{"title":"Evaluating the Associated Hyperuricemia Risk with Sodium-Glucose Cotransporter 2 Inhibitors: A Sequence Symmetry Analysis Using the Japanese Administrative Claims Database.","authors":"Satoshi Yokoyama, Chihiro Nakagawa, Takaya Uno, Kouichi Hosomi","doi":"10.1248/bpb.b24-00330","DOIUrl":"10.1248/bpb.b24-00330","url":null,"abstract":"<p><p>Hyperuricemia is defined as high uric acid levels within the bloodstream and is commonly associated with gout, type 2 diabetes mellitus, and kidney disease. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are novel drugs that prevent glucose reabsorption; additionally, this drug has shown promising results in patients at risk of developing cardiovascular or renal complications by lowering uric acid levels. This study aimed to investigate the association between SGLT2i and hyperuricemia. Here, a self-controlled sequence symmetry analysis using the JMDC administrative claims database (January 2005 to September 2022) consisting of 12396 patients, who were newly prescribed both SGLT2i and hypouricemic agents, was conducted. Trend-adjusted sequence ratios (SR) at intervals of 6, 12, 18, and 24 months were calculated. Significant inverse signals across all intervals were observed between SGLT2i and hypouricemic agents, with the strongest effect observed in the 24-month interval [adjusted SR 0.52 (95% CI 0.49-0.55)]. Significant inverse signals were observed for each of the six types of SGLT2i across all intervals. This indicates that SGLT2i initiation may be associated with a decreased risk of hyperuricemia. Further investigation of the efficacy of SGLT2i is needed in hypothesis-testing designs such as cohort studies.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 11","pages":"1851-1857"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614102","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}
{"title":"Thyrotropin-Releasing Hormone Analog Taltirelin Inhibits Acute and Chronic Itch in Mice.","authors":"Kei Eto, Masanori Ogata, Fumiaki Kojima, Hitoshi Ishibashi","doi":"10.1248/bpb.b24-00449","DOIUrl":"https://doi.org/10.1248/bpb.b24-00449","url":null,"abstract":"<p><p>Itch is an unpleasant sensation that induces a desire to scratch. Chronic itch is accompanied by inflammatory skin diseases and causes repetitive scratching leading to tissue damage. The thyrotropin-releasing hormone analog taltirelin exerts analgesic effects on acute and chronic pain by activating the descending inhibitory systems. However, little is known regarding its effects on acute and chronic itch. In this study, we examined the effects of taltirelin on acute and chronic itch. Subcutaneous injection of chloroquine increased the number of scratching bouts in 30 min, whereas intraperitoneal injection of taltirelin reduced these episodes in a dose-dependent manner. In addition, chronic itch induced by diphenylcyclopropenone treatment was alleviated by taltirelin injection. These findings indicate that taltirelin alleviates acute and chronic itch in mice, and can be a potent therapeutic antipruritic drug.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 11","pages":"1927-1930"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738190","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}
{"title":"Emedastine Inhibits Th1 and Th2 Cell Differentiation Mediated by Mast Cells.","authors":"Katsuhiko Matsui, Akari Kuroki, Aya Morishima","doi":"10.1248/bpb.b23-00765","DOIUrl":"10.1248/bpb.b23-00765","url":null,"abstract":"<p><p>We have previously clarified that emedastine, a second-generation antihistamine drug, inhibits T helper 1(Th1)/Th2 cell differentiation mediated by Langerhans cells (LCs). In addition, although we have recently found that mast cells also function as antigen-presenting cells (APCs) and induce Th1/Th2 cell differentiation, any influence of emedastine on this function remained unclear. Here we investigated the influence of emedastine on Th1/Th2 cell differentiation via mast cells. Mast cells were obtained by long-term culture of murine splenocytes in medium supplemented with tumor necrosis factor (TNF)-α. The mast cells were then incubated in the presence or absence of emedastine, and cultured with naïve CD4<sup>+</sup> T cells in the presence of ovalbumin (OVA) peptide. Five days later, Th cells in the culture were stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, and Th1/Th2 cytokine production was examined by enzyme-linked immunosorbent assay. When mast cells treated with emedastine were used as APCs, production of interferon (IFN)-γ and interleukin (IL)-4 from activated Th cells was significantly suppressed. This suppression was associated with inhibition of CD86 expression on mast cells, and mast cells treated with emedastine were shown to obstruct the differentiation of both Th1 and Th2 cells by down-regulating their cell surface expression of CD86. The present data provide additional information that topical application of emedastine to the lesional skin of patients with atopic dermatitis (AD) would reduce not only LC- but also mast cell-mediated skin inflammation.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 2","pages":"527-531"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139989258","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}
