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Article ; Online: [Development of Novel Methodology and Its Application for Clarifying the Transport Function of the Blood-brain Barrier].

Terasaki, Tetsuya

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan

2021 Volume 141, Issue 4, Page(s) 447–462

Abstract: The blood-brain barrier (BBB) consists of brain capillary endothelial cells linked by tight junctions and serves to regulate the transfer of endogenous compounds and xenobiotics between the circulating blood and brain interstitial fluid. We have ... ...

Abstract	The blood-brain barrier (BBB) consists of brain capillary endothelial cells linked by tight junctions and serves to regulate the transfer of endogenous compounds and xenobiotics between the circulating blood and brain interstitial fluid. We have developed a methodology to characterize brain-to-blood efflux transport in vivo, using the Brain Efflux Index and an in vitro culture model of the BBB, i.e., a conditionally immortalized cell line of the neurovascular unit. Employing these methods, we showed that the BBB plays an important role in protecting the brain by transporting neurotransmitters, neuromodulators, metabolites, uremic toxins, and xenobiotics together with atrial natriuretic peptide from the brain interstitial fluid to the circulating blood. We also developed a highly selective, sensitive LC-MS/MS method for simultaneous protein quantification. We found significant species differences in the expression amounts of various BBB transporter proteins among mice, rats, marmosets, cynomolgus monkeys, and humans. Among transporter proteins at the BBB, multidrug resistance protein 1 (Mdr1/Abcb1) is known to generate a concentration gradient of unbound substrate drugs between the blood and brain. Based on measurements of the intrinsic efflux transport rate of Mdr1 and the protein expression amounts of Mdr1 in mouse brain capillaries and Mdr1-expressing cell lines, we predicted the unbound drug concentration gradients of 7 drugs in the mouse brain in vivo. This was the first successful prediction of in vivo drug transport activity from in vitro experimental data and transporter protein concentration in tissues. This methodology and findings should greatly advance central nervous system barrier research.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Animals ; Biological Transport/physiology ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Cell Line ; Chromatography, Liquid/methods ; Humans ; Membrane Transport Proteins/metabolism ; Mice ; Neurotransmitter Agents/metabolism ; Proteomics/methods ; Proteomics/trends ; Rats ; Tandem Mass Spectrometry/methods ; Xenobiotics/metabolism
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Membrane Transport Proteins ; Neurotransmitter Agents ; Xenobiotics
Language	Japanese
Publishing date	2021-02-25
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	200514-1
ISSN	1347-5231 ; 0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
ISSN (online)	1347-5231
ISSN	0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
DOI	10.1248/yakushi.20-00232
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Article: [Molecular Mechanism Underlying the Function and Disintegration of the Central Nerve System Barrier Unraveled by Proteo-typing of Membrane Proteins].

Terasaki, Tetsuya

Brain and nerve = Shinkei kenkyu no shinpo

2020 Volume 73, Issue 1, Page(s) 59–78

Abstract: Although 82% of the cerebrospinal fluid (CSF) is localized in the subarachnoid space, the function of the blood-arachnoid barrier (BAB) has not been elucidated. We found an abundance of drug efflux transporter proteins in the BAB. Moreover, several ... ...

Abstract	Although 82% of the cerebrospinal fluid (CSF) is localized in the subarachnoid space, the function of the blood-arachnoid barrier (BAB) has not been elucidated. We found an abundance of drug efflux transporter proteins in the BAB. Moreover, several transporter proteins, including organic anion transporters and organic cation transporters have been found in the BAB. Significant in vivo transport activity of the BAB has been observed, suggesting that the BAB plays a pivotal role in the CNS barrier. Using quantitative targeted absolute proteomic analysis, we determined the similarities and differences in transport function and tight junction formation among the BBB, BAB, blood-CSF barrier (BCSFB), and blood-spinal cord barrier (BSCB). Furthermore, we proposed several hypotheses regarding the molecular mechanism underlying CNS barrier disintegration in the presence of oxidative stress, TNF-α release, and multiple sclerosis.
MeSH term(s)	Blood-Brain Barrier ; Central Nervous System ; Humans ; Membrane Proteins ; Proteomics ; Spinal Cord
Chemical Substances	Membrane Proteins
Language	Japanese
Publishing date	2020-12-23
Publishing country	Japan
Document type	Journal Article
ZDB-ID	390389-8
ISSN	1344-8129 ; 1881-6096 ; 0006-8969
ISSN (online)	1344-8129
ISSN	1881-6096 ; 0006-8969
DOI	10.11477/mf.1416201712
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Article ; Online: Quantitative Targeted Absolute Proteomics (QTAP)-based Pharmacoproteomics: The Importance of International Collaboration.

