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CELLULAR IMMUNE FUNCTION CHEMISTRY Fungal metabolites have major immunomodulating effects.
Polysaccharide-K, also known as PSK, is a proteoglycan found in several medicinal mushrooms. The results obtained from a large number of published scientific studies
and clinical trials show that PSK is a powerful immunomodulator capable of stimulating diverse immunological functions. For instance, PSK can improve cancer survival by restoring
and enhancing cellular immune functions in patients with depressed immunity due to radiation and/or chemotherapy or surgical stress after curative resection of cancer. PSK does not interact with other drugs nor affect hepatic drug-metabolizing
enzyme activities indicating that drug efficacy is not affected by PSK when used with other medications. PSK is most effective
when combined with a front-line anticancer treatment regimen (chemotherapy, radiation therapy or surgery) for patients with
many types of cancer. Randomized controlled clinical trials and meta-analysisshowed that overall survival and disease-free survival are improved in patients treated with adjuvant immunotherapy plus PSK.
PSK is also beneficial for maintaining general immune health with no reported adverse side effects. They include effects like mitogenicity, and activation of immune effector
cells, such as lymphocytes, macrophages, and natural killer cells, resulting in the production of cytokines, including interleukins,
tumor necrosis factor alpha, and interferon gamma. One particular effect is the ability to selectively
modulate the differentiation capacity of CD4 T cells to mature T helper 1 and or T helper 2 subsets. These
effects cause profound effects in response to disease states like chronic autoimmune T helper1 mediated or allergic T helper
2 mediated diseases, like HIV, listeriosis, tuberculosis, septic shock and cancer. Also go to the inflammation mechanisms tab for more information about how the immune system reacts to trauma, diseases and wounds. Various
metabolites from mushrooms, Beta-glucans, are reported to affect bone marrow cells, and to induce hematopoiesis.
Maitake, caused direct enhancement of the colony forming units, granulocytes/macrophages response of bone marrow cell’s
progenitors and enhance recovery of the CFU-GM response after clinically induced hematopoietic suppression. Treatment
of macrophages with Reshi increased levels of IL-1B, TNF-a, IL-6 by 5.1, 9.8, and 29 fold respectively, than in control samples. The
bactericidal activity of maitake on splenetic T cells was also enhanced, with listeria infected cells by 2.6 times. Excitingly,
Shitake interacts with macrophages and related cells and results in the activation of the transcription factor nuclear factor
kappa B, which sets off a series of reactions producing a variety of proinflammatory and anti-inflammatory cytokines, TNF-a,
IL-1B, IL-10, IL-12, GM-CSF, IL-18, in a sequential manner. The methanol extract of Cordyceps inhibited IL-1B, TNF-a,
NO and prostaglandins E2 (PGE2) in vitro and in vivo. The extract inhibited these inflammatory mediators
in LPS stimulated murine macrophage cell line by suppressing gene expression of IL-1b, TNF-a, iNOS, and
COX-2 through the inhibition of NF kappa beta activation. ____________________________________________________________________________________________________________________________
BIBLIOGRAPHY ____________________________________________________________________________________________________________________________
Cristina Lill, Harry
Wichers, and Huub Savelkoul, Anti-inflamatory and Immun-nomodulating properties of Fungal metabolites, Mediators
Inflamm, 2005; 2005(2); 63-80 Reshetnikov, Wasser, Tan, Higher basidiomycota as a source of antitumor
and immuno-stimulating polysaccharides. Int J Med Mush. 2001;3(4);361-394
Borchers, Stern,
Hackman, Mushroom, tumors, and immunity. Proc Soc Exp Biol Med. 1999:221(4):281-293 Gao,
Chan, Shou, Immunomodulating activities of Ganoderma, a mushroom with medicinal properties. Food
Rev Int. 2004:20:123-161 Li, Huang, Shang et al. The Chinese herbal medicine
formula MSSM-002 suppresses allergic airway hyperactivity and modulates TH1/TH2 responses in a murine model of allergic asthma.
