119 results on '"Masayoshi Tasaki"'
Search Results
102. Inhibitory effects of anti-IL-1β antibody in murine AA amyloidosis mode
- Author
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Masayoshi Tasaki, Yukio Ando, Yuko Tanabe, Yu Su, Makoto Shono, K. Obayashi, Hirofumi Jono, N. Kurata, H. Gram, Mitsuharu Ueda, N. Demura, and S. Murata
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Male ,Mice, Inbred C3H ,biology ,Base Sequence ,business.industry ,Amyloidosis ,Interleukin-1beta ,Enzyme-Linked Immunosorbent Assay ,medicine.disease ,Inhibitory postsynaptic potential ,Proinflammatory cytokine ,Mice ,AA amyloidosis ,Internal Medicine ,Cancer research ,medicine ,biology.protein ,Animals ,Serum amyloid A ,Antibody ,business ,DNA Primers - Abstract
It is not fully understood what kind of biologics targeting inflammatory cytokines is the most effective therapeutic agent for amyloid A (AA) amyloidosis. Moreover, biologics targeting in...
- Published
- 2011
103. Therapeutic approaches targeting midkine suppress tumor growth and lung metastasis in osteosarcoma
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Takanao Sueyoshi, Toshitake Yakushiji, Masayoshi Tasaki, Hirofumi Jono, Konen Obayashi, Tomoko Ota, Yukio Ando, Hiroshi Mizuta, Eri Atsuyama, Mitsuharu Ueda, Kazutoshi Ota, and Satoru Shinriki
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musculoskeletal diseases ,Adult ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Small interfering RNA ,Lung Neoplasms ,Adolescent ,Apoptosis ,Bone Neoplasms ,Cell Growth Processes ,medicine.disease_cause ,Young Adult ,In vivo ,anti-midkine antibody ,medicine ,Tumor Cells, Cultured ,Humans ,Molecular Targeted Therapy ,RNA, Small Interfering ,Child ,neoplasms ,Aged ,Midkine ,Gene knockdown ,Osteosarcoma ,biology ,Cell growth ,Chemistry ,lung metastasis ,Antibodies, Monoclonal ,Sarcoma ,Cell Cycle Checkpoints ,Middle Aged ,medicine.disease ,cell proliferation ,Cell Transformation, Neoplastic ,Oncology ,Gene Knockdown Techniques ,biology.protein ,Cancer research ,Cytokines ,Female ,Carcinogenesis - Abstract
Midkine (MK) plays important roles in tumorigenesis, however, the biological function of MK and whether MK can be a therapeutic target in osteosarcoma are unclear. Here, we found that osteosarcoma tissues showed high MK expression. MK knockdown by small interfering RNA significantly induced apoptosis in osteosarcoma cells, whereas recombinant MK increased cell proliferation. Inhibition of MK signaling by anti-MK monoclonal antibody (anti-MK mAb) suppressed growth of osteosarcoma cells both in vitro and in vivo. Moreover, inhibition of MK function significantly suppressed lung metastasis in xenograft transplantation model. Targeting MK by anti-MK mAb may have value in the treatment of osteosarcoma.
- Published
- 2011
104. Cyclodextrin, a novel therapeutic tool for suppressing amyloidogenic transthyretin misfolding in transthyretin-related amyloidosis
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Masayoshi Tasaki, Yohei Misumi, Toshinori Oshima, Keiichi Motoyama, Makoto Shono, Yoshimasa Mori, Yukio Ando, Mitsuharu Ueda, Hirofumi Jono, Takayuki Anno, Konen Obayashi, Mineyuki Mizuguchi, and Hidetoshi Arima
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endocrine system ,Conformational change ,Protein Folding ,Amyloid ,Oligosaccharides ,Amyloidogenic Proteins ,Biochemistry ,Turn (biochemistry) ,medicine ,Animals ,Humans ,Prealbumin ,Molecular Biology ,chemistry.chemical_classification ,Cyclodextrins ,biology ,Amyloidosis ,Tryptophan ,nutritional and metabolic diseases ,Cell Biology ,medicine.disease ,Amino acid ,Rats ,Transthyretin ,chemistry ,biology.protein ,Protein folding ,Rats, Transgenic - Abstract
TTR (transthyretin), a β-sheet-rich protein, is the precursor protein of familial amyloidotic polyneuropathy and senile systemic amyloidosis. Although it has been widely accepted that protein misfolding of the monomeric form of TTR is a rate-limiting step for amyloid formation, no effective therapy targeting this misfolding step is available. In the present study, we focused on CyDs (cyclodextrins), cyclic oligosaccharides composed of glucose units, and reported the inhibitory effect of CyDs on TTR amyloid formation. Of various branched β-CyDs, GUG-β-CyD [6-O-α-(4-O-α-D-glucuronyl)-D-glucosyl-β-CyD] showed potent inhibition of TTR amyloid formation. Far-UV CD spectra analysis showed that GUG-β-CyD reduced the conformational change of TTR in the process of amyloid formation. In addition, tryptophan fluorescence and 1H-NMR spectroscopy analyses indicated that GUG-β-CyD stabilized the TTR conformation via interaction with the hydrophobic amino acids of TTR, especially tryptophan. Moreover, GUG-β-CyD exerted its inhibitory effect by reducing TTR deposition in transgenic rats possessing a human variant TTR gene in vivo. Collectively, these results indicate that GUG-β-CyD may inhibit TTR misfolding by stabilizing its conformation, which, in turn, suppresses TTR amyloid formation.
