Gibbledygook's anti-viral log

[gibbledygook]

Digging around on MAPK in particular p38 which I believe is involved in the inflammation of microglia as per articles below I discovered that astragulus (main ingredient of chinese med to treat paralysis as per above) attenuates MAPKp38 signalling. This is VERY VERY exciting!!!!
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Mitogen activated protein kinase p38 (MAPKp38):

1: Exp Mol Pathol. 2008 Feb;84(1):1-8. Epub 2007 Oct 17. Links
Inducible IL-23p19 expression in human microglia via p38 MAPK and NF-kappaB signal pathways.Li Y, Chu N, Hu A, Gran B, Rostami A, Zhang GX.
Department of Neurology, Thomas Jefferson University, 300 JHN Building, 900 Walnut Street, Philadelphia, PA 19107, USA.

Activated microglia can release a variety of proinflammatory cytokines that play a crucial role in the pathogenesis of multiple sclerosis (MS). IL-23, a novel proinflammatory cytokine, is required for the induction of experimental autoimmune encephalomyelitis. Previously we demonstrated that IL-23 is expressed in MS lesions and that microglia are one cellular source of IL-23 in MS patients. In the present study we investigated the inducible expression and regulation of p19, a key subunit of IL-23, in human microglia. We demonstrated the inducible expression of IL-23p19 by lipopolysaccharide-stimulated microglial cells. Using signaling pathway-specific inhibitors, we showed that blocking p38 MAP kinase or NF-kappaB signaling pathway significantly reduced p19 expression in microglia. The regulatory role of p38 MAP kinase in p19 expression was further confirmed by decreased expression in microglia transduced with dominant-negative p38. We concluded that the p38 MAP kinase and NF-kappaB signaling pathways play an important role in regulation of IL-23p19 expression on human microglia, and are thus potential therapeutic targets in the treatment of MS.

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1: J Neurochem. 2007 Apr;101(2):364-76. Epub 2007 Jan 22. Links
A novel role of glia maturation factor: induction of granulocyte-macrophage colony-stimulating factor and pro-inflammatory cytokines.Zaheer A, Zaheer S, Sahu SK, Knight S, Khosravi H, Mathur SN, Lim R.
Veterans Affair Medical Center, Iowa City, Iowa, USA. asgar-zaheer@uiowa.edu

The glia maturation factor (GMF), which was discovered in our laboratory, is a highly conserved protein predominantly localized in astrocytes. GMF is an intracellular regulator of stress-related signal transduction. We now report that the overexpression of GMF in astrocytes leads to the destruction of primary oligodendrocytes by interactions between highly purified cultures of astrocytes, microglia, and oligodendrocytes. We infected astrocytes with a replication-defective adenovirus carrying the GMF cDNA. The overexpression of GMF caused the activation of p38 MAP kinase and transcription factor NF-kappaB, as well as the induction of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA and protein in astrocytes. Small interfering RNA-mediated GMF knockdown completely blocked the GMF-dependent activation of p38 mitogen-activated protein kinase (MAPK), NF-kappaB, and enhanced expression of GM-CSF by astrocytes. Inhibition of p38 MAPK or NF-kappaB by specific inhibitors prevented GM-CSF production. The cell-free conditioned medium from overexpressing GMF astrocytes contained 320 +/- 33 pg/mL of GM-CSF, which was responsible for enhanced production and secretion of TNF-alpha, IL-1beta, IL-6, and IP-10 by microglia. Presence of these inflammatory cytokines in the conditioned medium from microglia efficiently destroyed oligodendrocytes in culture. These results suggest that GMF-induced production of GM-CSF in astrocytes is depending on p38 MAPK and NF-kappaB activation. The GM-CSF-dependent expression and secretion of inflammatory cytokine/chemokine, TNF-alpha, IL-1beta, IL-6, and IP-10, is cytotoxic to oligodendrocytes, the myelin-forming cells in the central nervous system, and as well as neurons. Our results suggest a novel pathway of GMF-initiated cytotoxicity of brain cells, and implicate its involvement in inflammatory diseases such as multiple sclerosis.

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looks like andrographis paniculata is also good:

1: Mol Cell Biochem. 2007 Apr;298(1-2):49-57. Epub 2006 Nov 16. Links
Inhibitory effects of neoandrographolide on nitric oxide and prostaglandin E2 production in LPS-stimulated murine macrophage.Liu J, Wang ZT, Ji LL, Ge BX.
Institute of Chinese Material Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, P. R. China.

Activated macrophages express inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), produce excessive amounts of nitric oxide (NO) and prostaglandin E(2) (PGE(2)), which play key roles in the processes of inflammation. Andrographis paniculata Nees is a traditional Chinese herb commonly used for treatment of infection, inflammation, and diarrhea. However, the mechanism of its therapeutic function is not well known. In the present study, the effect of neoandrographolide, one of bioactive components in A. paniculata, on iNOS-mediated NO production and COX-2-mediated PGE(2) in bacterial lipopolysaccharide (LPS) stimulated-murine macrophages was investigated. Neoandrographolide at concentrations (30-90 microM) significantly (p<0.05) inhibited the productions of NO and PGE(2) in LPS stimulated macrophages without inducing cytotoxicity. The effect of neoandrographolide also has been investigated on iNOS and COX-2 expression in activated macrophage by using RT-PCR and immunoblotting. The inhibition of NO release by neoandrographolide can be attributed to the block of iNOS mRNA transcription followed by inhibiting protein expression. However, neoandrographolide inhibited COX-2 protein expression only but without inhibiting COX-2 mRNA expression, which was involved in the inhibitory activity against the PGE(2 )overproduction. This suggests that the effect of neoandrographolide on iNOS expression may occur at the transcriptional level and the inhibition of COX-2 expression occurs at the translational level. Furthermore, we have found that the addition of neoandrographolide inhibited the activation of p38 mitogen-activated protein kinase (MAPKs) instead of JNK, ERK1/2, or NF-kappaB. These results indicated that the anti-inflammatory properties of neoandrographolide might result from the inhibition of iNOS and COX-2 expression through inhibiting p38 MAPKs activation. Therefore, neoandrographolide isolated from A. paniculata could be offered as a leading compound for anti-inflammation.

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And peony

1: Int Immunopharmacol. 2007 Mar;7(3):343-50. Epub 2006 Dec 14. Links
Paeonol suppresses intercellular adhesion molecule-1 expression in tumor necrosis factor-alpha-stimulated human umbilical vein endothelial cells by blocking p38, ERK and nuclear factor-kappaB signaling pathways.Nizamutdinova IT, Oh HM, Min YN, Park SH, Lee MJ, Kim JS, Yean MH, Kang SS, Kim YS, Chang KC, Kim HJ.
Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Korea.

Paeonol (2'-hydroxy-4'-methoxyacetophenone), the main active compound of the traditionally used Chinese herb Paeonia lactiflora Pallas, has anti-inflammatory, antioxidant and cardiovascular protective activities. We studied how the levels of intercellular adhesion molecule-1 (ICAM-1), one of the key molecules in the development of atherosclerosis, might be affected by paeonol in tumor necrosis factor-alpha (TNF-alpha)-activated human umbilical vein endothelial cells (HUVECs). Paeonol concentration-dependently inhibited the production of ICAM-1; it inhibited nuclear factor-kappaB (NF-kappaB) p65 translocation into the nucleus and the phosphorylation of inhibitory factor kappaBalpha (IkappaBalpha). It also blocked the TNF-alpha-induced phosphorylation of p38 and extracellular signal-regulated kinase (ERK), which are involved in regulating ICAM-1 production by TNF-alpha. Paeonol inhibited U937 monocyte adhesion to HUVECs stimulated by TNF-alpha, suggesting that it may inhibit the binding of monocytes to endothelium by regulating the production of critical adhesion molecules by TNF-alpha. The inhibitory effect of paeonol on ICAM-1 production might be mediated by inhibiting p38, ERK and NF-kappaB signaling pathways, which are involved in TNF-alpha-induced ICAM-1 production. Thus, paeonol may be beneficial in the treatment of cardiovascular disorders such as atherosclerosis.

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oops, I see I missed the article on astragalus!

1: J Ethnopharmacol. 2008 Jan 17;115(2):184-93. Epub 2007 Oct 5. Links
Astragali Radix elicits anti-inflammation via activation of MKP-1, concomitant with attenuation of p38 and Erk.Ryu M, Kim EH, Chun M, Kang S, Shim B, Yu YB, Jeong G, Lee JS.
Department of Biological Sciences, Ajou University, Republic of Korea.

Although Astragali Radix (Astragalus, AR), the root of Astragalus membranaceus (Fisch) Bunge, is widely used in oriental medicine for tonifying the immune response and improving circulation, the underlying mechanism(s) by which these effects are induced remains unclear. Here, we report that AR displays anti-inflammatory effects in zymosan air-pouch mice by reducing the expression of iNOS, COX-2, IL-6, IL-1beta and TNF-alpha and by decreasing the production of nitric oxide (NO). In a similar manner, AR reduces the expression of IL-6, iNOS, and COX-2 in lipopolysaccharide (LPS)-treated Raw 264.7 cells. We further demonstrate that AR attenuates the activity of p38 and Erk1/2 and stimulates mitogen-activated protein kinase phosphatase-1 (MKP-1) in LPS-treated Raw 264.7 cells. Additionally, AR interferes with the translocation of NFkappaB to the nucleus, subsequently resulting in NFkappaB-dependent transcriptional repression. Taken together, these data reveal that AR has an anti-inflammatory effect that is mediated by the MKP-1-dependent inactivation of p38 and Erk1/2 and inhibition of NFkappaB-mediated transcription. These results imply that the AR herb has a potential anti-inflammatory activity.

PMID: 17996413 [PubMed - indexed for MEDLINE]

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other stuff on astragalus

1: Thromb Haemost. 2003 Nov;90(5):904-14. Links
Antiinflammatory activity of astragaloside IV is mediated by inhibition of NF-kappaB activation and adhesion molecule expression.Zhang WJ, Hufnagl P, Binder BR, Wojta J.
Department of Vascular Biology and Thrombosis Research, University of Vienna, Austria.