Terasaki, Tetsuya

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan

2017 Volume 137, Issue 6, Page(s) 685–689

Abstract: Proteins such as membrane transporters, enzymes, receptors and channels play key roles in drug absorption, distribution, metabolism, and elimination, and also influence efficacy and the likelihood of adverse reactions. Therefore, if we can quantify the ... ...

Abstract	Proteins such as membrane transporters, enzymes, receptors and channels play key roles in drug absorption, distribution, metabolism, and elimination, and also influence efficacy and the likelihood of adverse reactions. Therefore, if we can quantify the activities of these molecules, it may be possible to predict the behavior of candidate drugs in humans in disease states; such methodology would be extremely helpful for efficient drug development. We have developed an in silico method to select appropriate peptides within amino acid sequences in order to quantify targeted proteins by LC-MS/MS in selected reaction monitoring (SRM) mode. We have applied this method for the quantification of functional proteins in order to validate various in vitro and in vivo models. We found fairly good correlation between protein amounts and the enzymatic activities of microsomal cytochrome P450 (CYP) isoforms and uridine 5'-diphospho-glucuronosyltransferase (UGT) in human liver, as well as between protein amounts and the transport activities of multiple transporters in human lung cells. These results suggest that protein quantification can be useful in predicting activity. We have applied this approach to evaluate the usefulness and limitations of an immortalized human brain capillary endothelial cell line (D3 cells) and a P-glycoprotein humanized (hMDR1) mouse model by comparing the amounts of functional proteins in the models with those in isolated capillaries from human brain. In order to obtain sufficient human tissue specimens for further studies leading to clinical applications, we believe that international collaboration will be crucial.
MeSH term(s)	Amino Acid Sequence ; Animals ; Animals, Genetically Modified ; Blood-Brain Barrier ; Computer Simulation ; Databases, Genetic ; Drug Discovery ; Drug-Related Side Effects and Adverse Reactions ; Humans ; In Vitro Techniques ; International Cooperation ; Proteins/analysis ; Proteins/chemistry ; Proteomics/methods ; Proteomics/trends
Chemical Substances	Proteins
Language	Japanese
Publishing date	2017
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	200514-1
ISSN	1347-5231 ; 0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
ISSN (online)	1347-5231
ISSN	0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
DOI	10.1248/yakushi.16-00250-3
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Article ; Online: The Effects of N-Glycosylation on the Expression and Transport Activity of OATP1A2 and OATP2B1.

Kataoka, Hiroki / Akiyoshi, Takeshi / Uchida, Yasuo / Imaoka, Ayuko / Terasaki, Tetsuya / Ohtani, Hisakazu

Journal of pharmaceutical sciences

2024 Volume 113, Issue 5, Page(s) 1376–1384

Abstract: Organic anion transporting polypeptide (OATP)1A2 and OATP2B1 have potential N-glycosylation sites, but their influence remains unclear. This study aimed to identify the N-glycosylation sites of OATP1A2/2B1 and investigate their impact on the expression ... ...

Abstract	Organic anion transporting polypeptide (OATP)1A2 and OATP2B1 have potential N-glycosylation sites, but their influence remains unclear. This study aimed to identify the N-glycosylation sites of OATP1A2/2B1 and investigate their impact on the expression and function of OATP1A2/2B1. Human embryonic kidney cells expressing OATP1A2 or OATP2B1 (HEK293-OATP1A2/2B1) were exposed to tunicamycin, an N-glycosylation inhibitor, and a plasma membrane fraction (PMF) Western blot assay and an estrone 3-sulfate (E3S) uptake study were conducted. HEK293-OATP1A2/OATP2B1 cell lines with mutation(s) at potential N-glycosylation sites were established, and the Western blotting and uptake study were repeated. Tunicamycin reduced the PMF levels and E3S uptake of OATP1A2/OATP2B1. The Asn124Gln, Asn135Gln, and Asn492Gln mutations in OATP1A2 and Asn176Gln and Asn538Gln mutations in OATP2B1 reduced the molecular weights of the OATP molecules and their PMF levels. The PMF levels of OATP1A2 Asn124/135Gln, OATP1A2 Asn124/135/492Gln, and OATP2B1 Asn176/538Gln were further reduced. The maximum transport velocities of OATP1A2 Asn124Gln, OATP1A2 Asn135Gln, and OATP2B1 Asn176/538Gln were markedly reduced to 10 %, 4 %, and 10 % of the wild-type level, respectively. In conclusion, the N-glycans at Asn124 and Asn135 of OATP1A2 and those at Asn176 and Asn538 of OATP2B1 are essential for the plasma membrane expression of these molecules and also affect their transport function.
MeSH term(s)	Humans ; Biological Transport ; Estrone/metabolism ; Glycosylation ; HEK293 Cells ; Organic Anion Transporters/genetics ; Organic Anion Transporters/metabolism ; Tunicamycin/metabolism
Chemical Substances	Estrone (2DI9HA706A) ; Organic Anion Transporters ; Tunicamycin (11089-65-9) ; SLCO1A2 protein, human ; SLCO2B1 protein, human
Language	English
Publishing date	2024-03-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1016/j.xphs.2024.02.012
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Article ; Online: Physiologically based pharmacokinetics modeling and transporter proteomics to predict systemic and local liver and muscle disposition of statins.

