Danshen, the root and rhizome of Salvia miltiorrhiza Bge, a Traditional Chinese Medicine, especially for cardiovascular and cerebrovascular diseases, has unique immunomodulatory effects. Danshen is capable of anti-inflammation and antiallergy, which are immunosuppressive activities, whereas it is also able to promote immunity against cancer, viruses, and bacteria. Most previous reports were performed with use of a purified compound or compounds of Danshen. Since there are more than twenty active compounds in Danshen, it is very difficult to predict that one compound will act the same way when it is combined with other compounds. In order to overcome this limitation, we used the crude form of Danshen to study its immunomodulatory effects in a mouse model. The mice were fed daily diet supplements of Danshen for three months and then tested for their immunity, including leukocyte subsets in peripheral blood, humoral and cell-mediated immune responses, and host defenses against a Listeria monocytogenes (LM) infection. Different doses of Danshen caused different immunomodulatory effects. Danshen at 0.5% decreased serum IgE production in BALB/c mice; 1% Danshen promoted cell-mediated immunity; Danshen at 0.5 and 1% inhibited the production of oxygen free radicals in liver and spleen and NO production in liver; 2% Danshen enhanced the host resistance against LM with increased numbers of peripheral monocytes and natural killer (NK) cells and decreased production of IL-1β and NO. 1. Introduction Complementary and alternative medicine (CAM) is defined as any healing practice other than conventional medicine [1]. It includes naturopathy, chiropractic, herbalism, Traditional Chinese Medicine (TCM), yoga, acupuncture, diet-based therapies, and many other practices. The techniques in alternative medicine have been around for thousands of years. They have been widely used and taught in eastern countries. Now, people in western countries are more willing to try alternative medicine. Danshen belongs to the CAM category. It is the root and rhizome of Salvia miltiorrhiza Bge. It has been a TCM for at least two thousand years. The major functions of this herb in TCM are huo xue hua yu (activating blood circulation to disperse stasis), jie du xiao zhong (removing toxic substances and promoting subsidence of swelling), and qing xin an shen (nourishing the heart to calm the mind, tranquilizing the mind by nourishing the heart) [2]. Traditionally, it has been utilized for treatment of irregular menses, menstrual pain, amenorrhea, precordial pain, abdominal pain, abdominal
References
[1]
S. Bratman, The Alternative Medicine Sourcebook, Lowell House, Los Angeles, Calif, USA, 1997.
[2]
Y. Ling and Z. Yan, Traditional Chinese Pharmacology, Shanghai Science and Technology Press, 1984.
[3]
L. Song, National Traditional Chinese Medicine, Chinese Materia Medica Editorial Board, Science and Technology Press, Shanghai, China, 1999.
[4]
J. D. Adams, R. Wang, J. Yang, and E. J. Lien, “Preclinical and clinical examinations of Salvia miltiorrhiza and its tanshinones in ischemic conditions,” Chinese Medicine, vol. 1, article 3, 2006.
[5]
Y.-Y. Xu, R.-Z. Wan, Y.-P. Lin L, L. Yang, Y. Chen, and C.-X. Liu, “Recent Advance on research and application of Salvia miltiorrhiza,” Asian Journal of Pharmacodynamic and Pharmacokinetics, vol. 7, no. 2, pp. 99–130, 2007.
[6]
Y. S. Huang and J. T. Zhang, “Antioxidative effect of three water-soluble components isolated from Salvia miltiorrhiza in vitro,” Acta Pharmaceutica Sinica, vol. 27, no. 2, pp. 96–100, 1992.
[7]
J. Liu, C. F. Yang, B. L. Lee, H. M. Shen, S. G. Ang, and C. N. Ong, “Effect of Salvia miltiorrhiza on aflatoxin B1-induced oxidative stress in cultured rat hepatocytes,” Free Radical Research, vol. 31, no. 6, pp. 559–568, 1999.
[8]
T. Y. Lee, L. M. Mai, G. J. Wang, J. H. Chiu, Y. L. Lin, and H. C. Lin, “Protective mechanism of Salvia miltiorrhiza on carbon tetrachloride-induced acute hepatotoxicity in rats,” Journal Pharmacological Sciences, vol. 91, no. 3, pp. 202–210, 2003.
[9]
Z. M. Wu, T. Wen, Y. F. Tan, Y. Liu, F. Ren, and H. Wu, “Effects of salvianolic acid A on oxidative stress and liver injury induced by carbon tetrachloride in rats,” Basic and Clinical Pharmacology and Toxicology, vol. 100, no. 2, pp. 115–120, 2007.