J Allergy Clin. Immunol. 2000;106(4):660-668 Hsieh, Hsu, Lin, Tsai, Oral administration of an
edible mushroom derived protein inhibits the development of food allergic reactions in mice. Clin Exp Allergy. 2003:33(11);1595-1602 Li,
Zhang, Huang et al, Food allergy herbal FAHF-1 blocks peanut induced anaphylaxis in a murine model. J Allergy Clin
Immunol. 2001:108(4):639-646 Nanba, Kodama, Schar, Turner. Effects
of Maitake glucan in HIV infected patients. Mycoscience. 2000;41:293-295
Ngai, Ng,, Lentinan,
A novel and potent antifungal protein from Shiitake mushrooms with inhibitory effects on activity of human immunoodefieciency
virus-1 reverse transcriptase and proliferation of leukemia cells. Life Sci 2003;73(26);3363-3374 Markova,
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Morphological
and genetic characterization of a cultivated Cordyceps sinensis fungus and its polysaccharide component possessing antioxidant
property in H22 tumor-bearing mice. Chen J, Zhang W, Lu T, Li J, Zheng Y, Kong L.Medical School, Nanjing University, Nanjing 210093, People's
Republic of China.Cordyceps
sinensis, one of the most precious traditional Chinese medicines, possesses the antitumor activity, antioxidant activity and
the capability of modulating the immune system. In the present study, a fungus strain G1 isolated from wild C. sinensis was identified
and initially characterized. A phylogenetic tree was generated based on the sequences of the internal transcribed spacer (ITS)
region of related fungi. The analysis of ITS sequence showed that fungus G1 was clustered together with C. sinensis,
Tolypocladium cylindrosporum and Tolypocladium inflatum in the phylogenetic tree. Both the morphological character and
the ITS sequence analysis establish that fungus G1 is one of the anamorph strains of C. sinensis and belongs to Tolypocladium
genus. Furthermore, the polysaccharide (PS) extracted from fungus G1 and its antioxidant activity on H22-bearing mice
was investigated. H22 cells were hypodermically injected into the right oxter of each mouse after the ICR mice were treated
with PS by means of gavage for 7 days. Then the same administration process continued for 9 days. At the end of
the experiments, the tumor weight of each mouse was measured. Superoxide dismutase (SOD) activity and malondialdehyde (MDA)
level in mouse liver, brain and serum, as well as glutathione peroxidase (GSH-Px) activity in mouse liver and brain were assayed.
The results showed that the H22 tumor growth was significantly inhibited by PS. Moreover,
PS significantly enhanced SOD activity of liver, brain and serum as well as GSH-Px activity of liver and brain in tumor-bearing
mice. PS also significantly reduced the level of MDA in liver and brain of tumor-bearing mice.PMID: 16492382 [PubMed - indexed for
MEDLINE]
Relation
between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts. Leggas M, Stewart CF, Woo MH, Fouladi M, Cheshire PJ, Peterson JK, Friedman HS, Billups C, Houghton PJ.Department of Pharmaceutical Sciences, St. Jude Children's
Research Hospital, Memphis, Tennessee 38105, USA.Irofulven is a novel, small molecular weight semisynthetic compound, derived from a family of
mushroom toxins known as illudins. This DNA alkylating agent has a chemical structure unlike any other chemotherapeutic agent
in clinical use. The molecule is currently being studied in several Phase I, II, and III trials. The objectives of this study
were to evaluate the antitumor activity of Irofulven in a panel of 20 pediatric solid tumor xenografts and to relate the Irofulven
systemic exposure, defined as area under the concentration time curve, to the antitumor dose associated with tumor regression
in the tumor models. Irofulven was administered i.v. daily for 5 days with courses repeated every 21 days for a total of three
cycles. The minimum effective dose of Irofulven causing objective regression (> or =50% volume regression) of advanced
tumors was determined for each of 19 of 20 independently derived tumor models (12 brain tumors, 4 neuroblastomas, and 4 rhabdomyosarcomas).
At the maximum tolerated dose for three cycles of treatment (4.6 mg/kg/day) objective regressions were determined in 14 of
18 tumor lines (78%). However, the dose-response relationship was acute. At 2 mg/kg only 3 of 15 tumors tested demonstrated
objective regressions, and in 3 additional tumors volume regressions were not achieved at a higher dose level (3 mg/kg), hence
were not additionally tested. After administering the maximum tolerated dose (tolerated for one or two cycles of treatment)
of Irofulven, 7 mg/kg, to mice bearing sensitive and resistant human tumors plasma concentration-time profiles were determined.