The regulated expression of adhesion molecules on the surface of endothelial cells is a key process in the pathogenesis of inflammation. The saponin astragaloside IV (AS-IV), a 3-O-beta-D-xylopyranosyl-6-O-beta-D-glucopyranosylcycloastragenol purified from the Chinese medical herb Astragalus membranaceus (Fisch) Bge. has been shown to have anti-inflammatory effects in vivo. In this study we have investigated the effect of AS-IV on cytokine-and LPS-stimulated expression of adhesion molecules in and leukocyte adhesion to endothelial cells. We have demonstrated that AS-IV significantly reduced the adhesion promoting activity of LPS-stimulated HUVECs for polymorph-nuclear leukocytes (PMNs) and the monocytic cell line THP-1. Furthermore, by using specific cell ELISAs we could show that AS-IV decreased the LPS-induced expression of E-selectin and VCAM-1 on the surface of HUVECs in a dose and time dependent manner, whereas the expression of ICAM-1 was not affected by AS-IV. AS-IV also inhibits TNFalpha-induced VCAM-1 expression. The saponin octyl-D-glucopyranoside had no effect on the LPS-induced expression of E-selectin and VCAM-1 excluding an unspecific detergent-like effect of AS-IV. Moreover, AS-IV significantly inhibited LPS- and TNFalpha-induced specific mRNA levels for E-selectin and VCAM-1. Finally, we could show that AS-IV completely abolished LPS- and TNFalpha-induced nuclear translocation of NF-kappaB and NF-kappaB DNA binding activity in endothelial cells. We conclude that the ability of AS-IV to inhibit the NF-kappaB pathway might be one under-lying mechanism contributing to its anti-inflammatory potential in vivo.

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I think that epstein barr travels through the blood brain barrier endothelium via leukocytes

1: Clin Exp Immunol. 2008 Mar;151(3):519-27. Epub 2008 Jan 8. Links
Adhesion of Epstein-Barr virus-positive natural killer cell lines to cultured endothelial cells stimulated with inflammatory cytokines.Kanno H, Watabe D, Shimizu N, Sawai T.
Department of Pathology, Iwate Medical University School of Medicine, Morioka, Japan. hirokan@iwate-med.ac.jp

Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is characterized by chronic recurrent infectious mononucleosis-like symptoms. Approximately one-fourth of CAEBV patients develop vascular lesions with infiltration of EBV-positive lymphoid cells. Furthermore, EBV-positive natural killer (NK)/T cell lymphomas often exhibit angiocentric or angiodestructive lesions. These suggest an affinity of EBV-positive NK/T cells to vascular components. In this study, we evaluated the expression of adhesion molecules and cytokines in EBV-positive NK lymphoma cell lines, SNK1 and SNK6, and examined the role of cytokines in the interaction between NK cell lines and endothelial cells. SNKs expressed intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) at much higher levels than those in EBV-negative T cell lines. SNKs produced the larger amount of tumour necrosis factor (TNF)-alpha, which caused increased expression of ICAM-1 and VCAM-1 in cultured human endothelial cells, than that from EBV-negative T cell lines. Furthermore, SNKs exhibited increased adhesion to cultured endothelial cells stimulated with TNF-alpha or interleukin (IL)-1beta, and the pretreatment of cytokine-stimulated endothelial cells with anti-VCAM-1-antibodies reduced cell adhesion. These indicate that the up-regulated expression of VCAM-1 on cytokine-stimulated endothelial cells would be important for the adhesion of EBV-positive NK cells and might initiate the vascular lesions.

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1: Immunology. 1988 Apr;63(4):631-7. Links
Molecules mediating adhesion of T and B cells, monocytes and granulocytes to vascular endothelial cells.Prieto J, Beatty PG, Clark EA, Patarroyo M.
Department of Immunology, Karolinska Institutet, Stockholm, Sweden.

Leucocytes interact with vascular endothelial cells (EC), and adhesion between these two cell types in vitro is modulated by phorbol ester. Monocytes were found to display the highest basal adhesion to EC, followed by Epstein-Barr virus-immortalized normal B cells (EBV-B), T cells and granulocytes. Phorbol ester treatment increased the adhesion of all types of leucocytes, except monocytes. In the presence of this compound, monoclonal antibody 60.3 to GP90 (CD18, a leucocyte-adhesion protein which is non-covalently associated to either GP160, GP155, or GP130) was found to inhibit the adhesion of the four types of leucocytes to a considerable extent, while anti-lymphocyte function-associated antigen-1 (LFA-1) antibody to GP160 (CD11a) inhibited the adhesion of T and B cells only. Antibody 60.1 to GP155 (CD11b) had a major inhibitory activity exclusively on granulocytes, while antibody LB-2, which recognizes a distinct adhesion molecule (GP84) and, in contrast to the previous antibodies, reacts with EC, mainly inhibited adhesion of EBV-B and did not increase the inhibition obtained with antibody 60.3 alone. Fab fragments of antibody 60.3 inhibited leucocyte adhesion more efficiently, in either the absence or presence of phorbol ester, than the intact antibody molecule. It is concluded the GP90, either alone or associated to the larger glycoproteins, mediates the adhesion in all types of leucocytes, while GP84 mediates the adhesion of the activated B cells.

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[gibbledygook]

I meant to get my skullcap data down here! Known as scuttelleria radix. It is said to be effective against superantigen:

1: FEBS Lett. 2001 Jun 29;500(1-2):52-5. Links
The flavonoid baicalin inhibits superantigen-induced inflammatory cytokines and chemokines.Krakauer T, Li BQ, Young HA.
Department of Immunology and Molecular Biology, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, MD 21702-5011, USA. teresa.krakauer@det.amedd.army.mil

Excessive release of proinflammatory cytokines mediates the toxic effect of superantigenic staphylococcal exotoxins (SE). Baicalin, a flavone isolated from the Chinese herb Scutellaria baicalensis Georgi and used in China to treat infectious diseases, inhibited SE-stimulated T-cell proliferation (by 98%) and production of interleukin 1beta, interleukin 6, tumor necrosis factor, interferon gamma, monocyte chemotactic protein 1, macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta mRNA and protein by human peripheral blood mononuclear cells. These data suggest that baicalin may be therapeutically useful for mitigating the pathogenic effects of SE by inhibiting the signaling pathways activated by superantigens.

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1: Braz J Med Biol Res. 2007 Jul;40(7):1003-10. Links
Baicalin reduces the severity of experimental autoimmune encephalomyelitis.Zeng Y, Song C, Ding X, Ji X, Yi L, Zhu K.
Department of Neurology, The First Affiliated Hospital, Nanjing Medical University, China.

Scutellaria baicalensis Georgi is one of the important medicinal herbs widely used for the treatment of various inflammatory diseases in Asia. Baicalin (BA) is a bioactive anti-inflammatory flavone found abundantly in Scutellaria baicalensis Georgi. To explore the therapeutic potential of BA, we examined the effects of systemic administration of the flavone (5 and 10 mg/kg, ip) on relapsing/remitting experimental autoimmune encephalomyelitis (EAE) induced by proteolipid protein 139-151 in SJL/J mice, an experimental model of multiple sclerosis. The mice treated with PBS or BA at day -1 and for 3 consecutive days were observed daily for clinical signs of disease up to 60 days after immunization. In the PBS-EAE group, neurological scores were: incidence (100%), mean day of onset (8.0 +/- 0.73), peak clinical score (3.0 +/- 0.4), and cumulative disease index (141.8 +/- 19.4). In the BA-EAE group (5 or 10 mg kg(-1) day(-1), respectively), incidence (95 or 90%), mean day of onset (9.0 +/- 0.80 or 9.2 +/- 0.75; P = 0.000), peak clinical score (2.2 +/- 0.3 or 2.0 +/- 0.3; P = 0.000), and cumulative disease index (75.9 +/- 10.1 or 62.9 +/- 8.4; P = 0.000) decreased, accompanied by the histopathological findings (decrease of dense mononuclear infiltration surrounding vascellum) for the spinal cord. Additionally, the in vitro effects of BA (5, 10, and 25 microM) on mononuclear cells collected from popliteal and inguinal lymph nodes of day-10 EAE mice were evaluated using an MTT reduction assay for cell proliferation, and ELISA to measure IFN-gamma and IL-4 cytokines. Compared with the control group, BA caused an increase in IL-4 (EAE-DMSO: 3.56 +/- 0.42 pg/mL vs EAE-BA (5, 10, and 25 microM): 6.03 +/- 1.1, 7.83 +/- 0.65, 10.54 +/- 1.13 pg/mL, respectively; P < 0.001); but inhibited IFN-gamma (EAE-DMSO: 485.76 +/- 25.13 pg/mL vs EAE-BA (5, 10, and 25 microM): 87.08 +/- 9.24, 36.27 +/- 5.44, 19.18 +/- 2.93 pg/mL, respectively; P < 0.001) and the proliferation of mononuclear cells (EAE-DMSO: 0.73 +/- 0.021 vs EAE-BA (5, 10, and 25 microM): 0.41 +/- 0.015, 0.31 +/- 0.018, 0.21 +/- 0.11, respectively; P < 0.001) in a concentration-dependent manner. The results suggest that BA might be effective in the treatment of multiple sclerosis.

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1: Clin Mol Allergy. 2007 Nov 26;5:5. Links
Baicalein inhibits IL-1beta- and TNF-alpha-induced inflammatory cytokine production from human mast cells via regulation of the NF-kappaB pathway.Hsieh CJ, Hall K, Ha T, Li C, Krishnaswamy G, Chi DS.
Departments of Internal Medicine, James H, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614, USA. chi@etsu.edu.

ABSTRACT: BACKGROUND: Human mast cells are multifunctional cells capable of a wide variety of inflammatory responses. Baicalein (BAI), isolated from the traditional Chinese herbal medicine Huangqin (Scutellaria baicalensis Georgi), has been shown to have anti-inflammatory effects. We examined its effects and mechanisms on the expression of inflammatory cytokines in an IL-1beta- and TNF-alpha-activated human mast cell line, HMC-1. METHODS: HMC-1 cells were stimulated either with IL-1beta (10 ng/ml) or TNF-alpha (100 U/ml) in the presence or absence of BAI. We assessed the expression of IL-6, IL-8, and MCP-1 by ELISA and RT-PCR, NF-kappaB activation by electrophoretic mobility shift assay (EMSA), and IkappaBalpha activation by Western blot. RESULTS: BAI (1.8 to 30 muM) significantly inhibited production of IL-6, IL-8, and MCP-1 in a dose-dependent manner in IL-1beta-activated HMC-1. BAI (30 muM) also significantly inhibited production of IL-6, IL-8, and MCP-1 in TNF-alpha-activated HMC-1. Inhibitory effects appear to involve the NF-kappaB pathway. BAI inhibited NF-kappaB activation in IL-1beta- and TNF-alpha-activated HMC-1. Furthermore, BAI increased cytoplasmic IkappaBalpha proteins in IL-1beta- and TNF-alpha-activated HMC-1. CONCLUSION: Our results showed that BAI inhibited the production of inflammatory cytokines through inhibition of NF-kappaB activation and IkappaBalpha phosphorylation and degradation in human mast cells. This inhibitory effect of BAI on the expression of inflammatory cytokines suggests its usefulness in the development of novel anti-inflammatory therapies.

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The toll like receptor 4 is important in MS and baicalin reduces it = good!