- Published
- 2011
105. Loss of functional albumin triggers acceleration of transthyretin amyloid fibril formation in familial amyloidotic polyneuropathy
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Tomoe Kugimiya, Mitsuharu Ueda, Yu Su, Masayoshi Tasaki, Yoshinobu Hoshii, Masaki Otagiri, Yohei Misumi, Daisuke Kadowaki, Toru Maruyama, Yukio Ando, Shiori Saito, Makoto Shono, Hirofumi Jono, and Konen Obayashi
- Subjects
endocrine system ,medicine.medical_specialty ,Amyloid ,Enzyme-Linked Immunosorbent Assay ,medicine.disease_cause ,Antioxidants ,Pathology and Forensic Medicine ,Pathogenesis ,Rats, Sprague-Dawley ,Internal medicine ,medicine ,Animals ,Humans ,Prealbumin ,Protein Structure, Quaternary ,Molecular Biology ,Amyloid Neuropathies, Familial ,biology ,Chemistry ,Point mutation ,Amyloidosis ,Albumin ,nutritional and metabolic diseases ,Cell Biology ,medicine.disease ,Rats ,Transthyretin ,Oxidative Stress ,Endocrinology ,Biochemistry ,biology.protein ,Rats, Transgenic ,Polyneuropathy ,Oxidative stress - Abstract
Transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP) is characterized by systemic accumulation of amyloid fibrils caused by a point mutation in the TTR gene. Despite the urgent need for alternative therapeutic strategies, the pathogenesis of FAP still remains elusive. In our study reported here, we focused on albumin, the most abundant protein in plasma, and described the role of albumin in the TTR amyloid-formation process. Patients with FAP evidenced significantly decreased serum albumin levels as the disease progressed. Biacore analysis showed that albumin had a binding affinity for TTR and exhibited higher affinity for TTR amyloid than native TTR. Albumin functioning as an antioxidant effectively suppressed TTR amyloid formation. In patients with FAP, albumin was significantly oxidized as the disease progressed. Moreover, loss of functional albumin accelerated TTR deposition in analbuminemic rats possessing a human variant TTR gene. Taken together, these results indicate that albumin may have an inhibitory role in the TTR amyloid-formation process.
- Published
- 2011
106. Myopathic phenotype of familial amyloid polyneuropathy with a rare transthyretin variant: ATTR Ala45Asp
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Yukio Ando, Konen Obayashi, Akiko Tamura, Mitsuharu Ueda, Yohei Misumi, T. Doki, and Masayoshi Tasaki
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Pathology ,medicine.medical_specialty ,biology ,business.industry ,nutritional and metabolic diseases ,Muscle weakness ,Phenotype ,Amyloid Neuropathy ,Transthyretin ,Skeletal pathology ,Internal Medicine ,Amyloid polyneuropathy ,Macroglossia ,biology.protein ,Medicine ,medicine.symptom ,business ,Myopathy - Abstract
Proximal dominant muscle weakness and macroglossia, which appear in myopathy, are quite rare in transthyretin (TTR)-related familial amyloid polyneuropathy (FAP). We describe a patient with a novel...
