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  • Jefferson Adams
    Jefferson Adams

    Safe Way to Inhibit MLCK1 Enzyme Action Could Mean Better Treatment for Irritable Bowel Disease

      The potentially exciting part is that, under experimental inflammatory bowel disease conditions, divertin corrects barrier dysfunction, and prevents disease development and progression. 

    Caption: Image: CC--Oak Ridge National Laboratory

    Celiac.com 04/09/2019 - Epithelial barrier loss is a key factor in many intestinal and systemic diseases. Myosin light chain kinase (MLCK) is a key effector of barrier dysfunction, and a target for a potential treatment, but enzymatic inhibition has unacceptable toxicity. 

    A team of researchers recently demonstrated that a unique domain within the MLCK splice variant MLCK1 directs perijunctional actomyosin ring (PAMR) recruitment.

    The research team included W. Vallen Graham, Weiqi He, Amanda M. Marchiando, Juanmin Zha, Gurminder Singh, Hua-Shan Li, Amlan Biswas, Ma. Lora Drizella M. Ong, Zhi-Hui Jiang, Wangsun Choi, Harmon Zuccola, Yitang Wang, James Griffith, Jingshing Wu, Harry J. Rosenberg, Yingmin Wang, Scott B. Snapper, David Ostrov, Stephen C. Meredith, Lawrence W. Miller and Jerrold R. Turner.

    Using the domain structure and multiple screens, they revealed a domain-binding small molecule (divertin) that blocks MLCK1 recruitment without inhibiting enzymatic function. 

    Divertin blocks acute, tumor necrosis factor (TNF)-induced MLCK1 recruitment, in addition to downstream myosin light chain (MLC) phosphorylation, barrier loss, and diarrhea, both in vitro and in vivo. 

    The potentially exciting part is that, under experimental inflammatory bowel disease conditions, divertin corrects barrier dysfunction, and prevents disease development and progression. 

    Beyond applications of divertin in gastrointestinal disease, this general approach to enzymatic inhibition by preventing access to specific sub-cellular sites offers a new model for safe and precise targeting of specific properties of enzymes with numerous functions.

    The development of a safe way to inhibit MLCK1 enzyme action, and which could potentially correct gut barrier dysfunction, and prevent the development and progression of inflammatory bowel disease is exciting news.

    Read more in Nature Medicine

     

    The researchers are variously affiliated with the Department of Pathology, University of Chicago, Chicago, IL, USA; the Laboratory of Chemical Biology & Signal Transduction, The Rockefeller University, New York, NY, USA; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda Genomic Resource Center, Soochow University, and Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China; the Laboratory of Mucosal Barrier Pathobiology, Department of Pathology and the Division of Gastroenterology, Hepatology and Nutrition at Boston Children’s Hospital and Harvard Medical School in Boston, MA, USA; the Department of Pathology, Immunology and Laboratory Medicine, University of Florida, College of Medicine, Gainesville, FL, USA, the Department of Chemistry, University of Illinois at Chicago, Chicago, IL, USA, and Vertex Pharmaceuticals, Boston, MA, USA.

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  • About Me

    Jefferson Adams earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,000 articles on celiac disease. His coursework includes studies in biology, anatomy, medicine, science, and advanced research, and scientific methods. He previously served as Health News Examiner for Examiner.com, and devised health and medical content for Sharecare.com. Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of the book "Cereal Killers" by Scott Adams and Ron Hoggan, Ed.D.

