H1N1 Treatments: Anti-Inflammatory Properties of Herbal Medicines

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It is now commonly accepted that many severe or fatal reactions to influenza are caused by intense inflammatory overreactions of the immune system.    A group from the Research School of Biology, Australian National University released an article on September 24, 2009 compiling evidence on this topic.

Cytokines are chemicals which are produced in immunological inflammatory reactions in the body.  Studies indicate that certain plant extracts can be protective against lethal reactions for mice which are infected with a virulent influenza strain. This occurs through inhibition of novel inflammatory cytokine High Mobility Group Box 1 protein (HMGB1) by these plant extracts.  Angelica sinensis (also known as Dang Gui) and Salvia Miltiorrhzia (also known as Dan Shen) were two of the herbal medicines studied which had this effect on HMGB1.

A drug known as gemfibrozil (a drug normally used to lower blood lipids) prevented a significant proportion of mice infected with H1N2 influenza from developing a fatal disease in a 2007 study.  Gemfibrozil has a known ability to reduce expression of inflammatory cytokines, and this is thought to be the mechanism through which it protects against severe or fatal reactions in the mice.  The action of this drug adds to the evidence that it is the body’s overproduction of cytokines which is involved in these severe cases of influenza.

Other studies have investigated Red Clover, Ginseng, Isatis, and Andrographis indicating that they modulate and reduce various aspects of cytokine response.  Forsythia, Honeysuckle, Balloon Flower root, Licorice, Camilla sinensis (green tea) and Ginger have also been researched, results of which indicate that they reduce both production of pro-inflammatory cytokines and pro- inflammatory mediators (such as reactive oxygen species and nitric oxide).  This is likely caused by suppressing a gene known as NF-kB which is often elevated in severe viral disease states, and which is related to disease conditions leading to multiple organ failure such as those in fatal influenza sepsis.

Combinations of these herbs are often used in Traditional Chinese Medicine to treat influenza from the earliest stages onward.  For this reason it is particularly interesting to determine the immunological mechanisms through which they work.

In summary, this information indicates that it is the host response of the human body which may be involved in many of the fatal reactions in viral influenza infections.  Treatments which can modulate this response in a patient who has contracted a viral influenza are therefore of great interest.  More research needs to be done on these herbs since due to their mechanisms, they may be promising therapies to integrate with conventional influenza treatments.

References:

Alleva, L, Cai C, Clark I. 2009.  Using Complementary and Alternative Medicines to Target the Host Response in Severe Influenza.  Evid Based Complement Alternat Med.  Sep 24. [Epub ahead of print]

Aldieri E, Atragene D, Bergandi L, Riganti C, Costamagna C, Bosia A, et al. Artemisinin inhibits inducible nitric oxide synthase and nuclear factor NF-kB activation. FEBS Lett 2003; 552:141–4.

Budd A, Alleva L, Alsharifi M, Koskinen A, Smythe V, Mullbacher A, et al. Increased survival after gemfibrozil treatment of severe mouse influenza. Antimicrob Agents Chemother 2007;51: 2965–8.

Chao WW, Kuo YH, Li WC, Lin BF. The production of nitric oxide and prostaglandin E2 in peritoneal macrophages is inhibited by Andrographis paniculata, Angelica sinensis and Morus alba ethyl acetate fractions. J Ethnopharmacol 2009;122:68–75.

Chen X, Wu T, Liu G. Chinese medicinal herbs for influenza: a systematic review. J Altern Complement Med 2006;12:171–80.

Chen X, Li W, Wang H. More tea for septic patients?—green tea may reduce endotoxin-induced release of high mobility group box 1 and other pro-inflammatory cytokines. Med Hypotheses 2006;66:

Chen XY, Wu TX, Liu GJ, Wang Q, Zheng J, Wei J, et al. Chinesemedicinal herbs for influenza. Cochrane Database Syst Rev

Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, et al. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 2002;360:1831–7.

Czura CJ, Wang H, Tracey KJ. Dual roles for HMGB1: DNA binding and cytokine. J Endotoxin Res 2001;7:315–21.

Esmon CT. Inflammation and the activated protein C anticoagulant pathway. Semin Thromb Hemost 2006;1:49–60.

Hampton T. Virulence of 1918 influenza virus linked to inflammatory innate immune response. JAMA 2007;297:580.

Kwon HM, Choi YJ, Choi JS, Kang SW, Bae JY, Kang IJ, et al. Blockade of cytokine-induced endothelial cell adhesion molecule expression by licorice isoliquiritigenin through NF-kB signal disruption. Exp Biol Med (Maywood) 2007;232:235–45.

Lim DS, Bae KG, Jung IS, Kim CH, Yun YS, Song JY. Anti-septicaemic effect of polysaccharide from Panax ginseng by macrophage activation. J Infect 2002;45:32–8.

