Category Archives: Why It Works

Autoimmune Disease, Immunotherapy, in vitro, Medical Studies

Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators.

Spelman K, Burns J, Nichols D, Winters N, Ottersberg S, Tenborg M.

Clinical Division, Department of Herbal Medicine, Tai Sophia Institute, 7750 Montpelier Road, Laurel, MD 20723, USA. spelman123@earthlink.net.
Abstract

Modulation of cytokine secretion may offer novel approaches in the treatment of a variety of diseases. One strategy in the modulation of cytokine expression may be through the use of herbal medicines. A class of herbal medicines, known as immunomodulators, alters the activity of immune function through the dynamic regulation of informational molecules such as cytokines. This may offer an explanation of the effects of herbs on the immune system and other tissues. For this informal review, the authors surveyed the primary literature on medicinal plants and their effects on cytokine expression, taking special care to analyze research that utilized the multi-component extracts equivalent to or similar to what are used in traditional medicine, clinical phytotherapy, or in the marketplace.

METHODOLOGY: MEDLINE, EBSCO, and BIOSIS were used to identify research on botanical medicines, in whole or standardized form, that act on cytokine activity through different models, i.e., in vivo (human and animal), ex vivo, or in vitro.

RESULTS: Many medicinal plant extracts had effects on at least one cytokine. The most frequently studied cytokines were IL-1, IL-6, TNF, and IFN. Acalypha wilkesiana, Acanthopanax gracilistylus, Allium sativum, Ananus comosus, Cissampelos sympodialis, Coriolus versicolor, Curcuma longa, Echinacea purpurea, Grifola frondosa, Harpagophytum procumbens, Panax ginseng, Polygala tenuifolia, Poria cocos, Silybum marianum, Smilax glabra, Tinospora cordifolia, Uncaria tomentosa, and Withania somnifera demonstrate modulation of multiple cytokines.

CONCLUSION: The in vitro and in vivo research demonstrates that the reviewed botanical medicines modulate the secretion of multiple cytokines. The reported therapeutic success of these plants by traditional cultures and modern clinicians may be partially due to their effects on cytokines. Phytotherapy offers a potential therapeutic modality for the treatment of many differing conditions involving cytokines. Given the activity demonstrated by many of the reviewed herbal medicines and the increasing awareness of the broad-spectrum effects of cytokines on autoimmune conditions and chronic degenerative processes, further study of phytotherapy for cytokine-related diseases and syndromes is warranted.

PMID: 16813462 [PubMed – indexed for MEDLINE]Free Article

http://www.ncbi.nlm.nih.gov/pubmed/16813462

Macrophages, Medical Studies

Macrophage-stimulating activity of polysaccharides extracted from fruiting bodies of Coriolus versicolor (Turkey Tail Mushroom).

Jeong SC, Yang BK, Kim GN, Jeong H, Wilson MA, Cho Y, Rao KS, Song CH.

Department of Biotechnology, Daegu University, Gyungbuk, Korea.

Abstract

The macrophage-stimulating effect of Turkey Tail mushroom extracted from Coriolus versicolor (Turkey Tail mushroom) was investigated, and their effectiveness was compared with that of lipopolysaccharide (LPS). The purified polysaccharide (CV-S2-Fr.I) of C. versicolor obtained by Sepharose CL-6B gel chromatography stimulated macrophage lysosomal enzyme activity by 250% at a concentration of 100 microg/mL, which was higher than that of LPS at the same concentration. When CV-S2-Fr.I was used in combination with interferon-gamma, there was a marked cooperative induction of nitric oxide production. However, CV-S2-Fr.I had no effect on nitric oxide production by itself. The proportion of C3-positive macrophages in the CV-S2-Fr.I group increased by 7.2-fold compared with the control group.

PMID: 16822202 [PubMed – indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/16822202

Cancer, in vitro, Leukemia, Medical Studies

Coriolus versicolor (Yunzhi) extract attenuates growth of human leukemia xenografts and induces apoptosis through the mitochondrial pathway.

Ho CY, Kim CF, Leung KN, Fung KP, Tse TF, Chan H, Lau CB.

School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, PR China.