- Published
- 2014
107. Transmission of circulating cell-free AA amyloid oligomers in exosomes vectors via a prion-like mechanism
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Masayoshi Tasaki, Yu Su, Yuko Tanabe, Hirofumi Jono, Konen Obayashi, Yohei Misumi, Yukio Ando, Sho Murata, Satoru Shinriki, Sho Ochiai, Xuguo Sun, Makoto Shono, and Mitsuharu Ueda
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Male ,Mice, Inbred C3H ,Serum Amyloid A Protein ,Amyloid ,Chemistry ,Prions ,Amyloidosis ,Biophysics ,Cell Biology ,medicine.disease ,Exosomes ,Biochemistry ,Exosome ,Microvesicles ,Mice ,AA amyloidosis ,In vivo ,Rheumatoid arthritis ,Immunology ,medicine ,Animals ,Serum amyloid A ,Molecular Biology ,Glycoproteins - Abstract
Recent studies clearly demonstrated that several types of pathogenic amyloid proteins acted as agents that could transmit amyloidosis by means of a prion-like mechanism. Systemic AA amyloidosis is one of the most severe complications of chronic inflammatory disorders, particularly rheumatoid arthritis. It is well known that, similar to an infectious prion protein, amyloid-enhancing factor (AEF) acts as a transmissible agent in AA amyloidosis. However, how AEF transmits AA amyloidosis in vivo remained to be fully elucidated. In the present study, we focused on finding cell-free forms of AEF and its carriers in circulation by using the murine transfer model of AA amyloidosis. We first determined that circulating cell-free AEF existed in blood and plasma in mice with systemic AA amyloidosis. Second, we established that plasma exosomes containing AA amyloid oligomers derived from serum amyloid A had AEF activity and could transmit systemic AA amyloidosis via a prion-like mechanism. These novel findings should provide insights into the transmission mechanism of systemic amyloidoses.
- Published
- 2010
108. Deposition of Lambda Chain Constant Region within AL-Amyloid Lesion
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Hiroaki Mitsuya, Masayoshi Tasaki, Taro Yamashita, Nao Nishimura, Naoko Wada, Hiroyuki Hata, Yukio Ando, Shinya Endo, Shiho Fujiwara, Yutaka Okuno, Eri Fujii, Konen Obayashi, and Kennichi Iyama
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Pathology ,medicine.medical_specialty ,Amyloid ,biology ,business.industry ,Amyloidosis ,Immunology ,Cell Biology ,Hematology ,Plasma cell ,medicine.disease ,Immunoglobulin light chain ,Biochemistry ,Molecular biology ,medicine.anatomical_structure ,AL amyloidosis ,biology.protein ,Medicine ,Immunohistochemistry ,Antibody ,business ,Immunostaining - Abstract
[Introduction] Diagnosis of AL amyloidosis is dependent on the proof of light chains in amyloid lesions. However, immunostaining does not always successfully prove the presence of light chains in lesions in AL amylidosis patients. Here we report that the constant region of immunoglobulin lambda light chain (IGLC2) is seen in amyloid lesions where no positive signals are found with regular immunostaining. [Materials and Methods] Amyloid samples were stained with anti-human lambda light chain antibody (DAKO PO-0130) and analyzed with mass-spectrometry combining laser micro-dissection. Bone marrow samples were obtained from patients with amyloidosis, who gave written informed consent, and were subjected to plasma cell purification using CD138-immunomagnetic beads. Expression of immunoglobulin light chain mRNA was examined with RT-PCR. Anti-human IGLL5 antibody, capable of detecting immunoglobulin light chain constant region 2 (IGLC2) in paraffin embedded samples, was utilized. [Results and Discussion] We performed immunostaining for immunoglobulin light chains with 18 samples and found that six and eight cases were positive for kappa and lambda light chains, respectively, whereas light chains were not detected in remaining four cases (immunostaining-negative amyloidosis; INA). However, interestingly, mass spectrometry analysis revealed the presence of IGLC2 in all of the INA cases. RT-PCR analysis revealed the presence of IGLC2 mRNA in plasma cells from such INA cases. Surprisingly, amyloid lesions in all of the INA cases were positively stained with anti-IGLL5 antibody, whereas no staining was found in other samples positively stained with DAKO PO-0130. These observations suggest that the deposition of IGLC2 may cause AL amyloidosis, which otherwise could not be diagnosed with regular immunostaining. Although high dose chemotherapy produced hematological remission, half of such cases died within one year, suggesting irreversible and life-threatening amyloid fibril depositions in critical organs in IGLC2-related cases. We further examined additional twelve cases with AL amyloidosis to determine the incidence of IGLC2-related amyloidosis by immunostaining. With regular immunostaining, kappa and lambda chain were found in three and five cases, respectively. Interestingly, the remaining four cases were negative with regular immunostaining but positive with anti-IGLL5 antibody. Taken these observations together, eight IGLC2-related amyloidosis cases and thirteen lambda type amyloidosis were identified. Thus, the incidence of IGLC2-related amyloidosis should be approximately 38% (8/21) among lambda type AL amyloidosis. We conclude that diagnosis of IGLC2-related AL amyloidosis was possible only with the use of anti-IGLL5 antibody, but not with regular immunostaining. Given the relatively high incidence and often poor prognosis of IGLC2-related amyloidosis, it is important that this clinical entity is recognized to potentially improve outcomes of treatments. Analysis of mechanisms regulating amyloid formation with IGLC2 peptides is currently underway. Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
