{"title":"Skin Permeation of Hydrophilic Middle-to-High Molecular Weight Model Drugs from Decanoic Acid/Arginine Supramolecular Hydrogels.","authors":"Ryuichiro Mochizuki, Kohsuke Shibasaki, Kaname Hashizaki, Makiko Fujii, Hiroyuki Taguchi","doi":"10.1248/bpb.b24-00770","DOIUrl":"https://doi.org/10.1248/bpb.b24-00770","url":null,"abstract":"<p><p>Decanoic acid/arginine supramolecular hydrogels (C10/Arg) were prepared and evaluated for use as skin-application formulations to improve the skin permeation of hydrophilic middle-to-high-molecular-weight drugs. Dextran (Mw; 6000 Da [Dex]) was used to evaluate the physicochemical properties of the hydrogels, and fluorescein isothiocyanate-Dex (Mw; 4000 Da [FD4], Mw; 40000 Da [FD40]) was used as a model drug to evaluate skin permeability. The addition of 1% Dex to C10/Arg resulted in a translucent supramolecular hydrogel with a lamellar liquid crystal structure, and the addition of a low-molecular-weight model drug to this hydrogel did not significantly affect its physicochemical properties. However, the addition of middle-molecular-weight Dex (6000 Da) changed the rheological properties of the gel, strengthening its internal structure and increasing its elasticity. In vitro skin permeation experiments of model drugs released from C10/Arg gels were performed using Yucatan micropig skin. C10/Arg increased the cumulative amount of FD4 permeation by 40 times after 24 h compared to the application of aqueous FD4 solution. No skin permeation from the aqueous FD40 solution was observed, but permeation was observed following treatment of the skin sample with C10/Arg. The enhanced skin permeation of model drugs by hydrogels was largely due to the contribution of C10 in the hydrogels.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 5","pages":"733-743"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198242","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 Nanoparticle-Based Mucosal Drug Delivery Systems for Controlling Pharmacokinetic Behaviors.","authors":"Hideyuki Sato","doi":"10.1248/bpb.b25-00071","DOIUrl":"https://doi.org/10.1248/bpb.b25-00071","url":null,"abstract":"<p><p>The mucosal layer in various mucosal tissues acts as a barrier that protects the epithelial membrane from foreign substances. However, in the process of mucosal absorption of drugs, the mucus layer, a smart biological sieve to particles and molecules, can be an obstacle to effective drug delivery. Recently, functional nanoparticles (NPs) have attracted considerable interest in the field of biopharmaceutical science owing to their delivery potential and effectiveness. Among various pharmaceutical technologies, mucopenetrating NPs (MPP) and mucoadhesive NPs (MAP) are viable dosage options for controlling pharmacokinetic behavior by modifying drug absorption from the mucosal site. MPP and MAP can rapidly deliver encapsulated drugs to the absorption site by passing through the mucus layer and/or retaining NPs near the absorption membrane, possibly resulting in better drug delivery than that of conventional approaches. Modifying the surface properties of NPs is critical for determining their potential diffusiveness within the mucus layer owing to various types of interactions between the mucosal components and the surface of NPs. Additionally, the physiological characteristics of the mucus layer (thickness, viscosity, and turnover time) differ depending on the mucosal site. Thus, a deeper understanding of the design of NPs and the functional properties of the administration site is essential for developing mucosal drug delivery systems (mDDS) to maximize the potential of target drugs. This review summarizes the basic information and functions of the mucosal layer, highlights the recent progress in designing functional NPs for mDDS, and discusses the advantages and disadvantages of mucosal administration at major mucosal sites.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 6","pages":"759-768"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198243","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":"An Underlying Mechanism for the Altered Hypoglycemic Effects of Nateglinide in Rats with Acute Peripheral Inflammation.","authors":"Haruka Toko, Manami Ogino, Akane Nishiwaki, Moeko Kojina, Tetsuya Aiba","doi":"10.1248/bpb.b24-00582","DOIUrl":"10.1248/bpb.b24-00582","url":null,"abstract":"<p><p>The hypoglycemic effects of nateglinide (NTG) were examined in rats with acute peripheral inflammation (API) induced by carrageenan treatment, and the mechanisms accounting for altered hypoglycemic effects were investigated. NTG was administered through the femoral vein in control and API rats, and its plasma concentration profile was characterized. The time courses of the changes in plasma glucose and insulin levels were also examined. Although the plasma concentration profile of NTG in API rats was marginally distinguishable from