Researchers discover molecular secrets of ancient Chinese herbal remedy

February 13, 2012

For roughly two thousand years, Chinese herbalists have treated Malaria using a root extract, commonly known as Chang Shan, from a type of hydrangea that grows in Tibet and Nepal. More recent studies suggest that halofuginone, a compound derived from this extract's bioactive ingredient, could be used to treat many autoimmune disorders as well. Now, researchers from the Harvard School of Dental Medicine have discovered the molecular secrets behind this herbal extract's power.

It turns out that halofuginone (HF) triggers a stress-response pathway that blocks the development of a harmful class of immune cells, called Th17 cells, which have been implicated in many autoimmune disorders.

"HF prevents the autoimmune response without dampening immunity altogether," said Malcolm Whitman, a professor of developmental biology at Harvard School of Dental Medicine and senior author on the new study. "This compound could inspire novel therapeutic approaches to a variety of autoimmune disorders."

"This study is an exciting example of how solving the molecular mechanism of traditional herbal medicine can lead both to new insights into physiological regulation and to novel approaches to the treatment of disease," said Tracy Keller, an instructor in Whitman's lab and the first author on the paper.

This study, which involved an interdisciplinary team of researchers at Massachusetts General Hospital and elsewhere, will be published online February 12 in Nature Chemical Biology.

Prior research had shown that HF reduced scarring in tissue, scleroderma (a tightening of the skin), multiple sclerosis, scar formation and even cancer progression. "We thought HF must work on a signaling pathway that had many downstream effects," said Keller.

In 2009, Keller and colleagues reported that HF protects against harmful Th17 immune cells without affecting other beneficial immune cells. Recognized only since 2006, Th17 cells are "bad actors," implicated in many autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis and psoriasis. The researchers found that minute doses of HF reduced multiple sclerosis in a mouse model. As such, it was one of a new arsenal of drugs that selectively inhibits autoimmune pathology without suppressing the immune system globally. Further analysis showed that HF was somehow turning on genes involved in a newly discovered pathway called the amino acid response pathway, or AAR.

Scientists have only recently appreciated the role of the nutrient sensing-AAR pathway in immune regulation and metabolic signaling. There is also evidence that it extends lifespan and delays age-related inflammatory diseases in animal studies on caloric restriction. A conservationist of sorts, AAR lets cells know when they need to preserve resources. For example, when a cell senses a limited supply of amino acids for building proteins, AAR will block signals that promote inflammation because inflamed tissues require lots of protein.

"Think about how during a power outage we conserve what little juice we have left on our devices, foregoing chats in favor of emergency calls," said Whitman. "Cells use similar logic."

For the current study, the researchers investigated how HF activates the AAR pathway, looking at the most basic process that cells use to translate a gene's DNA code into the amino acid chain that makes up a protein.

The researchers were able to home in on a single amino acid, called proline, and discovered that HF targeted and inhibited a particular enzyme (tRNA synthetase EPRS) responsible for incorporating proline into proteins that normally contain it. When this occurred, the AAR response kicked in and produced the therapeutic effects of HF-treatment.

Providing supplemental proline reversed the effects of HF on Th17 cell differentiation, while adding back other amino acids did not, establishing the specificity of HF for proline incorporation. Added proline also reversed other therapeutic effects of HF, inhibiting its effectiveness against the malaria parasite as well as certain cellular processes linked to tissue scarring. Again, supplementation with other amino acids had no such effect. Such mounting evidence clearly demonstrated that HF acts specifically to restrict proline.

The researchers think that HF treatment mimics cellular proline deprivation, which activates the AAR response and subsequently impacts immune regulation. Researchers do not yet fully understand the role that amino acid limitation plays in disease response or why restricting proline inhibits Th17 cell production.

Nevertheless, "AAR pathway is clearly an interesting drug target, and halofuginone, in addition to its potential therapeutic uses, is a powerful tool for studying the AAR pathway," said Whitman.