[10]
T. Yokozawa, H. Y. Chung, T. W. Lee et al., “Effect of magnesium lithospermate b on urinary excretion of arachidonate metabolites in rats with renal failure,” Chemical and Pharmaceutical Bulletin, vol. 37, no. 10, pp. 2766–2769, 1989.
[11]
G. Liu, G. J. Guan, T. G. Qi et al., “Protective effects of Salvia miltiorrhiza on rats with streptozotocin diabetes and its mechanism,” Zhong Xi Yi Jie He Xue Bao, vol. 3, no. 6, pp. 459–462, 2005.
[12]
D. G. Kang, H. Oh, H. T. Chung, and H. S. Lee, “Inhibition of angiotensin converting enzyme by lithospermic acid B isolated from radix Salviae miltiorrhiza bunge,” Phytotherapy Research, vol. 17, no. 8, pp. 917–920, 2003.
[13]
X. P. Gao, D. Y. Xu, Y. L. Deng, and Y. Zhang, “Screening of angiotensin converting enzyme inhibitors from Salvia miltiorrhizae,” Zhongguo Zhongyao Zazhi, vol. 29, no. 4, pp. 359–362, 2004.
[14]
T. Makino, H. Wakushima, T. Okamoto, Y. Okukubo, K. I. Saito, and Y. Kano, “Effects of Kangen-karyu on coagulation system and platelet aggregation in mice,” Biological and Pharmaceutical Bulletin, vol. 25, no. 4, pp. 523–525, 2002.
[15]
J. W. Park, S. H. Lee, M. K. Yang et al., “15,16-Dihydrotanshinone I, a major component from Salvia miltiorrhiza Bunge (Dansham), inhibits rabbit platelet aggregation by suppressing intracellular calcium mobilization,” Archives of Pharmacal Research, vol. 31, no. 1, pp. 47–53, 2008.
[16]
S. Y. Kim, T. C. Moon, H. W. Chang, K. H. Son, S. S. Kang, and H. P. Kim, “Effects of tanshinone I isolated from Salvia miltiorrhiza Bunge on arachidonic acid metabolism and in vivo inflammatory responses,” Phytotherapy Research, vol. 16, no. 7, pp. 616–620, 2002.
[17]
X. Ji, B. K. H. Tan, Y. C. Zhu, W. Linz, and Y. Z. Zhu, “Comparison of cardioprotective effects using ramipril and DanShen for the treatment of acute myocardial infarction in rats,” Life Sciences, vol. 73, no. 11, pp. 1413–1426, 2003.
[18]
J. Sun, S. H. Huang, B. K. H. Tan et al., “Effects of purified herbal extract of Salvia miltiorrhiza on ischemic rat myocardium after acute myocardial infarction,” Life Sciences, vol. 76, no. 24, pp. 2849–2860, 2005.
[19]
C. S. Liu, Y. Cheng, J. F. Hu, W. Zhang, N. H. Chen, and J. T. Zhang, “Comparison of antioxidant activities between salvianolic acid B and Ginkgo biloba extract (EGb 761),” Acta Pharmacologica Sinica, vol. 27, no. 9, pp. 1137–1145, 2006.
[20]
J. Fu, H. Huang, J. Liu, R. Pi, J. Chen, and P. Liu, “Tanshinone IIA protects cardiac myocytes against oxidative stress-triggered damage and apoptosis,” European Journal of Pharmacology, vol. 568, no. 1–3, pp. 213–221, 2007.
[21]
J. Tian, G. Li, Z. Liu et al., “ND-309, a novel compound, ameliorates cerebral infarction in rats by antioxidant action,” Neuroscience Letters, vol. 442, no. 3, pp. 279–283, 2008.
[22]
J. Tian, F. Fu, G. Li et al., “SMND-309, a novel derivate of salvianolic acid B, ameliorates cerebral infarction in rats: characterization and role,” Brain Research, vol. 1263, pp. 114–121, 2009.
[23]
B. Y. Kang, S. W. Chung, S. H. Kim, S. Y. Ryu, and T. S. Kim, “Inhibition of interleukin-12 and interferon-γ production in immune cells by tanshinones from Salvia miltiorrhiza,” Immunopharmacology, vol. 49, no. 3, pp. 355–361, 2000.
