{"title":"Development of Research Foundation for Comprehensive Articulation of Drug Effects.","authors":"Tadahaya Mizuno","doi":"10.1248/bpb.b24-00509","DOIUrl":"https://doi.org/10.1248/bpb.b24-00509","url":null,"abstract":"<p><p>As unexpected adverse events and successful drug repositioning have shown, drug effects are complex and include aspects not recognized by developers. How can we understand these unrecognized drug effects? Drug effects can be numerized by encompassing biological responses to drugs. For instance, the transcriptome data of cultured cells and toxicopathological images of mice treated with a compound represent the effects of the compound in vitro and in vivo, respectively. As a next step, we focused on pattern recognition, a data science framework to extract essentially important low-dimensional latent variables from high-dimensional observed data such as latent variable models. Latent variables are low-dimensional, allowing us to visualize drug effects in an easily recognizable form, such as a radar chart. This bird's-eye view of drug effects enables us to compare them with existing knowledge, potentially articulating the effects of drugs as the known knowns and known unknowns. We believe that the three-step strategy of numerization, visualization, and articulation will allow us to understand drug effects comprehensively, and we are currently verifying this approach. In this review, we will introduce these candidate studies and hope to share our interest in \"pattern recognition of biological responses,\" the pillar of our group.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 1","pages":"1-5"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930619","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":"Vitamin D Receptor rs2228570 Gene Polymorphism Is Associated with Asthma Severity and Exacerbations.","authors":"Sekiko Uehara, Keita Hirai, Toshihiro Shirai, Hinako Otaki, Taisuke Akamatsu, Kunihiko Itoh","doi":"10.1248/bpb.b24-00684","DOIUrl":"https://doi.org/10.1248/bpb.b24-00684","url":null,"abstract":"<p><p>Vitamin D plays a crucial role in immune system function. Several studies have indicated that genetic variations in the vitamin D receptor (VDR) and vitamin D binding protein (VDBP, encoded by GC gene) increase the risk of developing asthma. However, the effect of these variations on the prognosis and clinical outcomes of asthma remains unclear. This study, involving 152 adult patients with asthma, aimed to assess the influence of VDR and GC polymorphisms on asthma severity and its exacerbation. Gene polymorphisms previously associated with asthma risk were analyzed, and VDR mRNA expression levels were evaluated in peripheral blood mononuclear cells. The AA genotype of the VDR rs2228570 polymorphism was associated with an elevated risk of severe asthma compared to the AG/GG genotype (odds ratio, 3.20; 95% confidence interval [CI], 1.24-8.28). Furthermore, patients with the rs2228570 AA genotype showed an elevated risk of exacerbation during the 1-year follow-up period (hazard ratio, 4.01; 95% CI, 1.75-9.15). VDR mRNA expression was significantly reduced in patients with the AA genotype. Furthermore, the mRNA expression levels of GLCCI1, HDAC2, NR3C1, and NFE2L2, which are associated with steroid response, were reduced in patients with the AA genotype. Our findings indicate that patients with the AA genotype of VDR rs2228570 are more likely to experience severe asthma and exacerbations. This polymorphism has the potential to reduce vitamin D efficacy by altering VDR function and expression, potentially resulting in increased inflammation and reduced steroid responsiveness in patients with asthma.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 1","pages":"86-92"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078582","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":"In Vitro Anti-inflammatory Activity of Tyrosol and Tryptophol: Metabolites of Yeast via the Ehrlich Pathway.","authors":"Toshio Niwa, Yoji Kato, Toshihiko Osawa","doi":"10.1248/bpb.b24-00625","DOIUrl":"https://doi.org/10.1248/bpb.b24-00625","url":null,"abstract":"<p><p>Soy isoflavonoids were applied to commercially available baker's yeast in vitro to find metabolites. Tyrosol, an ingredient in olive oil and wine, and tryptophol were found in the culture media. To test whether tyrosol is a metabolite of soy isoflavonoids, we prepared 2,4-dideuterated equol and applied it to yeast. According to LC-MS analysis of the culture media, deuterated tyrosol was not produced. Therefore, tyrosol is assumed to be a tyrosine metabolite of yeast known as the Ehrlich pathway. We then evaluated the in vitro activities of the 2 amino acid-derived alcohols. Both tyrosol and tryptophol similarly showed anti-inflammatory activity, as evaluated by monocyte chemoattractant protein-1 in 3T3-L1 murine adipocytes in vitro. Our results suggested that the amino acid-derived alcohols may contribute to the anti-inflammatory activity of fermented foods.