ASTHMA

In this section we will provide scientific studies related to the ingredients contained in the NMS Neuromuscular Support Formula that deal with Asthma. This is additional information that we feel relates to the efficacy of this amazing product and should also give you an idea of the breadth and scope of the information about the ingredients in the NMS Formula dealing with health conditions other than Pain & Inflammation.

ASTHMA --- CURCUMIN

Biochem Biophys Res Commun. 2008 Oct 17;375(2):275-9. Epub 2008 Aug 13.
Curcumin attenuates ovalbumin-induced airway inflammation by regulating nitric oxide.
Moon DO, Kim MO, Lee HJ, Choi YH, Park YM, Heo MS, Kim GY.
Faculty of Applied Marine Science, Cheju National University, Jeju Special Self-
Governing Province, Jeju 690-756, Republic of Korea.

Curcumin has been strongly implicated as an anti-inflammatory agent, but the precise mechanisms of its action are largely unknown. In this study, we show that curcumin contributes to anti-inflammatory activity in the murine asthma model and lung epithelial cell A549 through suppression of nitric oxide (NO). To address this problem, curcumin was injected into the peritoneum of ovalbumin (OVA)-sensitized mice before the last allergen challenge. OVA challenge resulted in activation of the production of inducible nitric oxide (iNOS) in lung tissue, inflammatory cytokines, recruitment of eosinophils to lung airways, and airway hyper-responsiveness to inhaled methacholine. These effects of ovalbumin challenge were all inhibited by pretreatment of mice with curcumin. Furthermore, supplementation with curcumin in the A549 human airway epithelial cells decreased iNOS and NO production induced by IFN-gamma. These findings show that curcumin may be useful as an adjuvant therapy for airway inflammation through suppression of iNOS and NO.

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Am J Respir Cell Mol Biol. 2008 Sep;39(3):312-23. Epub 2008 Apr 17.
Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2.
Meja KK, Rajendrasozhan S, Adenuga D, Biswas SK, Sundar IK, Spooner G,
Marwick JA, Chakravarty P, Fletcher D, Whittaker P, Megson IL, Kirkham
PA, Rahman I.
Novartis Institutes for Biomedical Research, Respiratory Disease, Horsham, UK.

Oxidative stress as a result of cigarette smoking is an important etiologic factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), a chronic steroid-insensitive inflammatory disease of the airways. Histone deacetylase-2 (HDAC2), a critical component of the corticosteroid anti-inflammatory action, is impaired in lungs of patients with COPD and correlates with disease severity. We demonstrate here that curcumin (diferuloylmethane), a dietary polyphenol, at nanomolar concentrations specifically restores cigarette smoke extract (CSE)- or oxidative stress-impaired HDAC2 activity and corticosteroid efficacy in vitro with an EC(50) of approximately 30 nM and 200 nM, respectively. CSE caused a reduction in HDAC2 protein expression that was restored by curcumin. This decrease in HDAC2 protein expression was reversed by curcumin even in the presence of cycloheximide, a protein synthesis inhibitor. The proteasomal inhibitor, MG132, also blocked CSE-induced HDAC2 degradation, increasing the levels of ubiquitinated HDAC2. Biochemical and gene chip analysis indicated that curcumin at concentrations up to 1 muM propagates its effect via antioxidant-independent mechanisms associated with the phosphorylation-ubiquitin-proteasome pathway. Thus curcumin acts at a post-translational level by maintaining both HDAC2 activity and expression, thereby reversing steroid insensitivity induced by either CSE or oxidative stress in monocytes. Curcumin may therefore have potential to reverse steroid resistance, which is common in patients with COPD and asthma.

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Mol Nutr Food Res. 2008 Sep;52(9):1031-9.
Immunomodulatory effects of curcumin in allergy.
Kurup VP, Barrios CS.
Allergy and Immunology Division, Department of Pediatric, Medical College of
Wisconsin, Milwaukee, WI, USA.

Recent years have witnessed a global increase in allergy and asthma, particularly in developed countries. Attempts to develop effective control measures for allergy and asthma resulted in the exploration of alternate medicines including herbal remedies traditionally used in old world countries. Turmeric is known for its multiple health restoring properties, and has been used in treating several diseases including several respiratory disorders. Turmeric is a common spice used in the culinary preparations in South and East Asian countries. The active component of turmeric is curcumin, a polyphenolic phytochemical, with anti-inflammatory, antiamyloid, antiseptic, antitumor, and antioxidative properties. Curcumin was reported to have antiallergic properties with inhibitory effect on histamine release from mast cells. The effectiveness of curcumin in allergy and asthma has been further investigated using a murine model of allergy. The results indicate a marked inhibition of allergic response in animals treated with curcumin suggesting a major role for curcumin in reducing the allergic response. The present review focuses on the results of research aimed to understand the immunomodulation induced by curcumin and its associated roles in the amelioration of allergy. These findings needed further evaluation, extrapolation, and confirmation before using curcumin for controlling allergy and asthma in humans.