1: Biomed Pharmacother. 2008 Feb 27. [Epub ahead of print] Links
Up-regulation of Toll-like receptor 4 was suppressed by emodin and baicalin in the setting of acute pancreatitis.Li Z, Xia X, Zhang S, Zhang A, Bo W, Zhou R.
Department of General Surgery, the Second Affiliated Hospital of Medical School, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, Shaanxi Province 710004, PR China.

Acute pancreatitis (AP) activates the systemic inflammatory response and is potentially lethal. Recent studies demonstrated that pancreatic enzymes could induce cytokine expression via Toll-like receptor 4 (TLR4) signal pathway, indicating a possible role of TLR4 in local pancreatic injury and systemic inflammatory response. Emodin, an anthraquinone derivative from Radix et Rhizoma Rhei, and baicalin, a flavone from Scutellaria baicalensis Georgi, both have been reported to possess anti-inflammatory activities. In present study, we investigated the combined effect of emodin and baicalin on pancreatic damage and pancreatitis associated lung injury, as well as tissue TLR4 expression in the setting of AP. The results showed that combination of emodin and baicalin significantly reduced serum amylase, tumor necrosis factor-alpha and interleukin-6, attenuated pancreatic and pulmonary damage, also suppressed TLR4 expression in pancreas and lung. It could be speculated that amelioration of pancreatic and pulmonary damage by emodin and baicalin might contribute, in part at least, to the suppression of TLR4 expression. The present study provides beneficial evidence as to simultaneous treatment for AP, and also suggests an important role of TLR4 in pathophysiology of AP.

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I have received some from Solgar and will swap 4.5g daily skullcap for the boswellia as I came across some rather less encouraging reports on boswellia below. I also think that in high doses the boswellia has had a negative effect especially an increase in stiffness so it will be interesting to see how the skullcap fares. I'll start with 4.5g and try to build up to 8g or so.

1: Phytother Res. 2008 Mar;22(3):340-8. Links
Immunomodulatory activity of biopolymeric fraction BOS 2000 from Boswellia serrata.Khajuria A, Gupta A, Suden P, Singh S, Malik F, Singh J, Gupta BD, Suri KA, Srinivas VK, Ella K, Qazi GN.
Division of Pharmacology, Indian Institute of Integrative Medicine, (CSIR, Jammu) 180001, India. anamikakhajuria@yahoo.com

Oral administration of BOS 2000 (1-10 mg/kg) elicited a dose related increase in the delayed hypersensitivity reaction (early 24 h and delayed 48 h) in mice. It also stimulated the IgM and IgG titre expressed in the form of plaques (PFC) and complement fixing antibody titre. The concentration of cytokines (IL-4, IFN-gamma and TNF-alpha) in serum with respect to T cell interactions, i.e. (CD4/CD8) and the proliferation of lymphocytes were significantly increased at 10 mg/kg compared with the control. The results in these studies demonstrated the immunostimulatory effect of BOS 2000 in a dose-dependent manner with respect to the macrophage activation possibly expressing the phagocytosis and nitrite production by the enhancement of TNF-alpha and IFN-gamma production as a mode of action.

1: Biochem Biophys Res Commun. 2002 Jan 11;290(1):185-90. Links
Boswellic acids activate p42(MAPK) and p38 MAPK and stimulate Ca(2+) mobilization.Altmann A, Fischer L, Schubert-Zsilavecz M, Steinhilber D, Werz O.
Institute of Pharmaceutical Chemistry, University of Frankfurt, Marie-Curie Strasse 9, D-60439 Frankfurt, Germany.

Here we show that extracts of Boswellia serrata gum resins and its constituents, the boswellic acids (BAs), activate the mitogen-activated protein kinases (MAPK) p42(MAPK) and p38 in isolated human polymorphonuclear leukocytes (PMNL). MAPK activation was rapid and transient with maximal activation after 1-2.5 min of exposure and occurred in a dose-dependent manner. The keto-BAs (11-keto-beta-BA and 3-O-acetyl-11-beta-keto-BA) gave substantial kinase activation at 30 microM, whereas other BAs lacking the 11-keto group were less effective. Moreover, 11-keto-BAs induced rapid and prominent mobilization of free Ca(2+) in PMNL. Inhibitor studies revealed that phosphatidylinositol 3-kinase (PI 3-K) is involved in BA-induced MAPK activation, whereas a minor role was apparent for protein kinase C. MAPK activation by 3-O-acetyl-11-beta-keto-BA was partially inhibited when Ca(2+) was removed by chelation. Our results suggest that 11-keto-BAs might function as potent activators of PMNL by stimulation of MAPK and mobilization of intracellular Ca(2+). (c)2002 Elsevier Science.

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1: Am J Chin Med. 2008;36(3):517-40. Links
Scutellaria baicalensis Enhances the Anti-Diabetic Activity of Metformin in Streptozotocin-Induced Diabetic Wistar Rats.Waisundara VY, Hsu A, Huang D, Tan BK.
Food Science and Technology Programme, Department of Chemistry, National University of Singapore, Science Drive 3, Singapore.

Oxidative stress is the root cause of diabetic macro- and microvascular complications. Biochemical and epidemiological studies indicate that current treatments for diabetes do not reduce risks of developing complications, suggesting their inability to alleviate the levels of oxidative stress. This study in streptozotocin (STZ)-induced diabetic rats was carried out to investigate the effect of combining the antidiabetic drug, metformin, with an ethanolic extract of Scutellaria baicalensis, a plant whose root is known for its radical scavenging activity. Three groups of STZ-induced diabetic rats were given the following treatments for 30 days: (1) metformin 500 mg/kg, (2) S. baicalensis 400 mg/kg, (3) metformin 500 mg/kg + S. baicalensis extract 400 mg/kg. In addition, vehicle-treated diabetic and nondiabetic controls were used in the experiment. The rats treated with S. baicalensis and metformin + S. baicalensis had elevated hepatic activities of the antioxidant enzymes - superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) compared to the vehicle- and metformin-treated diabetic groups (p < 0.05). Plasma and hepatic lipid peroxide concentrations in the herb-treated and herb + metformin-treated groups were also significantly reduced (p < 0.05). In addition, the combined treatment caused significant elevations of plasma and pancreatic insulin levels and reductions of plasma and hepatic triglycerides (TG) and cholesterol levels. The study thus showed that S. baicalensis enhanced the antidiabetic effect of metformin in STZ-induced diabetic rats by improving the antioxidant status. It also increased pancreatic insulin content as well as improved the lipid profile in these rats.

PMID: 18543386 [PubMed - in process]

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A couple of days ago the arthritis in my right finger vanished so at least something is working!

I'm also trying some chinese formulae for hayfever which have somewhat improved the sneezing but not dramatically so.

[gibbledygook]

Wow what a few days this has been. Unfortunately my tales concern hayfever rather than MS but I've had a funny experiment. Yesterday I went for a lovely lunch outside in the Chelsea Physic Garden, where they have a display of dried gelsemium super virens roots which are supposedly effective in brain and spinal disorders and multiple sclerosis. I "pubmeded" this plant and it's highly toxic!! Anyway after about an hour and a half and a walk of about 600meters, a lot of which was on unstable gravel, I returned home and sneezed and sneezed and sneezed. Manifestly the chinese herbal formula hadn't worked. I sneezed about twice a minute for the next 4 hours. I was in an air conditioned room as well, so the acute attack was shocking. I then had a hot bath with boswellia salts and this did temporarily stop the sneezing and was somewhat soothing. When I got out and looked in the mirror my nose was bright red and my face all blotchy. I then lay on the bed in the air conditioned and therefore relatively pollen-free room and started sneezing again and again and again. I had alreadly taken my full daily dose of the chinese meds which consists of about 80grams of herbs so I figured this wouldn't do. Thinking about the anti-spasmodic effects of cardamom (see below) I decided to make some cardamom and cinnamon tea. This is because it seems to me that in a hayfever attack one is not only allergic to the pollen but the nerves behind the mast cells go into some kind of uncontrollable spasm. Thus even if one is not in a highly pollinated room one continues to sneeze like I had just done. So initially I crushed the spices in a pessel and mortar and then boiled them for about 5 minutes and then drank down with honey. This was soothing but I continued to sneeze and stream. So then I decided to remake the tea but by grinding about 6 cardamom seeds and a stick of cinnamon in my coffee grinder and then boil and then add honey. For good measure I then decided to take 2 pills of capsaicin. After downing the capsaicin and tea within about 5 minutes I stopped streaming and sneezing. The reversal was sudden and unexpected. Of course the pollen count could suddenly have dropped but the windows had been sealed since 3.30 and it was now about 8pm.

1: J Ethnopharmacol. 2008 Feb 12;115(3):463-72. Epub 2007 Oct 22. Links
Gut modulatory, blood pressure lowering, diuretic and sedative activities of cardamom.Gilani AH, Jabeen Q, Khan AU, Shah AJ.
Natural Product Research Division, Department of Biological and Biomedical Sciences, Aga Khan University, Karachi 74800, Pakistan. anwar.gilani@aku.edu <anwar.gilani@aku.edu>

ETHNOPHARMACOLOGICAL RELEVANCE: Cardamom (Elettaria cardamomum) is traditionally used in various gastrointestinal, cardiovascular and neuronal disorders. AIM OF THE STUDY: To rationalize cardamom use in constipation, colic, diarrhea, hypertension and as diuretic. MATERIALS AND METHODS: Cardamom crude extract (Ec.Cr) was studied using in vitro and in vivo techniques. RESULTS: Ec.Cr caused atropine-sensitive stimulatory effect in isolated guinea-pig ileum at 3-10mg/ml. In rabbit jejunum preparations, Ec.Cr relaxed spontaneous and K+ (80 mM)-induced contractions as well as shifted Ca++ curves to right, like verapamil. Ec.Cr (3-100mg/kg) induced fall in the arterial blood pressure (BP) of anaesthetized rats, partially blocked in atropinized animals. In endothelium-intact rat aorta, Ec.Cr relaxed phenylephrine (1 microM)-induced contractions, partially antagonized by atropine and also inhibited K+ (80 mM) contractions. In guinea-pig atria, Ec.Cr exhibited a cardio-depressant effect. Ec.Cr (1-10mg/kg) produced diuresis in rats, accompanied by a saluretic effect. It enhanced pentobarbital-induced sleeping time in mice. Bio-assay directed fractionation revealed the separation of spasmogenic and spasmolytic components in the aqueous and organic fractions respectively. CONCLUSION: These results indicate that cardamom exhibits gut excitatory and inhibitory effects mediated through cholinergic and Ca++ antagonist mechanisms respectively and lowers BP via combination of both pathways. The diuretic and sedative effects may offer added value in its use in hypertension and epilepsy.

