Biological & pharmaceutical bulletin最新文献_第10页

Refining Hepatocyte Models to Capture the Impact of CYP2D6*10 Utilizing a PITCh System. 利用 PITCh 系统完善肝细胞模型以捕捉 CYP2D6*10 的影响

IF 1.7 4区医学

Biological & pharmaceutical bulletin Pub Date : 2024-01-01 DOI: 10.1248/bpb.b24-00202

Ryosuke Negoro, Ayu Ouchi, Sayaka Deguchi, Kazuo Takayama, Takuya Fujita

{"title":"Refining Hepatocyte Models to Capture the Impact of CYP2D6*10 Utilizing a PITCh System.","authors":"Ryosuke Negoro, Ayu Ouchi, Sayaka Deguchi, Kazuo Takayama, Takuya Fujita","doi":"10.1248/bpb.b24-00202","DOIUrl":"https://doi.org/10.1248/bpb.b24-00202","url":null,"abstract":"CYP2D6 variants contain various single nucleotide polymorphisms as well as differing levels of metabolic activity. Among these, one of the less active variants CYP2D6*10 (100C > T) is the most prevalent mutation in East Asians, including Japanese. This mutation leads to an amino acid substitution from proline to serine, which reduces the stability of CYP2D6 and consequently decreases its metabolic activity. In this study, we used a genome editing technology called the Precise Integration into Target Chromosome (PITCh) system to stably express six drug-metabolizing enzymes (CYP3A4, POR, uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), CYP1A2, CYP2C19, CYP2C9, and CYP2D6*10) in HepG2 (CYP2D6*10 KI-HepG2) cells to examine the effect of CYP2D6*10 on drug metabolism prediction. The protein expression levels of CYP2D6 in CYP2D6*10 KI-HepG2 cells were reduced relative to those in the CYP3A4-POR-UGT1A1-CYP1A2-CYP2C19-CYP2C9-CYP2D6 knock-in-HepG2 (CYPs-UGT1A1 KI-HepG2) cells. Consistent with the CYP2D6 protein expression results, CYP2D6 metabolic activity in CYP2D6*10 KI-HepG2 cells was reduced relative to CYPs-UGT1A1 KI-HepG2 cells. We successfully generated CYP2D6*10 KI-HepG2 cells with highly expressed, functional CYP2D6*10, as well as CYP1A2, 2C9, 2C19 and 3A4. CYP2D6*10 KI-HepG2 cells could be an invaluable model for hepatic metabolism and hepatotoxicity studies in East Asians, including Japanese.","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

EphA4 Induces the Phosphorylation of an Intracellular Adaptor Protein Dab1 via Src Family Kinases. EphA4通过Src家族激酶诱导细胞内适配蛋白Dab1磷酸化

IF 1.7 4区医学

Biological & pharmaceutical bulletin Pub Date : 2024-01-01 DOI: 10.1248/bpb.b24-00273

Mitsuki Hara, Keisuke Ishii, Mitsuharu Hattori, Takao Kohno

{"title":"EphA4 Induces the Phosphorylation of an Intracellular Adaptor Protein Dab1 via Src Family Kinases.","authors":"Mitsuki Hara, Keisuke Ishii, Mitsuharu Hattori, Takao Kohno","doi":"10.1248/bpb.b24-00273","DOIUrl":"10.1248/bpb.b24-00273","url":null,"abstract":"Dab1 is an intracellular adaptor protein essential for brain formation during development. Tyrosine phosphorylation in Dab1 plays important roles in neuronal migration, dendrite development, and synapse formation by affecting several downstream pathways. Reelin is the best-known extracellular protein that induces Dab1 phosphorylation. However, whether other upstream molecule(s) contribute to Dab1 phosphorylation remains largely unknown. Here, we found that EphA4, a member of the Eph family of receptor-type tyrosine kinases, induced Dab1 phosphorylation when co-expressed in cultured cells. Tyrosine residues phosphorylated by EphA4 were the same as those phosphorylated by Reelin in neurons. The autophosphorylation of EphA4 was necessary for Dab1 phosphorylation. We also found that EphA4-induced Dab1 phosphorylation was mediated by the activation of the Src family tyrosine kinases. Interestingly, Dab1 phosphorylation was not observed when EphA4 was activated by ephrin-A5 in cultured cortical neurons, suggesting that Dab1 is localized in a different compartment in them. EphA4-induced Dab1 phosphorylation may occur under limited and/or pathological conditions in the brain.","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Uptake of Fluorescein via a pH-Dependent Monocarboxylate Transporter by Human Kidney 2 (HK-2) Cells. 人肾 2 (HK-2) 细胞通过 pH 依赖性单羧酸盐转运体摄取荧光素

IF 2 4区医学

Biological & pharmaceutical bulletin Pub Date : 2024-01-01 DOI: 10.1248/bpb.b23-00570

