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Thread: Key component of COPD identified

  1. #1
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    Default Key component of COPD identified

    Sent by Dr. Payne Thank you.


    http://www.sciencedaily.com/releases...0912075154.htm - Key Component Of Debilitating Lung Disease Identified

    Excerpt: A study of lung tissue samples from COPD patients by scientists at the Johns Hopkins Bloomberg School of Public Health found that expression of the regulating gene NRF2 was significantly decreased in smokers with advanced COPD compared to smokers without COPD.

    http://content.karger.com/produktedb...file=000106447



    COMMENTS: Upregulation (activation) of the gene NRF2 and corresponding increases in the NRF2 protein will not only benefit advanced emphysema patients (see abstracts and such below), but IMO likely help reduces the chances of contracting the disease among current smokers. A green tea component called ECGC, trans-resveratrol and spearmint oil (among other things ? abstracts below) has been shown to upregulate this particular gene (Animal studies). I believe the effect will prove true in humans. You can get ECGC in tablet or pill form on-line and in some health food stores. Also, drinking green tea will provide low doses of it. Trans-Resveratrol also helps upregulate this gene and may slow aging -- and is available in capsule and tablet form and exists in low amounts in grapes and such. Spearmint tea is available in grocery stores across the lab (But I must throw in a cautionary note: Spearmint oil has an antiandrogen effect ? which for aging men could result in reduced testosterone availability and thus a lower libido as well as all kinds of other potential side effects (Interestingly and not surprisingly, one study showed that Spearmint oil?s antiandrogen effects reduced hirsutism in women. Also and MOST IMPOTANTLY: Upregulating Nfr2 is a big ?no, no? in persons with cancer ? especially those undergoing chemotherapy. I?ve provided 2 abstracts below concerning this).



    Anthony G. Payne, Ph.D.

    Weller Health Institute & Laboratory




    J Exp Med. 2005 Jul 4;202(1):47-59. Links
    Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice.

    Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S.

    Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.

    Oxidative stress has been postulated to play an important role in the pathogenesis of asthma; although a defect in antioxidant responses has been speculated to exacerbate asthma severity, this has been difficult to demonstrate with certainty. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive basic leucine zipper transcription factor that is involved in the transcriptional regulation of many antioxidant genes. We show that disruption of the Nrf2 gene leads to severe allergen-driven airway inflammation and hyperresponsiveness in mice. Enhanced asthmatic response as a result of ovalbumin sensitization and challenge in Nrf2-disrupted mice was associated with more pronounced mucus cell hyperplasia and infiltration of eosinophils into the lungs than seen in wild-type littermates. Nrf2 disruption resulted in an increased expression of the T helper type 2 cytokines interleukin (IL)-4 and IL-13 in bronchoalveolar lavage fluid and in splenocytes after allergen challenge. The enhanced severity of the asthmatic response from disruption of the Nrf2 pathway was a result of a lowered antioxidant status of the lungs caused by lower basal expression, as well as marked attenuation, of the transcriptional induction of multiple antioxidant genes. Our studies suggest that the responsiveness of Nrf2-directed antioxidant pathways may act as a major determinant of susceptibility to allergen-mediated asthma.

    PMID: 15998787 [PubMed - indexed for MEDLINE]

    PMCID: PMC2212893

    Clin Immunol. 2008 Sep;128(3):366-73. Epub 2008 Jul 9. Links

    Disruption of Nrf2 enhances susceptibility to airway inflammatory responses induced by low-dose diesel exhaust particles in mice.

    Li YJ, Takizawa H, Azuma A, Kohyama T, Yamauchi Y, Takahashi S, Yamamoto M, Kawada T, Kudoh S, Sugawara I.

    Department of Hygiene and Public Health, Nippon Medical School, Tokyo, Japan.

    To test our hypothesis that diesel exhaust particle (DEP)-induced oxidative stress and host antioxidant responses play a key role in the development of DEP-induced airway inflammatory diseases, C57BL/6 nuclear erythroid 2 P45-related factor 2 (Nrf2) knockout (Nrf2(-/-)) and wild-type mice were exposed to low-dose DEP for 7 h/day, 5 days/week, for 8 weeks. Nrf2(-/-) mice exposed to low-dose DEP showed significantly increased airway hyperresponsiveness and counts of lymphocytes and eosinophils, together with increased concentrations of IL-12 and IL-13, and thymus and activation-regulated chemokine (TARC), in BAL fluid than wild-type mice. In contrast, expression of antioxidant enzyme genes was significantly higher in wild-type mice than in Nrf2(-/-) mice. We have first demonstrated that disruption of Nrf2 enhances susceptibility to airway inflammatory responses induced by inhalation of low-dose DEP in mice. These results strongly suggest that DEP-induced oxidative stress and host antioxidant responses play some role in the development of DEP-induced airway inflammation.