PMID: 18037596 [PubMed - indexed for MEDLINE]

Related ArticlesStudies on spasmogenic and spasmolytic activities of Calendula officinalis flowers. [Phytother Res. 2006] Gastrointestinal, selective airways and urinary bladder relaxant effects of Hyoscyamus niger are mediated through dual blockade of muscarinic receptors and Ca2+ channels. [Fundam Clin Pharmacol. 2008] Antispasmodic and blood pressure lowering effects of Valeriana wallichii are mediated through K+ channel activation. [J Ethnopharmacol. 2005] Ginger lowers blood pressure through blockade of voltage-dependent calcium channels. [J Cardiovasc Pharmacol. 2005] Presence of cholinergic and calcium channel blocking activities explains the traditional use of Hibiscus rosasinensis in constipation and diarrhoea. [J Ethnopharmacol. 2005] » See all Related Articles...

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1: Z Lebensm Unters Forsch. 1996 Jul;203(1):71-6.Links
Inhibitory effect of spices on in vitro histamine production and histidine decarboxylase activity of Morganella morganii and on the biogenic amine formation in mackerel stored at 30 degrees C.Shakila RJ, Vasundhara TS, Rao DV.
Department of Food Technology, Defence Food Research Laboratory, India.

The inhibitory effects of clove, cinnamon, cardamom, turmeric and pepper on the histamine production and histidine decarboxylase activity of Morganella morganii (a potent histamine-producing bacteria in fish) was examined at 30 degrees C using HPLC. Cinnamon and clove exhibited a significant (P < 0.01) inhibitory effect, whereas turmeric and cardamom had a moderate effect. These spices were applied to whole mackerel at a level of 3% and their inhibitory effect on biogenic amine formation at 30 degrees C was also examined. As in the in vitro study, clove and cinnamon showed a significant (P < 0.05) inhibitory effect on histamine, putrescine and tyramine formation but not on that of cadaverine. Cardamom and turmeric exhibited a moderate effect and pepper was ineffective. Therefore, clove and cinnamon are more helpful than cardamom and turmeric in the minimization of the formation of toxic histamine in mackerel.

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I added the capsaicin as I was thinking that if it works in diabetes through the nerves in the pancreatic islets then maybe it would work in hayfever with the nerves controlling the mast cells, assuming of course that this is the biology of the nose. But then this article made me rethink:

1: Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2007 Oct;21(20):947-9.
[The experimental research about relationship between neuropeptides and maste cell in allergic rhinitis][Article in Chinese]


Chen J, Yang R, Huang Z.
Department of Otolaryngology, the People's Hospital of Jiangyin, Jiangyin, 214400, China.

OBJECTIVE: To explore the relationship between neuropeptides and maste cell in the initiation and development of allergic rhinitis. METHOD: Thirty healthy rats were randomly divided into three groups. The rat model of allergic rhinitis was established by using ovalbumin intraperitoneal immunizationand nasal antigen challenge. After treating with capsaicin for two weeks, the counts of mast cells and the density of SP distribution were observed routinely in the nasal mucosa obtained from each models by HE, toluidine blue and immunohistochemical staining. RESULT: The counts of mast cells in AR were greatly more than them in normal controls (P < 0.01). After treating with capsaicin the mast cells were rare and significantly fewer than the normals (P < 0.01); The expression of SP waslower than the AR (P < 0.01), but no diference between the capsaicin group and normal group (P > 0.05). CONCLUSION: Capsaicin can decrease the infiltration of mast cells, downregluate the SP expression, and improve the symptoms of AR greatly.

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So it looks like I have serendipidously discovered natural products which are just as or more effective than the absolute rubbish medicine available in chinese medicine shops or boots!!! Unfortunately I also today discovered that capsaicin MUST be consumed on a full stomach. Otherwise the burning in the belly will start and spread and turn into a fever of the brain and a palpitation and feeling of total pain and nausea and a need to use the toilet and possibly pass out in the hairdresser's that one is visiting and immediate succour via milk of magnesia and zantak is required. Then food is also necessary a bit later, once the pain has alleviated and calm restored.

PS I added the data on astragalus on one of my entries above as I only just saw I missed it originally. Astragalus is the principal ingredient of a chinese medical formula that "treats paralysis". It also attenuates mitogen actived protein kinase p38 which is involved in the inflammatory cascade in MS, I believe.

[lyndacarol]

gibbledygook--I admit that I really know nothing about herbs compared to you! And I don't have hayfever.

But in all my reading I seem to recall that stinging nettle is supposed to help hayfever. Have you ever heard of this?

[gibbledygook]

Hi, yes I drink stinging nettle tea but haven't bought any pills to try but the capsaicin is working just fine today again!!!! Unbelievable that there is a high pollen count and I'm not wearing my surgical mask and I'm not sneezing at all.

[gibbledygook]

Well, suprises to the upside with the capsaicin treatment don't cease. Since taking 5 pills a day since Saturday I have noticed a big improvement in bladder function and right leg motor function. Initially the capsaicin also involved a much much looser bowel although I hope that this has settled down now. I've got to nip out now but I'll post some of the research I found on capsaicin shortly. Put it this way, I believe that bladder function is known to helped by capsaicin.

[gibbledygook]

1: J Spinal Cord Med. 2008;31(2):157-65.Links
Neurotoxin treatments for urinary incontinence in subjects with spinal cord injury or multiple sclerosis: a systematic review of effectiveness and adverse effects.MacDonald R, Monga M, Fink HA, Wilt TJ.
Center for Chronic Disease Outcomes Research, Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota, 55417, USA. roderick.macdonald@va.gov

BACKGROUND/OBJECTIVE: The objective was to evaluate the effectiveness of neurotoxin treatments of urinary incontinence (UI) in individuals with spinal cord injury (SCI) or multiple sclerosis (MS). METHODS: Studies were included if published in English, presented randomized adults with SCI or MS, and reported UI outcomes. RESULTS: Ten trials randomizing 288 subjects with SCI (43%), MS (52%), or other spinal conditions (5%) and UI refractory to oral antimuscarinics were included. The overall mean age was 41 years, and 46% were women. Study durations ranged from 1 to 18 months. Treatments included botulinum toxin-A (BTX-A, 2 trials) and 2 vanilloid compounds, capsaicin (6 trials) and resiniferatoxin (4 trials). BTX-A was superior to placebo and resiniferatoxin in reducing daily UI episodes, mainly in individuals with SCI, although significant reductions vs placebo were not evident throughout the study duration. There were 1.1 fewer daily UI episodes in the BTX-A 200 unit group vs 0.1 fewer for the placebo group at the final week 24 assessment. Capsaicin was generally superior to placebo. The weighted difference between capsaicin and placebo in a pooled analysis of 2 trials enrolling subjects with either paraplegia or tetraplegia (n = 32) was -3.8 daily UI episodes [95% Cl -4.7 to -2.9] after 30 days. Capsaicin was comparable to resiniferatoxin. Pelvic pain and facial flushing were associated with capsaicin. CONCLUSION: Neurotoxins may improve refractive UI in adults with SCI or MS, although trial results were inconsistent. Trials were small in size and relatively short in duration. Further studies are needed to determine the efficacy and tolerability of long-term application.

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1: Neurourol Urodyn. 2006;25(7):752-7. Links
Intravesical glucidic capsaicin versus glucidic solvent in neurogenic detrusor overactivity: a double blind controlled randomized study.de Sèze M, Gallien P, Denys P, Labat JJ, Serment G, Grise P, Salle JY, Blazejewski S, Hazane C, Moore N, Joseph PA.
Physical Medicine and Neurorehabilitation Unit, Bordeaux University Hospital, Bordeaux, France. marianne.de-seze@chu-bordeaux.fr

AIMS: Many studies report the use of alcoholic capsaicin instillation to treat neurogenic detrusor overactivity (NDO) in spinal cord injured (SCI) and multiple sclerosis (MS) patients. However, poor tolerability due to the irritative effect of the ethanol solvent limits its use. Our study aimed to evaluate the efficacy and tolerability of a new formulation of capsaicin in a glucidic solution in a multicenter clinical trial. MATERIALS AND METHODS: Thirty-three patients (26MS/7SCI) suffering from urinary incontinence due to refractory NDO were prospectively enrolled in a double-blind placebo controlled study and randomized to capsaicin group (CG, N = 17) or solvent group (SG, N = 16). They respectively received an intravesical instillation of 100 ml capsaicin diluted in glucidic solvent (CG) or glucidic solvent alone (SG). Efficacy (voiding chart, maximum cystometric capacity (MCC)) and tolerability were evaluated on days 0 (D0), 30 and 90. RESULTS: On D0, groups were homogeneous. On D30, significant improvement of overactive bladder syndrome and an increase in MCC were shown in CG, whereas there were no improvement in SG. No significant improvement was shown on D90 in both groups. There were no significant differences between groups regarding prevalence, duration, or intensity of side effects, except for short duration pubic pain during instillation more often reported in CG (58.8%) than in SG (12.5%) (P < 0.01). CONCLUSION: This placebo controlled study using glucidic capsaicin confirms its short-term efficacy in NDO patients. Global tolerance of glucidic capsaicin appeared satisfactory. Long-term efficacy and tolerance of repeated glucidic capsaicin instillations need to be evaluated. (c) 2006 Wiley-Liss, Inc.

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1: J Neuroimmunol. 2006 Feb;171(1-2):110-9. Epub 2005 Oct 18. Links
Arvanil inhibits T lymphocyte activation and ameliorates autoimmune encephalomyelitis.Malfitano AM, Matarese G, Pisanti S, Grimaldi C, Laezza C, Bisogno T, Di Marzo V, Lechler RI, Bifulco M.
Dipartimento di Scienze Farmaceutiche, Universita' di Salerno, Via Ponte don Melillo 84084 Fisciano (Salerno), Italy.

This study examined the immunomodulatory effect of arvanil, a synthetic capsaicin-anandamide hybrid. Arvanil inhibits lymphocyte proliferation and IFN-gamma production. The phenotype of activated CD4+T cells treated with arvanil shows a down-regulation of T cell activation markers such as CD25, HLA-DR and CD134/OX40. Arvanil and anandamide do not induce apoptosis on CD4+T cells. Arvanil blocks the G1/S phase transition of the cell cycle in stimulated peripheral blood mononuclear cells, inducing activation of p21waf-1/cip-1 and phosphorylation of Akt/PKB. In vivo, arvanil ameliorates experimental autoimmune encephalomyelitis in the SJL/J mouse. Our findings have relevance for the use of arvanil and related compounds as a novel immunotherapeutic approach in the treatment of multiple sclerosis.

