{"title":"Probes with Tailored Pharmacokinetics for Radiotheranostics.","authors":"Masayuki Munekane, Hiroaki Echigo, Takeshi Fuchigami, Kazuma Ogawa","doi":"10.1248/bpb.b25-00195","DOIUrl":"https://doi.org/10.1248/bpb.b25-00195","url":null,"abstract":"<p><p>In recent years, radiotheranostics, a theranostic approach utilizing radioisotopes, has been gaining significant attention, primarily in the field of oncology. The success of this technology relies on the design of probes that specifically target desired sites, making the development of effective diagnostic and therapeutic agents a crucial area of research. This review provides an overview of the fundamental concepts and recent advancements in probe design for radiotheranostics, with a particular focus on pharmacokinetics and subcellular localization. Key topics discussed include: (1) multimerization, (2) introduction of the albumin-binding moiety, (3) charge modification, (4) glycosylation, (5) conjugation of cell-penetrating peptides, (6) introduction of the covalent binding moiety, (7) targeting the nucleus, and (8) utilizing drug release properties to control pharmacokinetics and intracellular localization. Through these strategies, we review the optimization and novel design possibilities for probes in radiotheranostics.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 9","pages":"1295-1318"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144941562","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":"Systemic mRNA Delivery into the Muscle of Duchenne Muscular Dystrophy Model Mice Using Alpha-Dystroglycan Binding Peptide Modified Lipid Nanoparticles.","authors":"Eri Sasaki, Yuki Itaya, Yoko Endo-Takahashi, Yusuke Yano, Nobuhito Hamano, Keisuke Hamada, Yamato Kikkawa, Kosuke Nakashima, Rui Tada, Tsuyoshi Miura, Hiroki Tanaka, Hidetaka Akita, Motoyoshi Nomizu, Yoichi Negishi","doi":"10.1248/bpb.b24-00898","DOIUrl":"10.1248/bpb.b24-00898","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a hereditary disease that requires gene or nucleic acid therapy, which involves muscle-targeted delivery of therapeutic material. We previously developed liposomes targeting muscle tissue in DMD model mice (mdx) using an A2G80 peptide, which has an affinity for α-dystroglycan abundantly expressed on the muscle cell membrane. However, these liposomes did not carry gene or nucleic acids. In this study, we aimed to develop muscle-targeting lipid nanoparticles (LNPs) encapsulating luciferase mRNA and evaluate gene expression levels after systemic administration of these LNPs. We first evaluated the efficiency of mRNA delivery based on luciferase activity using polyethylene glycol (PEG)-dimyristoyl glycerol (DMG) and PEG-distearoyl glycerol (DSG) in mdx systemic administration. PEG-DSG-LNPs showed lower luciferase expression in the liver and spleen and higher expression in mdx muscle tissue than PEG-DMG-LNPs. The addition of the A2G80 peptide to LNPs using PEG-DSG (A2G80-DSG-LNPs) significantly increased their activity in mdx but not in normal mice. These results suggest that A2G80-DSG-LNPs allow for muscle-targeted mRNA delivery and are useful tools for DMD treatment.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 5","pages":"721-727"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172431","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":"Reactivating Circadian Rhythms as a Therapeutic Strategy: Insights from Basic Research.","authors":"Masao Doi","doi":"10.1248/bpb.b25-00330","DOIUrl":"https://doi.org/10.1248/bpb.b25-00330","url":null,"abstract":"<p><p>One of the most significant conceptual changes brought about by the discovery of clock genes and development of circadian-clock mutant mice is the recognition that impaired circadian rhythmicity extends its impact far beyond sleep, driving pathogenesis of a wide variety of disorders such as cancer, obesity, and hypertension. However, despite this growing clinical evidence, chronobiology still lacks a coherent answer to the converse question: can restoration of circadian rhythms ameliorate-or even reverse-such diseases? In this review, three complementary pharmacological strategies-each still in preclinical development-are explored. First, direct modulation of the transcription-translation feedback loop (TTFL)-the core gene-regulatory circuit that generates 24-h rhythms in almost all nucleated cells-is reviewed as an approach to manipulation of cellular circadian biology. Second, the