[24]
S. I. Jang, S. I. Jeong, K. J. Kim et al., “Tanshinone IIA from Salvia miltiorrhiza inhibits inducible nitric oxide synthase expression and production of TNF-α, IL-1β and IL-6 in activated RAW 264.7 cells,” Planta Medica, vol. 69, no. 11, pp. 1057–1059, 2003.
[25]
S. Il Jang, H. Jin Kim, Y. J. Kim, S. I. Jeong, and Y. O. You, “Tanshinone IIA inhibits LPS-induced NF-κB activation in RAW 264.7 cells: possible involvement of the NIK-IKK, ERK1/2, p38 and JNK pathways,” European Journal of Pharmacology, vol. 542, no. 1–3, pp. 1–7, 2006.
[26]
W. F. Chiou and M. J. Don, “Cryptotanshinone inhibits macrophage migration by impeding F-actin polymerization and filopodia extension,” Life Sciences, vol. 81, no. 2, pp. 109–114, 2007.
[27]
M. J. Don, J. F. Liao, L. Y. Lin, and W. F. Chiou, “Cryptotanshinone inhibits chemotactic migration in macrophages through negative regulation of the PI3K signaling pathway,” British Journal of Pharmacology, vol. 151, no. 5, pp. 638–646, 2007.
[28]
W. Li, J. Li, M. Ashok et al., “A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinflammatory mediator, high mobility group box 1,” Journal of Immunology, vol. 178, no. 6, pp. 3856–3864, 2007.
[29]
S. Zhu, W. Li, J. Li, A. E. Sama, and H. Wang, “Caging a beast in the inflammation arena: use of chinese medicinal herbs to inhibit a late mediator of lethal sepsis,” International Journal of Clinical and Experimental Medicine, vol. 1, no. 1, pp. 64–75, 2008.
[30]
G. Zhou, W. Jiang, Y. Zhao et al., “Sodium tanshinone IIA sulfonate mediates electron transfer reaction in rat heart mitochondria,” Biochemical Pharmacology, vol. 65, no. 1, pp. 51–57, 2003.
[31]
A. M. Wang, S. H. Sha, W. Lesniak, and J. Schacht, “Tanshinone (Salviae miltiorrhizae extract) preparations attenuate aminoglycoside-induced free radical formation in vitro and ototoxicity in vivo,” Antimicrobial Agents and Chemotherapy, vol. 47, no. 6, pp. 1836–1841, 2003.
[32]
C. L. Liu, L. X. Xie, M. Li, S. S. K. Durairajan, S. Goto, and J. D. Huang, “Salvianolic acid B inhibits hydrogen peroxide-induced endothelial cell apoptosis through regulating PI3K/Akt signaling,” PLoS ONE, vol. 2, no. 12, Article ID e1321, 2007.
[33]
X. Wang, S. L. Morris-Natschke, and K. H. Lee, “New developments in the chemistry and biology of the bioactive constituents of Tanshen,” Medicinal Research Reviews, vol. 27, no. 1, pp. 133–148, 2007.
[34]
L. Cao, N. M. Filipov, and D. A. Lawrence, “Sympathetic nervous system plays a major role in acute cold/restraint stress inhibition of host resistance to Listeria monocytogenes,” Journal of Neuroimmunology, vol. 125, no. 1-2, pp. 94–102, 2002.
[35]
R. T. Emeny, D. Gao, and D. A. Lawrence, “β1-adrenergic receptors on immune cells impair innate defenses against Listeria,” Journal of Immunology, vol. 178, no. 8, pp. 4876–4884, 2007.
[36]
R. T. Emeny, G. Marusov, D. A. Lawrence, J. Pederson-Lane, X. Yin, and M. A. Lynes, “Manipulations of metallothionein gene dose accelerate the response to Listeria monocytogenes,” Chemico-Biological Interactions, vol. 181, no. 2, pp. 243–253, 2009.
[37]
D. Gao, J. Kasten-Jolly, and D. A. Lawrence, “The paradoxical effects of lead in interferon-gamma knockout BALB/c mice,” Toxicological Sciences, vol. 89, no. 2, pp. 444–453, 2006.
[38]
D. Gao and D. A. Lawrence, “Dendritic cells in immunotoxicity testing,” Methods in Molecular Biology, vol. 598, pp. 259–281, 2010.
[39]
L. C. Green, D. A. Wagner, and J. Glogowski, “Analysis of nitrate, nitrite, and [15]nitrate in biological fluids,” Analytical Biochemistry, vol. 126, no. 1, pp. 131–138, 1982.