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1: Ann N Y Acad Sci. 2004 Dec;1030:434-41. Links
Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning.Aggarwal BB, Shishodia S.
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Box 143, 1515 Holcombe Boulevard, Houston, TX 77030, USA. aggarwal@mdanderson.org

The activation of nuclear transcription factor kappaB has now been linked with a variety of inflammatory diseases, including cancer, atherosclerosis, myocardial infarction, diabetes, allergy, asthma, arthritis, Crohn's disease, multiple sclerosis, Alzheimer's disease, osteoporosis, psoriasis, septic shock, and AIDS. Extensive research in the last few years has shown that the pathway that activates this transcription factor can be interrupted by phytochemicals derived from spices such as turmeric (curcumin), red pepper (capsaicin), cloves (eugenol), ginger (gingerol), cumin, anise, and fennel (anethol), basil and rosemary (ursolic acid), garlic (diallyl sulfide, S-allylmercaptocysteine, ajoene), and pomegranate (ellagic acid). For the first time, therefore, research provides "reasoning for seasoning."

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1: J Spinal Cord Med. 2003 Winter;26(4):358-63.Links
Intravesical resiniferatoxin for refractory detrusor hyperreflexia: a multicenter, blinded, randomized, placebo-controlled trial.Kim JH, Rivas DA, Shenot PJ, Green B, Kennelly M, Erickson JR, O'Leary M, Yoshimura N, Chancellor MB.
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

OBJECTIVE: Resiniferatoxin (RTX) is an analogue of capsaicin with more than 1,000 times its potency in desensitizing C-fiber bladder afferent neurons. This study investigated the safety and efficacy of intravesical RTX in patients with refractory detrusor hyperreflexia (DH). METHODS: Thirty-six (22 males, 14 females) neurologically impaired patients (20 spinal cord injury, 7 multiple sclerosis, 9 other neurologic diseases) with urodynamically verified DH and intractable urinary symptoms despite previous anticholinergic drug use were treated prospectively with intravesical RTX using dose escalation in a double-blind fashion at 4 centers. Patients received a single instillation of 100 mL of placebo (n = 8 patients) or 0.005, 0.025, 0.05, 0.10, 0.2, 0.5, or 1.0 microM of RTX (n = 4 each group). A visual analog pain scale (VAPS) (0-10; 10 = highest level of pain) was used to quantify discomfort of application. Treatment effect was monitored using a bladder diary and cystometric bladder capacity at weeks 1, 3, 6, and 12 posttreatment. RESULTS: Mean VAPS scores revealed minimal to mild discomfort with values of 2.85 and 2.28 for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. Due to the small sample size, there were no statistically significant changes in mean cystometric capacity (MCC) or incontinence episodes in each treatment dose group. However, at 3 weeks, MCC increased by 53% and 48% for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. Patients in the 0.5-microM and 1.0-microM groups with MCC < 300 mL at baseline showed greater improvements in MCC at 120.5% and 48%, respectively. In some patients, MCC increased up to 500% over baseline, despite a low RTX dose. Incontinence episodes decreased by 51.9% and 52.7% for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. There were no long-term complications. CONCLUSION: Intravesical RTX administration, in general, is a well-tolerated new therapy for DH. This patient group was refractory to all previous oral pharmacologic therapy, yet some patients responded with significant improvement in bladder capacity and continence function shortly after RTX administration. Patients at risk for autonomic dysreflexia require careful monitoring during RTX therapy.

PMID: 14992337 [PubMed - indexed for MEDLINE]

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1: Eur J Pharmacol. 2002 Mar 29;439(1-3):83-92. Links
Arvanil-induced inhibition of spasticity and persistent pain: evidence for therapeutic sites of action different from the vanilloid VR1 receptor and cannabinoid CB(1)/CB(2) receptors.Brooks JW, Pryce G, Bisogno T, Jaggar SI, Hankey DJ, Brown P, Bridges D, Ledent C, Bifulco M, Rice AS, Di Marzo V, Baker D.
Pain Research Group, Department of Anaesthetics, Faculty of Medicine, Imperial College, Chelsea and Westminster Hospital Campus, London, UK.

Activation of cannabinoid receptors causes inhibition of spasticity, in a mouse model of multiple sclerosis, and of persistent pain, in the rat formalin test. The endocannabinoid anandamide inhibits spasticity and persistent pain. It not only binds to cannabinoid receptors but is also a full agonist at vanilloid receptors of type 1 (VR1). We found here that vanilloid VR1 receptor agonists (capsaicin and N-N'-(3-methoxy-4-aminoethoxy-benzyl)-(4-tert-butyl-benzyl)-urea [SDZ-249-665]) exhibit a small, albeit significant, inhibition of spasticity that can be attenuated by the vanilloid VR1 receptor antagonist, capsazepine. Arvanil, a structural "hybrid" between capsaicin and anandamide, was a potent inhibitor of spasticity at doses (e.g. 0.01 mg/kg i.v.) where capsaicin and cannabinoid CB(1) receptor agonists were ineffective. The anti-spastic effect of arvanil was unchanged in cannabinoid CB(1) receptor gene-deficient mice or in wildtype mice in the presence of both cannabinoid and vanilloid receptor antagonists. Likewise, arvanil (0.1-0.25 mg/kg) exhibited a potent analgesic effect in the formalin test, which was not reversed by cannabinoid and vanilloid receptor antagonists. These findings suggest that activation by arvanil of sites of action different from cannabinoid CB(1)/CB(2) receptors and vanilloid VR1 receptors leads to anti-spastic/analgesic effects that might be exploited therapeutically.

PMID: 11937096 [PubMed - indexed for MEDLINE]

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1: J Pharm Pharmacol. 2008 Apr;60(4):473-8. Links
Anti-inflammatory effects of red pepper (Capsicum baccatum) on carrageenan- and antigen-induced inflammation.Spiller F, Alves MK, Vieira SM, Carvalho TA, Leite CE, Lunardelli A, Poloni JA, Cunha FQ, de Oliveira JR.
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil. ferspiller@usp.br

Inflammation is a pivotal component of a variety of diseases, such as atherosclerosis and tumour progression. Various naturally occurring phytochemicals exhibit anti-inflammatory activity and are considered to be potential drug candidates against inflammation-related pathological processes. Capsicum baccatum L. var. pendulum (Willd.) Eshbaugh (Solanaceae) is the most consumed species in Brazil, and its compounds, such as capsaicinoids, have been found to inhibit the inflammatory process. However, the anti-inflammatory effects of C. baccatum have not been characterized. Thus, this study was designed to evaluate the effects of C. baccatum juice in animal models of acute inflammation induced by carrageenan and immune inflammation induced by methylated bovine serum albumin. Pretreatment (30 min) of rats with pepper juice (0.25-2.0 g kg(-1)) significantly decreased leucocyte and neutrophil migration, exudate volume and protein and LDH concentration in pleural exudates of a pleurisy model. This juice also inhibited neutrophil migration and reduced the vascular permeability on carrageenan-induced peritonitis in mice. C. baccatum juice also reduced neutrophil recruitment and exudate levels of pro-inflammatory cytokines TNF-alpha and IL-1beta in mouse inflammatory immune peritonitis. Furthermore, we demonstrated that the main constituent of C. baccatum juice, as extracted with chloroform, is capsaicin. In agreement with this, capsaicin was able to inhibit the neutrophil migration towards the inflammatory focus. To our knowledge, this is the first demonstration of the anti-inflammatory effect of C. baccatum juice and our data suggest that this effect may be induced by capsaicin. Moreover, the anti-inflammatory effect induced by red pepper may be by inhibition of pro-inflammatory cytokine production at the inflammatory site.

PMID: 18380920 [PubMed - indexed for MEDLINE]

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[gibbledygook]

Disappointingly taking 8 pills of capsaicin yesterday wasn't enough to stop a sneezing fit yesterday evening. Mind you I had spent all of yesterday either outside or with the flat windows open which is usually completely off my menu during the summer months and I only started sneezing in the late evening. I think my nose had had enough. However whilst I put my surgical mask on I had a mad plan. What if I were to use the capsaicin topically on those very cells where the sneezing etc originate? I have always wanted to burn those cells away during the hayfever months and what better than with capsaicin? This morning I did that very thing. I opened one cap of the capsaicin and mixed it with olive oil and then dabbed some of the mix on a cotton ear bud and very very briefly spread this around the mast cell area of the itchier nostril. As I had expected this was like sticking rocket up there!!!! For about 5 minutes there was a terrible burning in the nostril and burning liquid came briefly down the throat. I also sneezed about 5 times in quick succession. Thereafter however the burning was incredibly pleasant and soothing and I no longer have that sniffling prickling annoying as **** on the edge of sneezing feeling AT ALL!!!!!

Furthermore I continue to have much improved bladder function, much less spasticity and rather a too loose bowel!
Yesterday I added circa 4g of astragalus to the mix. I am now taking approx 7.2g of the bioavailable life extension brand of curcumin, 30mg of bioperine, circa 6g of skullcap, circa 4g of astragalus, the ren shen yang rong tang tea 3 x daily and 3.6g of capsaicin. I am now only missing one further herb as I want to be taking a combination of 5 main herbs, rather like the chinese herbs. Today I shall test my walking skills on one of the hottest days in London so far this year. It should be about 28C around midday.

1: Life Sci. 1983 Apr 18;32(16):1827-34.Links
Effects of capsaicin on inflammation and on the substance P content of nervous tissues in rats with adjuvant arthritis.Colpaert FC, Donnerer J, Lembeck F.
Capsaicin (20-80 mg/kg, s.c.) reduced the inflammatory response to inoculation with Mycobacterium butyricum in the rat. The effect was apparent within 24 h, was partial, persisted for well over 20 days, and occurred irrespective of whether capsaicin was administered before or after the onset of inflammation, or at the time when the pathology reached peak. Capsaicin also attenuated the increase in substance P content in sciatic nerve, saphenous nerve, dorsal root ganglia, dorsal roots, and dorsal spinal cord (L4, L5) which occurs in rats with adjuvant arthritis. The data are consistent with a possible role of substance P in the peripheral manifestations of adjuvant arthritis.