suprachiasmatic nucleus (SCN)-enriched G-protein-coupled receptor Gpr176 is highlighted as a central-clock target, given its ligand-independent, G<sub>z</sub>-mediated control of cAMP signaling and demonstrated ability to reset the master pacemaker. Third, the concept of rhythmic enhancement of output function is introduced and exemplified by describing re-activation of circadian oxidized form of nicotinamide adenine dinucleotide (NAD<sup>+</sup>)-dependent 3β-hydroxy-steroid dehydrogenase (3β-HSD) activity in the meibomian gland-using nicotinamide mononucleotide (NMN)-to restore peripheral clock-driven steroidogenesis in this tissue, which leads to amelioration of meibomian gland dysfunction, a leading cause of dry eye disease. This review aims to highlight the molecular logic of each strategy; both mechanistic insights and safety/efficacy considerations are discussed.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 8","pages":"1165-1171"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774678","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":"Effectiveness of Pharmacists' Recommendations for Dental Examinations for Prevention of Medication-Related Osteonecrosis of the Jaw.","authors":"Shinichi Watanabe, Satomi Sumikawa, Satoshi Watanabe, Takaaki Yano, Yukiro Kurokawa, Noriaki Hidaka, Satoshi Hino, Takumi Yamaguchi, Mamoru Tanaka","doi":"10.1248/bpb.b25-00371","DOIUrl":"https://doi.org/10.1248/bpb.b25-00371","url":null,"abstract":"<p><p>Bone resorption inhibitors, such as bisphosphonates, infrequently cause refractory medication-related osteonecrosis of the jaw (MRONJ). Oral care, including maintaining oral hygiene and preventing oral infections, is important for preventing MRONJ. However, the extent of oral care in patients taking bisphosphonates is unclear. We recommended dental visits to 790 outpatients taking bisphosphonates who visited the pharmacy at Ehime University Hospital. The effect of this recommendation was determined by evaluating changes in the rate of dental visits within 6 months among patients with and without a family dentist. Following recommendations by pharmacists, the dental visit rate increased from 46.2 to 67.6%, and the proportion of patients with a family dentist increased from 55.9 to 76.5%. Furthermore, patients with a family dentist had a significantly higher rate of dental visits than those without a family dentist (79.9 vs. 6.8%). The findings in this study suggest that pharmacists' recommendations for oral health care may lead to early detection and avoidance of MRONJ.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 9","pages":"1399-1403"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084607","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":"Cephalothin, a First-Generation Cephem Antibiotic, Works as a Potent Inducer of Parthanatos.","authors":"Ryo Ito, Takaya Komatsu, Takuya Noguchi, Tomohiro Kagi, Yusuke Hirata, Atsushi Matsuzawa","doi":"10.1248/bpb.b25-00401","DOIUrl":"https://doi.org/10.1248/bpb.b25-00401","url":null,"abstract":"<p><p>Parthanatos is a noncanonical form of regulated cell death mediated by the overactivation of poly(ADP-ribose) polymerase-1, yet its regulatory mechanisms are not fully understood. To fully elucidate its regulatory mechanisms, it is necessary to establish useful research tools to investigate parthanatos. We have previously identified the human fibrosarcoma HT1080 cells as highly sensitive cells to parthanatos, and cefotaxime, a 3rd-generation cephem antibiotic, as the parthanatos inducer. In this study, we comprehensively characterized the ability of various cephem antibiotics, including cephalothin (also called cefalotin) (CET), cefoxitin, ceftriaxone, cefoperazone, ceftezole, and cefalexin, to induce parthanatos. Among them, CET exhibited the lowest LD<sub>50</sub>. Therefore, our results show that CET works as the more potent and useful parthanatos inducer.