Methylene Blue

www.perpetualcommotion.com
"Give with a free hand, but give only your own."
-- J.R.R. Tolkien The Children of Hurin
- TNF Alpha -

********************************************************************************************
Observations:

********************************************************************************************
Known sources:

********************************************************************************************
Natural sources:

********************************************************************************************
References:

Uncaria tomentosa acts as a potent TNF-alpha inhibitor through NF-kappaB.
J Ethnopharmacol. 2010 Feb 17;127(3):685-93. Epub 2009 Dec 6.
Allen-Hall L, Arnason JT, Cano P, Lafrenie RM.

Laurentian University, Biomolecular Science, Sudbury Regional Hospital, Sudbury, Ontario, Canada.
Abstract

AIM OF THE STUDY: Uncaria tomentosa, commonly known as Cat's Claw or Uña de gato, is a medicinal plant that has been shown to have effective anti-inflammatory activities. We have previously shown that treatment of monocyte-like THP-1 cells with Uncaria tomentosa inhibits the production of the pro-inflammatory cytokine TNF-alpha while augmenting the production of IL-1beta. Since TNF-alpha and IL-1beta are usually regulated similarly and share a number of common promoter elements, including NF-kappaB and AP-1, the ability of Uncaria tomentosa to differentially regulate these inflammatory cytokines is of particular interest.

MATERIALS AND METHODS: To determine the mechanism of action of Uncaria tomentosa, we investigated the effects of specific inhibitors of NF-kappaB on cellular responses including transcription factor activation using TransAM assays, the expression of cytokines as measured by ELISA, and cell survival as measured by changes in cell number following treatment.

RESULTS: Treatment with Uncaria tomentosa inhibited the LPS-dependent activation of specific NF-kappaB and AP-1 components. In addition, treatment with Uncaria tomentosa enhanced cell death when NF-kappaB was inhibited. The ability of Uncaria tomentosa to inhibit TNF-alpha production was diminished when NF-kappaB activation was prevented by drugs that mask NF-kappaB subunit nuclear localization signals, while IL-1beta expression was unchanged.

CONCLUSIONS: These results demonstrate that Uncaria tomentosa is able to elicit a response via an NF-kappaB-dependent mechanism. Further studies to characterize the mechanism by which Uncaria tomentosa can affect this pathway could provide a means to develop anti-TNF-alpha therapies.
Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

PMID: 19995599 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/19995599

Treatment of THP-1 cells with Uncaria tomentosa extracts differentially regulates the expression if IL-1beta and TNF-alpha.
J Ethnopharmacol. 2007 Jan 19;109(2):312-7. Epub 2006 Aug 3.

Allen-Hall L, Cano P, Arnason JT, Rojas R, Lock O, Lafrenie RM.

Regional Cancer Program, Sudbury Regional Hospital, Sudbury, Ont, Canada.
Abstract

Uncaria tomentosa, commonly known as cat's claw, is a medicinal plant native to Peru, which has been used for decades in the treatment of various inflammatory disorders. Uncaria tomentosa can be used as an antioxidant, has anti-apoptotic properties, and can enhance DNA repair, however it is best know for its anti-inflammatory properties. Treatment with Uncaria tomentosa extracts inhibits the production of the pro-inflammatory cytokine, TNF-alpha, which is a critical mediator of the immune response. In this paper, we showed that treatment of THP-1 monocyte-like cells with Uncaria tomentosa extracts inhibited the MAP kinase signaling pathway and altered cytokine expression. Using ELISA assays, we showed that treatment with Uncaria tomentosa extracts augmented LPS-dependent expression of IL-1beta by 2.4-fold, while inhibiting the LPS-dependent expression of TNF-alpha by 5.5-fold. We also showed that treatment of LPS-stimulated THP-1 cells with Uncaria tomentosa extracts blocked ERK1/2 and MEK1/2 phosphorylation in a dose-dependent manner. These data demonstrate that treatment of THP-1 cells with Uncaria tomentosa extracts has opposite effects on IL-1beta and TNF-alpha secretion, and that these changes may involve effects on the MAP kinase pathway.

PMID: 16959454 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/16959454

Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators.
Altern Med Rev. 2006 Jun;11(2):128-50.
Spelman K, Burns J, Nichols D, Winters N, Ottersberg S, Tenborg M.

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

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

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

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

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

PMID: 16813462 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/16813462
Full text: http://www.ncbi.nlm.nih.gov/pubmed/16813462

Herbal medications commonly used in the practice of rheumatology: mechanisms of action, efficacy, and side effects.
Semin Arthritis Rheum. 2005 Jun;34(6):773-84.
Setty AR, Sigal LH.

Massachusetts General Hospital, Department of Rheumatology, Boston, USA.
Abstract

OBJECTIVE: To review the literature on herbal preparations commonly utilized in the treatment of rheumatic indications.

METHODS: Search of MEDLINE (PubMed) was performed using both the scientific and the common names of herbs. Relevant articles in English were collected from PubMed and reviewed.