that in control rats, the hypoglycemic effect of NTG was more persistent in API rats than in control rats. In addition, NTG elevated the plasma level of insulin more intensely in API rats than in control rats. Then, the islets of Langerhans were procured by perfusing the pancreas with collagenase solution in control and API rats, and the pancreatic mRNA expression of preproinsulin (Ins1), as well as that of sulfonylurea receptor ABCC8 (Abcc8), were examined. As a result, the expression of preproinsulin and ABCC8 mRNA increased in API rats. These findings suggest that the hypoglycemic effect of NTG was potentiated in API rats due to increased insulin secretion in the pancreas, which was caused by enhanced preproinsulin synthesis and expression of the sulfonylurea receptor.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 1","pages":"51-59"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063555","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":"Inhibitory Effects of Lysophospholipids on Survival and Interleukin-8 Secretion of HT-29, a Human Colon Cancer-Derived Epithelial Cell.","authors":"Yuya Ohtsuki, Erena Nakamura, Moe Asakami, Rena Morikawa, Akira Tokumura","doi":"10.1248/bpb.b24-00653","DOIUrl":"10.1248/bpb.b24-00653","url":null,"abstract":"<p><p>Lysophpsphospholipids (LPLs) are lipid mediators involved in various physiological functions. In daily diets, people consume large amounts of various lipids, including LPLs. Exogenous dietary LPLs initially affect epithelial cells and, finally, the entire colon and may be linked to the onset and prevention of colonic diseases, including inflammatory bowel disease. However, the effects of exogenous LPLs on epithelial cells remain poorly understood. In this study, we used HT-29, a human colon cancer-derived epithelial cell, to evaluate the effects of LPLs on epithelial cells under normal and inflammatory states. In the absence of lipopolysaccharide (LPS), several LPLs decreased interleukin-8 (IL-8) secretion from HT-29 cells in the following order of potency based on the reduction ratio at the highest concentration: lysophosphatidylglycerol > lysophosphatidylcholine > lysophosphatidyletanolamine > lysophosphatidylserine. In the presence of LPS, only lysophosphatidylinositol (LPI) decreased the IL-8 secretion induced by LPS. Focusing on the G protein-coupled receptors (GPCRs) that LPI acts on, PSN375963 and AS1269574, GPR119 agonists, decreased the IL-8 secretion induced by LPS. It is speculated that IL-8 secretion was reduced by LPI via GPR119 signaling under non-inflammatory conditions. Although the detailed mechanism remains to be elucidated, the findings that LPLs, except for LPI, have inhibitory effects and that LPI has an inhibitory/anti-inflammatory effect on IL-8 secretion will help to elucidate the mechanism on the onset of colonic diseases and the planning of treatment methods in the future.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 2","pages":"119-125"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432323","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":"Unique and Ingenious Mechanisms Underlying Antimicrobial Resistance and Spread of Haemophilus influenzae.","authors":"Takeaki Wajima, Emi Tanaka, Kei-Ichi Uchiya","doi":"10.1248/bpb.b23-00640","DOIUrl":"10.1248/bpb.b23-00640","url":null,"abstract":"<p><p>Antimicrobial resistance (AMR) is a serious global concern. AMR pathogens are found in hospitals and communities. Haemophilus influenzae is a common pathogen associated with community-acquired infections. H. influenzae infections are usually treated with β-lactams, macrolides, and quinolones. However, the drug-resistant strains have emerged. The resistance mechanisms of H. influenzae are complex but are roughly characterized by the acquisition of a mutation in antimicrobial-targeting genes and exogenous resistant genes. Generally, the former cannot be transferred horizontally to a susceptible strain. However, several studies have demonstrated that, in the case of H. influenzae, both the former and the latter can be transferred horizontally. In this review, we provide an overview of the bacterial features and antimicrobial resistance of H. influenzae. We also summarize the unique and ingenious antimicrobial resistance mechanisms used by this pathogen based on the findings of recent studies. These are expected to facilitate the understanding of AMR pathogens in the community and develop strategies to combat infections.