    PMID: 18614404 [PubMed - indexed for MEDLINE]









    Vol. 80, No. 4, 2007


    View or print article as PDF (2311 KB)





    Original Paper

    Inhibition of Epigallocatechin Gallate on Orthotopic Colon Cancer by Upregulating the Nrf2-UGT1A Signal Pathway in Nude Mice
    Jun-Hua Yuan, Yan-Qing Li, Xiao-Yun Yang

    Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, PR China

    Address of Corresponding Author

    Pharmacology 2007;80:269-278 (DOI: 10.1159/000106447)

    Key Words

    * Epigallocatechin gallate
    * Colon carcinoma
    * Orthotopic implantation
    * NF-E2-related factor 2
    * Uridine 5'-diphosphate-glucuronosyltransferase

    Abstract

    Epigallocatechin gallate (EGCG), a key active ingredient in green tea, has many anti-carcinogenic activities. The aim of the present study was to investigate whether EGCG could prevent the occurrence or metastases of orthotopic colon cancer and probe the underlined mechanisms. We observed the inhibition of EGCG on growth and metastases of colon tumor implanted orthotopically in the cecum of nude mice. Immunohistochemistry and Western-blotting analysis were used to detect NF-E2-related factor 2 (Nrf2) protein expressions. RT-PCR was also applied to detect the mRNA levels of Nrf2, uridine 5'-diphosphate-glucuronosyltransferase (UGT) 1A, UGT1A8 and UGT1A10 in colon tumors. As a result, the inhibition rates on tumor growth in the 3 EGCG groups were significantly different (all p < 0.001) compared with the control group. In addition, different doses of EGCG were able to inhibit liver and pulmonary metastases to varying degrees. The protein level of Nrf2 and the mRNA levels of Nrf2, UGT1A, UGT1A8 and UGT1A10 significantly increased in EGCG-treated mice in comparison with the control group (all p < 0.01). The results demonstrated that EGCG has a preventive effect on the growth and liver and pulmonary metastases of orthotopic colon cancer in nude mice, and this anticancer effect could be partly caused by activating the Nrf2-UGT1A signal pathway.

    Copyright ? 2007 S. Karger AG, Basel


    \

    Free Radic Biol Med. 2008 Jun 15;44(12):2002-12. Epub 2008 Mar 8. Links
    Zinc protects endothelial cells from hydrogen peroxide via Nrf2-dependent stimulation of glutathione biosynthesis.

    Cortese MM, Suschek CV, Wetzel W, Kr?ncke KD, Kolb-Bachofen V.

    Institute of Molecular Medicine, Research Group Immunobiology, Medical Faculty of the Heinrich-Heine-University D?sseldorf, Universit?tsstrasse 1, D-40225 D?sseldorf, Germany. mcortese@ukaachen.de

    Oxidative stress is one of the main causes of vascular disease. This study aims to investigate the antioxidant activity exerted by zinc in primary rat endothelial cells (EC). Using a 24-h treatment with hydrogen peroxide as a model for oxidative stress, we found that zinc supplementation protects from peroxide-induced cell death via increasing the transcription of the catalytic subunit (heavy chain) of glutamate-cysteine ligase (GCLC) and the concentrations of glutathione (GSH). Conversely, zinc depletion significantly decreased the expression of GCLC and the cellular GSH levels, resulting in an increased susceptibility of EC to oxidative stress. Using confocal microscopy and the RNA silencing technique, we found that zinc upregulates the expression of GCLC by activating the transcription factor Nrf2. Surprisingly, the intracellular zinc sensor, metal-responsive transcription factor-1, is not involved in the zinc-induced expression of GCLC. The present study shows that zinc controls the redox state of EC by regulating the de novo synthesis of GSH. This molecular mechanism may contribute to the elaboration of new nutritional and/or pharmaceutical approaches for protecting the endothelium against oxidative stress.

    PMID: 18355458 [PubMed - in process]
    Related Articles



    Arch Pharm Res. 2007 Dec;30(12):1590-8. Links
    Isoorientin induces Nrf2 pathway-driven antioxidant response through phosphatidylinositol 3-kinase signaling.

    Lim JH, Park HS, Choi JK, Lee IS, Choi HJ.

    College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Korea.