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maybe this is why my ms feels better:

1: Neurosci Lett. 1997 Jul 11;230(1):5-8. Links
Effect of capsaicin on substance P and nerve growth factor in adjuvant arthritic rats.Garrett NE, Cruwys SC, Kidd BL, Tomlinson DR.
Department of Pharmacology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, UK. neil.garrett@blacksci.co.uk

We have investigated the effect of capsaicin pretreatment (50 mg kg(-1) s.c.) on substance P, preprotachykinin (PPT) mRNA, and nerve growth factor (NGF), plus its high-affinity receptor, trkA, in adult rats with adjuvant arthritis. Twenty one days after induction of adjuvant arthritis, sciatic nerve levels of substance P were significantly increased whilst there was a small but non-significant increase in gamma-PPT mRNA and substance P in L4/L5 dorsal root ganglia (DRG). NGF levels in sciatic nerve and foot skin as well as DRG trkA mRNA were unaltered after 21 days arthritis suggesting that NGF may not play a role in chronic inflammation. Capsaicin treatment of naive rats significantly reduced substance P in all tissues and NGF levels in the sciatic nerve. In contrast, gamma-PPT mRNA and trkA mRNA expression in DRG were significantly increased after capsaicin treatment. The nervous and skin tissues used in this study were harvested from the same rats in which we had previously shown that capsaicin pretreatment significantly attenuated the severity of arthritis (Cruwys, S.C., Garrett, N.E. and Kidd, B.L., Sensory denervation with capsaicin attenuates inflammation and nociception in arthritic rats, Neurosci. Lett., 193 (1995) 205-207). Arthritis in capsaicin-treated rats had no effect on substance P or NGF levels in any tissue when compared with capsaicin-treated control rats, suggesting that pharmacological impairment of the sensory nervous system can reduce the severity of inflammatory joint disease.

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or

1: Brain Res. 1981 Oct 19;222(2):428-31. Links
Effect of capsaicin administration to neonatal rats on the substance P content of discrete CNS regions.Helke CJ, DiMicco JA, Jacobowitz DM, Kopin IJ.
Substance P (SP) levels were determined by radioimmunoassay in microdissected CNS regions of adult animals treated with capsaicin as neonates and of vehicle controls. Capsaicin treatment reduced the SP content of the spinal trigeminal nucleus and the dorsal horn of the spinal cord whereas it had no effect on the SP levels in the ventral horn of the spinal cord, the nucleus tractus solitarius or in midbrain and forebrain areas analyzed.

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1: J Neuroimmunol. 2006 Nov;180(1-2):117-25. Epub 2006 Aug 30. Links
Substance P receptor mediated maintenance of chronic inflammation in EAE.Reinke EK, Johnson MJ, Ling C, Karman J, Lee J, Weinstock JV, Sandor M, Fabry Z.
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison WI, United States.

Substance P (SP) is a modulatory, pro-inflammatory neuropeptide. We investigated the role of the SP receptor, neurokinin-1 (NK-1), in EAE. Our data show that in the chronic phase, mice lacking NK-1 have improved mobility and decreased numbers of LFA-1 high CD4+ T cells and MOG-specific, IFN-gamma producing CD4+ T cells. SR140333, an NK-1 antagonist, administered alone during the chronic phase of EAE was not sufficient to ameliorate symptoms. These results indicate that SP, through NK-1, contributes to maintenance of CNS inflammation, and combining NK-1 antagonists with conventional anti-inflammatory treatments may enhance the success of treatments for diseases like multiple sclerosis.

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I wonder if my MS is caused by a histamine imbalance:

1: J Neurochem. 1998 Apr;70(4):1577-83. Links
Substance P and histamine induce interleukin-6 expression in human astrocytoma cells by a mechanism involving protein kinase C and nuclear factor-IL-6.Lieb K, Schaller H, Bauer J, Berger M, Schulze-Osthoff K, Fiebich BL.
Abteilung Psychiatrie, Universität Freiburg, Germany.

Interleukin-6 (IL-6) is a proinflammatory cytokine whose synthesis is induced by a variety of stimuli including interleukin-1 (IL-1), substance P (SP), and histamine. Because IL-6 has been implicated in the etiopathology of different human diseases including multiple myeloma, rheumatoid arthritis, multiple sclerosis, acquired immunodeficiency syndrome dementia complex, and Alzheimer's disease, its inhibition may be of therapeutic interest. A main demand on an effective inhibitor of IL-6 expression is that it inhibits IL-6 synthesis independently of the inducing stimulus. We therefore used human astrocytoma cells to search for signal transduction cascades and transcription factors whose inhibition suppresses IL-6 synthesis after stimulation with three different inductors, IL-1beta, SP, and histamine. Whereas the antioxidant pyrrolidinedithiocarbamate was only able to inhibit IL-1beta-induced IL-6 expression, inhibition of protein kinase C prevented IL-6 expression induced by all three substances. Promoter deletion analysis revealed that IL-1beta-induced IL-6 expression required the transcription factor nuclear factor-kappaB (NF-kappaB), whereas SP- and histamine-induced IL-6 synthesis was essentially controlled by NF-IL-6. These findings suggest that inhibition of protein kinase C or a combinatory inhibition of NF-IL-6 and NF-kappaB binding are strategies to effectively suppress IL-6 synthesis. They therefore provide the basis for the development of antiinflammatory drugs used to treat disorders in which IL-6 is pathogenically involved.

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1: Med Hypotheses. 1992 Jan;37(1):40-3. Links
Substance P and multiple sclerosis.Barker R, Larner A.
Department of Experimental Psychology, Cambridge, UK.

Multiple sclerosis is an inflammatory disease which affects the white matter of the central nervous system (CNS). The aetiology of this condition is unknown but it is generally believed to represent an autoimmunological response to a component of myelin triggered by an environmental factor, in a genetically susceptible individual. The natural history of the disease, in terms of clinical disability, is unpredictable, and the factors responsible unknown. Substance P is an undecapeptide that acts as a neurotransmitter in the CNS and as a regulator of immune responses. The recent discovery of substance P immunoreactive astrocytes in multiple sclerosis plaques raises the possibility that this peptide may be important both in the development of plaques and in governing the natural history of the disease.

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[gibbledygook]

I managed 600meters with a cane in incredible heat and wasn't too awkward in the coffee shop when I arrived (not lurching alarmingly into prams/unstable tables etc)! The temperature according to the BBC weather service is 27C though in London it usually is considerably warmer so say 29C!!!!!!!

I have been dabbing capsaicin and olive oil up my nostrils as well as ingesting 3.6g today of the capsaicin pills. I have no hayfever, good bladder control and less spasticity. It's disappointing that I haven't miraculously healed some of the lesions but the benefits of capsaicin are nevertheless very very clear from my perspective. I also no longer need to take anti-constipation tablets as the capsaicin does that very well! GREAT to have found another effective compound. Unfortunately I started my capsaicin experiment around the same time as starting the skullcap and the astragalus but as I'm feeling better I'm not too worried about disentangling cause and effect until the pollen goes in August.

[gibbledygook]

Interestingly one of the components of the chinese formula buwang wanhu tang above on page 3 of my log contains a herb that promotes progesterone in rats. I think I shall ask to get this formula as well.

1: Life Sci. 2006 Aug 22;79(13):1274-80. Epub 2006 Apr 15. Links
Dynamics of progestogenic activity in serum following administration of Ligusticum chuanxiong.Lim LS, Shen P, Gong YH, Lee LS, Yong EL.
Department of Obstetrics and Gynecology, National University Hospital, Yong Loo Lin School of Medicine, National University of Singapore, Lower Kent Ridge Road, Republic of Singapore 119074.

Many women are using botanical alternatives for menopausal hormone replacement therapy (HRT) because current progestins, compounds with progesterone activity, have adverse risk profiles. However the development of phyto-progestins for HRT is hampered by the absence of basic pharmacokinetic/pharmacodynamic (PK/PD) data due to the lack of methods to capture summated effects of the numerous compounds that contribute to bioactivity in vivo. In this study, we explored the utility of progesterone receptor (PR)-driven bioassays to track changes in serum progestogenic activity following administration of traditional Chinese medicinal herb, Ligusticum chuanxiong, with potent progestogenic activity. Sensitive and specific (>300-fold) increases in progestogenic activity were observed when HeLa cells transfected with PR and a PR-driven promoter were exposed to the progestogenic drug, medroxy-progesterone acetate (MPA), suggesting the utility of the bioassay to measure progestogenic effects for PK/PD studies. Progestogens were administered to male Sprague-Dawley rats and serum extracted for measurement of progestogenic activity. Effect-time studies indicate that injection of MPA and L. chuanxiong extract raised area-under-curve of progestogenic activity in sera by 8.2-fold (p<0.001) and 4.5-fold (p<0.01) respectively, compared to sera from rats administered vehicle only. Administration of MPA and L. chuanxiong extract by the oral route resulted in a 5.4 (p<0.001) and 2.3-fold (p=0.07) increase respectively. Our data suggest that PR-responsive reporter gene bioassays can measure bioavailability of compounds, known and unknown, of complex botanicals for hormone replacement therapy. L. chuanxiong extracts exert progestogenic activity in vivo, and may have utility for progesterone-replacement therapy.

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I'm very sad to say that taking 2 pills of capsaicin 3 times a day is just too much on the poor gut and I had a pretty terrible day yesterday. So I've backed off to just 2 pills or 1.2g today and for over the weekend until my gut responds. This is sad as the capsaicin has really helped my hayfever, though smearing a bit in the nostrils seems to work pretty well AND it has indubitably improved my spasticity and bladder control, the former of which seems to be reverting to the old mean of stiff after sitting for any length of time. I shall try to get back to 2.4g of capsaicin as soon as I think my gut will take it!

Here's a vascular reason to take capsaicin:

1: Regul Pept. 2008 Jun 3. [Epub ahead of print] Links
Transient receptor potential vanilloid 1-mediated expression and secretion of endothelial cell-derived calcitonin gene-related peptide.Luo D, Zhang YW, Peng WJ, Peng J, Chen QQ, Li D, Deng HW, Li YJ.
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University; Changsha, Hunan 410078, China.

Calcitonin gene-related peptide (CGRP), the principal transmitter in sensory nerves, could also be expressed in vascular endothelium. Transient receptor potential vanilloid 1(TRPV1), which modulates the synthesis and release of CGRP in sensory nerves, is also present in endothelial cells. The present study tested whether TRPV1 modulates the release and synthesis of CGRP in endothelial cells, and evaluated the protective effect of endothelial cell-derived CGRP. Human umbilical vein endothelial cells (HUVECs) were treated with capsaicin or hyperthermia. The level of CGRP mRNA was detected by RT-PCR, and protein level was measured by radioimmunoassay. Endothelial cell injury was induced by lysophosphatidylcholine, and evaluated by cell viability and lactate dehydrogenase activity. HUVECs expressed CGRP, both alpha- and beta-subtype. Capsaicin increased the level of CGRP in the culture medium, and up-regulated the expression of CGRP in endothelial cells. Hyperthermia also increased the level of CGRP mRNA. These effects were abolished by capsazepine, a competitive antagonist of TRPV1. Capsaicin significantly attenuated the endothelial cell damage induced by LPC, which was prevented and aggravated by capsazepine or CGRP(8-37,) antagonist of CGRP receptor. These results indicate that TRPV1 also regulates the expression and secretion of endothelial cell-derived CGRP, which affords protective effects on endothelial cells.

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I keep seeing capsaicin referred to as a neurotoxin...not so good

I wonder if these stat3 pathways referred to in the below articles are the same?