Harvard Medical School

---

---

	The Autoimmune Epidemic by Donna Jackson Nakazawa (Author), Dr. Douglas Kerr (Foreword) From the foreword by Dr. Douglas Kerr, Director, Johns Hopkins Transverse Myelitis Center "The Autoimmune Epidemic by Donna Jackson Nakazawa is an astounding book....It is the kind of book that will rivet you and scare you. It will make you angry. It will amaze you with the courage of some of the people described in the book...The Autoimmune Epidemic is every bit as compelling as Upton Sinclair's The Jungle...It is also every bit as necessary as An Inconvenient Truth.... You will leave this book with no reservations about the veracity of the conclusions: put simply, there is no doubt that autoimmune diseases are on the rise and increasing environmental exposures of toxins and chemicals is fueling this rise. The research is sound. The conclusions unassailable.... Reading The...
	The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life by Rita Baron-Faust (Author), Jill Buyon (Author) As featured in the New York Times and recommended by the National Women's Health Resource Center and the Society for Women's Health Research, The Autoimmune Connection discusses the links between autoimmune diseases and offers up-to-date information on diagnosis, treatments, and risks for women with one or more autoimmune disease, such as lupus, rheumatoid arthritis, or Crohn's disease.
	Living Well with Autoimmune Disease: What Your Doctor Doesn't Tell You...That You Need to Know by Mary J. Shomon (Author) A complete guide to understanding the mysterious and often difficult-to-pinpoint disorders of the immune system--and finding the keys to diagnosis, treatment, and recovery. An estimated fifty million people suffer from symptoms including fatigue, joint pains, depression, or heart palpitations — signs that the immune system has turned on itself, causing conditions such as thyroid disease, hepatitis, or multiple sclerosis. And while doctors may prescribe treatments to relieve these surface ailments, when asked about the life-long health implications of an autoimmune condition, they often just shrug their shoulders. Yet much like cancer, having one autoimmune disease puts you at high risk for developing another, and understanding the underlying immune process can reverse a patients...
	Autoimmune Disorders (Diseases and Disorders) by Melissa Abramovitz (Editor) "This series objectively and thoughtfully explores topics of medical importance. Books include sections on a description of the disease or disorder and how it affects the body, as well as diagnosis and treatment of the condition"--
	What Your Doctor May Not Tell You About(TM): Autoimmune Disorders: The Revolutionary Drug-free Treatments for Thyroid Disease, Lupus, MS, IBD, Chronic Fatigue, Rheumatoid Arthritis, and Other Diseases by Stephen B. Edelson (Author), Deborah Mitchell (Author) Autoimmune disorders are not well understood and therefore difficult to treat. The result is that there are millions of Americans who are suffering because they aren't being diagnosed properly, or getting the correct medical treatment they need. Here, Dr. Edelson discusses the most common types of autoimmune diseases, including lupus, Chron's disease, thyroid disease, rheumatoid arthritis, and chronic fatigue syndrome, outlining their symptoms, causes, and risk factors. He describes his own revolutionary program for treating the root of all autoimmune disorders-without drugs-providing readers with new hope for getting back on the road to better health.
	Women and Autoimmune Disease by HarperCollins e-books A cutting-edge examination of the mysterious world of autoimmune disease—and the new discoveries made daily that may save women's livesAutoimmune diseases—including chronic fatigue syndrome, vasculitis, juvenile diabetes, alopecia, Graves' disease, Sjogren's syndrome, lupus, rheumatoid arthritis, and multiple sclerosis—are among the most devastating conditions afflicting women today and the most resistant to diagnosis and treatment. In all of them, the body's immune system begins to attack healthy and normally functioning cells. And one of the biggest puzzles is why 80 percent of autoimmune disease sufferers are women. In this groundbreaking book, world-class immunologist Dr. Robert Lahita brings years of intensive research, patient care, and diagnostics to shed light on the...
	Thriving with Your Autoimmune Disorder: A Woman's Mind-Body Guide by Simone Ravicz Ph.D. M.B.A. (Author) An autoimmune disorder is a noninfectious syndrome or set of symptoms in which the body's immune system attacks the body's tissues. Autoimmune disorders are found to be much more prevalent in women than in men, and this comprehensive and caring guide is designed to provide a wide range of suggestions to help these women take an active role in improving their health.
	Inflammatory and Autoimmune Disorders of the Nervous System in Children (Clinics in Developmental Medicine) by Russell C. Dale (Editor), Angela Vincent (Editor) Inflammatory disorders of the nervous system, although individually uncommon, collectively make up 10-20% of acute paediatric neurology presentations and many are potentially treatable. Research into them is lagging behind adult research, but better diagnosis and often simple treatments could lead to substantial clinical benefit and reduction in long-term disability.This book provides a detailed and comprehensive summary of the childhood diseases that are, or are likely to be, caused by the immune system. The authors not only describe these disorders and their treatments comprehensively, helping pediatricians and pediatric neurologists to improve their understanding and recognition of the conditions, but also highlight recent and exciting developments that will be of considerable...
	The Bible Cure For Auto-immune Diseases: Ancient truths, natural remedies and the latest findings for your health. (New Bible Cure (Siloam)) by Donald Colbert (Author) You can have a normal, healthy immune system! Having an autoimmune disease, a condition in which the immune system becomes confused and turns the body's attack against itself, is not a life sentence. In this practical, informative book, Dr. Don Colbert offers a natural, scriptural plan for your complete recovery from autoimmune diseases, which afflict about 40 million Americans. Autoimmune diseases such as rheumatoid arthritis, lupus, chronic fatigue syndrome and multiple sclerosis do not have to rob you of the vital health God intended for you to enjoy. You will learn how to: Restore gastrointestinal health Reduce stress Break the link between autoimmune diseases and hormonal imbalances Combat toxic overload Strengthen your immune system You want to be healthy....
	Autoimmune Diseases (Perspectives on Diseases and Disorders) (English and English Edition) by Jacqueline Langwith (Author)