Abstract

Coriolus versicolor (CV), also called Yunzhi, has been demonstrated to exert anti-tumor effects on various types of cancer cells. Our previous studies have demonstrated that a standardized aqueous ethanol extract prepared from CV inhibited the proliferation of human leukemia cells via induction of apoptosis. The present study aimed to evaluate the underlying mechanisms of apoptosis through modulation of Bax, Bcl-2 and cytochrome c protein expressions in a human pro-myelocytic leukemia (HL-60) cell line, as well as the potential of the CV extract as anti-leukemia agent using the athymic mouse xenograft model. Our results demonstrated that the CV extract dose-dependently suppressed the proliferation of HL-60 cells (IC50 = 150.6 microg/ml), with increased nucleosome production from apoptotic cells. Expression of pro-apoptotic protein Bax was significantly up-regulated in HL-60 cells treated with the CV extract, especially after 16 and 24 h. Meanwhile, expression of anti-apoptotic protein Bcl-2 was concomitantly down-regulated, as reflected by the increased Bax/Bcl-2 ratio. The CV extract markedly, but transiently, promoted the release of cytochrome c from mitochondria to cytosol after 24-h incubation. In vivo studies in the athymic nude mouse xenograft model also confirmed the growth-inhibitory activity of the CV extract on human leukemia cells. In conclusion, the CV extract attenuated the human leukemia cell proliferation in vivo, and in vitro possibly by inducing apoptosis through the mitochondrial pathway. The CV extract is likely to be valuable for the treatment of some forms of human leukemia.

PMID: 16865263 [PubMed – indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/16865263

Autoimmune Disease, Cancer, Immunotherapy, Leukemia, Medical Studies, PSP

Induction of cell cycle changes and modulation of apoptogenic/anti-apoptotic and extracellular signaling regulatory protein expression by water extracts of I’m-Yunity (PSP).

1 Comment

Hsieh TC, Wu P, Park S, Wu JM.

Department of Biochemistry & Molecular Biology, New York Medical College, Valhalla, NY 10595, USA. Tze-Chen_Hsieh@nymc.edu

Abstract

BACKGROUND: I’m-Yunity (PSP) is a mushroom extract derived from deep-layer cultivated mycelia of the patented Cov-1 strain of Coriolus versicolor (CV), which contains as its main bioactive ingredient a family of polysaccharo-peptide with heterogeneous charge properties and molecular sizes. I’m-Yunity (PSP) is used as a dietary supplement by cancer patients and by individuals diagnosed with various chronic diseases. Laboratory studies have shown that I’m-Yunity (PSP) enhances immune functions and also modulates cellular responses to external challenges. Recently, I’m-Yunity (PSP) was also reported to exert potent anti-tumorigenic effects, evident by suppression of cell proliferation and induction of apoptosis in malignant cells. We investigate the mechanisms by which I’m-Yunity (PSP) elicits these effects.

METHODS: Human leukemia HL-60 and U-937 cells were incubated with increasing doses of aqueous extracts of I’m-Yunity (PSP). Control and treated cells were harvested at various times and analyzed for changes in: (1) cell proliferation and viability, (2) cell cycle phase transition, (3) induction of apoptosis, (4) expression of cell cycle, apoptogenic/anti-apoptotic, and extracellular regulatory proteins.

RESULTS: Aqueous extracts of I’m-Yunity (PSP) inhibited cell proliferation and induced apoptosis in HL-60 and U-937 cells, accompanied by a cell type-dependent disruption of the G1/S and G2/M phases of cell cycle progression. A more pronounced growth suppression was observed in treated HL-60 cells, which was correlated with time- and dose-dependent down regulation of the retinoblastoma protein Rb, diminution in the expression of anti-apoptotic proteins bcl-2 and survivin, increase in apoptogenic proteins bax and cytochrome c, and cleavage of poly(ADP-ribose) polymerase (PARP) from its native 112-kDa form to the 89-kDa truncated product. Moreover, I’m-Yunity (PSP)-treated HL-60 cells also showed a substantial decrease in p65 and to a lesser degree p50 forms of transcription factor NF-kappaB, which was accompanied by a reduction in the expression of cyclooxygenase 2 (COX2). I’m-Yunity (PSP) also elicited an increase in STAT1 (signal transducer and activator of transcription) and correspondingly, decrease in the expression of activated form of ERK (extracellular signal-regulated kinase).

