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EGCG Amyloidosis

Manuel Hora, Martin Carballo-Pacheco, Benedikt Weber, Vanessa K Morris, Antje Wittkopf, Johannes Buchner, Birgit Strodel, Bernd Reif
Antibody light chain amyloidosis is a rare disease caused by fibril formation of secreted immunoglobulin light chains (LCs). The huge variety of antibody sequences puts a serious challenge to drug discovery. The green tea polyphenol epigallocatechin-3-gallate (EGCG) is known to interfere with fibril formation in general. Here we present solution- and solid-state NMR studies as well as MD simulations to characterise the interaction of EGCG with LC variable domains. We identified two distinct EGCG binding sites, both of which include a proline as an important recognition element...
January 27, 2017: Scientific Reports
Kathrin Andrich, Ute Hegenbart, Christoph Kimmich, Niraja Kedia, H Robert Bergen, Stefan Schönland, Erich Wanker, Jan Bieschke
Intervention into amyloid deposition with anti-amyloid agents like the polyphenol epigallocatechin-3-gallate (EGCG) is emerging as an experimental secondary treatment strategy in systemic light chain amyloidosis (AL). In both AL and multiple myeloma (MM), soluble immunoglobulin light chains (LC) are produced by clonal plasma cells, but only in AL do they form amyloid deposits in vivo We investigated the amyloid formation of patient-derived LC and their susceptibility to EGCG in vitro to probe commonalities and systematic differences in their assembly mechanisms...
February 10, 2017: Journal of Biological Chemistry
Sohsuke Meshitsuka, Sumito Shingaki, Masatoshi Hotta, Miku Goto, Makoto Kobayashi, Yuuichi Ukawa, Yuko M Sagesaka, Yasuyo Wada, Masanori Nojima, Kenshi Suzuki
Previous studies have suggested that an increase in mitochondrial reactive oxygen species may cause organ damage in patients with light-chain (AL) amyloidosis; however, this damage can be decreased by antioxidant-agent treatment. Epigallocatechin gallate (EGCG), the major natural catechin in green tea, has potent antioxidant activity. Because EGCG has recently been reported to have a favorable toxicity profile for treating amyloidosis, we sought to examine the clinical efficacy and toxicity of EGCG in patients with AL amyloidosis...
March 2017: International Journal of Hematology
Gabriella Ortore, Elisabetta Orlandini, Alessandra Braca, Lidia Ciccone, Armando Rossello, Adriano Martinelli, Susanna Nencetti
Misfolding and aggregation of the transthyretin (TTR) protein leads to certain forms of amyloidosis. Some nutraceuticals, such as flavonoids and natural polyphenols, have recently been investigated as modulators of the self-assembly process of TTR, but they generally suffer from limited bioavailability. To discover innovative and more bioavailable natural compounds able to inhibit TTR amyloid formation, a docking study was performed using the crystallographic structure of TTR. This computational strategy was projected as an ad hoc inspection of the possible relationship between binding site location and modulation of the assembly process; interactions with the as-yet-unexplored epigallocatechin gallate (EGCG) sites and with the thyroxine (T4) pocket were simultaneously analyzed...
August 19, 2016: ChemMedChem
Hiroyuki Nakajima, Kazuchika Nishitsuji, Hiroyuki Kawashima, Kaori Kuwabara, Shiho Mikawa, Kenji Uchimura, Kenichi Akaji, Yoshiki Kashiwada, Norihiro Kobayashi, Hiroyuki Saito, Naomi Sakashita
INTRODUCTION: Apolipoprotein A-I (apoA-I) amyloidosis is either a non-hereditary form with deposits of wild-type apoA-I proteins in atherosclerotic plaques or a hereditary form with progressive accumulation of mutant apoA-I proteins in different tissues. Several small polyphenolic molecules reportedly inhibited formation of fibrillar assemblies of some amyloidogenic proteins and their cytotoxicity, but small molecules that inhibit apoA-I fibril formation have never been reported. METHODS: Our methods included a thioflavin-T-binding assay, atomic force microscopy and dot blot and cell-based assays...
2016: Amyloid: the International Journal of Experimental and Clinical Investigation
Fabian aus dem Siepen, Ralf Bauer, Matthias Aurich, Sebastian J Buss, Henning Steen, Klaus Altland, Hugo A Katus, Arnt V Kristen
BACKGROUND: Causative treatment of patients with wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is lacking. Recent reports indicate the potential use of epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, to inhibit amyloid fibril formation. We sought to investigate changes of cardiac function and morphology in patients with wtATTR-CM after consumption of green tea extract (GTE). METHODS: Twenty-five male patients (71 [64; 80] years) with wtATTR-CM were submitted to clinical examination, echocardiography, cardiac magnetic resonance imaging (cMRI) (n=14), and laboratory testing before and after daily consumption of GTE capsules containing 600 mg epigallocatechin-3-gallate for at least 12 months...