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 3","pages":"205-212"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536368","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":"Ion Channel Function of Human TMEM16F Is Associated with Phospholipid Transport through Its Subunit Cavity.","authors":"Teppei Kageyama, Takahiro Shimizu, Kanon Shirai, Shota Nabeshima, Shigeki Ozawa, Takuto Fujii, Yoshiki Yonekawa, Hideki Sakai","doi":"10.1248/bpb.b24-00859","DOIUrl":"https://doi.org/10.1248/bpb.b24-00859","url":null,"abstract":"<p><p>Transmembrane protein 16F (TMEM16F), identified as the causative gene for Scott syndrome, which causes blood coagulation disorders, is known to function as not only a scramblase that bi-directionally transports phospholipids in the lipid bilayer but also a Ca<sup>2+</sup>-activated ion channel with low intracellular Ca<sup>2+</sup> sensitivity. However, how the dual functions of TMEM16F are controlled remains poorly understood. In this study, we investigated the properties of amino acid residues in human TMEM16F involved in the linkage between phospholipid and ion transports and the regulation of their transports using flow cytometry and whole-cell patch-clamp recordings. We demonstrated that ion and phospholipid transports induced by elevation of intracellular Ca<sup>2+</sup> concentration were tightly coupled in human embryonic kidney HEK293T cells overexpressing wild-type TMEM16F or its mutants. Mutations of amino acid residues in the hydrophilic subunit cavity of TMEM16F indicated that both substrates were transported through its subunit cavity. Importantly, the tail current analysis suggests that conformational changes of TMEM16F by the channel gating are required for its phospholipid transport. These results suggest that ion channel activities of human TMEM16F modulate its scramblase activities.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 5","pages":"595-605"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952813","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":"Solubilizing Effect of Caffeine on Precipitate of Risperidone Oral Solution and Tea Beverage.","authors":"Takeshi Goromaru, Nobuyuki Konishi, Mahiro Bunya, Takashi Ishizu","doi":"10.1248/bpb.b24-00775","DOIUrl":"https://doi.org/10.1248/bpb.b24-00775","url":null,"abstract":"<p><p>The rates of risperidone in precipitates from 5 risperidone oral solutions and tea beverages (green, black, and oolong teas) against risperidone used were measured by quantitative (q)NMR, indicating that as the amount of caffeine in the beverages increased, the rate decreased significantly. A solution of caffeine (0, 5, 10, and 30 μmol) in tartaric acid buffer (pH 3.0) was added to a solution of risperidone and (-)-epigallocatechin-3-O-gallate (EGCg) (each 3.0 μmol) in tartaric acid buffer (pH 3.0). Judging from the amounts of risperidone and EGCg in the precipitates, it was considered that risperidone formed a 1 : 1 complex with EGCg. As the amount of caffeine increased, the amounts of risperidone and EGCg in precipitates decreased significantly, suggesting that caffeine has a solubilizing effect on precipitates of the 1 : 1 complex of risperidone and EGCg. Furthermore, the amount of risperidone in precipitates formed when compounds with a xanthine derivative, such as diprophylline, theobromine, and theophylline, were added was less than when they were not added, indicating that such compounds with a xanthine derivative have the same solubilizing effect as caffeine on precipitate of the 1 : 1 complex of risperidone and EGCg.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 5","pages":"515-522"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953403","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":"Ginsenoside Rd Activates Ciliary Beat Frequency via Estrogen Receptor β and P2X7 Receptor.","authors":"Kouta Noriyama, Shigekuni Hosogi, Seikou Nakamura, Nobuhisa Todo, Nobuyo Tamiya, Masaki Shigeta, Yuki Toda, Koichi Takayama, Eishi Ashihara","doi":"10.1248/bpb.b24-00865","DOIUrl":"https://doi.org/10.1248/bpb.b24-00865","url":null,"abstract":"<p><p>Basal cells, goblet cells, and ciliated cells compose the human airway epithelium and protect the respiratory tract from foreign substances through their involvement in mucociliary clearance (MCC). In particular, ciliary beat frequency (CBF) is an important indicator of MCC efficiency. Although several herbal medicines have been reported to increase CBF, it is still unclear which compounds in these medicines are responsible for this effect. In the present study, we performed experiments to identify compounds that directly increase CBF and elucidated their mechanisms of action. We screened ginsenosides and their derivatives owned by Kyoto Pharmaceutical University and found that ginsenoside Rd was the most effective in increasing CBF and intracellular cAMP concentration ([cAMP]<sub>i</sub>). Furthermore, we identified the estrogen receptor β (ERβ) as a new target of ginsenoside Rd-mediated increases in [cAMP]<sub>i</sub> and CBF. We also found that ginsenoside Rd increased [Ca<sup>2+</sup>]<sub>i</sub> and potentiated the positive effect of ATP on CBF by acting as a positive allosteric modulator (PAM) for the P2X7 receptor in murine airway ciliated cells. In conclusion, the results suggest that ginsenoside Rd increases CBF and that its mechanism of action is as an agonist of ERβ and a PAM of the P2X7 receptor.