    Because oxidative stress is involved in the pathogenesis of various chronic diseases and the aging process, antioxidants that can increase the intrinsic antioxidant potency are proposed as desirable therapeutic agents to counteract oxidative stress-related diseases. NF-E2-related factor-2 (Nrf2) is a transcription factor that regulates important antioxidant and phase II detoxification genes, and therefore, the molecule that regulates nuclear translocation of Nrf2 and the induction of antioxidative proteins is thought to be a promising candidate as a cytoprotective agent for oxidative stress. In the present study, we show that isoorientin (luteolin 6-C-beta-D-glucoside) obtained from the leaves of Sasa borealis upregulates and activates Nrf2, and has protective ability against oxidative damage caused by reactive oxygen intermediates in HepG2 cells. Isoorientin induces increase in the level of antioxidant enzyme proteins, especially NQO1, and the cytoprotective and antioxidative effects of isoorientin are PI3K/Akt pathway-dependent. Together with direct radical scavenging activity, the novel effect of isoorientin on the regulation of antioxidative gene expression provides attractive strategy to prevent diseases associated with oxidative stress and attenuate the progress of the diseases.

    PMID: 18254247 [PubMed - indexed for MEDLINE]

    Biochem Biophys Res Commun. 2005 Jun 17;331(4):993-1000. Links
    Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells.

    Chen CY, Jang JH, Li MH, Surh YJ.

    National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, Republic of Korea.

    Resveratrol (3,4',5-trihydroxy stilbene), a phytoalexin found in the skin and seeds of grapes, has been reported to possess anti-inflammatory, anticarcinogenic, and antioxidant activities. In this work, we assessed the ability of resveratrol to upregulate heme oxygenase-1 (HO-1) gene expression via activation of NF-E2-related factor 2 (Nrf2) in cultured PC12 cells. Nrf2 is a transcription factor involved in the cellular protection against oxidative stress through antioxidant response element (ARE)-directed induction of several phase 2 detoxifying and antioxidant enzymes, such as HO-1. Here, we report that resveratrol induces HO-1 expression via the ARE-mediated transcriptional activation of Nrf2. Moreover, PC12 cells treated with resveratrol exhibited transient activation of Akt/protein kinase B and extracellular signal-regulated protein kinase 1/2 (ERK1/2). LY294002 and U0126, pharmacological inhibitors of phosphatidylinositol 3-kinase and MEK1/2 which are upstream of Akt and ERK1/2, respectively, attenuated resveratrol-induced HO-1 expression and exhibited antioxidant effects. Taken together, the above findings suggest that resveratrol augments cellular antioxidant defense capacity through induction of HO-1 via Nrf2-ARE signaling, thereby protecting PC12 cells from oxidative stress.

    PMID: 15882976 [PubMed - indexed for MEDLINE]





    J Neurosci Res. 2005 Feb 15;79(4):509-21. Links

    Acetylcarnitine induces heme oxygenase in rat astrocytes and protects against oxidative stress: involvement of the transcription factor Nrf2.

    Calabrese V, Ravagna A, Colombrita C, Scapagnini G, Guagliano E, Calvani M, Butterfield DA, Giuffrida Stella AM.

    Department of Chemistry, Biochemistry and Molecular Biology Section, Faculty of Medicine, University of Catania, Catania, Italy. calabres@mbox.unict.it

    Efficient functioning of maintenance and repair processes seem to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, under control of several genes termed vitagenes. These include members of the heat shock protein system, and there is now evidence that the heat shock response contributes to establishing a cytoprotective state in a wide variety of human conditions, including inflammation, neurodegenerative disorders, and aging. Among the various heat shock proteins, heme oxygenase-1 has received considerable attention; it has been recently demonstrated that heme oxygenase-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Acetyl-L-carnitine is proposed as a therapeutic agent for several neurodegenerative disorders. Accordingly, we report here that treatment of astrocytes with acetyl-L-carnitine induces heme oxygenase-1 in a dose- and time-dependent manner and that this effect was associated with up-regulation of heat shock protein 60 as well as high expression of the redox-sensitive transcription factor Nrf2 in the nuclear fraction of treated cells. In addition, we show that addition of acetyl-L-carnitine to astrocytes, prior to proinflammatory lipopolysaccharide- and interferon-gamma-induced nitrosative stress, prevents changes in mitochondrial respiratory chain complex activity, protein nitrosation and antioxidant status induced by inflammatory cytokine insult. Given the broad cytoprotective properties of the heat shock response, molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. Particularly, manipulation of endogenous cellular defense mechanisms via acetyl-L-carnitine may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. We hypothesize that maintenance or recovery of the activity of vitagenes may delay the aging process and decrease the risk of age-related diseases. Copyright (c) 2005 Wiley-Liss, Inc.

