of the "ramified" region of bupleuran 2IIc.

Shibata M, Yoshida R, Motoashi S, Fukushima M. [Pharmacological studies on Bupleurum falcatum L. IV. Some pharmacological effects of crude saikosides, saikogenin A and syrupy residue]. Yakugaku Zasshi. 1973 Dec;93(12):1660-1667. [Article in Japanese]

Shimaoka A, Seo S, Minato H. Saponins isolated from Bupleurum falcatum L.; components of saikosaponin b. J Chem Soc [Perkin 1]. 1975;(20):2043-2048.

Sugiyama, H, Nagai, M, Kotajima, F, Yoshizawa, A, Kamimura, M, Horiuchi T, Kudo K, Kabe J, Hayashi, S, Umeda, N. A case of interstitial pneumonia with chronic hepatitis C following interferon-alfa and sho-saiko-to therapy. Arerugi 1995 Jul;44(7):711-714. [Article in Japanese]

Takagi K, Shibata M. [Pharmacological studies on Bupleurum falcatum L. II. Antiinflammatory and other pharmacological actions of crude saikosides]. Yakugaku Zasshi. 1969 Oct;89(10):1367-1378. [Article in Japanese]

Tanaka S, Takahashi A, Onoda K, Kawashima K, Nakaura S, Nagao S, Ohno Y, Kawanishi T, Nakaji Y, Kobayashi K, et al. [Toxicological studies on biological effects of the herbal drug extracts in rats and mice. II. Moutan bark, Glycyrrhiza and Bupleurum root]. Yakugaku Zasshi. 1986 Aug;106(8):671-686. [Article in Japanese]

Ushio Y, Abe H. Effects of saikosaponin-d on the functions and morphology of macrophages. Int J Immunopharmacol. 1991;13(5):493-499.
Abstract: The effects of saikosaponin-d, isolated from Bupleurum Radix, on phagocytosis and spreading of mouse peritoneal macrophages were investigated. Macrophages from saikosaponin-d-treated mice showed a significant increase in spreading activity followed by an increase in phagocytic activity. An intense distribution of microfilaments and microtubules was also observed in these macrophages by immunofluorescence microscopy.

Yamada H, Sun XB, Matsumoto T, Ra KS, Hirano M, Kiyohara H. Purification of anti-ulcer polysaccharides from the roots of Bupleurum falcatum. Planta Med. 1991 Dec;57(6):555-559.
Abstract: A water-soluble crude polysaccharide fraction (BR-1) prepared from the root of Bupleurum falcatum L. (Japanese name = Saiko) prevented HCl/ethanol induced ulcerogenesis in mice significantly. BR-1 was fractionated into four polysaccharide fractions (BR-2, BR-3, BR-4, and BR-5) by the addition of cetyltrimethylammonium bromide, and the strongly acidic polysaccharide fraction BR-2 showed the most potent inhibition of gastric lesion formation. When BR-2 was further fractionated by anion-exchange chromatography, the most potent anti-ulcer activity was observed in the pectin-like polysaccharide, bupleuran 2IIc. Bupleuran 2IIc was homogeneous as determined by electrophoresis and gel filtration. Bupleuran 2IIc was composed mainly of galacturonic acid with small proportions of arabinose, rhamnose, and galactose, and its average relative molecular mass was estimated to be 63,000 d. BR-2 lost most of its activity after treatment with periodate or digestion with endo-polygalacturonase indicating that the polygalacturonan region and/or the molecular mass may contribute to activity.

Yamada H. [Structure and pharmacological activity of pectic polysaccharides from the roots of Bupleurum falcatum L]. Nippon Yakurigaku Zasshi. 1995 Sep;106(3):229-237. (Review) [Article in Japanese]
Abstract: Several pharmacological activities have been observed in pectic polysaccharides which were isolated from Chinese herbs containing Kampo medicines. We found two different bioactive pectic polysaccharides, bupleuran 2IIb and 2IIc, from the roots of Bupleurum falcatum. These bioactive pectic polysaccharides were comprised of an alpha (1-->4) linked galacturonan region, a ramified region that consists of a rhamnogalacturonan core substituted neutral sugar chains as the side chains and a rhamnogalacturonan II (RG II)-like region containing unique sugars such as 3-deoxy-manno-2-octulosonic acid (KDO). In order to understand the pharmacological activity of pectic polysaccharides on the molecular level, we have elucidated the essential carbohydrate structure for the expression of each pharmacological activity and their mode of actions. The ramified region in bupleuran 2IIb induced Fc receptor up-regulation in macrophages by a mechanism dependent on an increase of intracellular Ca2+, followed by the enhancement of immune complex clearance, whereas bupleuran 2IIc, which mainly consists of a partially branched galacturonan region, showed potent anti-ulcer activity. The major mechanism of its mucosal protection was suggested to be due to anti-secretory activity on acid and pepsin, its ability to provide a protective coating and radical scavenging effect. The future problems were also discussed in order to develop pectic polysaccharides as medicines.