Prieto Garcia, Luna / Vildhede, Anna / Nordell, Pär / Ahlström, Christine / Montaser, Ahmed B / Terasaki, Tetsuya / Lennernäs, Hans / Sjögren, Erik

CPT: pharmacometrics & systems pharmacology

2024

Abstract: Statins are used to reduce liver cholesterol levels but also carry a dose-related risk of skeletal muscle toxicity. Concentrations of statins in plasma are often used to assess efficacy and safety, but because statins are substrates of membrane ... ...

Abstract	Statins are used to reduce liver cholesterol levels but also carry a dose-related risk of skeletal muscle toxicity. Concentrations of statins in plasma are often used to assess efficacy and safety, but because statins are substrates of membrane transporters that are present in diverse tissues, local differences in intracellular tissue concentrations cannot be ruled out. Thus, plasma concentration may not be an adequate indicator of efficacy and toxicity. To bridge this gap, we used physiologically based pharmacokinetic (PBPK) modeling to predict intracellular concentrations of statins. Quantitative data on transporter clearance were scaled from in vitro to in vivo conditions by integrating targeted proteomics and transporter kinetics data. The developed PBPK models, informed by proteomics, suggested that organic anion-transporting polypeptide 2B1 (OATP2B1) and multidrug resistance-associated protein 1 (MRP1) play a pivotal role in the distribution of statins in muscle. Using these PBPK models, we were able to predict the impact of alterations in transporter function due to genotype or drug-drug interactions on statin systemic concentrations and exposure in liver and muscle. These results underscore the potential of proteomics-guided PBPK modeling to scale transporter clearance from in vitro data to real-world implications. It is important to evaluate the role of drug transporters when predicting tissue exposure associated with on- and off-target effects.
Language	English
Publishing date	2024-04-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.13139
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Article: [Ingenuity for the Uniportal Video-assisted Thoracic Surgery as a Minimally Invasive Procedure].

Tanaka, Nobuhiro / Terasaki, Kento / Yuki, Hirotaka / Takayama, Tetsuya / Saito, Daisuke / Yoshida, Shuhei / Matsumoto, Isao

Kyobu geka. The Japanese journal of thoracic surgery

2023 Volume 76, Issue 1, Page(s) 59–64

Abstract: Uniportal video-assisted thoracic surgery (VATS) is a minimally invasive, wound-reducing approach performed mainly in Europe and Asia. This approach is rapidly gaining popularity in Japan. We performed a technique with layer awareness, grasping and ... ...

Abstract	Uniportal video-assisted thoracic surgery (VATS) is a minimally invasive, wound-reducing approach performed mainly in Europe and Asia. This approach is rapidly gaining popularity in Japan. We performed a technique with layer awareness, grasping and dissection of tissue membrane even in uniport VATS as for open thoracotomy or multiport VATS. Interference is a problem with uniport VATS because surgical instruments are inserted and removed through a small incision of 4 cm or less;there-fore, instrument selection is critical. The use of curved forceps ensures more working space and reduced interference. The incision should be placed between the 4th or 5th intercostal space and should be 3.5 cm in size at our institution. For vascular manipulation, ligation and transection can be used when it is difficult to divide vessels with a stapler. During mediastinal lymph node dissection, a precise view can be achieved with the use of a custom-made spatula. Uniport VATS was performed in 51 cases from January 2019 to June 2022. Although recurrence was observed in two cases, no serious perioperative complications were observed, and the procedures were performed safely.
MeSH term(s)	Humans ; Thoracic Surgery, Video-Assisted ; Lymph Node Excision ; Thoracotomy ; Japan
Language	Japanese
Publishing date	2023-01-31
Publishing country	Japan
Document type	English Abstract ; Journal Article
ZDB-ID	603899-2
ISSN	0021-5252
ISSN	0021-5252
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Article ; Online: Carbon, nitrogen, and oxygen stable isotope ratios of striped dolphins and short-finned pilot whales stranded in Hokkaido, northern Japan, compared with those of other cetaceans stranded and hunted in Japan.