109. Early skin denervation in hereditary and iatrogenic transthyretin amyloid neuropathy.
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Teruaki Masuda, Mitsuharu Ueda, Genki Suenaga, Yohei Misumi, Masayoshi Tasaki, Ayane Izaki, Yukako Yanagisawa, Yasuteru Inoue, Hiroaki Motokawa, Sayaka Matsumoto, Mayumi Mizukami, Aiko Arimura, Takahisa Deguchi, Yoshihiko Nishio, Taro Yamashita, Yukihiro Inomata, Konen Obayashi, and Yukio Ando
- Published
- 2017
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110. Antibody therapy for familial amyloidotic polyneuropathy
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Satoru Shinriki, Masaharu Torikai, Yohei Misumi, Makoto Shono, Masayoshi Tasaki, Kenji Soejima, Jianying Guo, Yu Su, Toshihiro Nakashima, Keishin Sugawara, Mitsuharu Ueda, Hirofumi Jono, Akihiko Hosoi, Yukio Ando, and Konen Obayashi
- Subjects
endocrine system ,Amyloid ,medicine.drug_class ,Immunoblotting ,Thyroid Gland ,Enzyme-Linked Immunosorbent Assay ,In Vitro Techniques ,Kidney ,Monoclonal antibody ,Epitope ,Internal Medicine ,medicine ,Humans ,Prealbumin ,Amyloid Neuropathies, Familial ,biology ,Chemistry ,Myocardium ,Antibodies, Monoclonal ,nutritional and metabolic diseases ,Kidney metabolism ,Immunohistochemistry ,Virology ,Molecular biology ,Amyloid Neuropathy ,Transthyretin ,Monoclonal ,biology.protein ,Antibody - Abstract
Although it is believed that altered conformations exposing cryptic regions are intermediary and critical steps in the mechanism of transthyretin (TTR) amyloid formation, no effective therapy targeting this step is available. In this study, to establish the antibody therapy for familial amyloidotic polyneuropathy (FAP), we generated a monoclonal anti-TTR antibody, which specifically reacts with surface epitopes of TTR (MAb ATTR) and evaluated its binding affinity and specificity for TTR amyloid fibrils. MAb ATTR showed specific binding affinity for TTR amyloid fibrils, but not for native form of TTR. Moreover, MAb ATTR indeed showed the high consistency with Congo red positive areas in tissue specimens from FAP ATTR V30M patients, indicating that MAb ATTR showed binding affinity and specificity for TTR amyloid fibrils in vitro and in vivo. MAb ATTR may have a potential to suppress TTR amyloid deposition and become a candidate for the antibody therapy for FAP.
- Published
- 2012
111. Amyloid neuropathy in a younger domino liver transplanted recipient
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Hirofumi Jono, Katsuhiro Asonuma, Taro Yamashita, Konen Obayashi, Makoto Shono, Yukio Ando, Masayoshi Tasaki, Yukihiro Inomata, Yuki Ohya, Mitsuharu Ueda, and Toshinori Ohshima
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Cellular and Molecular Neuroscience ,Amyloid Neuropathy ,Physiology ,business.industry ,Physiology (medical) ,medicine.medical_treatment ,Immunology ,medicine ,Neurology (clinical) ,Liver transplantation ,business ,Domino - Published
- 2011
112. Shikonin, dually functions as a proteasome inhibitor and a necroptosis inducer in multiple myeloma cells.
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NAOKO WADA, YAWARA KAWANO, SHIHO FUJIWARA, YOSHITAKA KIKUKAWA, YUTAKA OKUNO, MASAYOSHI TASAKI, MITSUHARU UEDA, YUKIO ANDO, KAZUYA YOSHINAGA, MASAKI RI, SHINSUKE IIDA, TAKAYUKI NAKASHIMA, YUKIMASA SHIOTSU, HIROAKI MITSUYA, and HIROYUKI HATA
- Published
- 2015
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113. A patient with medulloblastoma in its early developmental stage.