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Mol Nutr Food Res. 2008 Sep;52(9):987-94.
Modulation of steroid activity in chronic inflammation:
a novel anti-inflammatory role for curcumin.
Biswas S, Rahman I.
Department of Environmental Medicine, Lung Biology and Disease Program, University
of Rochester Medical Center, Rochester, NY 14642, USA.

The expression of NF-kappaB (NF-kappaB)-dependent pro-inflammatory genes in response to oxidative stress is regulated by the acetylation-deacetylation status of histones bound to the DNA. It has been suggested that in severe asthma and in chronic obstructive pulmonary disease (COPD) patients, oxidative stress not only activates the NF-kappaB pathway but also alters the histone acetylation and deacetylation balance via post-translational modification of histone deacetylases (HDACs). Corticosteroids have been one of the major modes of therapy against various chronic respiratory diseases such as asthma and COPD. Failure of corticosteroids to ameliorate such disease conditions has been attributed to their inability to either recruit HDAC2 or to the presence of an oxidatively modified HDAC2 in asthmatics and COPD subjects. Naturally occurring polyphenols such as curcumin and resveratrol have been increasingly considered as safer nutraceuticals. Curcumin is a polyphenol present in the spice turmeric, which can directly scavenge free radicals such as superoxide anion and nitric oxide and modulate important signaling pathways mediated via NF-kappaB and mitogen-activated protein kinase pathways. Polyphenols also down-regulate expression of pro-inflammatory mediators, matrix metalloproteinases, adhesion molecules, and growth factor receptor genes and they up-regulate HDAC2 in the lung. Thus, curcumin may be a potential antioxidant and anti-inflammatory therapeutic agent against chronic inflammatory lung diseases.

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Adv Exp Med Biol. 2007;595:379-405.
Protection from acute and chronic lung diseases by curcumin.
Venkatesan N, Punithavathi D, Babu M.
Faculte de Medecine, UMR-7561, CNRS UHP, Vandoeuvre l�s Nancy, France.
vnar12@yahoo.com

The aim of this review has been to describe the current state of the therapeutic potential of curcumin in acute and chronic lung injuries. Occupational and environmental exposures to mineral dusts, airborne pollutants, cigarette smoke, chemotherapy, and radiotherapy injure the lungs, resulting in acute and chronic inflammatory lung diseases. Despite major advances in treating lung diseases, until now disease-modifying efficacy has not been demonstrated for any of the existing drugs. Current medical therapy offers only marginal benefit; therefore, there is an essential need to develop new drugs that might be of effective benefit in clinical settings. Over the years, there has been increasing evidence that curcumin, a phytochemical present in turmeric (Curcuma longa), has a wide spectrum of therapeutic properties and a remarkable range of protective effects in various diseases. Several experimental animal models have tested curcumin on lung fibrosis and these studies demonstrate that curcumin attenuates lung injury and fibrosis caused by radiation, chemotherapeutic drugs, and toxicants. The growing amount of data from pharmacological and animal studies also supports the notion that curcumin plays a protective role in chronic obstructive pulmonary disease, acute lung injury, acute respiratory distress syndrome, and allergic asthma, its therapeutic action being on the prevention or modulation of inflammation and oxidative stress. These findings give substance to the possibility of testing curcumin in patients with lung diseases.

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Clin Mol Allergy. 2007 Jan 25;5:1.
Immune response modulation by curcumin in a
latex allergy model.
Kurup VP, Barrios CS, Raju R, Johnson BD, Levy MB, Fink JN.
Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road,
Milwaukee, WI 53226, USA. vkurup@mcw.edu