Endo, Tetsuya / Kimura, Osamu / Terasaki, Masaru / Nakagun, Shotaro / Kato, Yoshihisa / Fujii, Yukiko / Haraguchi, Koichi / Baker, C Scott

Isotopes in environmental and health studies

2023 Volume 59, Issue 3, Page(s) 230–247

Abstract: Strandings of striped dolphins (SD) and short-finned pilot whales (PW) in Hokkaido, northern Japan, are rare but have recently increased, probably due to global warming. We ... ...

Abstract	Strandings of striped dolphins (SD) and short-finned pilot whales (PW) in Hokkaido, northern Japan, are rare but have recently increased, probably due to global warming. We quantified
MeSH term(s)	Animals ; Stenella ; Whales, Pilot ; Oxygen Isotopes ; Carbon ; Nitrogen ; Oxygen ; Japan ; Fin Whale
Chemical Substances	Oxygen Isotopes ; Carbon (7440-44-0) ; Nitrogen (N762921K75) ; Oxygen (S88TT14065)
Language	English
Publishing date	2023-08-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2100190-X
ISSN	1477-2639 ; 0021-1915 ; 1025-6016
ISSN (online)	1477-2639
ISSN	0021-1915 ; 1025-6016
DOI	10.1080/10256016.2023.2234590
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Article ; Online: Mass spectrometry in ocular drug research.

Del Amo, Eva M / Vellonen, Kati-Sisko / Urtti, Arto / Terasaki, Tetsuya / Hammid, Anam / Honkakoski, Paavo / Auriola, Seppo

Mass spectrometry reviews

2023

Abstract: Mass spectrometry (MS) has been proven as an excellent tool in ocular drug research allowing analyzes from small samples and low concentrations. This review begins with a short introduction to eye physiology and ocular pharmacokinetics and the relevance ... ...

Abstract	Mass spectrometry (MS) has been proven as an excellent tool in ocular drug research allowing analyzes from small samples and low concentrations. This review begins with a short introduction to eye physiology and ocular pharmacokinetics and the relevance of advancing ophthalmic treatments. The second part of the review consists of an introduction to ocular proteomics, with special emphasis on targeted absolute quantitation of membrane transporters and metabolizing enzymes. The third part of the review deals with liquid chromatography-MS (LC-MS) and MS imaging (MSI) methods used in the analysis of drugs and metabolites in ocular samples. The sensitivity and speed of LC-MS make simultaneous quantitation of various drugs and metabolites possible in minute tissue samples, even though ocular sample preparation requires careful handling. The MSI methodology is on the verge of becoming as important as LC-MS in ocular pharmacokinetic studies, since the spatial resolution has reached the level, where cell layers can be separated, and quantitation with isotope-labeled standards has come more reliable. MS will remain in the foreseeable future as the main analytical method that will progress our understanding of ocular pharmacokinetics.
Language	English
Publishing date	2023-08-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1491946-1
ISSN	1098-2787 ; 0277-7037
ISSN (online)	1098-2787
ISSN	0277-7037
DOI	10.1002/mas.21861
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Article ; Online: Establishment and validation of highly accurate formalin-fixed paraffin-embedded quantitative proteomics by heat-compatible pressure cycling technology using phase-transfer surfactant and SWATH-MS.

Uchida, Yasuo / Sasaki, Hayate / Terasaki, Tetsuya

Scientific reports

2020 Volume 10, Issue 1, Page(s) 11271

Abstract: The purpose of this study was to establish a quantitative proteomic method able to accurately quantify pathological changes in the protein expression levels of not only non-membrane proteins, but also membrane proteins, using formalin-fixed paraffin- ... ...

