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Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase
Keller, Tracy L,Zocco, Davide,Sundrud, Mark S,Hendrick, Margaret,Edenius, Maja,Yum, Jinah,Kim, Yeon-Jin,Lee, Hak-Kyo,Cortese, Joseph F,Wirth, Dyann F,Dignam, John David,Rao, Anjana,Yeo, Chang-Yeol,Maz Nature Publishing Group, a division of Macmillan P 2012 Nature chemical biology Vol.8 No.3
Febrifugine, the bioactive constituent of one of the 50 fundamental herbs of traditional Chinese medicine, has been characterized for its therapeutic activity, though its molecular target has remained unknown. Febrifugine derivatives have been used to treat malaria, cancer, fibrosis and inflammatory disease. We recently demonstrated that halofuginone (HF), a widely studied derivative of febrifugine, inhibits the development of T<SUB>H</SUB>17-driven autoimmunity in a mouse model of multiple sclerosis by activating the amino acid response (AAR) pathway. Here we show that HF binds glutamyl-prolyl-tRNA synthetase (EPRS), inhibiting prolyl-tRNA synthetase activity; this inhibition is reversed by the addition of exogenous proline or EPRS. We further show that inhibition of EPRS underlies the broad bioactivities of this family of natural product derivatives. This work both explains the molecular mechanism of a promising family of therapeutics and highlights the AAR pathway as an important drug target for promoting inflammatory resolution.
Functional and Metabolic Disorders in Celiac Disease: New Implications for Nutritional Treatment
Sara Farnetti,Maria Assunta Zocco,Matteo Garcovich,Antonio Gasbarrini,Esmeralda Capristo 한국식품영양과학회 2014 Journal of medicinal food Vol.17 No.11
Celiac disease (CD) is a chronic disease causing the inflammation of the proximal small intestine, in genetically predisposed individuals. This is triggered by the consumption of the gluten protein and the side effects of the disease are mitigated by a lifelong gluten-free diet (GFD) treatment. The predominant consequence of CD is malnutrition due to malabsorption (with diarrhea, weight loss, nutritional deficiencies, and altered blood parameters), especially in patients who do not show strict adherence to GFD treatment. Recent evidence shows that, despite a lifelong GFD, some functional disorders persist, such as compromised gallbladder function and motility, exocrine pancreatic insufficiency, increased gut permeability, small-intestinal bowel overgrowth, nonalcoholic fatty liver disease (NAFLD), lactose intolerance, and milk allergy. These abnormalities may predispose to the occurrence of overweight and obesity even in CD patients. This review focuses on the principal functional and metabolic disorders in both treated and untreated CD, ranging from alterations of the gastrointestinal system to impaired glucose and lipid metabolism and insulin secretion with the aim of providing new implications beyond a GFD, for an ad hoc nutrition treatment in these patients.