CONCLUSION: Aqueous extracts of I’m-Yunity (PSP) induces cell cycle arrest and alterations in the expression of apoptogenic/anti-apoptotic and extracellular signaling regulatory proteins in human leukemia cells, the net result being suppression of proliferation and increase in apoptosis. These findings may contribute to the reported clinical and overall health effects of I’m-Yunity (PSP).

PMID: 16965632 [PubMed – indexed for MEDLINE]PMCID: PMC1574346Free PMC Article

http://www.ncbi.nlm.nih.gov/pubmed/16965632

Medical Studies, Preventative

Fungicidal value of wood tar from pyrolysis of treated wood.

Mazela B.

Institute of Chemical Wood Technology, Agricultural University of Pozna?, Wojska Polskiego 38/42, PL-60637 Pozna?, Poland. bartsimp@au.poznan.pl

Abstract

The objective of the paper was to estimate the fungicidal value of wood tar extracted as a product of pyrolysis of wood previously treated with either creosote oil or CCB-type salt preservative. The effectiveness of wood treated with one of these two wood tar residuals was compared to the effectiveness of wood treated with virgin creosote oil (type WEI-B) and an untreated control. Wood was impregnated with alcohol solutions of the two extracted preservatives or virgin creosote oil and then subjected to the Coniophora puteana, Poria placenta and Coriolus versicolor fungi. The fungicidal values of the investigated preservatives were determined with the use of the short agar-block method and the aging test according to the standard EN 84. It was found that wood tar extracted by pyrolysis of old creosote-treated wood and then used to treat wood may have potential as a preservative for wood protection or as a component of preservatives.

PMID: 17011772 [PubMed – indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/17011772

Immunotherapy, Medical Studies, PSP

Effects of polysaccharide peptides from COV-1 strain of Coriolus versicolor on glutathione and glutathione-related enzymes in the mouse.

Yeung JH, Or PM.

Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China. johnyeung@cuhk.edu.hk

Abstract

The effects of polysaccharide peptide (PSP), an immunomodulator isolated from Coriolus versicolor COV-1, on glutathione (GSH) and GSH-related enzymes was investigated in C57 mouse. Administration of PSP (1-4 micromole/kg, i.p.) produced a transient, dose-dependent depletion (10-37%) of hepatic GSH, with no effect on serum glutamic-pyruvic transaminase (SGPT) activity. Blood GSH was depleted (6-25%) at 3 h, followed by a rebound increase above the control GSH level (20%) at 18 h. The GSSG/GSH ratio, a measure of oxidative stress, was increased 3 h after PSP treatment but returned to normal levels at 24 h. Sub-chronic treatment of PSP (1-4 micromole/kg/day, i.p.) for seven days did not produce any significant changes in hepatic GSH levels and the GSSG/GSH ratio when measured 24 h after the final dose of PSP. PSP had little effect on glutathione transferase (GST), glutathione reductase (GSSG reductase) and glutathione peroxidase (GPX) activities in the liver. However, a dose-dependent increase in blood GPX activity (30-48%) was observed at 3h, which coincided with the increase in the GSSG/GSH ratio. The increase in blood GPX activity may be a responsive measure to deal with the transient oxidative stress induced by PSP treatment. The results showed that PSP only caused a transient perturbation on hepatic glutathione without affecting the GSH-related enzymes such as GST, GSSG reductase and GPX. The observed changes in blood GSH simply reflected the intra-organ translocation of glutathione, as the glutathione-related enzymes were not significantly affected by PSP treatment.

PMID: 17240508 [PubMed – indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/17240508

in vitro, Medical Studies, PSP

In vivo effect of I’m-Yunity on hepatic cytochrome P450 3A4.

Nicandro JP, Tsourounis C, Frassetto L, Guglielmo BJ.

Dept of Clinical Pharmacy, University of California, San Francisco, CA 94143, USA. ps01459@itsa.ucsf.edu