{"title":"Association between Early Guanfacine Discontinuation and Somnolence for Attention-Deficit/Hyperactivity Disorder.","authors":"Kinuka Doi, Rintaro Sogawa, Yuko Eguchi, Muneaki Matsuo, Chisato Shimanoe","doi":"10.1248/bpb.b24-00147","DOIUrl":"https://doi.org/10.1248/bpb.b24-00147","url":null,"abstract":"<p><p>Guanfacine, used as a medication for attention-deficit/hyperactivity disorder (ADHD), leads to a high incidence of somnolence, in contrast to methylphenidate, which leads to a high incidence of insomnia. The impact of somnolence on continuing guanfacine treatment is unclear. Therefore, we investigated the reasons for discontinuing guanfacine and analyzed the factors associated with discontinuation caused by somnolence. We surveyed 96 patients under guanfacine from July 2017 to December 2021 at the Saga University Hospital. Patients who discontinued guanfacine by the end date of our study were divided into a median early and late group. We compared the reasons for discontinuation in both groups. Of all patients, 47 continued and 49 discontinued guanfacine. A higher percentage of patients discontinued guanfacine caused by somnolence for ≤70 d than for >70 d of treatment (44.0 vs. 8.3%; p = 0.008). When stratified by the concomitant use of other ADHD drugs, somnolence resulted in a higher discontinuation rate for ≤70 d than for >70 d of treatment without concomitant use (55.0 vs. 7.1%; p = 0.009). Nonetheless, concomitant use resulted in no difference. In conclusion, somnolence affects the early discontinuation of guanfacine as an ADHD drug. The combination of methylphenidate or atomoxetine may decrease withdrawal caused by somnolence.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 6","pages":"1204-1208"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442103","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}
{"title":"Heterogenous Gene Expression of Bicellular and Tricellular Tight Junction-Sealing Components in the Human Intestinal Tract.","authors":"Keisuke Tachibana, Lin Bai, Sayaka Sugimura, Hijiri Fujioka, Wataru Kishimoto, Hiroyuki Mizuguchi, Hiroshi Nakase, Masuo Kondoh","doi":"10.1248/bpb.b23-00927","DOIUrl":"https://doi.org/10.1248/bpb.b23-00927","url":null,"abstract":"<p><p>A major site for the absorption of orally administered drugs is the intestinal tract, where the mucosal epithelium functions as a barrier separating the inside body from the outer environment. The intercellular spaces between adjacent epithelial cells are sealed by bicellular and tricellular tight junctions (TJs). Although one strategy for enhancing intestinal drug absorption is to modulate these TJs, comprehensive gene (mRNA) expression analysis of the TJs components has never been fully carried out in humans. In this study, we used human biopsy samples of normal-appearing mucosa showing no endoscopically visible inflammation collected from the duodenum, jejunum, ileum, colon, and rectum to examine the mRNA expression profiles of TJ components, including occludin and tricellulin and members of the claudin family, zonula occludens family, junctional adhesion molecule (JAM) family, and angulin family. Levels of claudin-3, -4, -7, -8, and -23 expression became more elevated in each segment along the intestinal tract from the upper segments to the lower segments, as did levels of angulin-1 and -2 expression. In contrast, expression of claudin-2 and -15 was decreased in the large intestine compared to the small intestine. Levels of occludin, tricellulin, and JAM-B and -C expression were unchanged throughout the intestine. Considering their segment specificity, claudin-8, claudin-15, and angulin-2 appear to be targets for the development of permeation enhancers in the rectum, small intestine, and large intestine, respectively. These data on heterogenous expression profiles of intestinal TJ components will be useful for the development of safe and efficient intestinal permeation enhancers.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 6","pages":"1209-1217"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141455191","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}