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NAOKI SHINOJIMA, HIDEO NAKAMURA, MASAYOSHI TASAKI, KOUKI KAMENO, SHIGEO ANAI, KEN-ICHI IYAMA, YUKIO ANDO, HIROSHI SETO, and JUN-ICHI KURATSU
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- 2014
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114. Changes in pathological and biochemical findings of systemic tissue sites in familial amyloid polyneuropathy more than 10 years after liver transplantation.
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Toshinori Oshima, Satomi Kawahara, Mitsuharu Ueda, Yushi Kawakami, Rina Tanaka, Takahiro Okazaki, Yohei Misumi, Konen Obayashi, Taro Yamashita, Yuki Ohya, Ihse, Elisabet, Satoru Shinriki, Masayoshi Tasaki, Hirofumi Jono, Katsuhiro Asonuma, Yukihiro Inomata, Westermark, Per, and Yukio Ando
- Subjects
LIVER transplantation ,TRANSTHYRETIN ,AMYLOIDOSIS ,NEUROPATHY ,JAPANESE people ,CLINICAL pathology ,PATIENTS ,DISEASES - Abstract
Objective: To elucidate the long-term effects of liver transplantation (LT) on familial amyloid polyneuropathy (FAP). Methods: We investigated clinicopathological and biochemical characteristics of systemic tissues in four autopsied cases of FAP patients surviving more than 10 years after LT and seven autopsied cases without LT. For analysing the truncated form of transthyretin (TTR) in amyloid, we also employed specimens from additional 18 FAP patients. Results: Several tissue sites such as the heart, tongue and spinal cord had moderate-to-severe amyloid deposits but other tissues showed no or mild amyloid deposition. Those findings seemed similar to those observed in senile systemic amyloidosis (SSA), a sporadic amyloidosis caused by wild-type (WT) TTR. Also, amyloid deposits in systemic tissue sites except for the spinal cord in patients after LT derived mostly from WT TTR secreted from the normal liver grafts. In addition, in non-transplantation patients, proportions of WT TTR seemed to be relatively high in those tissue sites in which patients after LT had severe amyloid deposition, which suggests that WT TTR tends to form amyloid in those tissue sites. Finally, although the truncation of TTR in amyloid deposits did not depend on undergoing LT, we elucidated the truncation of TTR occurred predominantly in patients from non-endemic areas of Japan, where FAP amyloidogenic TTR V30M patients are late onset and low penetrance, compared with patients from an endemic area of Japan. Conclusions: FAP may shift to systemic WT TTR amyloid formation after LT, which seems to be similar to the process in SSA. The truncation of TTR in amyloid deposits may depend on some genetic or environmental factors other than undergoing LT. [ABSTRACT FROM AUTHOR]
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- 2014
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115. Cyclodextrin, a novel therapeutic tool for suppressing amyloidogenic transthyretin misfolding in transthyretin-related amyloidosis.