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 5","pages":"657-671"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118629","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":"Quetiapine Reverses the Behavior and Myelination in Alcohol-Exposed Gestational Diabetes Mellitus Offspring Mice via ERK1/2 Signaling.","authors":"Dong Huang, Maolin Li, Zhifei Qiao, Hongli Zhou, Zuo Zhang, Jiyin Zhou","doi":"10.1248/bpb.b24-00642","DOIUrl":"10.1248/bpb.b24-00642","url":null,"abstract":"<p><p>Gestational diabetes mellitus (GDM) is a glucose metabolism abnormality that first emerges during pregnancy and may negatively affect the behavioral and neurodevelopmental outcomes of offspring. Quetiapine (QUE) has been shown to promote differentiation of oligodendrocyte precursor cells (OPCs) and protect oligodendrocytes and myelination. To explore the effects of QUE on improving the expression of conditioned place preference (CPP) and myelination in the infralimbic cortex (IL) of the medial prefrontal cortex in alcohol-exposed GDM offspring mice, we evaluated CPP expression in 5-week-old alcohol-exposed GDM offspring and treated them with QUE and the extracellular-regulated protein kinase (ERK) inhibitor U0126. Immunohistochemical staining compared the numbers of mature oligodendrocytes, OPCs, and myelin expression levels. Immunofluorescence staining was employed to examine OPC differentiation and the activation of the ERK1/2 signaling pathway. In GDM offspring, CPP expression increased considerably following alcohol exposure, whereas early treatment with QUE or U0126 significantly decreased CPP expression. Meanwhile, alcohol exposure resulted in substantial activation of the ERK1/2 signaling pathway within OPCs in the IL region, as well as a substantial reduction in OPC differentiation, mature oligodendrocyte count, and myelin expression. QUE or U0126 inhibited the activation of the ERK1/2 signaling pathway within OPCs in the IL region of alcohol-exposed GDM offspring and markedly restored OPC differentiation, mature oligodendrocyte numbers, and myelin expression. Collectively, QUE enhanced the differentiation of OPCs in the IL region of GDM offspring after alcohol exposure by regulating the overactivation of the ERK1/2 signaling pathway, thus partially reversing myelination loss and ultimately improving CPP expression.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 3","pages":"323-335"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750933","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}
Mana Mitsutani, Mei Yokoyama, Hiromi Hano, Midori Matsushita, Misa Hayashi, Ichiro Yamauchi, Tetsuya Tagami, Kenji Moriyama
{"title":"Estradiol Regulates the Expression of Type 3 Deiodinase in a Chondrocyte Cell Line.","authors":"Mana Mitsutani, Mei Yokoyama, Hiromi Hano, Midori Matsushita, Misa Hayashi, Ichiro Yamauchi, Tetsuya Tagami, Kenji Moriyama","doi":"10.1248/bpb.b24-00825","DOIUrl":"10.1248/bpb.b24-00825","url":null,"abstract":"<p><p>Although accelerated growth is observed in both sexes upon reaching puberty, the growth of girls ceases around menarche (the average age at menarche is 12-13 years in Japan). However, the molecular basis of the action of estrogen remains unclear. In this study, we investigated whether estrogen is involved in the differences in growth between males and females while focusing on thyroid hormone metabolic enzymes. We analyzed the promoters of iodothyronine deiodinase (DIO)2 and DIO3 by 17β-estradiol (E<sub>2</sub>). ATDC5 cells (mouse chondrocytes cell line) were treated with E<sub>2</sub>, and the expression of DIO2 and DIO3 mRNA and proteins was evaluated. Sham-operated (sham) or ovariectomized (OVX) female mice were treated daily with E<sub>2</sub> or vehicle for three consecutive weeks. Subsequently, the left femur was removed to evaluate the effect of E<sub>2</sub> on DIO2/DIO3 gene and protein expression. E<sub>2</sub> increased the transcriptional activity of DIO3 in a concentration-dependent manner. On the DIO3 promoter indicates the presence of an estrogen response element. DIO2 and DIO3 mRNA and protein expression in ATDC5 cells in the presence of E<sub>2</sub> was significantly increased, while DIO2 expression was unchanged. In vivo, we used OVX mice and E<sub>2</sub> supplementation as a model of amenorrhea for further investigation. DIO3 expression was significantly increased in mice treated with E<sub>2</sub> in OVX compared to that in mice treated with vehicle in sham. E<sub>2</sub> increases DIO3 expression in chondrocytes and long bone tissues, suggesting that E<sub>2</sub> may affect bone growth and cause sexual dimorphism during puberty.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 3","pages":"267-278"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699178","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}