{"title":"Suppression of the Epithelial-Mesenchymal Transition and Maintenance of the Liver Functions in Primary Hepatocytes through Dispersion Culture within a Dome-Shaped Collagen Matrix.","authors":"Yoshino Tonooka, Tomoyuki Takaku, Manabu Toyoshima, Yasuhiko Takahashi, Sachiko Kitamoto","doi":"10.1248/bpb.b24-00180","DOIUrl":"10.1248/bpb.b24-00180","url":null,"abstract":"<p><p>Primary hepatocytes are valuable for studying liver diseases, drug-induced liver injury, and drug metabolism. However, when cultured in a two-dimensional (2D) environment, primary hepatocytes undergo rapid dedifferentiation via an epithelial-mesenchymal transition (EMT) and lose their liver-specific functions. On the other hand, a three-dimensional (3D) culture of primary hepatocyte organoids presents challenges for analyzing cellular functions and molecular behaviors due to strong cell-cell adhesion among heterogeneous cells. In this study, we developed a novel dispersion culture method of hepatocytes within a dome-shaped collagen matrix, overcoming conventional limitations. The expression levels of EMT-related genes were lower in rat primary hepatocytes cultured using this method for 4 d than in cells cultured using the 2D method. Furthermore, albumin production, a marker of liver function, declined sharply in rat primary hepatocytes cultured in two dimensions from 6.40 µg/mL/48 h on day 4 to 1.35 µg/mL/48 h on day 8, and declined gradually from 4.92 µg/mL/48 h on day 8 to 3.89 µg/mL/48 h on day 14 in rat primary hepatocytes cultured using our new method. These findings indicate that the newly developed culture method can suppress EMT and maintain liver functions for 14 d in rat primary hepatocytes, potentially expanding the utility of primary hepatocyte cultured by using conventional 3D methods.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 7","pages":"1241-1247"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466012","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}
{"title":"Application of Recombinant Monoclonal Antibodies from Transgenic Chicken Bioreactors in Enzyme-Linked Immunosorbent Assay.","authors":"Takehiro Mukae, Kyoko Yoshii, Isao Oishi","doi":"10.1248/bpb.b24-00175","DOIUrl":"10.1248/bpb.b24-00175","url":null,"abstract":"<p><p>Transgenic chicken bioreactors can efficiently produce egg whites containing large quantities of recombinant proteins. We previously developed transgenic chickens that produce recombinant monoclonal antibodies (mAbs) against epidermal growth factor receptor 2 (HER2). However, the practical applications of mAbs derived from transgenic eggs have not yet been examined. Therefore, we aimed to evaluate whether these recombinant mAbs can be used in enzyme-linked immunosorbent assay (ELISA). Recombinant HER2 mAbs from transgenic eggs were dissolved in phosphate-buffered saline and applied directly to 96-well microplates as immobilized antibodies without purification. The performance of ELISA using the unpurified recombinant HER2 mAbs from transgenic eggs was comparable to that of ELISA using commercially available purified recombinant HER2 mAbs. Moreover, ELISA using unpurified recombinant HER2 mAbs from transgenic eggs demonstrated high antigen specificity and was successfully applied to samples from cultured cell lysates derived from HER2-positive and HER2-negative cell lines. The unpurified recombinant HER2 mAbs from transgenic eggs were also efficiently used as immobilized antibodies in paper-based ELISA. In conclusion, our findings suggest that recombinant mAbs from transgenic eggs have the potential to be used to develop economic ELISA devices. To the best of our knowledge, this study is the first to use recombinant HER2 mAbs from transgenic eggs in ELISA.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 9","pages":"1532-1541"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307074","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}