Takaharu Takiguchi, Kazuaki Sugio, Masayuki Masuda, Shotaro Sasaki, Seiji Miyauchi

{"title":"Uptake of Fluorescein via a pH-Dependent Monocarboxylate Transporter by Human Kidney 2 (HK-2) Cells.","authors":"Takaharu Takiguchi, Kazuaki Sugio, Masayuki Masuda, Shotaro Sasaki, Seiji Miyauchi","doi":"10.1248/bpb.b23-00570","DOIUrl":"10.1248/bpb.b23-00570","url":null,"abstract":"Herein, we investigated whether a fluorescent probe for an organic anion transporter (OAT), fluorescein (FLS), could be accumulated by human kidney 2 (HK-2) cells derived from human kidney proximal tubular epithelia. HK-2 cells took up FLS in a pH-dependent and concentration-dependent manner. FLS accumulation by HK-2 cells was inhibited by monocarboxylic acids, ibuprofen, rosuvastatin, and indoleacetic acid but not by typical substrates for OATs. A typical protonophore, carbonyl cyanide p-trichloromethoxyphenylhydrazone completely abolished FLS accumulation by HK-2 cells. The FLS efflux process from the preloaded HK-2 cells exhibited substantial trans-stimulation by the excess amount of extracellular FLS transport inhibitable monocarboxylate compounds such as 2,4-dichloro phenoxyacetic acid, fluvastatin, ibuprofen, indoleacetic acid, salicylic acid and rosuvastatin, indicating that the FLS transporter can recognize and accumulate them into the cells in a pH-dependent manner. The involvement of the FLS transporter in the reabsorption of monocarboxylic compounds was indicated by demonstrating that the pH-dependent FLS uptake is inhibited by various monocarboxylates in rabbit renal brush border membrane vesicles. pH-dependent FLS uptake was trans-stimulated by the inhibitable monocarboxylates. Collectively, the present data indicate that the pH-dependent transporters expressed in HK-2 cells are involved in the reabsorption of monocarboxylates from the urinary fluid into the tubular epithelia.","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139085734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Phosphatidylcholine-Plasmalogen-Oleic Acid Reduces BACE1 Expression in Human SH-SY5Y Cells. 磷脂酰胆碱-质原油酸可降低人 SH-SY5Y 细胞中 BACE1 的表达。

IF 2 4区医学

Biological & pharmaceutical bulletin Pub Date : 2024-01-01 DOI: 10.1248/bpb.b23-00787

Haruka Okabayashi, Miki Yasuda, Chinatsu Nii, Ryo Sugishita, Keijo Fukushima, Kouki Yuasa, Satoshi Kotoura, Hiromichi Fujino

引用次数: 0

A Novel Strategy for the Discovery of Drug Targets: Integrating Clinical Evidence with Molecular Studies. 发现药物靶点的新策略：将临床证据与分子研究相结合。

IF 2 4区医学

Biological & pharmaceutical bulletin Pub Date : 2024-01-01 DOI: 10.1248/bpb.b23-00831

Shuji Kaneko

{"title":"A Novel Strategy for the Discovery of Drug Targets: Integrating Clinical Evidence with Molecular Studies.","authors":"Shuji Kaneko","doi":"10.1248/bpb.b23-00831","DOIUrl":"10.1248/bpb.b23-00831","url":null,"abstract":"The mechanisms of several drugs remain unclear, limiting our understanding of how they exert their effects. Receptor affinities have not been comprehensively measured during drug development, and the safety investigations in humans are limited. Therefore, numerous unknown adverse and beneficial effects of drugs in humans persist. In this review, I highlight our achievements in identifying the unexpected beneficial effects of drugs through the analysis of real-world clinical data, which can contribute to drug repositioning and target finding. (1) Through the analysis of real-world data, we found that the anti-arrhythmic amiodarone induced interstitial lung disease, leading to fibrosis. Surprisingly, concurrent use of an anti-thrombin drug, dabigatran mitigated these adverse events. Pharmacological studies using animal models have mimicked this phenomenon and revealed the molecular mechanisms associated with the platelet-derived growth factor-alpha receptors. (2) The antidiabetic dipeptidyl-peptidase 4 inhibitors increased the risk of an autoimmune disease, bullous pemphigoid, which was reduced by the concomitant use of lisinopril. Pharmacological studies using human peripheral blood mononuclear cells have revealed that lisinopril suppressed the skin disorders by inhibiting the expression of cutaneous matrix metalloproteinase 9 in macrophages. (3) The antimicrobial fluoroquinolones increased the risk of tendinopathy, which was reduced by the concomitant use of dexamethasone. However, clinical guidelines have suggested that corticosteroid increases the risk of tendinopathy. Our investigation demonstrated that fluoroquinolones impaired tendon cells through DNA damage by generating reactive oxygen species. In contrast, dexamethasone exhibited an acute beneficial effect on tendon tissue by upregulating the expression of a radical scavenger, glutathione peroxidase 3.","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139721483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Temperature-Dependent Upregulation of Per2 Protein Expression Is Mediated by eIF2α Kinases PERK and PKR through PI3K Activation. eIF2α 激酶 PERK 和 PKR 通过 PI3K 激活介导温度依赖性 Per2 蛋白表达上调

