Biological & pharmaceutical bulletin最新文献

{"title":"Potential Therapeutic Strategies and Drugs That Target Vascular Permeability in Severe Infectious Diseases.","authors":"Yoshiaki Okada","doi":"10.1248/bpb.b24-00028","DOIUrl":"10.1248/bpb.b24-00028","url":null,"abstract":"<p><p>Severe infection pathogenicity is induced by processes such as pathogen exposure, immune cell activation, inflammatory cytokine production, and vascular hyperpermeability. Highly effective drugs, such as antipathogenic agents, steroids, and antibodies that suppress cytokine function, have been developed to treat the first three processes. However, these drugs cannot completely suppress severe infectious diseases, such as coronavirus disease 2019 (COVID-19). Therefore, developing novel drugs that inhibit vascular hyperpermeability is crucial. This review summarizes the mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced vascular hyperpermeability and identifies inhibitors that increase endothelial cell (EC) junction-related proteins and determines their efficacy in COVID-19 and endotoxemia models. Analyzing the effects of SARS-CoV-2 on vascular permeability revealed that SARS-CoV-2 suppresses Claudin-5 (CLDN5) expression, which is responsible for adhesion between ECs, thereby increasing vascular permeability. Inhibiting CLDN5 function in mice induced vascular hyperpermeability and pulmonary edema. In contrast, Enhancing CLDN5 expression suppressed SARS-CoV-2-induced endothelial hyperpermeability, suggesting that SARS-CoV-2-induced vascular hyperpermeability contributes to pathological progression, which can be suppressed by upregulating EC junction proteins. Based on these results, we focused on Roundabout4 (Robo4), another EC-specific protein that stabilizes EC junctions. EC-specific Robo4 overexpression suppressed vascular hyperpermeability and mortality in lipopolysaccharide-treated mice. An ALK1 inhibitor (a molecule that increases Robo4 expression), suppressed vascular hyperpermeability and mortality in lipopolysaccharide- and SARS-CoV-2-treated mice. These results indicate that Robo4 expression-increasing drugs suppress vascular permeability and pathological phenotype in COVID-19 and endotoxemia models.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 3","pages":"549-555"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140020888","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":"Combined Experiments with in Vivo Fiber Photometry and Behavior Tests Can Facilitate the Measurement of Neuronal Activity in the Primary Somatosensory Cortex and Hyperalgesia in an Inflammatory Pain Mice Model.","authors":"Tatsuya Ishikawa, Daisuke Uta, Hiroaki Okuda, Ilia Potapenko, Kiyomi Hori, Toshiaki Kume, Noriyuki Ozaki","doi":"10.1248/bpb.b23-00700","DOIUrl":"10.1248/bpb.b23-00700","url":null,"abstract":"<p><p>The pain matrix, which includes several brain regions that respond to pain sensation, contribute to the development of chronic pain. Thus, it is essential to understand the mechanism of causing chronic pain in the pain matrix such as anterior cingulate (ACC), or primary somatosensory (S1) cortex. Recently, combined experiment with the behavior tests and in vivo calcium imaging using fiber photometry revealed the interaction between the neuronal function in deep brain regions of the pain matrix including ACC and the phenotype of chronic pain. However, it remains unclear whether this combined experiment can identify the interaction between neuronal activity in S1, which receive pain sensation, and pain behaviors such as hyperalgesia or allodynia. In this study, to examine whether the interaction between change of neuronal activity in S1 and hyperalgesia in hind paw before and after causing inflammatory pain was detected from same animal, the combined experiment of in vivo fiber photometry system and von Frey hairs test was applied. This combined experiment detected that amplitude of calcium responses in S1 neurons increased and the mechanical threshold of hind paw decreased from same animals which have an inflammatory pain. Moreover, we found that the values between amplitude of calcium responses and mechanical thresholds were shifted to negative correlation after causing inflammatory pain. Thus, the combined experiment with fiber photometry and the behavior tests has a possibility that can simultaneously consider the interaction between neuronal activity in pain matrix and pain induced behaviors and the effects of analgesics or pain treatments.