Biological & pharmaceutical bulletin最新文献

{"title":"Evaluation of Puberulic Acid-Induced Nephrotoxicity Using 3D-RPTEC.","authors":"Hanwei Peng, Etsushi Takahashi, Tomohiro Murakami, Yohei Saito, Kento Kamezaki, Ayari Watanabe, Hiroyuki Kusuhara, Kyoko Nakagawa-Goto, Yoichi Jimbo, Hiroshi Arakawa","doi":"10.1248/bpb.b24-00654","DOIUrl":"https://doi.org/10.1248/bpb.b24-00654","url":null,"abstract":"<p><p>Renal proximal tubular injury was reported as a result of Red Yeast Rice supplements intake, with puberulic acid identified as one of the causative agents. Although the compound has shown nephrotoxicity in animal models, the cytotoxicity of this compound on human kidney cells has not been investigated. In this study, we evaluated the cytotoxic effects of puberulic acid using three-dimensional cultured primary human renal proximal tubular epithelial cells (3D-RPTECs). Upon exposure to puberulic acid, the spheroid surface area and mitochondrial fluorescence intensity were reduced. Moreover, a time-dependent decrease in intracellular ATP levels was observed with the EC₅₀ value at 7 d of 24.7 μM. Based on the carboxylic acid structure of puberulic acid, we investigated the effect of probenecid, a non-selective organic anion transporter (OAT) inhibitor, on puberulic acid cytotoxicity. The ATP reduction effect of puberulic acid was partially alleviated by probenecid. Furthermore, the uptake of OAT1 substrate furosemide by OAT1-expressing HEK293 cells was reduced by puberulic acid with an IC₅₀ value of 5.4 μM. These findings suggest that puberulic acid has a highly cytotoxic effect on the proximal tubules.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 6","pages":"928-931"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504817","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":"Stimulation of α7 Nicotinic Acetylcholine Receptors by PNU282987 Demonstrates Efferocytosis-Like Activation and Neuroprotection in Human Models of Microglia and Cholinergic Neurons under the Pathophysiological Conditions of Alzheimer's Disease.","authors":"Mari Sueyoshi, Koki Harada, Masaki Okawa, Teruki Matsuhara, Momona Ando, Riona Araki, Yuka Minote, Keiichi Ishihara, Shun Shimohama, Kazuyuki Takata","doi":"10.1248/bpb.b25-00308","DOIUrl":"https://doi.org/10.1248/bpb.b25-00308","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) peptide accumulation, leading to neuroinflammation and neurodegeneration. In early AD stages, neurodegeneration of basal forebrain cholinergic neurons occurs. Microglia, which are brain immune cells, contribute to Aβ clearance and neuroinflammation. This study investigated the therapeutic effects of PNU282987, a selective full agonist of α7 nicotinic acetylcholine receptor (nAChR), using human models of microglia (hiMacs) and basal forebrain cholinergic neurons (hiBFChNs), both differentiated from human induced pluripotent stem cells (hiPSCs). Our findings indicated that PNU282987 markedly enhanced Aβ phagocytosis by microglia and extracellular Aβ clearance. Furthermore, PNU282987 injection reduced Aβ accumulation in the brain of a mouse model. Treatment of hiMacs with PNU282987 upregulated the expressions of efferocytosis-related genes, such as ASAP2, OSM, and THBD. Efferocytosis-like activation by PNU282987 in hiMacs was further suggested by an increased release of the anti-inflammatory cytokine interleukin-10 (IL-10), along with suppression of the pro-inflammatory cytokine IL-1β produced from microglia with Aβ treatment. This indicates a transformation from Aβ-induced inflammatory phagocytosis to an efferocytosis-like anti-inflammatory phagocytosis. PNU282987 also exerted direct neuroprotective effects on hiBFChNs against Aβ and tumor necrosis factor-α. Furthermore, PNU282987 changed the extracellular contents released from Aβ-treated hiMacs and attenuated the neurotoxicity. These results suggest that α7 nAChR stimulation by PNU282987 enhances the therapeutic effects against AD by promoting Aβ clearance with anti-neuroinflammatory regulation in the microglia and providing direct protection to neurons, thereby addressing the inflammatory and neurodegenerative aspects of AD.