    PMID: 15641110 [PubMed - indexed for MEDLINE]

    Zhejiang Da Xue Xue Bao Yi Xue Ban. 2008 Jul;37(4):357-63. Links

    [Effect of Spearmint oil on inflammation, oxidative alteration and Nrf2 expression in lung tissue of COPD rats.]

    [Article in Chinese]

    Zhao CZ, Wang Y, Tang FD, Zhao XJ, Xu QP, Xia JF, Zhu YF.

    Zhejiang Respiratory Drugs Research Laboratory of State Food and Drugs Administration, College of Medicine, Zhejiang University, Hangzhou 310058,China.

    OBJECTIVE: To investigate the effect of Spearmint oil on inflammation, oxidative alteration and Nrf2 expression in rats with chronic obstructive pulmonary disease(COPD). METHODS: COPD model was induced by intratracheal instillation of Klebsiella pneumonia and lipopolysaccharide (LPS) for 12 weeks in rats, and COPD rats were treated with Spearmint oil for 3 weeks. After COPD was induced, the pathological changes, changes in leucocyte number in blood and bronchoalveolar lavage fluid (BALF), MDA in lung homogenate and Nrf2 expression were observed. The effects of Spearmint oil on these changes were determined. RESULT: Spearmint oil 100 mg*kg(-1)significantly reduced leucocyte numbers in BALF, and attenuated bronchiolitis, pulmonary interstitial inflammation and inflammation cell infiltration. Spearmint oil 30-300 mg*kg(-1)decreased the destruction of pulmonary alveolus and the thickness of bronchioles walls, and inhibited goblet cell proliferation. Spearmint oil significantly reduced MDA in lung homogenate, and decreased the expression of Nrf2 protein in lung tissues. Conclusion: Spearmint oil has protective effect on lung injury in COPD rats, since it improves pulmonary inflammation,oxidative alteration, and enhances Nrf2 protein expression.

    PMID: 18705008 [PubMed - in process]



    Carcinogenesis. 2008 Jun;29(6):1235-43. Epub 2008 Apr 15. Links

    Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2.

    Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, Chen W, Yi X, Zheng W, Wondrak GT, Wong PK, Zhang DD.

    Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.

    Drug resistance during chemotherapy is the major obstacle to the successful treatment of many cancers. Here, we report that inhibition of NF-E2-related factor 2 (Nrf2) may be a promising strategy to combat chemoresistance. Nrf2 is a critical transcription factor regulating a cellular protective response that defends cells against toxic insults from a broad spectrum of chemicals. Under normal conditions, the low constitutive amount of Nrf2 protein is maintained by the Kelch-like ECH-associated protein1 (Keap1)-mediated ubiquitination and proteasomal degradation system. Upon activation, this Keap1-dependent Nrf2 degradation mechanism is quickly inactivated, resulting in accumulation and activation of the antioxidant response element (ARE)-dependent cytoprotective genes. Since its discovery, Nrf2 has been viewed as a 'good' transcription factor that protects us from many diseases. In this study, we demonstrate the dark side of Nrf2: stable overexpression of Nrf2 resulted in enhanced resistance of cancer cells to chemotherapeutic agents including cisplatin, doxorubicin and etoposide. Inversely, downregulation of the Nrf2-dependent response by overexpression of Keap1 or transient transfection of Nrf2-small interfering RNA (siRNA) rendered cancer cells more susceptible to these drugs. Upregulation of Nrf2 by the small chemical tert-butylhydroquinone (tBHQ) also enhanced the resistance of cancer cells, indicating the feasibility of using small chemical inhibitors of Nrf2 as adjuvants to chemotherapy to increase the efficacy of chemotherapeutic agents. Furthermore, we provide evidence that the strategy of using Nrf2 inhibitors to increase efficacy of chemotherapeutic agents is not limited to certain cancer types or anticancer drugs and thus can be applied during the course of chemotherapy to treat many cancer types.

    PMID: 18413364 [PubMed - indexed for MEDLINE]

    ?

    Lung Cancer. 2008 Apr;60(1):47-56. Epub 2007 Nov 19. Links

    Suppression of Nrf2-driven heme oxygenase-1 enhances the chemosensitivity of lung cancer A549 cells toward cisplatin.