RESULTS: This review summarizes the efficacy and toxicities of herbal remedies used in complementary and alternative medical (CAM) therapies for rheumatologic conditions, by elucidating the immune pathways through which these preparations have antiinflammatory and/or immunomodulatory activity and providing a scientific basis for their efficacy. Gammalinolenic acid suppresses inflammation by acting as a competitive inhibitor of prostaglandin E2 and leukotrienes (LTs) and by reducing the auto-induction of interleukin1alpha (IL-1alpha)-induced pro-IL-1beta gene expression. It appears to be efficacious in rheumatoid arthritis (RA) but not for Sjogrens disease. The antiinflammatory actions of Harpagophytum procumbens is due to its action on eicosanoid biosynthesis and it may have a role in treating low back pain. While in vitro experiments with Tanacetum parthenium found inhibition of the expression of intercellular adhesion molecule-1, tumor necrosis factor alpha (TNF-alpha), interferon-gamma, IkappaB kinase, and a decrease in T-cell adhesion, to date human studies have not proven it useful in the treatment of RA. Current experience with Tripterygium wilfordii Hook F, Uncaria tomentosa, finds them to be efficacious in the treatment of RA, while Urtica diocia and willow bark extract are effective for osteoarthritis. T. wilfordii Hook F extract inhibits the production of cytokines and other mediators from mononuclear phagocytes by blocking the up-regulation of a number of proinflammatory genes, including TNF-alpha, cyclooxygenase 2 (COX-2), interferon-gamma, IL-2, prostaglandin, and iNOS. Uncaria tomentosa and Urtica diocia both decrease the production of TNF-alpha. At present there are no human studies on Ocimum spp. in rheumatic diseases. The fixed oil appears to have antihistaminic, antiserotonin, and antiprostaglandin activity. Zingiber officinale inhibits TNF-alpha, prostaglandin, and leukotriene synthesis and at present has limited efficacy in the treatment of osteoarthritis.

CONCLUSIONS: Investigation of the mechanism and potential uses of CAM therapies is still in its infancy and many studies done to date are scientifically flawed. Further systematic and scientific inquiry into this topic is necessary to validate or refute the clinical claims made for CAM therapies. An understanding of the mechanism of action of CAM therapies allows physicians to counsel effectively on their proper and improper use, prevent adverse drug-drug interactions, and anticipate or appreciate toxicities.

RELEVANCE: The use of CAM therapies is widespread among patients, including those with rheumatic diseases. Herbal medications are often utilized with little to no physician guidance or knowledge. An appreciation of this information will help physicians to counsel patients concerning the utility and toxicities of CAM therapies. An understanding and elucidation of the mechanisms by which CAM therapies may be efficacious can be instrumental in discovering new molecular targets in the treatment of diseases.

PMID: 15942912 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/15942912

Antioxidant properties of proanthocyanidins of Uncaria tomentosa bark decoction: a mechanism for anti-inflammatory activity.
Phytochemistry. 2005 Jan;66(1):89-98.
Gonçalves C, Dinis T, Batista MT.

Abstract

Decoctions prepared from the bark of Uncaria tomentosa (cat's claw) are widely used in the traditional Peruvian medicine for the treatment of several diseases, in particular as a potent anti-inflammatory agent. Therefore, the main purpose of this study was to determine if the well-known anti-inflammatory activity of cat's claw decoction was related with its reactivity with the oxidant species generated in the inflammatory process and to establish a relationship between such antioxidant ability and its phenolic composition. We observed that the decoction prepared according to the traditional Peruvian medicine presented a potent radical scavenger activity, as suggested by its high capacity to reduce the free radical diphenylpicrylhydrazyl, and by its reaction with superoxide anion, peroxyl and hydroxyl radicals as well as with the oxidant species, hydrogen peroxide and hypochlorous acid. It also protected membrane lipids against peroxidation induced by the iron/ascorbate system, as evaluated by the formation of thiobarbituric acid-reactive substances (TBARs). The decoction phenolic profile was established by chromatographic analysis (HPLC/DAD and TLC) revealing essentially the presence of proanthocyanidins (oligomeric procyanidins) and phenolic acids, mainly caffeic acid. Thus, our results provide evidence for an antioxidant mechanism underlying the anti-inflammatory activity of cat's claw and support some of the biological effects of proanthocyanidins, more exactly its antioxidant and radical scavenging activities.

PMID: 15649515 [PubMed]
http://www.ncbi.nlm.nih.gov/pubmed/15649515

Cat's claw inhibits TNFalpha production and scavenges free radicals: role in cytoprotection.
Free Radic Biol Med. 2000 Jul 1;29(1):71-8.
Sandoval M, Charbonnet RM, Okuhama NN, Roberts J, Krenova Z, Trentacosti AM, Miller MJ.