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 7","pages":"972-985"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574793","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":"Process Optimization of Charge-Reversible Lipid Nanoparticles for Cytosolic Protein Delivery Using the Design-of-Experiment Approach.","authors":"Dai Oyama, Masako Okada, Furan Song, Chiori Nitta, Hiroyuki Koide, Sei Yonezawa, Tomohiro Asai","doi":"10.1248/bpb.b24-00722","DOIUrl":"10.1248/bpb.b24-00722","url":null,"abstract":"<p><p>This study aimed to elucidate the manufacturing process parameters with optimal quality characteristics of protein-encapsulated dioleoylglycerophosphate-diethylenediamine (DOP-DEDA)-based lipid nanoparticles (LNPs) for intracellular protein drug delivery. DOP-DEDA is a pH-responsive and charge-reversible lipid for intracellular cargo delivery. In this study, bovine serum albumin (BSA) was used as a weakly acidic protein model, and LNPs were prepared using microfluidic technology, which has many advantages for practical applications. BSA-encapsulated DOP-DEDA-based LNPs showed pH-responsive charge reversibility and excellent quality characteristics for the intracellular delivery of proteins. A process optimization study was conducted by applying the Box-Behnken design in a design-of-experiment approach. The particle size, ζ-potential, and encapsulation efficiency were evaluated in response to the total flow rate, lipid concentration, and lipid solution ratio. The lipid solution ratio and total flow rate significantly affected the particle size and encapsulation efficiency, respectively. On the contrary, none of the process parameters affected the ζ-potential. Moreover, a map of the predicted values was constructed for the particle size and encapsulation efficiency using a multiple regression equation. In the predicted particle size range of 77-215 nm and encapsulation efficiency of 14-35%, the observed values were close to the predicted values, and 100-nm LNPs were reproduced with an encapsulation efficiency of 27%. Therefore, manufacturing process parameters were established to obtain protein-encapsulated DOP-DEDA-based LNPs with optimal quality characteristics.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 3","pages":"286-297"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699212","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":"Trends of Strong and Weak Opioid Prescriptions in Japan: A Cross-Sectional Study Based on Open Data from the National Database and Hospital Claims Data from Fiscal Years 2015 to 2021.","authors":"Tomokazu Shoji, Manabu Akazawa, Nonoka Nakagomi, Miwako Kobayashi, Fumihiko Kitta, Ryo Inose, Yuichi Muraki, Tetsuya Iijima, Takaaki Suzuki","doi":"10.1248/bpb.b24-00584","DOIUrl":"10.1248/bpb.b24-00584","url":null,"abstract":"<p><p>Trends in opioid use for patients with cancer in Japan remain unclear. This study investigated the prescription trends of strong and weak opioids in Japan and the prescription trends among patients with or without support from a palliative care team. Open data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) and administrative claims data from the University of Yamanashi Hospital from fiscal years 2015 to 2021 were used. Opioid consumption was reported using the defined daily dose (DDD) per 1000 inhabitants per day (DID) and DDD per 100 bed-days. The NDB open data showed a decrease from 0.3111 to 0.2271 in the DID for inpatients (p = 0.0001) and an increase from 0.5971 to 0.8597 in the DID for outpatients (p = 0.0003). Consumption of tramadol, a weak opioid, increased in both inpatient and outpatient settings. In University of Yamanashi Hospital, the annual percentage of opioid consumption changed little among strong opioids (98.1-97.1%) and weak opioids (1.8-2.8%) for patients supported by a palliative care team (p = 0.2842), but changed more noticeably among strong opioids (86.6-69.6%) and weak opioids (13.3-30.3%) for patients without support from a palliative care team (p < 0.001). Opioid prescription patterns in Japan changed during the 7-year study period, which indicated shifts in the types of opioids used. Additionally, the trend in opioid prescriptions was characterized by the presence or absence of palliative care team support.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 3","pages":"279-285"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699342","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":"Influence of Selenium-Binding Protein 1 on the Inhibitory Effect of Methionine in 1-Fluoro-2,4-dinitrobenzene-Induced Dermatitis.","authors":"Takayuki Koga, Makoto Hiromura, Masayo Hirao-Suzuki, Shuso Takeda, Yuji Ishii, Takumi Ishida, Akihisa Toda, Fumio Soeda","doi":"10.1248/bpb.b25-00303","DOIUrl":"https://doi.org/10.1248/bpb.b25-00303","url":null,"abstract":"<p><p>Allergic contact dermatitis (ACD) is a common skin disorder caused by contact with allergens. ACD treatment is based on patient education to avoid contact with allergens. However, sometimes patients may not be able to avoid the allergen because of its close proximity to their living environment. Thus, a novel therapeutic strategy that does not involve the avoidance of allergens is required. We previously reported that methionine, an essential amino acid, significantly