- Author
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Hirofumi Jono, Takayuki Anno, Keiichi Motoyama, Yohei Misumi, Masayoshi Tasaki, Toshinori Oshima, Yoshimasa Mori, Mineyuki Mizuguchi, Mitsuharu Ueda, Makoto Shono, Konen Obayashi, Hidetoshi Arima, and Yukio Ando
- Subjects
AMYLOIDOSIS ,CYCLODEXTRINS ,TRANSTHYRETIN ,NEUROPATHY ,OLIGOSACCHARIDES ,SPECTRUM analysis ,TRYPTOPHAN - Abstract
TTR (transthyretin), a β-sheet-rich protein, is the precursor protein of familial amyloidotic polyneuropathy and senile systemic amyloidosis. Although it has been widely accepted that protein misfolding of the monomeric form of TTR is a rate-limiting step for amyloid formation, no effective therapy targeting this misfolding step is available. In the present study, we focused on CyDs (cyclodextrins), cyclic oligosaccharides composed of glucose units, and reported the inhibitory effect of CyDs on TTR amyloid formation. Of various branched β-CyDs, GUG-β-CyD [6-O-α-(4-O-α-D-glucuronyl)-D-glucosyl-β-CyD] showed potent inhibition of TTR amyloid formation. Far-UV CD spectra analysis showed that GUG-β-CyD reduced the conformational change of TTR in the process of amyloid formation. In addition, tryptophan fluorescence and 1H-NMR spectroscopy analyses indicated that GUG-β-CyD stabilized the TTR conformation via interaction with the hydrophobic amino acids of TTR, especially tryptophan. Moreover, GUG-β-CyD exerted its inhibitory effect by reducing TTR deposition in transgenic rats possessing a human variant TTR gene in vivo. Collectively, these results indicate that GUG-β-CyD may inhibit TTR misfolding by stabilizing its conformation, which, in turn, suppresses TTR amyloid formation. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
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116. Novel function of transthyretin in pancreatic alpha cells
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Mitsuharu Ueda, Hirofumi Jono, Yohei Misumi, Konen Obayashi, Makoto Shono, Yu Su, Takafumi Senokuchi, Yukio Ando, Eiichi Araki, Masayoshi Tasaki, Kazuya Yamagata, Satoru Shinriki, and Jianying Guo
- Subjects
Blood Glucose ,medicine.medical_specialty ,endocrine system ,Biophysics ,Alpha (ethology) ,Glucose homeostasis ,Biochemistry ,Glucagon ,Transthyretin ,Alpha cell ,Mice ,Structural Biology ,Internal medicine ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Prealbumin ,Molecular Biology ,Pancreas ,Mice, Knockout ,geography ,geography.geographical_feature_category ,biology ,Pancreatic alpha cell ,Insulin tolerance test ,nutritional and metabolic diseases ,Cell Biology ,Fasting ,Hep G2 Cells ,Islet ,Mice, Inbred C57BL ,Endocrinology ,medicine.anatomical_structure ,Glucagon-Secreting Cells ,biology.protein - Abstract
Although transthyretin (TTR) is expressed in pancreatic alpha (glucagon) cells in the islets of Langerhans, the function of TTR in pancreatic alpha cells remains unknown. In this study, by using TTR knockout (TTR KO) mice, we determined the novel role of TTR in glucose homeostasis. We demonstrated that TTR KO mice evidenced impaired recovery of blood glucose and glucagon levels. Lack of TTR induced significantly lower levels of glucagon in the islets of Langerhans. These results suggest that TTR expressed in pancreatic alpha cells may play important roles in glucose homeostasis via regulating the expression of glucagon.
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117. SIRT7 suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions in mice
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Tatsuya Yoshizawa, Yoshifumi Sato, Shihab U. Sobuz, Tomoya Mizumoto, Tomonori Tsuyama, Md. Fazlul Karim, Keishi Miyata, Masayoshi Tasaki, Masaya Yamazaki, Yuichi Kariba, Norie Araki, Eiichi Araki, Shingo Kajimura, Yuichi Oike, Thomas Braun, Eva Bober, Johan Auwerx, and Kazuya Yamagata
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Mice, Knockout ,Mammals ,obesity ,Multidisciplinary ,General Physics and Astronomy ,Thermogenesis ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology ,resistance ,Mice ,stress ,Adipose Tissue, Brown ,age ,fat ,ucp1 messenger-rna ,Animals ,Sirtuins ,transcriptional regulation ,RNA, Messenger ,mitochondrial uncoupling protein ,Energy Metabolism ,gene ,metabolism ,Uncoupling Protein 1 - Abstract
Brown adipose tissue plays a central role in the regulation of the energy balance by expending energy to produce heat. NAD(+)-dependent deacylase sirtuins have widely been recognized as positive regulators of brown adipose tissue thermogenesis. However, here we reveal that SIRT7, one of seven mammalian sirtuins, suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions. Whole-body and brown adipose tissue-specific Sirt7 knockout mice have higher body temperature and energy expenditure. SIRT7 deficiency increases the protein level of UCP1, a key regulator of brown adipose tissue thermogenesis. Mechanistically, we found that SIRT7 deacetylates insulin-like growth factor 2 mRNA-binding protein 2, an RNA-binding protein that inhibits the translation of Ucp1 mRNA, thereby enhancing its inhibitory action on Ucp1. Furthermore, SIRT7 attenuates the expression of batokine genes, such as fibroblast growth factor 21. In conclusion, we propose that SIRT7 serves as an energy-saving factor by suppressing brown adipose tissue functions. Sirtuins have been reported to positively regulate brown adipose tissue thermogenesis. Here the authors report that brown adipocytic SIRT7 suppresses whole-body energy expenditure and thermogenesis in mice, potentially by attenuating batokine gene expressions and Ucp1 mRNA translation.