BACKGROUND: There has been a worldwide increase in allergy and asthma over the last few decades, particularly in industrially developed nations. This resulted in a renewed interest to understand the pathogenesis of allergy in recent years. The progress made in the pathogenesis of allergic disease has led to the exploration of novel alternative therapies, which include herbal medicines as well. Curcumin, present in turmeric, a frequently used spice in Asia has been shown to have anti-allergic and inflammatory potential. METHODS: We used a murine model of latex allergy to investigate the role of curcumin as an immunomodulator. BALB/c mice were exposed to latex allergens and developed latex allergy with a Th2 type of immune response. These animals were treated with curcumin and the immunological and inflammatory responses were evaluated. RESULTS: Animals exposed to latex showed enhanced serum IgE, latex specific IgG1, IL-4, IL-5, IL-13, eosinophils and inflammation in the lungs. Intragastric treatment of latex-sensitized mice with curcumin demonstrated a diminished Th2 response with a concurrent reduction in lung inflammation. Eosinophilia in curcumin-treated mice was markedly reduced, co-stimulatory molecule expression (CD80, CD86, and OX40L) on antigen-presenting cells was decreased, and expression of MMP-9, OAT, and TSLP genes was also attenuated. CONCLUSION: These results suggest that curcumin has potential therapeutic value for controlling allergic responses resulting from exposure to allergens.

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J Clin Immunol. 2007 Jan;27(1):19-35. Epub 2007 Jan 9.
"Spicing up" of the immune system by curcumin.
Jagetia GC, Aggarwal BB.
Cytokine Research Laboratory, Department of Experimental Therapeutics, The
University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Curcumin (diferuloylmethane) is an orange-yellow component of turmeric (Curcuma longa), a spice often found in curry powder. Traditionally known for its an antiinflammatory effects, curcumin has been shown in the last two decades to be a potent immunomodulatory agent that can modulate the activation of T cells, B cells, macrophages, neutrophils, natural killer cells, and dendritic cells. Curcumin can also downregulate the expression of various proinflammatory cytokines including TNF, IL-1, IL-2, IL-6, IL-8, IL-12, and chemokines, most likely through inactivation of the transcription factor NF-kappaB. Interestingly, however, curcumin at low doses can also enhance antibody responses. This suggests that curcumin's reported beneficial effects in arthritis, allergy, asthma, atherosclerosis, heart disease, Alzheimer's disease, diabetes, and cancer might be due in part to its ability to modulate the immune system. Together, these findings warrant further consideration of curcumin as a therapy for immune disorders.

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ASTHMA --- BOSWELLIA SERRATA

BMJ. 2008 Dec 17;337:a2813. doi: 10.1136/bmj.a2813
Frankincense: systematic review.
Ernst E.
Complementary Medicine, Peninsula Medical School, Universities of Exeter and
Plymouth, Exeter EX2 4NT, UK. edzard.ernst@pms.ac.uk

OBJECTIVE: To assess evidence from randomised clinical trials about the effectiveness of extracts of Boswellia serrata (frankincense). DESIGN: Systematic review. DATA SOURCES: Electronic searches on Medline, Embase, Cinahl, Amed, and Cochrane Library. Hand searches of conference proceedings, bibliographies, and departmental files. REVIEW METHODS: All randomised clinical trials of B serrata extract as a treatment for any human medical condition were included and studies of B serrata preparations combined with other ingredients were excluded. Titles and abstracts of all retrieved articles were read and hard copies of all relevant articles were obtained. Selection of studies, data extraction and validation were done by the author. The Jadad score was used to evaluate the methodological quality of all included trials. RESULTS: Of 47 potentially relevant studies, seven met all inclusion criteria (five placebo controlled, two with active controls). The included trials related to asthma, rheumatoid arthritis, Crohn's disease, osteoarthritis, and collagenous colitis. Results of all trials indicated that B serrata extracts were clinically effective. Three studies were of good methodological quality. No serious safety issues were noted. CONCLUSIONS: The evidence for the effectiveness of B serrata extracts is encouraging but not compelling.

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Wien Med Wochenschr. 2002;152(15-16):373-8.
[Boswellic acids (components of frankincense) as the
active principle in treatment of chronic inflammatory
diseases]
[Article in German]
Ammon HP.
Lehrstuhl Pharmakologie f�r Naturwissenschaftler, Pharmazeutisches Institut der
Universit�t T�bingen, Deutschland. sekretariat.ammon@uni-tuebingen.de

Preparations from the gum resin of Boswellia serrata have been used as a traditional remedy in Ayurvedic medicine in India for the treatment of inflammatory diseases. Compounds from the gum with genuine antiinflammatory effects are pentacyclic triterpenes of the boswellic acid type. Boswellic acids inhibit the leukotriene biosynthesis in neutrophilic granulocytes by a non-redox, noncompetitive inhibition of 5-lipoxygenase. The effect is triggered by boswellic acids binding to the enzyme. Moreover certain boswellic acids have been described to inhibit elastase in leukocytes, to inhibit proliferation, induce apoptosis and to inhibit topoisomerases of leukoma- and glioma cell lines. A series of chronic inflammatory diseases are thought to be perpetuated by leukotrienes. In clinical trials promising results were observed in patients with rheumatoid arthritis, chronic colitis, ulcerative colitis, Crohn's disease, bronchial asthma und peritumoral brains edemas.