Tumors were highly sensitive to Irofulven, but the systemic exposure required for a significant rate of objective response
in this panel of tumors is in excess of that achievable in patients at tolerable doses, using this schedule of drug administration.PMID: 12231547 [PubMed - indexed for
MEDLINE]
Nerve growth factor-inducing activity
of Hericium erinaceus in 1321N1 human astrocytoma cells. Mori K, Obara Y, Hirota M, Azumi Y, Kinugasa S, Inatomi S, Nakahata N.Department of Cellular Signaling, Graduate School of Pharmaceutical
Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai, Japan.Neurotrophic factors are essential to maintain and organize neurons functionally; thereby
neurotrophic factor-like substances or their inducers are expected to be applied to the treatment of neurodegenerative diseases
such as Alzheimer's disease. In the present study, we firstly examined the effects of ethanol
extracts of four edible mushrooms, Hericium erinaceus (Yamabushitake), Pleurotus eryngii (Eringi), Grifola frondosa (Maitake),
and Agaricus blazei (Himematsutake), on nerve growth factor (NGF) gene expression in 1321N1 human astrocytoma cells. Among
the four mushroom extracts, only H. erinaceus extract promoted NGF mRNA expression in a concentration-dependent manner.In addition, secretion of NGF protein from 1321N1 cells was enhanced by H. erinaceus extracts, and the conditioned
medium of 1321N1 cells incubated with H. erinaceus extract enhanced the neurite outgrowth of PC12 cells. However, hericenones
C, D and E, constituents of H. erinaceus, failed to promote NGF gene expression in 1321N1 cells. The enhancement of NGF gene
expression by H. erinaceus extracts was inhibited by the c-jun N-terminal kinase (JNK) inhibitor SP600125. In addition, H.
erinaceus extracts induced phosphorylation of JNK and its downstream substrate c-Jun, and increased c-fos expression, suggesting
that H. erinaceus promotes NGF gene expression via JNK signaling. Furthermore we examined the efficacy of H. erinaceus in
vivo. ddY mice given feed containing 5% H. erinaceus dry powder for 7 d showed an increase in the level of NGF mRNA expression
in the hippocampus. In conclusion, H. erinaceus contains active compounds that stimulate NGF synthesis via activation of the
JNK pathway; these compounds are not hericenones.PMID: 18758067 [PubMed - indexed for MEDLINE]
Nerve growth factor-inducing activity of Hericium erinaceus
in 1321N1 human astrocytoma cells. Mori K, Obara Y, Hirota M, Azumi Y, Kinugasa S, Inatomi S, Nakahata N.Department of Cellular Signaling, Graduate School of Pharmaceutical
Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai, Japan. Neurotrophic factors are essential to maintain and organize neurons functionally; thereby
neurotrophic factor-like substances or their inducers are expected to be applied to the treatment of neurodegenerative diseases
such as Alzheimer's disease. In the present study, we first examined the effects of ethanol extracts of four edible
mushrooms, Hericium erinaceus (Yamabushitake), Pleurotus eryngii (Eringi), Grifola frondosa (Maitake), and Agaricus blazei
(Himematsutake), on nerve growth factor (NGF) gene expression in 1321N1 human astrocytoma cells. Among the four mushroom extracts,
only H. erinaceus extract promoted NGF mRNA expression in a concentration-dependent manner. In addition, secretion of NGF
protein from 1321N1 cells was enhanced by H. erinaceus extracts, and the conditioned medium of 1321N1 cells incubated with
H. erinaceus extract enhanced the neurite outgrowth of PC12 cells. However, hericenones C, D and E, constituents of H. erinaceus,
failed to promote NGF gene expression in 1321N1 cells. The enhancement of NGF gene expression by H. erinaceus extracts was
inhibited by the c-jun N-terminal kinase (JNK) inhibitor SP600125. In addition, H. erinaceus extracts induced phosphorylation
of JNK and its downstream substrate c-Jun, and increased c-fos expression, suggesting that H. erinaceus promotes NGF gene
expression via JNK signaling. Furthermore we examined the efficacy of H. erinaceus in vivo. ddY mice given feed containing
5% H. erinaceus dry powder for 7 d showed an increase in the level of NGF mRNA expression in the hippocampus. In conclusion, H. erinaceus contains active compounds that stimulate NGF synthesis via activation of the
JNK pathway; these compounds are not hericenones. PMID: 18758067 [PubMed - indexed for MEDLINE]
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