118. Mass spectrometry characterization of light chain fragmentation sites in cardiac AL amyloidosis: insights into the timing of proteolysis.
- Author
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Lavatelli, Francesca, Mazzini, Giulia, Ricagno, Stefano, Iavarone, Federica, Rognoni, Paola, Milani, Paolo, Nuvolone, Mario, Swuec, Paolo, Caminito, Serena, Masayoshi Tasaki, Chaves-Sanjuan, Antonio, Urbani, Andrea, Merlini, Giampaolo, and Palladini, Giovanni
- Subjects
- *
CARDIAC amyloidosis , *MASS spectrometry , *PROTEOLYSIS , *C-terminal residues , *AMYLOID , *COLLISION induced dissociation - Abstract
Amyloid fibrils are polymeric structures originating from aggregation of misfolded proteins. In vivo, proteolysis may modulate amyloidogenesis and fibril stability. In light chain (AL) amyloidosis, fragmented light chains (LCs) are abundant components of amyloid deposits; however, site and timing of proteolysis are debated. Identification of the N and C termini of LC fragments is instrumental to understanding involved processes and enzymes. We investigated the N and C terminome of the LC proteoforms in fibrils extracted from the hearts of two AL cardiomyopathy patients, using a proteomic approach based on derivatization of N- and C-terminal residues, followed by mapping of fragmentation sites on the structures of native and fibrillar relevant LCs. We provide the first high-specificity map of proteolytic cleavages in natural AL amyloid. Proteolysis occurs both on the LC variable and constant domains, generating a complex fragmentation pattern. The structural analysis indicates extensive remodeling by multiple proteases, largely taking place on poorly folded regions of the fibril surfaces. This study adds novel important knowledge on amyloid LC processing: although our data do not exclude that proteolysis of native LC dimers may destabilize their structure and favor fibril formation, the data show that LC deposition largely precedes the proteolytic events documentable in mature AL fibrils. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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119. A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH.
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Mitsuharu Ueda, Masamitsu Okada, Mineyuki Mizuguchi, Kluve-Beckerman, Barbara, Kyosuke Kanenawa, Aito Isoguchi, Yohei Misumi, Masayoshi Tasaki, Akihiko Ueda, Akinori Kanai, Ryoko Sasaki, Teruaki Masuda, Yasuteru Inoue, Toshiya Nomura, Satoru Shinriki, Tsuyoshi Shuto, Hirofumi Kai, Taro Yamashita, Hirotaka Matsui, and Benson, Merrill D.
- Subjects
- *
AMYLOID beta-protein , *CARDIAC amyloidosis , *TRANSTHYRETIN , *NEUROGLIA , *AMYLOIDOSIS , *GENE expression , *IN vitro studies - Abstract
Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of in vitro studies, these fragments have been proposed to play important roles in amyloid formation. Here, we found that experimentally-formed aggregates of full-length TTR are cleaved into C-terminal fragments, which were also identified in patients' amyloid-laden tissues and in SH-SY5Y neuronal and U87MG glial cells. We observed that a 5-kDa C-terminal fragment of TTR, TTR81- 127, is highly amyloidogenic in vitro, even at neutral pH. This fragment formed amyloid deposits and induced apoptosis and inflammatory gene expression also in cultured cells. Using the highly amyloidogenic TTR81-127 fragment, we developed a cell-based high-throughput screening method to discover compounds that disrupt TTR amyloid fibrils. Screening a library of 1280 off-patent drugs, we identified two candidate repositioning drugs, pyrvinium pamoate and apomorphine hydrochloride. Both drugs disrupted patient-derived TTR amyloid fibrils ex vivo, and pyrvinium pamoate also stabilized the tetrameric structure ofTTRex vivo in patient plasma.Weconclude that our TTR81-127-based screening method is very useful for discovering therapeutic drugs that directly disrupt amyloid fibrils. We propose that repositioning pyrvinium pamoate and apomorphine hydrochloride as TTR amyloid-disrupting agents may enable evaluation of their clinical utility for managing ATTR amyloidosis. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
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