Abstract	The purpose of this study was to establish a quantitative proteomic method able to accurately quantify pathological changes in the protein expression levels of not only non-membrane proteins, but also membrane proteins, using formalin-fixed paraffin-embedded (FFPE) samples. Protein extraction from FFPE sections of mouse liver was increased 3.33-fold by pressure cycling technology (PCT) and reached the same level as protein extraction from frozen sections. After PCT-assisted processing of FFPE liver samples followed by SWATH-MS-based comprehensive quantification, the peak areas of 88.4% of peptides agreed with those from matched fresh samples within a 1.5-fold range. For membrane proteins, this percentage was remarkably increased from 49.1 to 93.8% by PCT. Compared to the conventional method using urea buffer, the present method using phase-transfer surfactant (PTS) buffer at 95 °C showed better agreement of peptide peak areas between FFPE and fresh samples. When our method using PCT and PTS buffer at 95 °C was applied to a bile duct ligation (BDL) disease model, the BDL/control expression ratios for 80.0% of peptides agreed within a 1.2-fold range between FFPE and fresh samples. This heat-compatible FFPE-PCT-SWATH proteomics technology using PTS is suitable for quantitative studies of pathological molecular mechanisms and biomarker discovery utilizing widely available FFPE samples.
MeSH term(s)	Animals ; Bile Ducts/surgery ; Biomarkers/chemistry ; Buffers ; Formaldehyde ; Hot Temperature ; Liver/metabolism ; Mass Spectrometry/methods ; Mice ; Paraffin Embedding ; Peptides/chemistry ; Proteins/chemistry ; Proteomics/methods ; Reproducibility of Results ; Surface-Active Agents
Chemical Substances	Biomarkers ; Buffers ; Peptides ; Proteins ; Surface-Active Agents ; Formaldehyde (1HG84L3525)
Language	English
Publishing date	2020-07-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-68245-2
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Article ; Online: A case of proliferative glomerulonephritis with monoclonal IgG3κ deposits accompanied by glomerular capillary microaneurysms.

Mii, Akiko / Terasaki, Mika / Kunugi, Shinobu / Seki, Miyako / Kashiwagi, Tetsuya / Sakai, Yukinao / Shimizu, Akira

CEN case reports

2022 Volume 11, Issue 3, Page(s) 333–338

Abstract: Glomerular capillary aneurysms are distinctly rare and specific glomerular lesions characterized by aneurysmal dilatation of the glomerular capillaries. This formation is associated with glomerular capillary injuries with focal mesangiolysis. Here, we ... ...

Abstract	Glomerular capillary aneurysms are distinctly rare and specific glomerular lesions characterized by aneurysmal dilatation of the glomerular capillaries. This formation is associated with glomerular capillary injuries with focal mesangiolysis. Here, we report a case of proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID) presenting with multiple glomerular capillary microaneurysms. A 53-year-old woman presented with persistent proteinuria and microhematuria. She had no underlying diseases, such as hematopoietic or lymphoproliferative disorders. A renal biopsy showed diffuse membranoproliferative lesions with foam cell infiltration and multiple microaneurysms of the glomerular capillary on light microscopy. Immunofluorescence analysis showed granular deposits of monoclonal immunoglobulin G3 kappa (IgG3κ), C1q, C3, and C4 in the glomeruli. Electron microscopy revealed different sizes of non-organized electron-dense deposits in the mesangial, subendothelial, and subepithelial areas. In addition, glomerular endothelial cells showed swelling and loss of fenestra or diffuse formation of fenestrated diaphragms, accompanied by irregular thinning of the glomerular basement membrane. Furthermore, immunostaining for CD31 (a marker for endothelial cell) and low-vacuum scanning electron microscopy study identified loss of endothelial cells in microaneurysm, suggesting severe glomerular endothelial cell injury. After a renal biopsy, only the medication for dyslipidemia was continued because there were no physical symptoms, such as edema, and urinary abnormalities continued with stable renal function. Further studies are needed to elucidate the pathogenesis of glomerular capillary injury in PGNMID and clarify the clinical and pathological characteristics of PGNMID with glomerular capillary microaneurysms.
MeSH term(s)	Antibodies, Monoclonal ; Endothelial Cells/chemistry ; Endothelial Cells/pathology ; Female ; Glomerular Basement Membrane/pathology ; Glomerulonephritis/diagnosis ; Glomerulonephritis/pathology ; Humans ; Immunoglobulin G/analysis ; Immunoglobulin kappa-Chains ; Microaneurysm ; Middle Aged
Chemical Substances	Antibodies, Monoclonal ; Immunoglobulin G ; Immunoglobulin kappa-Chains
Language	English
Publishing date	2022-01-13
Publishing country	Japan
Document type	Case Reports ; Journal Article
ZDB-ID	2660492-9
ISSN	2192-4449 ; 2192-4449
ISSN (online)	2192-4449
ISSN	2192-4449
DOI	10.1007/s13730-021-00676-w
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