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 3","pages":"591-599"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140048678","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":"Pharmacokinetics of a Natural Self-emulsifying Reversible Hybrid-Hydrogel (N'SERH) Formulation of Full-Spectrum Boswellia serrata Oleo-Gum Resin Extract: Randomised Double-Blinded Placebo-Controlled Crossover Study.","authors":"Ashil Joseph, Maliakkal Balakrishnan Abhilash, Johannah Natinga Mulakal, Krishnakumar Illathu Madhavamenon","doi":"10.1248/bpb.b24-00306","DOIUrl":"10.1248/bpb.b24-00306","url":null,"abstract":"<p><p>The oleo-gum-resin of Boswellia serrata, an Ayurvedic herb for the treatment of chronic inflammatory diseases, contains both volatile (terpenes) and nonvolatile (boswellic acids) molecules as responsible for its bioactivity. The present randomized, double-blinded, placebo-controlled, crossover study evaluated the human pharmacokinetics of a 'natural' hybrid-hydrogel formulation of a unique full-spectrum boswellia extract (BFQ-20) (standardized for both volatile and nonvolatile bioactives) in comparison with unformulated extract (U-BE), for the first time. Mass spectrometry coupled with LC (UPLC-MS/MS) and gas chromatography (GC-MS/MS) measurements of the plasma concentration of boswellic acids and α-thujene at different post-administration time points followed by a single dose (400 mg) of U-BE and BFQ-20, to healthy volunteers (n = 16), offered 4-fold enhancement in the overall bioavailability of boswellic acids from BFQ-20, [area under the curve (AUC) (BFQ-20) = 9484.17 ± 767.82 ng * h/mL vs. AUC (U-BE) = 2365.87 ± 346.89 ng * h/mL], with the absorption maximum (T_max) at 6.3 h post-administration and elimination half-life (T_1/2) of 15.5 h (p < 0.001). While plasma α-thujene was not detectable upon U-BE administration, BFQ-20 provided significant absorption, [AUC (BFQ-20): 298.60 ± 35.48 ng * h/mL; C_max: 68.80 ± 18.60 ng/mL; T_max: 4.12 ± 0.38 h; T_1/2: 16.24 ± 1.12 h]. Further investigation of the anti-inflammatory effect revealed 70.5% inhibition of paw edema in rats compared to 38.0% for U-BE. In summary, the natural self-emulsifying reversible hybrid-hydrogel (N'SERH) formulation of boswellia extract using fenugreek mucilage (FenuMat^®) significantly increased the solubility (58-fold), stability, and bioavailability of both the volatile and non-volatile bioactives which in turn improved the anti-inflammatory efficacy of Boswellia extract.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 9","pages":"1583-1593"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142341003","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":"Bactericidal Efficacy of So-Called Sanitizers in Japan.","authors":"Ryosuke Funaki, Saki Nomura, Akira Ushima, Shigeharu Oie, Makoto Takada, Mitsuhiro Wada","doi":"10.1248/bpb.b24-00439","DOIUrl":"https://doi.org/10.1248/bpb.b24-00439","url":null,"abstract":"<p><p>Commercially available so-called sanitizers in Japan are often touted as having remarkable \"sanitizing (jokin)\" effect, \"virus-removal\" capabilities, and \"99.99%\" removal rate of microbes and pathogens. In this study, we investigated the bactericidal efficacy of these so-called sanitizers for environmental surfaces against Enterococcus faecalis and Pseudomonas aeruginosa. Of note, out of 43 products, 24 (55.8%) did not exhibit bactericidal effects on either Enterococcus or Pseudomonas. Among these 43 products, there were no bactericidal effects in 9 (47.4%) of 19 products that stated as containing \"alcohol\" as the formula; as well as 4 (80%) of 5 products stating only \"benzalkonium chloride\"; similarly no effect in 5 (83.3%) of 6 stating only\"chlorine chemicals.