Department of Pediatrics and Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, USA. sandovm@mail.amc.edu
Abstract

Cat's claw (Uncaria tomentosa) is a medicinal plant from the Amazon River basin that is widely used for inflammatory disorders and was previously described as an inhibitor of NF-kappaB. Cat's claw was prepared as a decoction (water extraction) of micropulverized bark with and without concentration by freeze-drying. Murine macrophages (RAW 264.7 cells) were used in cytotoxicity assays (trypan blue exclusion) in response to the free radical 1, 1-diphenyl-2-picrilhydrazyl (DPPH, 0.3 microM) and ultraviolet light (UV) light. TNFalpha production was induced by lipopolysaccharide (LPS 0.5 microg/ml). Cat's claw was an effective scavenger of DPPH; the EC(50) value for freeze-dried concentrates was significantly less than micropulverized (18 vs. 150 microg/ml, p <.05). Cat's claw (10 microg/ml freeze-dried) was fully protective against DPPH and UV irradiation-induced cytotoxicity. LPS increased TNFalpha media levels from 3 to 97 ng/ml. Cat's claw suppressed TNFalpha production by approximately 65-85% (p <.01) but at concentrations considerably lower than its antioxidant activity: freeze-dried EC(50) = 1.2 ng/ml, micropulverized EC(50) = 28 ng/ml. In conclusion, cat's claw is an effective antioxidant, but perhaps more importantly a remarkably potent inhibitor of TNFalpha production. The primary mechanism for cat's claw anti-inflammatory actions appears to be immunomodulation via suppression of TNFalpha synthesis.

PMID: 10962207 [PubMed]
http://www.ncbi.nlm.nih.gov/pubmed/10962207

Potential Risks of Anti-Tumor Necrosis Factor Therapy for People with MS

May 26, 2003-We have received a number of questions from people about medications that block Tumor Necrosis Factor alpha (TNF alpha). TNF, a substance that is part of the immune system, plays a role in the inflammation that occurs in a variety of autoimmune diseases. It has additional functions in the immune system that are still unclear.1 While medications that block TNF have been found to be useful in other autoimmune diseases, they should not be used in the treatment of multiple sclerosis (MS) because they may actually worsen the disease. Cases of new onset multiple sclerosis, optic neuritis and other demyelinating disorders have been associated with the use of some of these agents.2 When this class of medications was tested on people who already had MS, there was an increase in disease activity.3

Autoimmune Disease and Treatment
Medications called tumor necrosis factor antagonists or anti-tumor necrosis factor agents, such as Enbrel(r) (etanercept), Remicade(r) (infliximab), and a Humira(r) (adalimubab), are used in the treatment of rheumatoid arthritis and other autoimmune diseases, including psoriatic arthritis and Crohn's disease.

Drugs that inhibit TNF decrease the inflammation in these diseases and have been shown to halt the progression of joint destruction and reduce the signs and symptoms of both rheumatoid and psoriatic arthritis. Enbrel(r) is now recommended as an initial therapy for rheumatoid arthritis. It appears, however, that drugs that inhibit TNF may also have a negative impact on the immune system. Some patients have developed serious infections, such as tuberculosis, while taking Enbrel(r).

Tumor necrosis factor and MS
Although TNF seems to be involved in the inflammation seen in other autoimmune diseases, its precise role in MS is controversial. When TNF was blocked in EAE, an animal model of MS, severity of EAE was decreased. In humans, MS plaques and cerebrospinal fluid have been shown to contain high levels of TNF. However, anti-tumor necrosis factor medications have been associated with an increase in exacerbations and a worsening of symptoms in people who have MS.4 This may be because TNF alpha antagonists cannot cross the blood brain barrier and work on the cells in the central nervous system that are affected in MS, whereas in rheumatoid arthritis and Crohn's disease, they can go to work directly on the diseased cells in the joints and in the bowel. Another explanation is that when TNF alpha antagonists exert their effect outside the central nervous system, they heighten the activity of a type of T cell involved in the autoimmune response, precipitating further MS symptoms.

Although the causal relationship between TNF alpha antagonists and either the onset or worsening of MS remains unclear, the National MS Society advises against the use of TNF alpha antagonists in people with MS. Patients who develop new neurological symptoms while on any TNF alpha antagonist medication should be seen by a neurologist and monitored with frequent MRIs.5

1 Mohan, N., et al. "Demyelination Occurring During Anti-Tumor Necrosis Factor Alpha Therapy for Inflammatory Arthritides." Arthritis and Rheumatism; 44: no.12 (December 2001) 2862.
2 Immunex Corporation. "Enbrel(r) package insert." Seattle, Washington: 2002.
3 Robinson, W.H., Genovese, M.C., and Moreland, L.W. Demyelinating and Neurologic Events Reported in Association With Tumor Necrosis Factor Alpha Antagonism. Arthritis and Rheumatism; 44: no. 9 (September, 2001) 1978.
4 Robinson, W.H. "Demyelinating and Neurologic Events..." 1978.
5 Mohan, N. et al. "Demyelination Occurring During Anti-Tumor Necrosis Factor Therapy...) 2868.

********************************************************************************************

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

********************************************************************************************