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Altern Med Rev. 2001 Feb;6(1):20-47.
The etiologies, pathophysiology, and
alternative/complementary treatment of asthma.
Miller AL.
Thorne Research, Inc, Dover, ID 83825, USA. alan@thorne.com

A chronic inflammatory disorder of the respiratory airways, asthma is characterized by bronchial airway inflammation resulting in increased mucus production and airway hyper-responsiveness. The resultant symptomatology includes episodes of wheezing, coughing, and shortness of breath. Asthma is a multifactorial disease process with genetic, allergic, environmental, infectious, emotional, and nutritional components. The underlying pathophysiology of asthma is airway inflammation. The underlying process driving and maintaining the asthmatic inflammatory process appears to be an abnormal or inadequately regulated CD4+ T-cell immune response. The T-helper 2 (Th2) subset produces cytokines including interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10, and IL-13, which stimulate the growth, differentiation, and recruitment of mast cells, basophils, eosinophils, and B-cells, all of which are involved in humoral immunity, inflammation, and the allergic response. In asthma, this arm of the immune response is overactive, while Th1 activity, generally corresponding more to cell-mediated immunity, is dampened. It is not yet known why asthmatics have this out-of-balance immune activity, but genetics, viruses, fungi, heavy metals, nutrition, and pollution all can be contributors. A plant lipid preparation containing sterols and sterolins has been shown to dampen Th2 activity. Antioxidant nutrients, especially vitamins C and E, selenium, and zinc appear to be necessary in asthma treatment. Vitamins B6 and B12 also may be helpful. Omega-3 fatty acids from fish, the flavonoid quercetin, and botanicals Tylophora asthmatica, Boswellia serrata and Petasites hybridus address the inflammatory component. Physical modalities, including yoga, massage, biofeedback, acupuncture, and chiropractic can also be of help.

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Eur J Med Res. 1998 Nov 17;3(11):511-4.
Effects of Boswellia serrata gum resin in patients with
bronchial asthma: results of a double-
blind, placebo-controlled, 6-week clinical study.
Gupta I, Gupta V, Parihar A, Gupta S, L�dtke R, Safayhi H, Ammon HP.
Pharmakologie f�r Naturwissenschaftler, Pharmazeutisches Institut der Universit�t
T�bingen, Auf der Morgenstelle 8, D-72076 T�bingen, Germany.

The gum resin of Boswellia serrata, known in Indian Ayurvedic system of medicine as Salai guggal, contains boswellic acids, which have been shown to inhibit leukotriene biosynthesis. In a double-blind, placebo-controlled study forty patients, 23 males and 17 females in the age range of 18 - 75 years having mean duration of illness, bronchial asthma, of 9.58 +/- 6.07 years were treated with a preparation of gum resin of 300 mg thrice daily for a period of 6 weeks. 70% of patients showed improvement of disease as evident by disappearance of physical symptoms and signs such as dyspnoea, rhonchi, number of attacks, increase in FEV subset1, FVC and PEFR as well as decrease in eosinophilic count and ESR. In the control group of 40 patients 16 males and 24 females in the age range of 14-58 years with mean of 32.95 +/- 12.68 were treated with lactose 300 mg thrice daily for 6 weeks. Only 27% of patients in the control group showed improvement. The data show a definite role of gum resin of Boswellia serrata in the treatment of bronchial asthma.

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ASTHMA --- QUERCETIN

Int Immunopharmacol. 2008 Dec 2. [Epub ahead of print]
Quercetin regulates Th1/Th2 balance in a murine model
of asthma.
Park HJ, Lee CM, Jung ID, Lee JS, Jeong YI, Chang JH, Chun SH, Kim MJ, Choi
IW, Ahn SC, Shin YK, Yeom SR, Park YM.
Department of Pediatrics, Pusan National University College of Medicine,
Busan 602-739, South Korea.