2015: Drug Design, Development and Therapy
Angel E Pelaez-Aguilar, Lina Rivillas-Acevedo, Leidys French-Pacheco, Gilberto Valdes-Garcia, Roberto Maya-Martinez, Nina Pastor, Carlos Amero
Light chain amyloidosis (AL) is a deadly disease characterized by the deposition of monoclonal immunoglobulin light chains as insoluble amyloid fibrils in different organs and tissues. Germ line λ VI has been closely related to this condition; moreover, the R24G mutation is present in 25% of the proteins of this germ line in AL patients. In this work, five small molecules were tested as inhibitors of the formation of amyloid fibrils from the 6aJL2-R24G protein. We have found by thioflavin T fluorescence and transmission electron microscopy that EGCG inhibits 6aJL2-R24G fibrillogenesis...
August 18, 2015: Biochemistry
Ling-Hsien Tu, Lydia M Young, Amy G Wong, Alison E Ashcroft, Sheena E Radford, Daniel P Raleigh
The process of amyloid formation by the normally soluble hormone islet amyloid polypeptide (IAPP) contributes to β-cell death in type 2 diabetes and in islet transplants. There are no clinically approved inhibitors of islet amyloidosis, and the mode of action of existing inhibitors is not well-understood. Resveratrol, a natural polyphenol, has been reported to inhibit amyloid formation by IAPP and by the Alzheimer's disease Aβ peptide. The mechanism of action of this compound is not known, nor is its mode of interaction with IAPP...
January 27, 2015: Biochemistry
Maria Rosário Almeida, Maria João Saraiva
Increasing evidence indicates that accumulation of misfolded proteins in the form of oligomers, protofibrils or amyloid fibrils, and their consequences in triggering intracellular signaling cascades with toxic consequences represent unifying events in many of slowly progressive neurodegenerative disorders. Studies with small compounds or molecules, known to recognize and disrupt amyloidogenic structures, have proven efficient in promoting clearance of protein aggregates in experimental models of systemic and localized forms of amyloidoses...
August 31, 2012: FEBS Letters
Arnt V Kristen, Stephanie Lehrke, Sebastian Buss, Derliz Mereles, Henning Steen, Philipp Ehlermann, Stefan Hardt, Evangelos Giannitsis, Rupert Schreiner, Uwe Haberkorn, Philipp A Schnabel, Reinhold P Linke, Christoph Röcken, Erich E Wanker, Thomas J Dengler, Klaus Altland, Hugo A Katus
BACKGROUND: Treatment options in patients with amyloidotic transthyretin (ATTR) cardiomyopathy are limited. Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea (GT), inhibits fibril formation from several amyloidogenic proteins in vitro. Thus, it might also halt progression of TTR amyloidosis. This is a single-center observational report on the effects of GT consumption in patients with ATTR cardiomopathy. METHODS: 19 patients with ATTR cardiomyopathy were evaluated by standard blood tests, echocardiography, and cardiac MRI (n = 9) before and after consumption of GT and/or green tea extracts (GTE) for 12 months...
October 2012: Clinical Research in Cardiology: Official Journal of the German Cardiac Society
Nelson Ferreira, Maria João Saraiva, Maria Rosário Almeida
BACKGROUND: Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disease caused by the extracellular deposition of mutant transthyretin (TTR), with special involvement of the peripheral nervous system (PNS). Currently, hepatic transplantation is considered the most efficient therapy to halt the progression of clinical symptoms in FAP since more than 95% of TTR is produced by the liver. However, less invasive and more reliable therapeutic approaches have been proposed for FAP therapy, namely based on drugs acting as inhibitors of amyloid formation or as amyloid disruptors...
2012: PloS One
Nelson Ferreira, Maria João Saraiva, Maria Rosário Almeida
Several natural polyphenols with potent inhibitory effects on amyloid fibril formation have been reported. Herein, we studied modulation of transthyretin (TTR) fibrillogenesis by selected polyphenols. We demonstrate that both curcumin and nordihydroguaiaretic acid (NDGA) bind to TTR and stabilize the TTR tetramer. However, while NDGA slightly reduced TTR aggregation, curcumin strongly suppressed TTR amyloid fibril formation by generating small "off-pathway" oligomers and EGCG maintained most of the protein in a non-aggregated soluble form...