    Kim HR, Kim S, Kim EJ, Park JH, Yang SH, Jeong ET, Park C, Youn MJ, So HS, Park R.

    Department of Internal Medicine, Wonkwang University, School of Medicine, 344-2 Shinyong-dong Iksan, Jeonbuk 570-749, Republic of Korea.

    Heme oxygenase-1 (HO-1) is highly expressed in various tumor tissues and plays an important role in tumor cell growth through anti-oxidative and anti-apoptotic effects. Herein, we demonstrate that A549 cells express high levels of HO-1, Nrf2, and NF-kappaB compared to other lung cancer cell lines, including H23, H157, and H460. Ectopic expression of HO-1 small interfering RNA (siRNA) increased both apoptosis and degradation of procaspase-3. Transfection studies with siRNA specific for Nrf2 and NF-kappaB revealed that HO-1 expression in A549 cells is mediated by transcriptional activation of Nrf2, but not NF-kappaB. A549 cells are less susceptible to cisplatin cytotoxicity than other lung cancer cell lines, concomitant with increases in HO-1 expression and MAPK phosphorylation in a time-dependent fashion. Furthermore, inhibition of HO-1 by siRNA and a specific HO-1 inhibitor ZnPP augments cisplatin cytotoxicity toward A549 cells. Pharmacologic suppression of HO-1 activity resulted in a marked increase in the ROS generation in cisplatin-treated cells. In addition, pharmacologic inhibitors of MAPK suppressed the induction of HO-1 and Nrf2 expression by cisplatin. These findings suggest that HO-1 may modulate the chemosensitivity of lung cancer A549 cells to cisplatin through the MAPK-Nrf2 pathway.

    PMID: 18006113 [PubMed - indexed for MEDLINE]
    First treatment in 2007. Pioneering ever since.

    Barbara

  2. #2

    Default key component of copd identified

    does anyone have an opinion on whether this discovery will compliment stemcell treatment for copd sufferers.

  3. #3
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    Default

    Dr. Payne's reply:


    There are no studies of any kind I am aware of that would suggest that increasing the NRF2 protein will in some way enhance stem cell activity or longevity or such. However, any repair or restoration effected by a stem cell treatment will likely eventually be lost to disease progression. This erosion of gains, however, might be slowed, delayed or obviated by the compounds contained in my communication.

    Anthony G. Payne, Ph.D.
    First treatment in 2007. Pioneering ever since.

    Barbara

  4. #4

    Default

    thank you for your prompt response, one can but hope for more in the future.

  5. #5

    Default

    Has anyone been pursuing this route? That is, has anyone been taking "ECGC" or spearmint oil/tea in regular amounts? And has anyone seen results? I know some people on here are religious about green tea--is this because of these findings, or just its overall health-promoting properties?

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    The "brew" I use is one bag white tea, 1 bag green tea, 1 bag Panax Ginseng and 1 bag Chamomile tea to 1 quart boiling water. Drink 4-12 cups per day hot or cold.
    I was given this recipe by one of my stem cell doctors for post treatment use. I honestly couldn't tell you why this particular combination was given, but I do try to drink as much of it as possible, however, I find that anything over 8 cups is all but impossible for me.

    Maybe others will answer your question more precisely.
    First treatment in 2007. Pioneering ever since.

    Barbara

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    Thumbs down Dr. Payne's reply

    Dr. Payne's reply is alarming, to say the least, when he says any improverment from stemcell treatments will eventually be lost due to thwe progression of the disease. What are your opinions on this? So we get our stem cells then nothing just the same? Am scared to death.

  8. #8
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    Default Better news than you thought

    Dr. Payne replies:

    Unless a progressive disease is utterly halted, there is going to be some progression eventually. The nature, degree and kind will vary greatly with the disease. In some instances gains from stem cell therapy will last for years if not a decade or longer. It all depends on the aggressiveness of the disease and how well progression is controlled/slowed -- whether via disease-specific stem cells or use of drugs, hormones, nutraceuticals, etc. -- or both. Of course, if all defective cells underlying a particular disease are replaced with healthy versions then the disease process is likely to be utterly halted.

    Of course, gains made in non-progressive diseases or medical conditions like cerebral palsy typically do not dissipate at all (At least this is what I noted in tracking hundreds of patients treated from 2003-7).
    First treatment in 2007. Pioneering ever since.

    Barbara

  9. #9
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    Smile Thank you Barbara

    Thank you for clearing up the issue. I really hope that more doctors get into this forum, I'ver been prodding Dr. Bill to do so but he must be very busy. Hope to have good news for you soon from him.

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