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 2","pages":"115-118"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405549","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":"Stress Response Kinase MK2 Induces Non-canonical Activation of EphA2 in EML4-ALK Lung Cancer Cells.","authors":"Fang Zhang, Yue Zhou, Naru Hamada, Akihiro Tanaka, Satoru Yokoyama, Seiji Yano, Kunio Matsumoto, Hiroyuki Mano, Hiroaki Sakurai","doi":"10.1248/bpb.b24-00747","DOIUrl":"https://doi.org/10.1248/bpb.b24-00747","url":null,"abstract":"<p><p>The non-canonical phosphorylation of the receptor tyrosine kinase ephrin type-A receptor 2 (EphA2) at Ser-897 plays crucial roles in tumor progression in a tyrosine kinase-independent manner. This phosphorylation is catalyzed by p90 ribosomal S6 kinase (RSK), a kinase downstream of extracellular signal-regulated kinase (ERK). We recently reported that stress-responsive kinase mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), instead of ERK, regulates RSK under cellular stress conditions; however, the function of MK2 in ERK-activated cells is still unknown. We herein clarified that MK2 regulates the RSK-EphA2 axis in ERK-activated echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) lung cancer cells. In addition, an MK2 inhibitor blocked enhancements in cell motility induced by the constitutively activated RSK-EphA2 axis. The present results reveal the importance of MK2 in the ERK-activated non-canonical activation of EphA2.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 2","pages":"172-176"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536427","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":"Preventive and Therapeutic Effects of Intracerebroventricular Administration of Maresin-1 on Lipopolysaccharide-Induced Depression-Like Behaviors in Mice.","authors":"Satoshi Deyama, Katsuyuki Kaneda, Masabumi Minami","doi":"10.1248/bpb.b24-00743","DOIUrl":"https://doi.org/10.1248/bpb.b24-00743","url":null,"abstract":"<p><p>Enhanced inflammatory and immune responses have been observed in patients with major depressive disorder, pointing to anti-inflammatory substances as potential seeds for developing novel antidepressants. Omega-3 polyunsaturated fatty acid metabolites, such as resolvin D and E series, maresins, and protectins (collectively known as specialized pro-resolving mediators) demonstrate anti-inflammatory effects. This study examined the antidepressant-like effects of maresin-1 (MaR1) on lipopolysaccharide (LPS)-induced depression-like behaviors in mice. Using the tail suspension test (TST) and the forced swim test (FST), we assessed depression-like behaviors 26 and 28 h after intraperitoneal injection of LPS (0.8 mg/kg), respectively. An open field test (OFT) was also conducted to evaluate locomotor activity 24 h after LPS injection. Intracerebroventricular (i.c.v.) injection of MaR1 (10 ng/mouse) immediately after the LPS challenge mitigated the increased immobility time in the TST and FST, without affecting locomotor activity in the OFT, indicating the preventive effects of MaR1 on LPS-induced depression-like behaviors. Furthermore, i.c.v. injection of MaR1 23 h after the LPS challenge reduced the immobility time in both tests, underscoring its therapeutic potential. These findings suggest that MaR1 could be a promising seed for developing novel antidepressants.