Pan TL, Leu YL, Chang YK, Tai PJ, Lin KH, et al. Antiviral effects of Salvia miltiorrhiza (Danshen) against enterovirus

Quan FS, Compans RW, Cho YK, Kang SM. Ginseng and Salviae herbs play a role as immune activators and modulate immune responses during influenza virus infection. Vaccine 2007;25:272–82.

Surh YJ, Lee JY, Choi KJ, Ko SR. Effects of selected ginsenosides on phorbol ester-induced expression of cyclooxygenase-2 and activation of NF-kB and ERK1/2 in mouse skin. Ann NY Acad Sci 2002;973:396–401.

Utsunomiya T, Kobayashi M, Pollard RB, Suzuki F. Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus. Antimicrob Agents Chemother 1997;41:551–6. 53.

Wang J, Zhou H, Zheng J, Cheng J, Liu W, Ding G, et al. The antimalarial artemisinin synergizes with antibiotics to protect against lethal live Escherichia coli challenge by decreasing pro- inflammatory cytokine release. Antimicrob Agents Chemother 2006;50:2420–7. May 1215.

Wang H, Li W, Li J, Rendon Mitchell B, Ochani M, Ashok M, et al. The aqueous extract of a popular herbal nutrient supplement,
Angelica sinensis, protects mice against lethal endotoxemia and sepsis. J Nutr 2006;136:360–5.

Weir Chiang You, Wen Chuan Lin, Jia Tsz Huang and Chang Chi Hsieh.  2009. Indigowood root extract protects hematopoietic cells, reduces tissue damage and modulates inflammatory cytokines after total-body irradiation: Does Indirubin play a role in radioprotection? Phytomedicine.  July

Xie CH, Zhang MS, Zhou YF, Han G, Cao Z, Zhou FX, et al. Chinese medicine Angelica sinensis suppresses radiation-induced expression of TNF-alpha and TGF-beta1 in mice. Oncol Rep 2006;15:1429–36.

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Green Tea EGCG: a Natural Treatment for Uterine Fibroids

Green Tea

Uterine fibroids can be a very difficult condition to treat clinically.  The treatment is often surgical when symptoms are significant enough to cause problems.   Uterine fibroids are believed to affect at least 1/3 of North American Women.  They cause symptoms such as heavy bleeding, pressure effects on other organs, and fertility concerns:  all of which have large impacts on a woman’s health.   A study has recently come out from the Centre for Women’s Health Research at Meharry Medical College which concludes that EGCG, an extract from Green tea, may induce apoptosis (cell death) and reduce proliferation of uterine fibroid cells by affecting gene expression.  This is the second study from Meharry Medical College on this topic, the first having been released in May 2008.  The mechanism studied is in line with recent research indicating that uterine fibroids are correlated with genetic factors and gene expression,  evidence for which was examined in a review from the National Institute of Health Sciences, Comparative Pathobiology Group.  A study was also released in February 2008 which showed a positive effect of EGCG on fibroids in quail, an animal which is especially prone to these tumors.

Genetic effects of Green Tea on Fibroid Growth

In the study, the EGCG from green tea significantly decreased the expression of the genes PCNA, CDK4, and BCL2(genes which promote growth of fibroid cells) as well as increased the expression of the pro-apoptotic BAX(a gene which promotes cell degeneration in a fibroid cell) in a dose-dependent manner.   This indicates that EGCG works along multiple genetic pathways to inhibit fibroid tumor growth.

Fibroids and Hormones : Risk Factors

Factors which are currently thought to promote growth of fibroids are periods of excess estrogen, periods of unopposed estrogen(when there is insufficient progesterone to balance out estrogens), and xenoestrogens (environmental chemicals such as those found in some plastics or pesticides which mimic the effects of estrogen in the body). Risk factors for fibroids are many, and factors such as having an early age of onset of the menses or lack of ovulation give unopposed estrogen more time to stimulate fibroid growth.  Risk of fibroids is reduced by having children (also known as the effects of parity- risk is reduced most for women who have several children) which is now thought to be related to ischemic effects on the uterus after birth (reduced blood flow to the uterine tissues and involution of the uterus) which appear to reduce formation and growth of fibroids.  Fibroids are more common in women over 40, and this may be related to changes in hormonal mediators during perimenopause, or alternately from 20-30 consecutive years of exposure to estrogen.

Although it has been traditionally thought that estrogen is the only promoter of fibroid growth, research now points to progesterone as a stimulator of fibroid growth.  Fibroids contain both progesterone and estrogen receptors which are up and down regulated during the menstrual cycle.  A key to stimulation of fibroid growth may be in conversion enzymes.  Studies point to increased expression of an enzyme known as aromatase in women who have fibroids.  Aromatase is an enzyme which converts androgens to estrogen (androgens are male hormones, and the precursors to estrogen).  This information indicates that treatments which work at the level of this enzymatic activity (such as aromatase inhibitors – to be discussed on a future blog post) can bring more balance to the effects of of estrogen on tissues, especially if started at an early stage of the condition.