1: Clin Cancer Res. 2007 May 15;13(10):3024-32. Links
Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation.Bhutani M, Pathak AK, Nair AS, Kunnumakkara AB, Guha S, Sethi G, Aggarwal BB.
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

PURPOSE: Capsaicin, a constituent of green and red peppers, has been linked with suppression of tumorigenesis through a mechanism that is not well understood. Because the transcription factor signal transducer and activator of transcription 3 (STAT3) has been closely linked with tumorigenesis, we investigated the effect of this vanilloid on the STAT3 pathway in human multiple myeloma cells. EXPERIMENTAL DESIGN: The effect of capsaicin on both constitutive and interleukin-6-induced STAT3 activation, associated protein kinases, and STAT3-regulated gene products involved in proliferation, survival and angiogenesis, cellular proliferation, and apoptosis in multiple myeloma cells was investigated. RESULTS: We found that capsaicin inhibited constitutive activation of STAT3 in multiple myeloma cells in a dose- and time-dependent manner, with minimum effect on STAT5. Capsaicin also inhibited the interleukin-6-induced STAT3 activation. The activation of Janus-activated kinase 1 and c-Src, implicated in STAT3 activation, was also inhibited by the vanilloid, with no effect on extracellular signal-regulated kinase 1/2 activation. Pervanadate reversed the capsaicin-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Capsaicin down-regulated the expression of the STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, and vascular endothelial growth factor. Finally, capsaicin induced the accumulation of cells in G(1) phase, inhibited proliferation, and induced apoptosis, as indicated by caspase activation. Capsaicin also significantly potentiated the apoptotic effects of Velcade and thalidomide in multiple myeloma cells. When administered i.p., capsaicin inhibited the growth of human multiple myeloma xenograft tumors in male athymic nu/nu mice. CONCLUSION: Overall, these results suggest that capsaicin is a novel blocker of the STAT3 activation pathway, with a potential role in the prevention and treatment of multiple myeloma and other cancers.

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1: J Immunol. 2008 May 1;180(9):6070-6. Links
Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases.Liu X, Lee YS, Yu CR, Egwuagu CE.
Section of Molecular Immunology, Laboratory of Immunology, National Eye Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.

Th17 cells are implicated in CNS autoimmune diseases. We show that mice with targeted-deletion of Stat3 in CD4(+) T cells (CD4(Stat3)(-/-)) do not develop experimental autoimmune uveoretinitis (EAU) or experimental autoimmune encephalomyelitis. Defective Th17 differentiation noted in CD4(Stat3)(-/-) mice is compensated by exaggerated increases in Foxp3-, IL-10-, IL-4-, and IFN-gamma-expressing T cells, suggesting critical roles of STAT3 in shaping Ag-specific CD4(+) T cell repertoire. In mice with EAU, a high percentage of IL-17-expressing T cells in their peripheral lymphoid organs also secrete IFN-gamma while these double-expressors are absent in CD4(Stat3)(-/-) and wild-type mice without EAU, raising the intriguing possibility that uveitis maybe mediated by Th17 and IL-17-expressing Th1 cells. Resistance of Stat3-deficient mice to EAU derives in part from an inability of uveitogenic Th17 and Th1 cells to enter eyes or brain of the CD4(Stat3)(-/-) mouse because of the reduction in the expression of activated alpha4/beta1 integrins on CD4(Stat3)(-/-) T cells. Adoptive transfer of activated interphotoreceptor retinoid-binding protein-specific uveitogenic T cells induced in CD4(Stat3)(-/-) mice a severe EAU characterized by development of retinal folds, infiltration of inflammatory cells into the retina, and destruction of retinal architecture, underscoring our contention that the loss of STAT3 in CD4(+) T cells results in an intrinsic developmental defect that renders CD4(Stat3)(-/-) resistant to CNS inflammatory diseases. STAT3 requirement for IL-17 production by Th17, generation of double positive T cells expressing IL-17 and IFN-gamma, and for T cell trafficking into CNS tissues suggests that STAT3 may be a therapeutic target for modulating uveitis, sceritis, or multiple sclerosis.

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I really felt good on the higher doses of capsaicin but boy oh boy did it do some damage to the internals!

[gibbledygook]

Owing to a post of rainer's about a dimer that controls STAT3 I discovered that capsaicin blocks this and IL6, at least in myeloma:

1: Clin Cancer Res. 2007 May 15;13(10):3024-32. Links
Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation.Bhutani M, Pathak AK, Nair AS, Kunnumakkara AB, Guha S, Sethi G, Aggarwal BB.
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

PURPOSE: Capsaicin, a constituent of green and red peppers, has been linked with suppression of tumorigenesis through a mechanism that is not well understood. Because the transcription factor signal transducer and activator of transcription 3 (STAT3) has been closely linked with tumorigenesis, we investigated the effect of this vanilloid on the STAT3 pathway in human multiple myeloma cells. EXPERIMENTAL DESIGN: The effect of capsaicin on both constitutive and interleukin-6-induced STAT3 activation, associated protein kinases, and STAT3-regulated gene products involved in proliferation, survival and angiogenesis, cellular proliferation, and apoptosis in multiple myeloma cells was investigated. RESULTS: We found that capsaicin inhibited constitutive activation of STAT3 in multiple myeloma cells in a dose- and time-dependent manner, with minimum effect on STAT5. Capsaicin also inhibited the interleukin-6-induced STAT3 activation. The activation of Janus-activated kinase 1 and c-Src, implicated in STAT3 activation, was also inhibited by the vanilloid, with no effect on extracellular signal-regulated kinase 1/2 activation. Pervanadate reversed the capsaicin-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Capsaicin down-regulated the expression of the STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, and vascular endothelial growth factor. Finally, capsaicin induced the accumulation of cells in G(1) phase, inhibited proliferation, and induced apoptosis, as indicated by caspase activation. Capsaicin also significantly potentiated the apoptotic effects of Velcade and thalidomide in multiple myeloma cells. When administered i.p., capsaicin inhibited the growth of human multiple myeloma xenograft tumors in male athymic nu/nu mice. CONCLUSION: Overall, these results suggest that capsaicin is a novel blocker of the STAT3 activation pathway, with a potential role in the prevention and treatment of multiple myeloma and other cancers.

PMID: 17505005 [PubMed - indexed for MEDLINE]

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STAT3 looks bad in MS;

1: J Immunol. 2008 May 1;180(9):6070-6. Links
Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases.Liu X, Lee YS, Yu CR, Egwuagu CE.
Section of Molecular Immunology, Laboratory of Immunology, National Eye Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.

Th17 cells are implicated in CNS autoimmune diseases. We show that mice with targeted-deletion of Stat3 in CD4(+) T cells (CD4(Stat3)(-/-)) do not develop experimental autoimmune uveoretinitis (EAU) or experimental autoimmune encephalomyelitis. Defective Th17 differentiation noted in CD4(Stat3)(-/-) mice is compensated by exaggerated increases in Foxp3-, IL-10-, IL-4-, and IFN-gamma-expressing T cells, suggesting critical roles of STAT3 in shaping Ag-specific CD4(+) T cell repertoire. In mice with EAU, a high percentage of IL-17-expressing T cells in their peripheral lymphoid organs also secrete IFN-gamma while these double-expressors are absent in CD4(Stat3)(-/-) and wild-type mice without EAU, raising the intriguing possibility that uveitis maybe mediated by Th17 and IL-17-expressing Th1 cells. Resistance of Stat3-deficient mice to EAU derives in part from an inability of uveitogenic Th17 and Th1 cells to enter eyes or brain of the CD4(Stat3)(-/-) mouse because of the reduction in the expression of activated alpha4/beta1 integrins on CD4(Stat3)(-/-) T cells. Adoptive transfer of activated interphotoreceptor retinoid-binding protein-specific uveitogenic T cells induced in CD4(Stat3)(-/-) mice a severe EAU characterized by development of retinal folds, infiltration of inflammatory cells into the retina, and destruction of retinal architecture, underscoring our contention that the loss of STAT3 in CD4(+) T cells results in an intrinsic developmental defect that renders CD4(Stat3)(-/-) resistant to CNS inflammatory diseases. STAT3 requirement for IL-17 production by Th17, generation of double positive T cells expressing IL-17 and IFN-gamma, and for T cell trafficking into CNS tissues suggests that STAT3 may be a therapeutic target for modulating uveitis, sceritis, or multiple sclerosis.

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related:

1: J Neuroimmunol. 2008 Feb;194(1-2):132-42. Epub 2008 Jan 22. Links
Angiocidin promotes pro-inflammatory cytokine production and antigen presentation in multiple sclerosis.Kremlev SG, Gaurnier-Hausser AL, Del Valle L, Perez-Liz G, Dimitrov S, Tuszynski G.
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA 19122, United States. skremlev@temple.edu

Angiocidin was originally identified as a potent inhibitor of angiogenesis and tumor growth in vivo. In addition to its involvement in the regulation of carcinogenesis, recent studies indicate that angiocidin may also play a significant role in immune system modulation. This report describes the expression and potential function of angiocidin in multiple sclerosis (MS), a severe demyelinating, inflammatory and autoimmune disease of the central nervous system (CNS). We demonstrated that angiocidin and interleukin-7 (IL-7) are over-expressed in brain lesions of MS patients. Angiocidin-treated monocytes, peripheral blood T cells and primary astrocytes secreted various cytokines and chemokines including, IL-6, IL-7, GM-CSF, and MCP-1. Addition of recombinant angiocidin to cell cultures was able to promote differentiation of monocytes into a macrophage-like cell, induce MHC class I and class II gene expression and activate CD4(+) and CD8(+) T lymphocytes. Consistent with these findings, angiocidin induced mononuclear phagocyte migration and adhesion as well as increased the IL-2 response by antigen-specific T cells to myelin basic protein peptide presented to them by autologous mononuclear phagocytes. Furthermore, we examined STAT3 expression in angiocidin stimulated mononuclear phagocytes, T cells, and primary astrocytes. We found that angiocidin markedly stimulates STAT3 expression in these cell populations. Angiocidin, therefore appears to play a previously unappreciated and potentially important role in the regulation of immune response during the clinical course of MS.

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STAT3 upregulated during relapse:

1: J Neuroimmunol. 2007 Dec;192(1-2):174-83. Epub 2007 Sep 29. Links
The effect of disease activity on leptin, leptin receptor and suppressor of cytokine signalling-3 expression in relapsing-remitting multiple sclerosis.Frisullo G, Mirabella M, Angelucci F, Caggiula M, Morosetti R, Sancricca C, Patanella AK, Nociti V, Iorio R, Bianco A, Tomassini V, Pozzilli C, Tonali PA, Matarese G, Batocchi AP.
Istituto di Neurologia, Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, 00168 Roma, Italy.