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 1","pages":"6-10"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977401","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":"Antipruritic Effects of Single Administration of Paroxetine on Acute and Chronic Itch.","authors":"Kosuke Matsuda, Hikaru Ishisaka, Masahito Sawahata, Toshiaki Kume, Daisuke Uta","doi":"10.1248/bpb.b24-00657","DOIUrl":"https://doi.org/10.1248/bpb.b24-00657","url":null,"abstract":"<p><p>Itch is described as an unpleasant sensation, and chronic itch, such as that in atopic dermatitis (AD), often decreases a patient's QOL. There are few effective treatments for various chronic pruritic disorders that are not limited to inflammation. Selective serotonin reuptake inhibitors (SSRIs) are antidepressants used to treat some chronic pruritus disorders. However, there is little evidence from clinical and basic studies using animal models. In this study, we found that paroxetine suppressed acute and chronic itch in mouse models. Single administration of paroxetine (10 mg/kg) inhibited scratching behavior caused by histamine-dependent or histamine-independent itch. Moreover, paroxetine (10 mg/kg) inhibited spontaneous scratching behavior in AD model using NC/Nga mice without affecting locomotor function. These results suggest that paroxetine suppresses chronic itch caused by AD via histamine-dependent and -independent pathways. This study provides one of the few pieces of evidence that SSRIs suppress itch.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 2","pages":"184-187"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536410","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}
Jisung Hwang, Deok Yong Sim, Chi-Hoon Ahn, Su-Yeon Park, Jin-Suk Koo, Bum-Sang Shim, Bonglee Kim, Sung-Hoon Kim
{"title":"Inhibition of LGR5/β-Catenin Axis and Activation of miR134 Are Critically Involved in Apoptotic Effect of Sanggenol L in Hepatocellular Carcinoma.","authors":"Jisung Hwang, Deok Yong Sim, Chi-Hoon Ahn, Su-Yeon Park, Jin-Suk Koo, Bum-Sang Shim, Bonglee Kim, Sung-Hoon Kim","doi":"10.1248/bpb.b24-00213","DOIUrl":"https://doi.org/10.1248/bpb.b24-00213","url":null,"abstract":"<p><p>Although Sanggenol L (SL), derived from the root bark of Morus alba, has hepatoprotective, neuroprotective, and antitumor effects, the antitumor mechanism of SL remains unclear to date. Thus, in the current work, the apoptotic mechanisms of SL were investigated in HepG2 and Huh hepatocellular carcinoma (HCC) cells in relation to leucine-rich repeat containing G protein-coupled receptor 5 (LGR5)/β-catenin and miR134 signaling axis. Herein, SL significantly incremented cytotoxicity, sub-G1 population, and the number of terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) positive apoptotic bodies and also inhibited proliferation in HCCs. Consistently, SL activated pro-Caspase7 and pro-Caspase3 and induced the cleavage of Poly ADP-ribose polymerase (PARP) in HCCs. Of note, the pivotal role of LGR5/β-catenin signaling was verified in SL-induced apoptosis in LGR5 overexpressed AML-12 cells and LGR5 depleted HepG2 cells. Furthermore, SL upregulated miR134 expression levels in HepG2 cells, while miR134 inhibitors disturbed the capacity of SL to cleave PARP and pro-Caspase3 in HepG2 cells. Taken together, our findings highlight evidence that inhibition of the LGR5/β-catenin axis and upregulation of miR134 play critical roles in SL-induced apoptosis in HCCs.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 2","pages":"126-131"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432318","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":"Recent Antimicrobial Resistance Situation and Mechanisms of Resistance to Key Antimicrobials in Enterotoxigenic Escherichia coli.","authors":"Daichi Morita, Teruo Kuroda","doi":"10.1248/bpb.b24-00649","DOIUrl":"https://doi.org/10.1248/bpb.b24-00649","url":null,"abstract":"<p><p>Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea in developing countries and is regularly imported into developed countries as a major cause of traveler's diarrhea. ETEC is usually self-limiting and not necessarily treated with antimicrobials, although antimicrobial treatment is recommended in malnourished children, severe cases, and traveler's diarrhea. However, resistant strains to representative therapeutic agents such as ciprofloxacin and azithromycin have been reported in recent years, and multidrug-resistant ETEC has also emerged. This review discusses the recent antimicrobial resistance surveillance in ETEC and the mechanisms of resistance to major antimicrobials.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"48 3","pages":"222-229"},"PeriodicalIF":1.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536441","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}
Dai Oyama, Masako Okada, Furan Song, Chiori Nitta, Hiroyuki Koide, Sei Yonezawa, Tomohiro Asai
{"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":"https://doi.org/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":"https://doi.org/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}