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 9","pages":"1351-1357"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032727","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 a Hyperglycemic Fish Model and Analysis of Bone Metabolism.","authors":"Kouhei Kuroda, Yoshiaki Tabuchi, Harumi Takino, Yusuke Maruyama, Masato Honda, Hajime Matsubara, Jun Hirayama, Atsuhiko Hattori, Nobuo Suzuki","doi":"10.1248/bpb.b25-00316","DOIUrl":"https://doi.org/10.1248/bpb.b25-00316","url":null,"abstract":"<p><p>The high plasma glucose induced in glucose metabolism disorders leads to secondary pathologies, including bone disease. Fish scales, similar to mammalian bone, are composed of osteoblasts, osteoclasts, and calcified bone matrix and have been used as a system to analyze hyperglycemia-induced bone abnormalities. Here, we developed a hyperglycemia model in fish to study abnormalities in bone metabolism linked to increased plasma glucose and to analyze the function of calcitonin, the suppressor of osteoclastic activity, while maintaining high glucose levels. Following a 1-d fast and exposure to 5% glucose, plasma glucose concentrations increased significantly. We then examined plasma calcium and osteoclast activity of scales related to bone metabolism in goldfish treated with glucose for 5 d after a 1-d fast. The results showed that glucose treatment significantly increased plasma calcium levels at 3 and 5 d with a decrease in calcium content in the scales of goldfish. Hyperglycemia in glucose-exposed goldfish induced osteoclastic activation in scales, as indicated by the ratio of the osteoclastic activating factor (rankl) to the osteoclast inhibiting factor (osteoprotegerin, opg). Plasma calcitonin was found to be increased in glucose-exposed goldfish, which appears to suppress bone resorption by regulating the rankl/opg ratio. This hyperglycemia model, capable of examining both glucose and bone metabolism, would be valuable for analyzing the mechanism underlying abnormal bone metabolism caused by hyperglycemia.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 9","pages":"1435-1443"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136365","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":"Activated Fibroblast Growth Factor Receptor 1 Mitigated Poly-PR-Induced Oxidative Stress and Protein Translational Impairment.","authors":"Taisei Ito, Kazuki Ohuchi, Hisaka Kurita, Takanori Murakami, Shinnosuke Takizawa, Ayaka Fujimaki, Junya Murata, Yasuhisa Oida, Isao Hozumi, Kiyoyuki Kitaichi, Masatoshi Inden","doi":"10.1248/bpb.b24-00794","DOIUrl":"10.1248/bpb.b24-00794","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron cell death. A GGGGCC hexanucleotide repeat expansion (HRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is a major causative factor in ALS. This abnormal HRE triggers five types of dipeptide repeat protein (DPR), each composed of two alternating amino acid expressions. Among the DPRs, arginine-rich Poly-PR localizes predominantly to the nucleus, exerting particularly strong toxicity on motor and cortical neurons. Several mechanisms have been proposed for poly-PR-induced neurotoxicity. In this study, poly-PR-expressing NSC34 motor neuron-like cells showed an increase in oxidative stress. Fibroblast growth factor receptor 1 (FGFR1) is known to promote neurogenesis and inhibit apoptosis in neurons. However, its neuroprotective effects against DPR-induced toxicity have not been previously reported. Here, we demonstrated that FGFR1 activation reduced oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (NRF2) expression. Furthermore, we propose that the increase in NRF2 through FGFR1 activation may result from the alleviation of protein translation impairment. Overall, these findings suggest that FGFR1 activation provides neuroprotection against poly-PR toxicity and may represent a potential therapeutic strategy for ALS.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 2","pages":"93-100"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078594","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}
Go Kamoshida, Noriteru Yamada, Daiki Yamaguchi, Kinnosuke Yahiro, Yuji Morita
{"title":"Colistin Resistance in Acinetobacter baumannii: Basic and Clinical Insights.","authors":"Go Kamoshida, Noriteru Yamada, Daiki Yamaguchi, Kinnosuke Yahiro, Yuji Morita","doi":"10.1248/bpb.b23-00642","DOIUrl":"10.1248/bpb.b23-00642","url":null,"abstract":"<p><p>The emergence of drug-resistant bacteria has posed a significant problem in medical institutions worldwide. Colistin, which targets lipopolysaccharide (LPS), serves as a last-resort antimicrobial agent against multidrug-resistant Gram-negative bacteria. Nevertheless, Acinetobacter baumannii, a pathogen with a worldwide prevalence of antimicrobial resistance, has been reported to develop resistance to colistin frequently. In this review, we discuss how A. baumannii acquires resistance to colistin, focusing on modification as well as loss of LPS present in its outer