In this study we observed higher serum leptin levels in relapsing-remitting multiple sclerosis (RRMS) patients during remission than in controls. The expression of leptin receptor (ObR) was higher in CD8+ T cells and monocytes from RRMS patients in relapse than in patients in remission and in controls. Relapsing patients showed high levels of pSTAT3 and low expression of SOCS3 and leptin administration induced an up-regulation of pSTAT3 only in monocytes from patients in relapse. Our data suggest that ObR may be involved in the development of clinical relapses in RRMS patients and suggest a rationale for potential targeting of the leptin axis during MS.

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Here's part of the report which rainer posted:

Research published online in Proceedings of the National Academy of Sciences details that when HLA-G dimer binds with its inhibitory receptor, ILT4, it triggers a signaling pathway in which immune molecules IL-6 and STAT3 play a major role.

"Biologically this is an interaction that requires several important suppressive molecules," says Dr. Horuzsko, the study's corresponding author and a faculty member in the MCG Schools of Medicine and Graduate Studies.

They looked at the resulting strong signaling in culture, then measured its impact on skin graft survival in mice and found it prolonged survival.

Now Dr. Horuzsko is working with Dr. Laura Mulloy, chief of the Section of Nephrology, Hypertension and Transplantation Medicine in the MCG School of Medicine, to see if this dimer form is at work in kidney transplant patients who avoid rejection.

HLA-G dimer's target is another MHC molecule, which is essentially an individual's unique tissue signature; HLA-G itself is a type of MHC. In fact, HLA - human leukocyte antigen - matching is done for organ and bone marrow transplants to try minimize the recipient's reaction to the new organ.

Transplant patients also take drugs that broadly dampen the immune response but can leave them more vulnerable to infections and disease.

Dr. Horuzsko notes that HLA-G can work through other cells, not just MHC molecules, and that not every HLA-G form is good at down-regulating MHC.

He plans to look at HLA-G dimer levels in tumor patients as well. "Tumors already down- regulate MHC molecules," he says, referencing how tumors turn down their tissue expression so they can fly below the radar of the immune system.

"We need to see what form of HLA-G cancers - including leukemia, lymphoma, melanoma and breast cancer - use and see their level of expression." He notes that HLA-G isn't the only mechanism cancers use to escape the immune response but that being able to control a tumor's use of this molecule could offer a new way to target tumors for natural destruction.

[gibbledygook]

In August we head back to the Austrian spa/fat farm where there will be no alcohol. I shall give up alcohol from then on and the weed.

1: Wei Sheng Yan Jiu. 1999 May 30;28(3):153-4.Links
[Effects of alcohol on membrane lipid fluidity of astrocytes and oligodendrocytes][Article in Chinese]


Qu W, Zhang B, Wu D, Xiao B.
Department of Nutrition and Food Hygiene, College of Public Health, West China University of Medical Science, Chengdu 610041, China.

To explore the mechanism of neuron development retardation and myelination abnormality caused by alcohol, the membrane lipid fluidity of astrocytes and oligodendrocytes which is related to neuron and myelin development were measured by using DPH fluorescence probe. The results showed that 5 mmol/L alcohol could lead to decrease the polarization of fluorescence (Pr) and increase the lipid fluidity unit of membrane in both cells. The alteration was in obvious dose-response relationship. The effect of alcohol on astrocytes was stronger than that of oligodendrocytes. It indicated that alcohol could change lipid fluidity of cell membrane. Alcohol probably plays major role in the dysfunction of astrocytes and oligodendrocytes.

PMID: 12712719 [PubMed - indexed for MEDLINE]

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honghua Yu Fang Yi Xue Za Zhi. 2001 Jan;35(1):55-6.Links
[The effect of alcohol on c-fos gene expression in rat embryo neuroglial][Article in Chinese]


Qu W, Xiao B, Wu D.
Department of Environmental Health, School of Public Health, West China University of Medical Sciences, Chengdu 610041, China.

OBJECTIVE: This paper is aimed to explore the mechanisms of brain development abnormality induced by alcohol. METHODS: Astrocytes and oligodendrocytes of 19-day rat embryo were exploited and cultured in vitro, and alcohol and its metabolite product (acetaldehyde) were added to DMEMF(12) medium. After different exposure times, c-fos expression of astrocytes and oligodendrocytes was measured by the immunocytochemistry technique. RESULTS: Changes in c-fos gene expression induced by alcohol and acetaldehyde was time and dose dependent. After 1 hr exposure, alcohol and acetaldehyde affected c-fos gene expression in two kinds of neuralglia. C-fos positive expression reached peak value after 2 hr, but recovered after 72 hr and showed special time phase expression. CONCLUSIONS: Alcohol and acetaldehyde cause abnormal increase of c-fos gene expression in astrocytes and oligodendrocytes. This abnormal expression may play an important role in abnormal brain development induced by alcohol

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Total detox in the offing which should help in a number of different ways, especially if I want to get pregnant. Farewell, then, grape of joy and sorrow.

[SarahLonglands]

Good luck Alex. The fat farm is a good way to start the new regime!!

Sarah

[gibbledygook]

Thanks Sarah! I hope you're enjoying the summer. Am actually rather dreading the Austrian fat farm. They are very strict!

[gibbledygook]

1: Biochem Biophys Res Commun. 2008 May 16;369(4):989-93. Epub 2008 Mar 10. Links
TRPV1 mediates cell death in rat synovial fibroblasts through calcium entry-dependent ROS production and mitochondrial depolarization.Hu F, Sun WW, Zhao XT, Cui ZJ, Yang WX.
Department of Biophysics, The School of Physics, The Ministry of Education Key Laboratory of Bioactive Materials, Nankai University, #94 Weijin Road, Nankai District, Tianjin 300071, China.

Synoviocyte hyperplasia is critical for rheumatoid arthritis, therefore, potentially an important target for therapeutics. It was found in this work that a TRPV1 agonist capsaicin, and acidic solution (pH 5.5) induced increases in cytosolic calcium concentration ([Ca(2+)](c)) and reactive oxygen species (ROS) production in synoviocytes isolated from a rat model of collagen-induced arthritis. The increases in both [Ca(2+)](c) and ROS production were completely abolished in calcium-free buffer or by a TRPV1 antagonist capsazepine. Further experiments revealed that capsaicin and pH 5.5 solution caused mitochondrial membrane depolarization and reduction in cell viability; such effects were inhibited by capsazepine, or the NAD(P)H oxidase inhibitor diphenylene iodonium. Both capsaicin and pH 5.5 buffer induced apoptosis as shown by nuclear condensation and fragmentation. Furthermore, RT-PCR readily detected TRPV1 mRNA expression in the isolated synoviocytes. Taken together, these data indicated that TRPV1 activation triggered synoviocyte death by [Ca(2+)](c) elevation, ROS production, and mitochondrial membrane depolarization.

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1: Rev Prat. 1994 Jun 15;44(12):1569-71.Links
[Substance P and rheumatic diseases][Article in French]


Menkès CJ, Renoux M.
Service de rhumatologie A, hôpital Cochin, Paris.

Substance pertains to a group of linear molecules of 10-30 amino-acid residues produced by nervous fibers and called neuropeptides. It is a mediator of pain transmission, and modulates or stimulates the activity of several cell types, i.e. lymphocytes and mast cells. The concept of neurogenic inflammation is based on the release of substance P and related peptides by an axon eflex mechanism. In rheumatic diseases, substance P may enhance inflammatory joint reactions. In rheumatoid arthritis, high SP levels were demonstrated in synovial fluid by our group and others. Results in fibromyalgia are contradictory. Algoneurodystrophia may be modulated by substance P release. Topical use or capsaicin and development of peripheral inhibitory drugs offer novel treatments based on this concept.

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1: Clin Ther. 1991 May-Jun;13(3):383-95.Links
Treatment of arthritis with topical capsaicin: a double-blind trial.Deal CL, Schnitzer TJ, Lipstein E, Seibold JR, Stevens RM, Levy MD, Albert D, Renold F.
Case Western Reserve University, Cleveland, Ohio.

The neuropeptide substance P has been implicated in the pathogenesis of inflammation and pain in arthritis. In this double-blind randomized study, 70 patients with osteoarthritis (OA) and 31 with rheumatoid arthritis (RA) received capsaicin (a substance P depletor) or placebo for four weeks. The patients were instructed to apply 0.025% capsaicin cream or its vehicle (placebo) to painful knees four times daily. Pain relief was assessed using visual analog scales for pain and relief, a categorical pain scale, and physicians' global evaluations. Most of the patients continued to receive concomitant arthritis medications. Significantly more relief of pain was reported by the capsaicin-treated patients than the placebo patients throughout the study; after four weeks of capsaicin treatment, RA and OA patients demonstrated mean reductions in pain of 57% and 33%, respectively. These reductions in pain were statistically significant compared with those reported with placebo (P = 0.003 and P = 0.033, respectively). According to the global evaluations, 80% of the capsaicin-treated patients experienced a reduction in pain after two weeks of treatment. Transient burning was felt at the sites of drug application by 23 of the 52 capsaicin-treated patients; two patients withdrew from treatment because of this side effect. It is concluded that capsaicin cream is a safe and effective treatment for arthritis.

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but it also seems to increase collagenase which I think may be bad..

1: Scand J Rheumatol. 1991;20(2):98-103.Links
Collagenase synthesis of rheumatoid arthritis synoviocytes: dose-dependent stimulation by substance P and capsaicin.Partsch G, Matucci-Cerinic M, Marabini S, Jantsch S, Pignone A, Cagnoni M.
Ludwig Boltzmann Institute of Rheumatology and Balneology, Vienna-Oberlaa, Austria.

The synthesis and release of collagenase in the presence of the neuropeptide substance P (SP) and capsaicin, were investigated in vitro using identical synoviocyte cultures from patients with rheumatoid arthritis (RA). On average 10(-12) M SP augmented statistically significantly the collagenase production by approximately a factor of five. An increase in the concentrations up to 10(-6) M SP resulted in a decreased collagenase synthesis, which, however, was still above the level of that of the untreated synoviocytes. Capsaicin, a homovanillic acid derivative that acts as a releaser of SP from primary afferent neurons, caused a strong stimulation of collagenase production and release at 10(-8) and 10(-6) M (about 7 times the amount of the control). With increasing concentrations up to 10(-3) M capsaicin this effect diminished continuously. The experiments clearly show that in RA synoviocytes in vitro SP and capsaicin in low concentrations act as potent inducers of the synthesis and release of collagenase.

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Herbs seem to have good and bad effects in much of the research but I do wonder if on balance they don't have more good effects than bad. That certainly seems the effect so far of capsaicin on my MS. Mind you it has only been a week or two since my discovery.