Immunomodulatory effects of Yun Zhi and Danshen capsules in health subjects—a randomized, double-blind, placebo-controlled, crossover study
Introduction
Polysaccharides isolated from different medicinal plants in traditional Chinese medicine (TCM) have many immunomodulating activities including the enhancement of the humoral and cell-mediated immunity. They have been shown to activate various types of immune effector cells such as B lymphocytes, T lymphocytes, cytotoxic T cells (CTL), macrophages, polymorphonuclear cells, natural killer cells, lymphokine activated killer cells and tumor infiltrating lymphocytes [1]. Besides the activation of cell-mediated immunity, many anti-tumor polysaccharides can also stimulate the in vivo production of cytokines with anti-tumor activities such as tumor necrosis factor (TNF)-α [2], [3], [4]. Therefore, these polysaccharides may be immunostimulating and beneficial for enhancing immune functions against neoplasm and infections.
Yun Zhi polysaccharopeptide (PSP) and polysaccharide Kureha (PSK, Krestin) are a new type of Biological Response Modifier (BRM) extracted from the deep-layer cultivated mycelia of the Cov-1 and CM-101 strains of Yun Zhi (Coriolus versicolor), respectively. Their active ingredient is a protein-bound polysaccharide with beta-1,3-glycosidic bond. They have been used in the BRM therapy of tumors and enhancement of the immune system. PSP and PSK have been shown by in vitro studies to possess anti-tumor activities [5], [6], [7], [8], immunorestoration of CTL and natural killer (NK) cell functions [9], activation of macrophage [10] and polymorphonuclear leukocytes [11], enhancement of chemokine and cytokine [e.g. monocyte chemoattractant protein 1 and interferon (IFN)-γ] expression [12], [13], and reduction of oxidative injury [14]. In animal studies, PSP was found to upregulate the immune response in cancer radiotherapy [15], restore immunosuppression [16], and exhibit chemopreventive activity [17], [18].
Clinical trials have also shown PSK to be effective in immunochemotherapy in gastric, esophageal, colorectal, breast and lung cancers [13], [19], [20]. In phases II and III double-blind trials in China, the use of PSP could boost immune cell proliferation, alleviate chemotherapy symptoms, and enhance tumor infiltration by dendritic cells and CTL [21]. In a recent clinical trial, PSP treatment slowed down deterioration of patients with advanced non-small cell lung cancer by increasing blood leucocyte and neutrophil counts, as well as serum IgG and IgM concentrations [22]. Therefore, immunomodulatory activities of Yun Zhi may have potential benefits on survival and quality of life, and is compatible with chemotherapy and radiation therapy of cancer.
Danshen (Salvia miltiorrhiza) is a Chinese herbal medicine that has been widely used for the treatment of cardiovascular disease [23]. Experimental studies have shown that Danshen extract can dilate coronary arteries, increase coronary blood flow and scavenge free radicals in ischemic diseases, thereby reducing the cellular damage from ischemia and improve heart function [24], [25]. Its active ingredient, sodium tanshinone IIA sulfonate, a derivative of tanshinone IIA, can protect the myocardium from hypertrophy [25]. Apart from it, Danshen also contains other active ingredients including protocatechuic aldehyde, tanshinone I, cryptotanshinone, hydroxytanshinone, methyltanshinonate, methylene tanshiquinone, przewatanshinquinone A, przewatanshinquinone B, miltirone, dihydrotanshinone, tanshinol A, tanshinol B etc. A recent study indicated that Danshen has an anti-hypertensive effect through the inhibition of angiotensin converting enzyme [26]. Therefore, Danshen is beneficial for the prevention and treatment of cardiovascular disease [27]. Other studies have shown that Danshen exhibits chemopreventive effect against alfatoxin B1-induced hepatocarcinogenesis, inhibit cell growth, and induce apoptosis in a human hepatoma cell line [28], [29]. Moreover, one of the active ingredients of Danshen, Tanshinone IIA, is a newly confirmed antioxidant that inhibited the association of lipid peroxidation products with DNA [30]. Therefore, it is believed that Danshen can be beneficial for the protection of immune system and cardiovascular system by scavenging free radicals.
Since antioxidants in diet supplements may have potential to indirectly improve the immune function in human beings [31], supplementation of Danshen may further promote the immunomodulatory activities of Yun Zhi. We used a combination capsule of Yun Zhi and Danshen in the present clinical trail to investigate if regular oral consumption could enhance cellular immunity in healthy subjects. The induction of T helper (Th) cytokines and the activation of immune effector cells were the targeted end points.
Section snippets
Endotoxin assay
Gram negative bacterial endotoxin level of the Yun Zhi and Danshen capsule was measured by the QCL-1000® Chromogenic Limulus Amebocyte Lysate Kit (Bio-Whittaker, Walkersville, MD, USA).
Yun Zhi–Danshen capsule
Yun Zhi and Danshen combination capsule and the matching placebo capsule were supplied by Winsor Health Products, Ltd. and were manufactured conforming to the Good Manufacturing Practice (GMP) standard. The active drug and placebo capsules were prepared by the GMP qualified Hong Kong Institute of Biotechnology,
Dropout of subjects during study
Within the 10 months study period, there were a total of 18 dropout cases, 3 of them withdrew from the trial during the first treatment period (before M2), 5 withdrew during the second treatment period (before M4), 1 withdrew before the wash-out period (M6), 2 withdrew during the third treatment period (before M8) and 6 withdrew during the forth treatment period (before M10). They discontinued study due to different reasons such as no time for blood collection, unpleasant feeling in stomach for
Discussion
Several clinical trials on patients receiving chemotherapy or radiotherapy have found Yun Zhi PSP to significantly improve appetite, alleviate weakness, anorexia, vomiting, dryness of throat, spontaneous or night sweat and pain, increase weight, and stabilize white blood cell counts, NK cells, IL-2 and CD4/CD8 ratio [37], [38]. In the present study, the increase in percentage and absolute count of only CD4+ Th cells in healthy subjects taking Yun Zhi–Danshen indicated that Yun Zhi–Danshen could
Acknowledgments
This study was supported by the Innovation and Technology Fund, Hong Kong and Winsor Health Products Ltd.
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