Yamamoto M, Kumagai A, Yamamura Y. Structure and actions of saikosaponins isolated from Bupleurum falcatum L. I. Anti-inflammatory action of saikosaponins. Arzneimittelforschung. 1975 Jul;25(7):1021-1023.
Abstract: Anti-inflammatory action of saikosaponins isolated from the root of Bupleurum falcatum L were examined using female albino rats. The anti-exudative action by granuloma pouch method and the antigranulomatous action by cotton pellet method were demonstrated with i.m. and oral administrations of saikosaponins. The oral administration of saikosaponins in 10 times the dosage of i.m. injection showed almost the same effect. Among saikosaponins isolated from Bupleurum falcatum, saikosaponins a and d, not c, were demonstrated to have anti-inflammatory action. The relationship between structure and action of saikosaponins was discussed. No changes in body weight, adrenal weight, plasma-11-OH-corticosteroid level and hematocrit value were observed.

Yamamoto M, Kumagai A, Yamamura Y. Structure and action of saikosaponins isolated from Bupleurum falcatum L. II. Metabolic actions of saikosaponins, especially a plasma cholesterol-lowering action. Arzneimittelforschung. 1975 Aug;25(8):1240-1243.
Abstract: Several metabolic actions of saikosaponins isolated from the root of Bupleurum falcatum L. were examined using albino rats. Hepatic protein synthesis from leucine-14C(U) was enhanced. Glycogen content in the liver was increased, but oxidation of glucose-14C(U) in the liver was not changed. Elevation of plasma levels of cholesterol, triglycerides and p-ospholipids by cholesterol feeding was reduced. Although hepatic lipogenesis and cholesterogenesis from acetate-1-14C of glucose-14C(U) were stimulated, the elimination of i.p. injected cholesterol-4-14C from plasma was acclerated. Fecal excretion of i.p. injected cholesterol-4-14C, expressed as total-14C including bile acids-14C and neutral sterols-14C, was increased. Among the saikosaponins isolated from Bupleurum falcatum L., saikosaponins a and d, but not c, had metabolic actions as well as anti-inflammatory action. These metabolic actions and anti-inflammatory action of saikosaponins may confirm the clinical application of Bupleurum falcatum L, which has been widely used in the prescriptions of the oriental medicine, and may suggest possible mechanisms for the actions of its active principles.

Yamashiki M, et al. Efficacy of a herbal medicine "sho-saiko-to" on the improvement of impaired cytokine production of peripheral blood mononuclear cells in patients with chronic viral hepatitis. J Clin Lab Immunol. 1992; 37(3): 111-121.
Abstract: Peripheral blood samples were collected from normal subjects and chronic viral hepatitis patients, and the in vitro capability of the peripheral blood mononuclear cells to produce various cytokine (interleukin-1 beta, interleukin-6, interferon-gamma, and granulocyte-macrophage colony-stimulating factor) were analyzed by adding pokeweed mitogen. We then investigated the effects of a herbal medicine "Sho-saiko-to" on the levels of cytokine production. The production levels of the 4 cytokines were significantly lower in the peripheral blood mononuclear cells of the patients (Patient Group) than in those of normal subjects (Control Group). The addition of Sho-saiko-to to the Patient Group resulted in improved productions of those cytokines, as well as an remarkable improvement of interleukin-1 beta production. The results demonstrated that Sho-saiko-to acts to improve such immunological abnormalities as decreased cytokine productions. Administration of Sho-saiko-to to chronic viral hepatitis patients is also expected to have immunological benefits.

Yeung H. Handbook of Chinese Herbs and Formulas. Volumes I and II. Los Angeles CA: Institute of Chinese Medicine, 1989.