August 4, 2011: FEBS Letters
Masanori Miyata, Takashi Sato, Miyuki Kugimiya, Misato Sho, Teruya Nakamura, Shinji Ikemizu, Mami Chirifu, Mineyuki Mizuguchi, Yuko Nabeshima, Yoshiaki Suwa, Hiroshi Morioka, Takao Arimori, Mary Ann Suico, Tsuyoshi Shuto, Yasuhiro Sako, Mamiko Momohara, Tomoaki Koga, Saori Morino-Koga, Yuriko Yamagata, Hirofumi Kai
Amyloid fibril formation is associated with protein misfolding disorders, including neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Familial amyloid polyneuropathy (FAP) is a hereditary disease caused by a point mutation of the human plasma protein, transthyretin (TTR), which binds and transports thyroxine (T(4)). TTR variants contribute to the pathogenesis of amyloidosis by forming amyloid fibrils in the extracellular environment. A recent report showed that epigallocatechin 3-gallate (EGCG), the major polyphenol component of green tea, binds to TTR and suppresses TTR amyloid fibril formation...
July 27, 2010: Biochemistry
Derliz Mereles, Sebastian J Buss, Stefan E Hardt, Werner Hunstein, Hugo A Katus
BACKGROUND: Amyloid light chain (AL) amyloidosis is a rare disease with poor prognosis and limited therapeutic alternatives. Recently, one clinical case with cardiac involvement, as well as a compelling evidence of green tea polyphenol, epigallocatechin-3-gallate (EGCG), inducing the formation of benign aggregation products that do not polymerize into fibrils were published. This is a report of the cardiac effects of green tea consumption in these patients. METHODS: Patients with known cardiac involvement in AL amyloidosis were examined by routine cardiovascular examinations that took place every 3-6 months...
August 2010: Clinical Research in Cardiology: Official Journal of the German Cardiac Society
Nelson Ferreira, Isabel Cardoso, Maria Rosário Domingues, Rui Vitorino, Margarida Bastos, Guangyue Bai, Maria João Saraiva, Maria Rosário Almeida
More than 100 transthyretin (TTR) variants are associated with hereditary amyloidosis. Approaches for TTR amyloidosis that interfere with any step of the cascade of events leading to fibril formation have therapeutic potential. In this study we tested (-)-epigallocatechin-3-gallate (EGCG), the most abundant catechin of green tea, as an inhibitor of TTR amyloid formation. We demonstrate that EGCG binds to TTR "in vitro" and "ex vivo" and that EGCG inhibits TTR aggregation "in vitro" and in a cell culture system...
November 19, 2009: FEBS Letters
Brian Giunta, Yuyan Zhou, Huayan Hou, Elona Rrapo, Francisco Fernandez, Jun Tan
Human immunodeficiency virus (HIV)-associated dementia (HAD) is a subcortical neuropsychiatric syndrome that has increased in prevalence in the era of highly active antiretroviral therapy (HAART). Several studies demonstrated increased amyloidosis in brains of HIV patients and suggested that there may be a significant number of long-term HIV survivors with co-morbid Alzheimer's disease (AD) in the future. We show HIV-1 Tat protein inhibits microglial uptake of Abeta1-42 peptide, a process that is enhanced by interferon-gamma (IFN-gamma) and rescued by the STAT1 inhibitor (-)-epigallocatechin-3-gallate (EGCG)...
January 1, 2008: International Journal of Clinical and Experimental Pathology
Demian F Obregon, Kavon Rezai-Zadeh, Yun Bai, Nan Sun, Huayan Hou, Jared Ehrhart, Jin Zeng, Takashi Mori, Gary W Arendash, Doug Shytle, Terrence Town, Jun Tan
Recently, we have shown that green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) exerts a beneficial role on reducing brain Abeta levels, resulting in mitigation of cerebral amyloidosis in a mouse model of Alzheimer disease. EGCG seems to accomplish this by modulating amyloid precursor protein (APP) processing, resulting in enhanced cleavage of the alpha-COOH-terminal fragment (alpha-CTF) of APP and corresponding elevation of the NH(2)-terminal APP product, soluble APP-alpha (sAPP-alpha). These beneficial effects were associated with increased alpha-secretase cleavage activity, but no significant alteration in beta-or gamma-secretase activities...
June 16, 2006: Journal of Biological Chemistry
Kavon Rezai-Zadeh, Doug Shytle, Nan Sun, Takashi Mori, Huayan Hou, Deborah Jeanniton, Jared Ehrhart, Kirk Townsend, Jin Zeng, David Morgan, John Hardy, Terrence Town, Jun Tan
Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of beta-amyloid (Abeta) peptides as senile plaques in the brain. Recent studies suggest that green tea flavonoids may be used for the prevention and treatment of a variety of neurodegenerative diseases. Here, we report that (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, reduces Abeta generation in both murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP) and in primary neurons derived from Swedish mutant APP-overexpressing mice (Tg APPsw line 2576)...
September 21, 2005: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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