suppressed ACD development caused by the repeated application of 1-fluoro-2,4-dinitrobenzene (DNFB). However, the magnitude of this suppressive effect of methionine depended on the mouse strain used to establish ACD, and the mechanism of this difference was still unclear in past studies. In this study, we investigated the mechanism underlying these strain differences and found that a lack of selenium-binding protein 1 (SBP1) enhanced the ACD-suppressive effect of methionine. The lack of SBP1 does not affect ACD progression; however, it reduces the hepatic beta-homocysteine methyltransferase (Bhmt) expression suppression by ACD. In support of this hypothesis, the lack of SBP1 reduced the suppression of hepatic dimethylglycine (DMG) production by ACD. These results suggest that the lack of SBP1 enhances the suppressive effects of methionine on ACD by suppressing DMG production.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 9","pages":"1384-1390"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074474","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":"Effect of Benzo[a]pyrene on Cellular Senescence in MCF7 Breast Cancer Cells.","authors":"Natsuko Kitamoto, Yuya Haga, Yuki Tsujii, Minami Kubo, Kazuma Higashisaka, Yasuo Tsutsumi","doi":"10.1248/bpb.b25-00309","DOIUrl":"https://doi.org/10.1248/bpb.b25-00309","url":null,"abstract":"<p><p>Studies on the effect of environmental chemicals on cancer has primarily focused on the early stages, while the impact on later stages, particularly cancer progression, has been less explored. Cellular senescence, a response to stress such as DNA damage and oxidative stress, has been reported to play a crucial role in cancer progression. Environmental chemicals are suspected to promote cancer progression, yet it is unclear whether this is mediated through cellular senescence. Benzo[a]pyrene (BP) is known to induce DNA damage, a key trigger of senescence, but whether it directly induces senescence in cancer cells remains uncertain. This study aims to evaluate the senescence-inducing potential of BP in breast cancer cells to better understand its role in cancer progression. We examined the effects of BP, a polycyclic aromatic hydrocarbon primarily generated via incomplete combustion of organic matter and commonly found in water, soil, automobile exhaust, and tobacco smoke, on MCF7 breast cancer cells. BP enters the human body via inhalation, ingestion, and dermal contact. Here, as indicated by multiple senescence markers, including nuclear elongation, senescence-associated β-galactosidase activity, DNA damage, and increased p21 expression, BP induced cellular senescence in MCF7 cells. As cellular senescence is associated with malignant cell transformation, our results might suggest that BP contributes to cancer progression by inducing cellular senescence.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 10","pages":"1540-1546"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145298435","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":"Foreword.","authors":"Yuji Morita","doi":"10.1248/bpb.b25-ctf4803","DOIUrl":"https://doi.org/10.1248/bpb.b25-ctf4803","url":null,"abstract":"","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 3","pages":"195"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536431","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":"Development of Sensitive and Specific Determination Methods of Bioactive Compounds Based on Generation of High-Performance Antibodies.","authors":"Norihiro Kobayashi","doi":"10.1248/bpb.b25-00073","DOIUrl":"https://doi.org/10.1248/bpb.b25-00073","url":null,"abstract":"<p><p>Immunoassays enable the sensitive determination of various compounds and have been widely utilized in pharmaceutical and medical sciences. To develop practical assays, it is essential to obtain antibodies that capture the target analytes with high specificity and affinity. To date, we have generated high-performance antibodies and developed immunoassays for determining bioactive compounds, particularly focusing on haptens, such as steroids and synthetic drugs. In previous studies, we have produced specific anti-hapten antibodies by immunizing animals with reasonably prepared hapten-carrier conjugates. However, the resulting antibodies sometimes lacked sufficient affinity for a sensitive determination. Therefore, we challenged genetic engineering to produce artificially modified antibodies with improved affinity. Therein, native antibodies with insufficient affinities were converted into single-chain Fv fragments (scFvs), to which random point mutations were introduced to generate diverse scFv libraries. Mutated scFv species with increased affinities were selected and isolated with the