membrane, which is the primary mechanism of A. baumannii's resistance to colistin. Basic and clinical insights regarding colistin resistance in A. baumannii have been discussed in isolation. Therefore, we discuss the relationship between these 2 colistin resistance mechanisms in terms of the frequency and fitness of genetic mutations based on the insights from basic studies and clinical settings. We concluded that understanding the detailed mechanisms of colistin drug resistance requires a comprehensive understanding of both the frequency of mutations and the effects of selection pressure. Finally, we highlight the importance of promoting research from both basic science and clinical perspectives.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 3","pages":"213-221"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536429","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":"Curcumin Is Primarily Distributed in Lung, Spleen and Liver, Metabolized to Glucuronide and Sulfate, and Excreted through Bile and Urine by Using an Amorphous Curcumin Formulation with High Absorbability.","authors":"Tomohiro Nakao, Michiko Nakamura, Kazuya Nagano, Mariko Takeda, Haruna Hirai, Hikaru Maekita, Jian-Qing Gao, Hirofumi Tsujino, Makoto Sakata, Masayuki Nishino, Yuya Haga, Kazuma Higashisaka, Yasuo Tsutsumi","doi":"10.1248/bpb.b24-00877","DOIUrl":"10.1248/bpb.b24-00877","url":null,"abstract":"<p><p>Curcumin (CUR), a polyphenol, is a promising compound for use in functional foods owing to various biological properties. However, the kinetics of CUR remains unclear because CUR has extremely low water solubility and absorbability. Here, we tried to elucidate the distribution, metabolism, and excretion of CUR by using amorphous CUR, a novel formulation that has dramatically improved water solubility and absorbability. When amorphous CUR was orally administered, CUR was predominantly distributed in the lungs, spleen, and liver, with low levels of accumulation over 24 h. Moreover, most of the CUR metabolites were observed to be glucuronide and sulfate conjugates. Furthermore, CUR was found to be excreted not only in bile but also in urine. Taken together, we have systematically demonstrated the kinetics of CUR by using a highly absorbable CUR formulation. In order to develop functional foods with high quality, it is important to not only evaluate the function and toxicity of CUR but also to correctly understand its kinetics, such as absorption, distribution, accumulation, metabolism, and excretion.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 3","pages":"314-322"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750926","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 a Digital Image-Based Method to Screen Molecules That Regulate Melanization.","authors":"Waka Shimosako, Susumu Tanimura, Taiki Baba, Megumi Kuroiwa, Hiroyuki Murota, Kohsuke Takeda","doi":"10.1248/bpb.b24-00851","DOIUrl":"10.1248/bpb.b24-00851","url":null,"abstract":"<p><p>Vitiligo vulgaris is an acquired disorder that is thought to arise from the suppression of melanin synthesis by melanocytes in the basal epidermal layer. To develop therapeutic agents for vitiligo vulgaris, it is critical to identify compounds that promote melanization. In this study, we established a digital image-based method to quantify melanization that does not require biochemical procedures. B16F10 cells were seeded in a white-bottom 96-well microplate. After treatment with or without α-melanocyte-stimulating hormone, followed by fixation of the cells, digital images of the microplates were captured, and the total signal intensity of each well on the image was measured. The extent of melanization in the cells in each well was defined after the subtraction of the signal from the corresponding blank well. This method was found to quantify melanization more sensitively than the conventional technique that measures the absorbance of cell lysates at UV-A wavelengths. We obtained statistical parameters showing that this method was applicable to a high-throughput screening assay; thus, this method appears to be useful for screening and identifying molecules that suppress or promote melanization, the latter of which may be developed as therapeutic agents for vitiligo vulgaris.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 3","pages":"308-313"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728345","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}