Fibroids:  The Liver and Diet

Another factor which can cause growth of fibroids relates to the clearance of hormones and conversion of estrogen to weaker forms by the liver.  If liver function is poor, more estradiol will circulate and increase growth of the fibroids.   Dietary factors which are also linked to risk of fibroids  include low fibre diets (fibre improves elimination of hormones).  Higher fat and lower fibre diets have also been linked to higher levels of estradiol according to a meta analysis of date from the Journal of the National Cancer institute, and obesity is also correlated with a higher risk for fibroids (androgens are converted to estrogens in adipose tissue).  Green tea  also has thermogenic (fat burning) effects according to multiple studies (effects beyond that of the caffeine it contains), so it may be helpful for women with fibroids from this standpoint as well.

A study from Japan indicated that green tea and other caffeinated beverages reduced serum estrogen by increasing sex hormone binding globulin, which is also of benefit in reducing the rate of estrogen stimulated fibroid growth.  Although other caffeinated beverages such as coffee also appeared to increase sex hormone binding globulin, only green tea was correlated to a day 11 lower serum estradiol.

Although more research is needed in this area before firm conclusions can be drawn on this topic, it seems that EGCG has multiple benefits for women who are at risk for fibroid development.  Though unlikely to shrink larger developed fibroids to a great extent, it may have a role to play in earlier stages and in prevention of these benign yet troublesome growths.

References

Alan A.Arslan, Leslie I.Gold, Khushbakhat Mittal, Ting-Chung Suen, Ilana Belitskaya-Levy, Moon-Shong Tang and Paolo Toniolo. 2005. Gene expression studies provide clues to the pathogenesis of uterine leiomyoma: new evidence and a systematic review. Human Reproduction 20(4) pp. 852–863.

Baird D, and Dunson, D.  2003.  Why is Parity Protective for Uterine Fibroids.  Epidemiology.  March 14(2): 247-250.

Dong Zhang, Mohamed Al-Hendy, Ayman Al-Hendy. Green Tea Extract (EGCG) Inhibits Proliferation of Human Leiomyoma Cells. Biology of Reproduction. 67. 63. (2008)

Dulloo, A G : Seydoux, J : Girardier, L : Chantre, P : Vandermander, J. 2000.  Green tea and thermogenesis:  interactions between catechin-polyphenols, caffeine and sympathetic activity.  Int-J-Obes-Relat-Metab-Disord. 2000 Feb; 24(2): 252-8.

Folkerd EJ, Newton CJ, Davidson K, Anderson MC, James VH. 1984. Aromatase activity in uterine leiomyomata. J Steroid Biochem 20:1195–1200.

Gordon P. Flake, Janet Andersen, and Darlene Dixon. 2003.  Etiology and Pathogenesis of Uterine Leiomyomas: A Review. Environ Health Perspect.  June; 111(8): 1037–1054.

Ibrahim H. Ozercan, Nurhan Sahin, Fatih Akdemir, Muhittin Onderci, Soley Seren, Kazim Sahin, Omer Kucuk. 2008. Chemoprevention of fibroid tumors by [−]-epigallocatechin-3-gallate in quail.  Nutrition Research – February 28(2): 92-97

Kawaguchi K, Fujii S, Konishi I, Nanbu Y, Nonogaki H, Mori T. 1989. Mitotic activity in uterine leiomyomas during the menstrual cycle. Am J Obstet Gynecol 160:637–641.

Nagata C, Kabuto M, Shimizu H. 1998.  Association of coffee, green tea, and caffeine intakes with serum concentrations of estradiol and sex hormone-binding globulin in premenopausal Japanese Women.  Nutr Cancer 30(1):21-4

Sumitani H, Shozu M, Segawa T, Murakami K, Yang HJ, Shimada K, et al. 2000. In situestrogen synthesized by aromatase P450 in uterine leiomyoma cells promotes cell growth probably via an autocrine/intracrine mechanism. Endocrinology 141:3852–3861.

Wu A, et al. 1999.  Meta-analysis: Dietary Fat Intake, Serum Estrogen Levels, and the Risk of Breast Cancer. J Natl Cancer Inst 1999; 91:492-494, 529-534.

Yamamoto T, Takamori K, Okada H. 1984. Estrogen biosynthesis in leiomyoma and myometrium of the uterus. Horm Metab Res 16:678–679.

Zhang D, Al-Hendy M, Richard-Davis G, Montgomery-Rice V, Rajaratnam V, Al-Hendy A.  2009.  Antiproliferative and proapoptotic effects of epigallocatechin gallate on human leiomyoma cells.  Fertil Steril. Oct 2009.  Epub ahead of print.