Abstract

The inhibition or induction of hepatic cytochrome P450 3A4 (CYP3A4) enzyme associated with herbal medicines such as I’m-Yunity (Coriolus versicolor) can result in clinically significant herb-drug interactions. The active ingredient of I’m-Yunity is believed to be polysaccharopeptide polymer (PSP). Drug interactions between I’m-Yunity and other medications or supplements are yet to be investigated. The objective of this single-treatment, one-period, three-phase, open-labeled study was to evaluate the ability of I’m-Yunity to inhibit or induce CYP3A4 in 12 healthy adult volunteers (8 women and 4 men) aged between 23 and 54 years through the use of a CYP3A4-specific assay, the erythromycin breath test (EBT). EBT measurements are reported as percentage of 14C-Erythromycin metabolized/hr. Participants were given a 14-day supply of I’m-Yunity and instructed to take 1200 mg, three times daily with meals. Comparisons of all subjects’ mean CYP3A4 activities were performed with the EBT before and after taking I’m- Yunity. Results revealed a mean EBT change (SD) from baseline of 0.08% (0.56%) 14C-Erythromycin metabolized/hr, which was not significant (p = 0.63). Therefore, 14 days of exposure to I’m-Yunity was not associated with clinically significant CYP3A4 inhibition or induction, suggesting that short-term administration of I’m-Yunity with medications primarily metabolized by CYP3A4 is safe and not expected to be associated with significant herb-drug interactions. However, it is still unknown whether interactions exist between I’m-Yunity and other medications metabolized by other CYP450 isozymes or enzyme/transporter systems.

PMID: 17594986 [PubMed – indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/17594986

in vitro, Medical Studies, Melanoma, Tumor

Anti-tumor effect of Coriolus versicolor methanol extract against mouse B16 melanoma cells: in vitro and in vivo study.

Harhaji Lj, Mijatovi? S, Maksimovi?-Ivani? D, Stojanovi? I, Momcilovi? M, Maksimovi? V, Tufegdzi? S, Marjanovi? Z, Mostarica-Stojkovi? M, Vucini? Z, Stosi?-Grujici? S.

Department of Immunology, Institute for Biological Research Sinisa Stankovi?, Belgrade University, Belgrade, Serbia.

Abstract

Numerous studies have shown immunostimulatory and anti-tumor effects of water and standardized aqueous ethanol extracts derived from the medicinal mushroom, Coriolus versicolor, but the biological activity of methanol extracts has not been examined so far. In the present study we investigated the anti-tumor effect of C. versicolor methanol extract (which contains terpenoids and polyphenols) on B16 mouse melanoma cells both in vitro and in vivo. In vitro treatment of the cells with the methanol extract (25-1600 microg/ml) reduced melanoma cell viability in a dose-dependent manner. Furthermore, in the presence of the methanol extract (200 microg/ml, concentration IC(50)) the proliferation of B16 cells was arrested in the G(0)/G(1) phase of the cell cycle, followed by both apoptotic and secondary necrotic cell death. In vivo methanol extract treatment (i.p. 50 mg/kg, for 14 days) inhibited tumor growth in C57BL/6 mice inoculated with syngeneic B16 tumor cells. Moreover, peritoneal macrophages collected 21 days after tumor implantation from methanol extract-treated animals exerted stronger tumoristatic activity ex vivo than macrophages from control melanoma-bearing mice. Taken together, our results demonstrate that C. versicolor methanol extract exerts pronounced anti-melanoma activity, both directly through antiproliferative and cytotoxic effects on tumor cells and indirectly through promotion of macrophage anti-tumor activity.

PMID: 18313195 [PubMed – indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/18313195

Cancer, Immunotherapy, Medical Studies, PSK

The immunomodulator PSK induces in vitro cytotoxic activity in tumour cell lines via arrest of cell cycle and induction of apoptosis.

Jiménez-Medina E, Berruguilla E, Romero I, Algarra I, Collado A, Garrido F, Garcia-Lora A.

Servicio de Análisis Clínicos e Inmunologia, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Av, de las Fuerzas Armadas 2, 18014 Granada, Spain. evajimenez@fundacionhvn.org

Abstract

BACKGROUND: Protein-bound polysaccharide (PSK) is derived from the CM-101 strain of the fungus Coriolus versicolor and has shown anticancer activity in vitro and in in vivo experimental models and human cancers. Several randomized clinical trials have demonstrated that PSK has great potential in adjuvant cancer therapy, with positive results in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunomodulator of biological responses. The precise molecular mechanisms responsible for its biological activity have yet to be fully elucidated.

METHODS: The in vitro cytotoxic anti-tumour activity of PSK has been evaluated in various tumour cell lines derived from leukaemias, melanomas, fibrosarcomas and cervix, lung, pancreas and gastric cancers. Tumour cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of PSK on human peripheral blood lymphocyte (PBL) proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in PSK-treated cells.