aid of phage-display system combined with panning. Using this strategy, we obtained scFvs specific to several haptens, such as estradiol-17β (E₂) and cotinine, that show significantly improved affinity (K_a) than that of the parental scFv, enabling more sensitive enzyme-linked immunosorbent assays. However, the panning step often fails in straightforward selection and requires laborious trial-and-error work. Thus, we developed a \"clonal array profiling (CAP)\" system for more efficient isolation of the mutants with enhanced affinities, which successfully functioned generating multiple anti-cortisol scFvs with the K_a improved up to 63-fold and an anti-E₂ scFv with 372-fold larger K_a. In this study, we identified new strategies that allow for efficient site-directed mutagenesis to improve affinity. We expect that the engineered antibodies described here will open the door to next-generation immunoassays that will enable simpler and more reliable determination of bioactive compounds.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 5","pages":"475-494"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972593","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":"Incidence of Myocarditis Caused by Drugs Used for Ulcerative Colitis as Examined Using VigiBase, a Spontaneous Adverse Drug Reaction Reporting Database.","authors":"Yumi Kawai, Yasuko Kurata, Hirofumi Hamano, Takahiro Niimura, Mitsuhiro Goda, Yoshito Zamami, Keisuke Ishizawa, Hideki Nawa","doi":"10.1248/bpb.b24-00766","DOIUrl":"https://doi.org/10.1248/bpb.b24-00766","url":null,"abstract":"<p><p>Although myocarditis is listed as a serious adverse reaction in the package inserts of mesalazine and some other anti-ulcerative colitis (UC) drugs currently in use, and regulatory authorities have issued related warnings, the detailed characteristics of anti-UC drug-induced myocarditis remain unknown. We aimed to investigate the association between UC drugs and myocarditis development as an adverse event and its characteristics using data from a spontaneous adverse drug reaction reporting database. We searched for adverse event signals of five drugs, mesalazine, sulfasalazine, azathioprine, mercaptopurine, and budesonide, listed in the treatment guidelines for UC, using VigiBase. The information component was calculated, and a signal was considered present when the lower limit of the 95% confidence interval of the information component exceeded zero. The total number of VigiBase and myocarditis (as a target adverse event) reports was 38459016 and 71571, respectively. No trend was identified based on age or sex. Analysis of the five UC drugs for severity in VigiBase showed that most patients recovered, with a low reported mortality rate. However, the time to onset of adverse drug reactions varied among the drugs. Mesalazine signals were detected regardless of age or sex. This finding suggests that myocarditis, an adverse event, may be a potential complication regardless of patient characteristics. Our results also indicate that UC itself may induce myocarditis. Our findings warrant multifaceted investigations, including basic and clinical studies, on the characteristics of each drug regarding the development of myocarditis as an adverse event.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 4","pages":"383-389"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961087","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":"Effects of Calcineurin Inhibitors on Intestinal Barrier in Caco-2 Cells.","authors":"Reina Suzuki, Naohide Hirashima, Masahiko Tanaka","doi":"10.1248/bpb.b24-00875","DOIUrl":"https://doi.org/10.1248/bpb.b24-00875","url":null,"abstract":"<p><p>One of the side effects of calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporin A (CsA), is intestinal mucosal damage leading to ulceration and bleeding. However, it remains to be elucidated whether these side effects are direct effects of calcineurin inhibitors on intestinal epithelial cells (IECs). To determine whether IECs are directly damaged by calcineurin inhibitors, we analyzed the effects of calcineurin inhibitors on the intestinal barrier in Caco-2 cells, a human intestinal cell line. Treatment of Caco-2 with calcineurin inhibitors such as FK506, CsA, and deltamethrin inhibited expression of zonula occludens-1, a tight junction protein, and increased permeability of Lucifer Yellow. These effects were observed in confluent cells, but not clear in subconfluent cells. Our findings suggest that calcineurin inhibitors can directly damage IECs.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 4","pages":"457-462"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956729","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}