[40]
H. J. Gould and B. J. Sutton, “IgE in allergy and asthma today,” Nature Reviews Immunology, vol. 8, no. 3, pp. 205–217, 2008.
[41]
D. MacGlashan, “IgE receptor and signal transduction in mast cells and basophils,” Current Opinion in Immunology, vol. 20, no. 6, pp. 717–723, 2008.
[42]
C. B. Mathias, E. J. Freyschmidt, B. Caplan et al., “IgE influences the number and function of mature mast cells, but not progenitor recruitment in allergic pulmonary inflammation,” Journal of Immunology, vol. 182, no. 4, pp. 2416–2424, 2009.
[43]
S. Y. Ryu, M. H. Oak, and K. M. Kim, “Inhibition of mast cell degranulation by tanshinones from the roots of Salvia miltiorrhiza,” Planta Medica, vol. 65, no. 7, pp. 654–655, 1999.
[44]
H. S. Choi and K. M. Kim, “Tanshinones inhibit mast cell degranulation by interfering with IgE receptor-mediated tyrosine phosphorylation of PLCγ2 and MAPK,” Planta Medica, vol. 70, no. 2, pp. 178–180, 2004.
[45]
J. H. Yang, K. H. Son, J. K. Son, and H. W. Chang, “Anti-allergic activity of an ethanol extract from Salviae miltiorrhiza,” Archives of Pharmacal Research, vol. 31, no. 12, pp. 1597–1603, 2008.
[46]
E. S. Vitetta, K. Brooks, and Y. W. Chen, “T cell-derived lymphokines that induced IgM and IgG secretion in activated murine B cells,” Immunological Reviews, vol. 78, pp. 137–157, 1984.
[47]
A. Bossie, K. H. Brooks, P. H. Krammer, and E. S. Vitetta, “Activation of murine B cells from different tissues with different mitogens. II. Isotype distribution of secreted immunoglobulins in the presence and absence of IL-4-containing T cell supernatants,” The Journal of Molecular and Cellular iImmunology, vol. 3, no. 4, pp. 221–226, 1987.
[48]
P. Kiesler, A. Shakya, D. Tantin, and D. Vercelli, “An allergy-associated polymorphism in a novel regulatory element enhances IL13 expression,” Human Molecular Genetics, vol. 18, no. 23, pp. 4513–4520, 2009.
[49]
C. M. Snapper and W. E. Paul, “Interferon-γ and B cell stimulatory factor-1 reciprocally regulate Ig isotype production,” Science, vol. 236, no. 4804, pp. 944–947, 1987.
[50]
T. L. Stevens, A. Bossie, V. M. Sanders et al., “Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells,” Nature, vol. 334, no. 6179, pp. 255–258, 1988.
[51]
L. A. Zenewicz and H. Shen, “Innate and adaptive immune responses to Listeria monocytogenes: a short overview,” Microbes and Infection, vol. 9, no. 10, pp. 1208–1215, 2007.
[52]
T. E. Mandel and C. Cheers, “Resistance and susceptibility of mice to bacterial infection: histopathology of listeriosis in resistant and susceptible strains,” Infection and Immunity, vol. 30, no. 3, pp. 851–861, 1980.
[53]
I. Guleria and J. W. Pollard, “Aberrant macrophage and neutrophil population dynamics and impaired Th1 response to Listeria monocytogenes in colony-stimulating factor 1-deficient mice,” Infection and Immunity, vol. 69, no. 3, pp. 1795–1807, 2001.
[54]
E. A. Havell, “Production of tumor necrosis factor during murine listeriosis,” Journal of Immunology, vol. 139, no. 12, pp. 4225–4231, 1987.
[55]
C. S. Tripp, S. F. Wolf, and E. R. Unanue, “Interleukin 12 and tumor necrosis factor α are costimulators of interferon γ production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 8, pp. 3725–3729, 1993.
[56]
C. S. Hsieh, S. E. Macatonia, C. S. Tripp, S. F. Wolf, A. O'Garra, and K. M. Murphy, “Development of T(H)1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages,” Science, vol. 260, no. 5107, pp. 547–549, 1993.
[57]
J. A. Carrero, B. Calderon, and E. R. Unanue, “Listeriolysin O from Listeria monocytogenes Is a Lymphocyte Apoptogenic Molecule,” Journal of Immunology, vol. 172, no. 8, pp. 4866–4874, 2004.