RESULTS: PSK showed in vitro inhibition of tumour cell proliferation as measured by BrdU incorporation and viable cell count. The inhibition ranged from 22 to 84%. Inhibition mechanisms were identified as cell cycle arrest, with cell accumulation in G0/G1 phase and increase in apoptosis and caspase-3 expression. These results indicate that PSK has a direct cytotoxic activity in vitro, inhibiting tumour cell proliferation. In contrast, PSK shows a synergistic effect with IL-2 that increases PBL proliferation.

CONCLUSION: These results indicate that PSK has cytotoxic activity in vitro on tumour cell lines. This new cytotoxic activity of PSK on tumour cells is independent of its previously described immunomodulatory activity on NK cells.

PMID: 18366723 [PubMed – indexed for MEDLINE]PMCID: PMC2291471Free PMC Article

http://www.ncbi.nlm.nih.gov/pubmed/18366723

Clinical Trials, Immunotherapy, Medical Studies, Melanoma, PSK, PSP

Evaluation of widely consumed botanicals as immunological adjuvants.

1 Comment

Ragupathi G, Yeung KS, Leung PC, Lee M, Lau CB, Vickers A, Hood C, Deng G, Cheung NK, Cassileth B, Livingston P.

Laboratory of Tumor Vaccinology, Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States. ragupatg@mskcc.org

Abstract

BACKGROUND: Many widely used botanical medicines are claimed to be immune enhancers. Clear evidence of augmentation of immune responses in vivo is lacking in most cases. To select botanicals for further study based on immune enhancing activity, we study them here mixed with antigen and injected subcutaneously (s.c.). Globo H and GD3 are cell surface carbohydrates expressed on glycolipids or glycoproteins on the cell surface of many cancers. When conjugated to keyhole limpet hemocyanin (KLH), mixed with an immunological adjuvant and administered s.c. the magnitude of the antibody responses against globo H, GD3 and KLH depend largely on the potency of the adjuvant. We describe here the results obtained using this s.c. immunization model with seven botanicals purported to have immune stimulant effects.

METHODS: Groups of 5-10 mice were immunized with globo H-KLH or GD3-KLH mixed with botanical, saline or positive control immunological adjuvant, s.c. three times at 1 week intervals. Antibody responses were measured 1 and 2 weeks after the 3rd immunization. The following seven botanicals and fractions were tested: (1) H-48 (Honso USA Co.), (2) Coriolus versicolor raw water extract, purified polysaccharide-K (PSK) or purified polysaccharide-peptide (PSP) (Institute of Chinese Medicine (ICM)), (3) Maitake extract (Yukiguni Maitake Co. Ltd. and Tradeworks Group), (4) Echinacea lipophilic, neutral and acidic extracts (Gaia Herbs), (5) Astragalus water, 50% or 95% ethanol extracts (ICM), (6) Turmeric supercritical (SC) or hydro-ethanolic (HE) extracts (New Chapter) or 60% ethanol extract (ICM) and (7) yeast beta-glucan (Biotec Pharmacon). Purified saponin extract QS-21 (Antigenics) and semisynthetic saponin GPI-0100 (Advanced BioTherapies) were used as positive control adjuvants. Sera were analyzed by ELISA against synthetic globo H ceramide or GD3 and KLH.

RESULTS: Consistent significant adjuvant activity was observed after s.c. vaccination with the Coriolus extracts (especially PSK), a 95% ethanol extract of Astragalus and yeast beta-glucan, and (to a lesser extent) Maitake. Antibodies against KLH in all cases and against globo H in most cases were induced by these botanicals. Little or no adjuvant activity was demonstrated with H-48 or Echinacea extracts or the Astragalus water extract. Experiments with GD3-KLH as immunogen confirmed the adjuvant activity of the Coriolus, yeast beta-glucan and Astragalus extracts. While extraction with ethanol concentrated the active ingredients in Astragalus, it had no impact on Coriolus where the 90% ethanol precipitate and solute were equally active.

CONCLUSIONS: Some, but not all, botanicals purported to be immune stimulants had adjuvant activity in our model. PSK and Astragalus were surprisingly active and are being further fractionated to identify the most active adjuvant components.

PMID: 18640165 [PubMed – indexed for MEDLINE]PMCID: PMC2565601

http://www.ncbi.nlm.nih.gov/pubmed/18640165