  • Related Articles

    Jefferson Adams
    Celiac.com 02/24/2015 - I've posted recipes for chicken and beef broth lately, and now it's time for what may be the healthiest of all broths, fish broth.
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    Ideally, fish broth is made from the bones of sole or turbot. Unfortunately, it's hard to get whole sole fish in America. However, you can make a great broth using any non-oily fish, such as snapper, rock fish, or lingcod. Ask your fish merchant to save the carcasses for you.
    Avoid using oily fish such as salmon for making broth, mainly because oily fish will make the broth turn rancid during the long cooking process.
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    Ingredients:
    3 or 5 whole carcasses, including heads, of non-oily fish such as sole, turbot, rockfish or snapper about 3 quarts cold filtered water 2 or 3 sprigs fresh thyme 2 or 3 sprigs parsley 2 onions, coarsely chopped ¼ cup dry sake, white wine or vermouth ⅓ cup vinegar Sea salt to taste Directions:
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    Jefferson Adams
    Will a new treatment enable people with celiac disease to ditch a gluten-free diet?
    About one in a hundred people in the United States is affected by celiac disease. If you're one of them, you know how hard it can be to maintain a strict gluten-free diet.
    Everyone's got their horror stories about trying to simply eat a meal, only to have a tiny amount of gluten wreck havoc on their digestive system.
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    If the therapy proves successful, many celiac patients won't have to worry about minute amounts of cross-contamination when eating outside.
    Those are pretty strong claims. Many people with celiac disease might likely say that it sounds too good to be true. Still, the company is moving in a direction that few others have gone. No word on if or when we might expect to see a finished treatment come to market. For all the company's claims, there is much to work out, and a long, winding road to get FDA approval.
    Stay tuned to see if the evidence from trials and from potential consumer use supports those claims.
    Read more at TheAggie.org.
    Editor's note: We've received a correction on this story from PvP Biologics, makers of KumaMax, which states that their product is designed for accidental gluten ingestion, and not as a replacement for a gluten-free diet in people with celiac disease. Their enzyme could lessen the effects of accidental consumption of small amounts of gluten.

    Jefferson Adams
    Celiac.com 12/25/2017 - In the very near future, your personal microbiome may be the key to creating a customized treatment for celiac disease.
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    Writing in the Mayo Clinic Proceedings, ad team of researches expounded on this approach. The research team included Purna C. Kashyap, Nicholas Chia, PhD, Heidi Nelson, MD, Eran Segal, PhD, and Eran Elinav, MD, PhD. They are variously affiliated with the Enteric Neuroscience Program, Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN; the Department of Surgery, Mayo Clinic, Rochester, MN; the Department of Computer Science at the Weizmann Institute of Science in Rehovot, Israel and with the Department of Immunology, at the Weizmann Institute of Science in Rehovot, Israel.
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    In their review for the Mayo Clinic Proceedings, the team highlights the importance of the microbiome in all aspects of human disease, including pathogenesis, phenotype, prognosis, and treatment response. The microbiome also plays a crucial role as a diagnostic and therapeutic biomarker.
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    Basically, as we further unlock the human genome, we can begin to better understand the role played by the myriad microbes that make up the human microbiome. As we unlock the role of various parts of the microbiome, look for major advances and refinements to diagnosing, treating, and even conquering conditions like celiac disease, and many others. And, with advances coming at breakneck speed, look for this to happen sooner, rather than later.
    Source:
    PlumX Metrics - mayoclinicproceedings.org

    Jefferson Adams
    Celiac.com 03/20/2019 - Sensitivities to gluten are becoming more common. Patients with celiac disease have wheat-specific immune responses, but researchers have remained uncertain about the potential role of non-wheat proteins in triggering symptoms in celiac or gluten-sensitive patients.
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    Intestinal tissues from control mice show that ATI triggered an innate immune response by activating TLR4 signaling to MD2 and CD14, and impaired barrier function even in the absence of mucosal damage. 
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    Strategies to alter the gut microbiome, such as the ingestion of bacteria that can degrade and reduce  ATI, may be helpful for people with various wheat-sensitivities, including celiac disease.

    Read more at Gastroenterology
     
    The researchers are variously affiliated with the Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; the Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany; the Department of Medicine, Columbia University, New York, NY, USA; the Institute of Human Nutrition, Columbia University, New York, NY, USA; the Department of Microbiology. Universidad de Leon, Leon, Spain Division of Gastroenterology and Hepatology, Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota; the Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany; and the Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

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