Quercetin is found to be the most active of the flavonoids in studies and many medicinal plants owe much of their activity to their high Quercetin content. Quercetin has demonstrated significant anti-inflammatory activity because of direct inhibition of several initial processes of inflammation. However, its anti-allergic effect in the Th1/Th2 immune response was poorly understood. Recently, it was shown that T-bet and GATA-3 were master Th1 and Th2 regulatory transcription factors. In this study, we have attempted to determine whether Quercetin regulates Th1/Th2 cytokine production, T-bet and GATA-3 gene expression in OVA-induced asthma model mice. Quercetin reduced the increased levels of IL-4, Th2 cytokine production in OVA-sensitized and -challenged mice. The other side, it increased IFN-gamma, Th1 cytokine production in Quercetin administrated mice. We also examined to ascertain whether Quercetin could influence Eosinophil peroxidase (EPO) activity. The administration of Quercetin before the last airway OVA challenge resulted in a significant inhibition of all asthmatic reactions. Accordingly, this study may provide evidence that Quercetin plays a critical role in the amelioration of the pathogenetic process of asthma in mice. These findings provide new insight into the immunopharmacological role of Quercetin in terms of its effects in a murine model of asthma, and also broaden current perspectives in our understanding of the immunopharmacological functions of Quercetin.

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Planta Med. 2008 Oct;74(13):1608-24. Epub 2008 Oct 14.
Cancer chemopreventive potential of apples, apple
juice, and apple components.
Gerhauser C.
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center
(DKFZ), Heidelberg, Germany. c.gerhauser@dkfz.de

Apples ( MALUS sp., Rosaceae) are a rich source of nutrient as well as non-nutrient components and contain high levels of polyphenols and other phytochemicals. Main structural classes of apple constituents include hydroxycinnamic acids, dihydrochalcones, flavonols (quercetin glycosides), catechins and oligomeric procyanidins, as well as triterpenoids in apple peel and anthocyanins in red apples. Several lines of evidence suggest that apples and apple products possess a wide range of biological activities which may contribute to health beneficial effects against cardiovascular disease, asthma and pulmonary dysfunction, diabetes, obesity, and cancer (reviewed by Boyer and Liu, Nutr J 2004). The present review will summarize the current knowledge on potential cancer preventive effects of apples, apple juice and apple extracts (jointly designated as apple products). In brief, apple extracts and components, especially oligomeric procyanidins, have been shown to influence multiple mechanisms relevant for cancer prevention in IN VITRO studies. These include antimutagenic activity, modulation of carcinogen metabolism, antioxidant activity, anti-inflammatory mechanisms, modulation of signal transduction pathways, antiproliferative and apoptosis-inducing activity, as well as novel mechanisms on epigenetic events and innate immunity. Apple products have been shown to prevent skin, mammary and colon carcinogenesis in animal models. Epidemiological observations indicate that regular consumption of one or more apples a day may reduce the risk for lung and colon cancer.

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Arch Pharm Res. 2007 Dec;30(12):1599-607.
Anti-asthmatic action of quercetin and rutin in
conscious guinea-pigs challenged with aerosolized
ovalbumin.
Jung CH, Lee JY, Cho CH, Kim CJ.
Division of Pathophysiology and Pharmacology, College of Pharmacy, Chung-Ang
University, Seoul 156-756, Korea.

The effects of quercetin and rutin on the asthmatic responses were studied in ovalbumin (OA)-sensitized conscious guinea pigs challenged with aerosolized-OA. We measured the specific airway resistance (sRaw) in the double-chambered plethysmograph during the immediate-phase response (IAR) and late-phase response (LAR) at 3 approximately 10 min and 24 hr after OA challenge, respectively. We counted leukocytes in bronchoalveolar lavage fluid (BALF) using Wright's stain, as well as in lung tissue fixed with 10% formalin and stained with H & E stain. Quercetin and rutin (7.5 mg/kg, p.o.) significantly and dose-dependently inhibited both sRaw on IAR (31.60 and 26.44%) and LAR (29.87 and 28.69%) but with less efficacy than dexamethasone (3 mg/kg) and salbutamol (0.3 mg/kg), which inhibited IAR by 36.71 and 69.45%, and LAR by 67.23 and 0%, respectively, Quercetin and rutin (15 mg/kg) also inhibited production of histamine, PLA2, and EPO, and recruitment of leukocytes, particularly neutrophils and eosinophils, during LAR. respectively. Dexamethasone (3 mg/kg) also significantly reduced the recruitment of neutrophils, eosinophils, and lymphocytes in BALF, and salbutamol (0.3 mg/kg) reduced neutrophils and eosinophils with lower activity than dexamethasone. These results indicate that quercetin and rutin may be useful in the treatment of IAR and LAR in asthma via inhibition of histamine release, PLA2, and EPO, and reduced recruitment of neutrophils and eosinophils into the lung.

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