[58]
O. Kepp, L. Galluzzi, and G. Kroemer, “Mitochondrial control of the NLRP3 inflammasome,” Nature Immunology, vol. 12, no. 3, pp. 199–200, 2011.
[59]
R. Zhou, A. S. Yazdi, P. Menu, and J. Tschopp, “A role for mitochondria in NLRP3 inflammasome activation,” Nature, vol. 469, no. 7329, pp. 221–226, 2011.
[60]
K. P. Beckerman, H. W. Rogers, J. A. Corbett, R. D. Schreiber, M. L. McDaniel, and E. R. Unanue, “Release of nitric oxide during the T cell-independent pathway of macrophage activation: its role in resistance to Listeria monocytogenes,” Journal of Immunology, vol. 150, no. 3, pp. 888–895, 1993.
[61]
T. Gotoh and M. Mori, “Nitric oxide and endoplasmic reticulum stress,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 7, pp. 1439–1446, 2006.
[62]
A. W. Segal, “How neutrophils kill microbes,” Annual Review of Immunology, vol. 23, pp. 197–223, 2005.
[63]
A. Meister, “Glutathione metabolism and its selective modification,” The Journal of Biological Chemistry, vol. 263, no. 33, pp. 17205–17208, 1988.
[64]
L. Cao, C. A. Hudson, and D. A. Lawrence, “Immune changes during acute cold/restraint stress-induced inhibition of host resistance to Listeria,” Toxicological Sciences, vol. 74, no. 2, pp. 325–334, 2003.
[65]
L. Cao, C. A. Hudson, and D. A. Lawrence, “Acute cold/restraint stress inhibits host resistance to Listeria monocytogenes via β1-adrenergic receptors,” Brain, Behavior, and Immunity, vol. 17, no. 2, pp. 121–133, 2003.
[66]
R. T. Emeny and D. A. Lawrence, Psychoneuroimmunology, vol. 4, Elsevier Academic, 2006.
[67]
S. Hamada, M. Umemura, T. Shiono et al., “IL-17A produced by γδ T cells plays a critical role in innate immunity against Listeria monocytogenes infection in the liver,” Journal of Immunology, vol. 181, no. 5, pp. 3456–3463, 2008.
[68]
K. D. Meeks, A. N. Sieve, J. K. Kolls, N. Ghilardi, and R. E. Berg, “IL-23 is required for protection against systemic infection with Listeria monocytogenes,” Journal of Immunology, vol. 183, no. 12, pp. 8026–8034, 2009.
[69]
S. B. Mukherjee, M. Das, G. Sudhandiran, and C. Shaha, “Increase in cytosolic Ca2+ levels through the activation of non-selective cation channels induced by oxidative stress causes mitochondrial depolarization leading to apoptosis-like death in Leishmania donovani promastigotes,” The Journal of Biological Chemistry, vol. 284, no. 23, pp. 15496–15504, 2002.
[70]
G. Ermak and K. J. A. Davies, “Calcium and oxidative stress: from cell signaling to cell death,” Molecular Immunology, vol. 38, no. 10, pp. 713–721, 2002.
[71]
C. Blenn, P. Wyrsch, J. Bader, M. Bollhalder, and F. R. Althaus, “Poly(ADP-ribose)glycohydrolase is an upstream regulator of Ca2+ fluxes in oxidative cell death,” Cellular and Molecular Life Sciences, vol. 68, no. 8, pp. 1455–1466, 2011.
[72]
D. Flipo, M. Fournier, C. Benquet et al., “Increased apoptosis, changes in intracellular Ca2+, and functional alterations in lymphocytes and macrophages after in vitro exposure to static magnetic field,” Journal of Toxicology and Environmental Health A, vol. 54, no. 1, pp. 63–76, 1998.
[73]
S. Andjeli？, A. Khanna, M. Suthanthiran, and J. Nikoli？-？ugi？, “Intracellular Ca2+ Elevation and Cyclosporin A Synergistically Induce TGF-β1-Mediated Apoptosis in Lymphocytes,” Journal of Immunology, vol. 158, no. 6, pp. 2527–2534, 1997.
[74]
S. J. Wadsworth and H. Goldfine, “Listeria monocytogenes phospholipase C-dependent calcium signaling modulates bacterial entry into J774 macrophage-like cells,” Infection and Immunity, vol. 67, no. 4, pp. 1770–1778, 1999.