{"title":"A Novel Cross-Immune Antigen Vaccine Platform for Influenza Virus Type A.","authors":"Kenji Sekikawa, Haniyeh Bidadi, Miki Maeda, Liat Fux, Yakir Nataf, Hirofumi Komatsubara, Yutaka Komiyama, Osamu Kobayashi","doi":"10.1248/bpb.b24-00337","DOIUrl":"https://doi.org/10.1248/bpb.b24-00337","url":null,"abstract":"<p><p>We have developed a novel cross-immune antigen vaccine platform for influenza A virus. The vaccine antigen is a fusion protein of headless hemagglutinin (HA) and matrix protein 1 (M1), which possess B-cell and T-cell epitopes, respectively, that are conserved among subgroup A viruses. The single molecule of headless HA and M1 fusion protein forms an oligomer by self-assembly of M1. T-Helper 1 (Th1) and Th2 cells were activated in an antigen-specific manner in lymphocyte cultures of antigen-immunized mice. The antigen-immunized antiserum neutralized influenza virus A subtypes H1N1 and H3N2, and intranasal administration of the antigen reduced mortality to less than 30% in a protection assay.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 12","pages":"2028-2031"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794316","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}
{"title":"Exploration of Novel Metabolic Features Reflecting Statin Sensitivity in Lung Cancer Cells.","authors":"Jiro Tashiro, Tomoko Warita, Akihiro Sugiura, Kana Mizoguchi, Takuro Ishikawa, Katsuhiko Warita","doi":"10.1248/bpb.b24-00346","DOIUrl":"https://doi.org/10.1248/bpb.b24-00346","url":null,"abstract":"<p><p>Statins are cholesterol-lowering drugs often used for the treatment of dyslipidemia. Statins also exert anti-cancer effects by inhibiting hydroxymethylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis. We previously reported that the susceptibility to statin treatment differs among cancer cells and that functional E-cadherin expression on the plasma membrane could be a biomarker of statin sensitivity in cancer cells. However, the detailed qualitative and molecular differences between statin-sensitive and statin-resistant cancer cells remain unclear. Here, we explored novel parameters related to statin sensitivity by comparing gene expression profiles and metabolite contents between statin-sensitive and statin-resistant lung cancer cell lines. We found that the expression of most cholesterol synthesis genes was lower in the statin-sensitive cancer cell line, HOP-92, than in the statin-resistant cancer cell line, NCI-H322M. Moreover, HOP-92 cells originally exhibited lower levels of CoA and HMG-CoA. Additionally, atorvastatin decreased the mRNA expression of PANK2, a rate-limiting enzyme in CoA synthesis. Atorvastatin also reduced the mRNA levels of the cholesterol esterification enzyme SOAT1, which was consistent with a decrease in the ratio of cholesterol ester to total cholesterol in HOP-92 cells. Our data suggest that the cholesterol synthetic flow and CoA content may be limited in statin-sensitive cancer cells. We also suggest that CoA synthesis and cholesterol storage may fluctuate with atorvastatin treatment in statin-sensitive cancer cells.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 12","pages":"1992-2002"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794350","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}
{"title":"Royal Jelly Maintains Epidermal Stem Cell Properties by Repressing Senescence.","authors":"Mariko Moriyama, Yuko Miyake, Nobuaki Okumura, Hiroyuki Moriyama","doi":"10.1248/bpb.b24-00607","DOIUrl":"https://doi.org/10.1248/bpb.b24-00607","url":null,"abstract":"<p><p>Royal jelly (RJ), a natural product secreted by honeybees, is widely used in topical skincare products to help maintain cutaneous homeostasis. Despite its popularity, the mechanism through which RJ exerts its effects on the skin has not been fully elucidated. This study aimed to explore the impact of RJ on the proliferative ability and senescence of human primary epidermal keratinocytes (HPEKs). Our data suggested that epidermal equivalents became thicker with more p63-expressing proliferative cells upon RJ addition to the culture medium. In a two-dimensional culture system, we evaluated the effect of RJ on the proliferation of HPEKs and observed only a slight increase in cell proliferation. This suggests that RJ does not significantly enhance the proliferation of HPEKs in the short term. However, long-term culture experiments demonstrated enhanced population doubling in the RJ-treated group, indicating that RJ inhibits senescence. RJ was found to suppress cellular senescence by modulating the expression levels of ΔNp63, p16, and p21. These results were further supported by the identification of major fatty acids, such as 10-hydroxy-2-decenoic acid, in RJ. Our findings indicate that RJ can maintain epidermal stem cell properties by repressing cellular senescence, providing insights into its mechanism of action in skincare applications.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 12","pages":"2041-2049"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827170","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}