IF 2 4区医学

Biological & pharmaceutical bulletin Pub Date : 2024-01-01 DOI: 10.1248/bpb.b23-00739

Xinyan Shao, Takahito Miyake, Yuichi Inoue, Emi Hasegawa, Masao Doi

{"title":"Temperature-Dependent Upregulation of Per2 Protein Expression Is Mediated by eIF2α Kinases PERK and PKR through PI3K Activation.","authors":"Xinyan Shao, Takahito Miyake, Yuichi Inoue, Emi Hasegawa, Masao Doi","doi":"10.1248/bpb.b23-00739","DOIUrl":"10.1248/bpb.b23-00739","url":null,"abstract":"Temperature-dependent translational control of the core clock gene Per2 plays an important role in establishing entrainment of the circadian clock to physiological body temperature cycles. Previously, we found an involvement of the phosphatidylinositol 3-kinase (PI3K) in causing Per2 protein expression in response to a warm temperature shift (WTS) within a physiological range (from 35 to 38.5 °C). However, signaling pathway mediating the Per2 protein expression in response to WTS is only sparsely understood. Additional factor(s) other than PI3K remains unknown. Here we report the identification of eukaryotic initiation factor 2α (eIF2α) kinases, protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), as a novel mediator of WTS-dependent Per2 protein expression. Canonically, eIF2α has been regarded as a major downstream target of PERK and PKR. However, we found that PERK and PKR mediate WTS response of Per2 in a manner not involving eIF2α. We observed that PERK and PKR serve as an upstream regulator of PI3K rather than eIF2α in the context of WTS-dependent Per2 protein expression. There have been studies reporting PI3K activation occurring depending on PERK and PKR, while its physiological contribution has remained elusive. Our finding therefore not only helps to enrich the knowledge of how WTS affects Per2 protein expression but also extends the region of cellular biology involving the PERK/PKR-mediated PI3K activation to include entrainment-mechanism of the circadian clock.","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140048679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural Impact Assessment of Cytochrome P450 2A13 Polymorphisms Using Molecular Dynamics Simulations. 利用分子动力学模拟评估细胞色素 P450 2A13 多态性的结构影响。

IF 2 4区医学

Biological & pharmaceutical bulletin Pub Date : 2024-01-01 DOI: 10.1248/bpb.b23-00908

Koichi Kato, Tomoki Nakayoshi, Sho Hioki, Masahiro Hiratsuka, Yoshinobu Ishikawa, Eiji Kurimoto, Akifumi Oda

{"title":"Structural Impact Assessment of Cytochrome P450 2A13 Polymorphisms Using Molecular Dynamics Simulations.","authors":"Koichi Kato, Tomoki Nakayoshi, Sho Hioki, Masahiro Hiratsuka, Yoshinobu Ishikawa, Eiji Kurimoto, Akifumi Oda","doi":"10.1248/bpb.b23-00908","DOIUrl":"10.1248/bpb.b23-00908","url":null,"abstract":"One of the members of CYP, a monooxygenase, CYP2A13 is involved in the metabolism of nicotine, coumarin, and tobacco-specific nitrosamine. Genetic polymorphisms have been identified in CYP2A13, with reported loss or reduction in enzymatic activity in CYP2A13 allelic variants. This study aimed to unravel the mechanism underlying the diminished enzymatic activity of CYP2A13 variants by investigating their three-dimensional structures through molecular dynamics (MD) simulations. For each variant, MD simulations of 1000 ns were performed, and the obtained results were compared with those of the wild type. The findings indicated alterations in the interaction with heme in CYP2A13.4, .6, .8, and .9. In the case of CYP2A13.5, observable effects on the helix structure related to the interaction with the redox partner were identified. These conformational changes were sufficient to cause a decrease in enzyme activity in the variants. Our findings provide valuable insights into the molecular mechanisms associated with the diminished activity in the CYP2A13 polymorphisms.","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140118687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Wild-Type DCTN1 Suppresses the Aggregation of DCTN1 Mutants Associated with Perry Disease. 野生型 DCTN1 可抑制与佩里病有关的 DCTN1 突变体的聚集。

IF 2 4区医学

Biological & pharmaceutical bulletin Pub Date : 2024-01-01 DOI: 10.1248/bpb.b23-00828

Yuto Fukui, Hisashi Shirakawa, Shuji Kaneko, Kazuki Nagayasu

{"title":"Wild-Type DCTN1 Suppresses the Aggregation of DCTN1 Mutants Associated with Perry Disease.","authors":"Yuto Fukui, Hisashi Shirakawa, Shuji Kaneko, Kazuki Nagayasu","doi":"10.1248/bpb.b23-00828","DOIUrl":"10.1248/bpb.b23-00828","url":null,"abstract":"Perry disease, a rare autosomal dominant neurodegenerative disorder, is characterized by parkinsonism, depression or apathy, unexpected weight loss, and central hypoventilation. Genetic analyses have revealed a strong association between point mutations in the dynactin I gene (DCTN1) coding p150glued and Perry disease. Although previous reports have suggested a critical role of p150glued aggregation in Perry disease pathology, whether and how p150glued mutations affect protein aggregation is not fully understood. In this study, we comprehensively investigated the intracellular distribution of the p150glued mutants in HEK293T cells. We further assessed the effect of co-overexpression of the wild-type p150glued protein with mutants on the formation of mutant aggregates. Notably, overexpression of p150glued mutants identified in healthy controls, which is also associated with amyotrophic lateral sclerosis, showed a thread-like cytoplasmic distribution, similar to the wild-type p150glued. In contrast, p150glued mutants in Perry disease and motor neuron disease caused aggregation. In addition, the co-overexpression of the wild-type protein with p150glued mutants in Perry disease suppressed aggregate formation. In contrast, the p150glued aggregation of motor neuron disease mutants was less affected by the wild-type p150glued. Further investigation of the mechanism of aggregate formation, contents of the aggregates, and biological mechanisms of Perry disease could help develop novel therapeutics.","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139545352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Substrate-Dependent Alteration in the C- and O-Prenylation Specificities of Cannabis Prenyltransferase. 大麻异戊烯基转移酶 C-和 O-异戊烯基特异性的底物依赖性改变

IF 2 4区医学

Biological & pharmaceutical bulletin Pub Date : 2024-01-01 DOI: 10.1248/bpb.b23-00868

Ryosuke Tanaya, Takeshi Kodama, Juthamart Maneenet, Yoko Yasuno, Atsushi Nakayama, Tetsuro Shinada, Hironobu Takahashi, Takuya Ito, Hiroyuki Morita, Suresh Awale, Futoshi Taura

{"title":"Substrate-Dependent Alteration in the C- and O-Prenylation Specificities of Cannabis Prenyltransferase.","authors":"Ryosuke Tanaya, Takeshi Kodama, Juthamart Maneenet, Yoko Yasuno, Atsushi Nakayama, Tetsuro Shinada, Hironobu Takahashi, Takuya Ito, Hiroyuki Morita, Suresh Awale, Futoshi Taura","doi":"10.1248/bpb.b23-00868","DOIUrl":"10.1248/bpb.b23-00868","url":null,"abstract":"CsPT4 is an aromatic prenyltransferase that synthesizes cannabigerolic acid (CBGA), the key intermediate of cannabinoid biosynthesis in Cannabis sativa, from olivetolic acid (OA) and geranyl diphosphate (GPP). CsPT4 has a catalytic potential to produce a variety of CBGA analogs via regioselective C-prenylation of aromatic substrates having resorcylic acid skeletons including bibenzyl 2,4-dihydroxy-6-phenylethylbenzoic acid (DPA). In this study, we further investigated the substrate specificity of CsPT4 using phlorocaprophenone (PCP) and 2',4',6'-trihydroxydihydrochalcone (THDC), the isomers of OA and DPA, respectively, and demonstrated that CsPT4 catalyzed both C-prenylation and O-prenylation reactions on PCP and THDC that share acylphloroglucinol substructures. Interestingly, the kinetic parameters of CsPT4 for these substrates differed depending on whether they underwent C-prenylation or O-prenylation, suggesting that this enzyme utilized different substrate-binding modes suitable for the respective reactions. Aromatic prenyltransferases that catalyze O-prenylation are rare in the plant kingdom, and CsPT4 was notable for altering the reaction specificity between C- and O-prenylations depending on the skeletons of aromatic substrates. We also demonstrated that enzymatically synthesized geranylated acylphloroglucinols had potent antiausterity activity against PANC-1 human pancreatic cancer cells, with 4'-O-geranyl THDC being the most effective. We suggest that CsPT4 is a valuable catalyst to generate biologically active C- and O-prenylated molecules that could be anticancer lead compounds.","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Beneficial Effect of Brazilian Propolis for Liver Damage through Endoplasmic Reticulum Stress. 巴西蜂胶对通过内质网应激造成的肝损伤的益处

IF 1.7 4区医学

Biological & pharmaceutical bulletin Pub Date : 2024-01-01 DOI: 10.1248/bpb.b24-00092

Tomohiro Ogawa, Takumi Terada

引用次数: 0