\" Furthermore, 6 (46.2%) of 13 products that stated components other than alcohol, benzalkonium chloride, and chlorine chemicals on the product container or with no description of constituent components failed to show any bactericidal effects. Four disinfectants (alcohol for disinfection, 0.1% benzalkonium chloride, 0.05% (500 ppm) hypochlorite, 0.1% (1000 ppm) hypochlorite) as control showed bactericidal effect. The lack of bactericidal activity in nearly half of sanitizers may be explained by the low concentration of the effective ingredient such as alcohol, benzalkonium chloride, and hypochlorite. In sanitizers containing hypochlorite, degradation of hypochlorite with prolongation of time after manufacturing may be another reason.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 10","pages":"1644-1647"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457197","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":"Differential Suppressive Effects of Rho Kinase Inhibitor Fasudil on Serotonin- and Noradrenaline-Induced Contractions of Human Internal Thoracic Arteries and Saphenous Veins.","authors":"Takayuki Matsumoto, Takayuki Nagano, Atsuko Yokota, Eisaku Nakamura, Masachika Kuwabara, Ryuichi Yamamoto, Naoko Tanaka-Totoribe","doi":"10.1248/bpb.b24-00502","DOIUrl":"10.1248/bpb.b24-00502","url":null,"abstract":"<p><p>Rho kinase inhibitor fasudil exerts therapeutic effects against vasospasms. In this study, we aimed to compare its suppressive effects on serotonin (5-HT)- and noradrenaline (NAd)-induced contractions of human endothelium-denuded internal thoracic arteries (ITAs) and saphenous veins (SVs). NAd and 5-HT induced concentration-dependent contractions in both ITAs and SVs. However, fasudil (3 µmol/L) pretreatment decreased these constrictor-induced contractions in both ITAs and SVs. Fasudil exerted similar inhibitory effects on 5-HT and NAd in ITAs. However, in SVs, fasudil exerted stronger inhibitory effects on NAd-induced contractions than on 5-HT-induced contractions. Therefore, inhibitory effects of fasudil on 5-HT-induced contractions were stronger in ITAs than in SVs. Overall, these results suggest that Rho kinases exert different effects on the two vasoconstrictors in SVs, but not in ITAs, thus explaining their different graft patencies.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 10","pages":"1657-1661"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457198","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":"Involvement of Proton-Coupled Organic Cation Antiporter in Human Blood-Brain Barrier Transport of Mesoridazine and Metoclopramide.","authors":"Yasuyuki Debori, Tomoko Igari, Masanori Nakakariya, Hideki Hirabayashi, Kazunobu Aoyama, Nobuyuki Amano, Toshiki Kurosawa, Yoshiyuki Kubo, Yoshiharu Deguchi","doi":"10.1248/bpb.b24-00329","DOIUrl":"10.1248/bpb.b24-00329","url":null,"abstract":"<p><p>Mesoridazine and metoclopramide are cationic drugs that are distributed in the human brain despite being substrates of multidrug resistance protein 1 (MDR1), an efflux transporter expressed at the blood-brain barrier (BBB). We investigated their transport mechanisms at the BBB using hCMEC/D3, a human cerebral microvascular endothelial cell line often used as an in vitro BBB model. The cells exhibited time- and concentration-dependent uptake of mesoridazine and metoclopramide, with K_m values of 34 and 277 µM, respectively. The uptake of both drugs significantly decreased in the presence of typical inhibitors and/or substrates of the H⁺-coupled organic cation (H⁺/OC) antiporter but not in the presence of inhibitors or substrates of organic cation transporters (OCTs), OCTN2, OATPs, SLC35F2, or the plasma membrane monoamine transporter (PMAT). Furthermore, metoclopramide uptake by hCMEC/D3 cells was pH- and energy-dependent, whereas mesoridazine uptake was unaffected by intracellular acidification and treatment with metabolic inhibitors. These results suggest that the H⁺/OC antiporter is involved in the influx of mesoridazine and metoclopramide into the brain across the BBB.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 10","pages":"1662-1667"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457199","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":"Different Effects of Berberine Delivery to Mitochondria on Cells Derived from the Neural Crest.","authors":"Ikuma Hori, Hideyoshi Harashima, Yuma Yamada","doi":"10.1248/bpb.b24-00463","DOIUrl":"https://doi.org/10.1248/bpb.b24-00463","url":null,"abstract":"<p><p>Energy metabolism is crucial for cell polarity and pathogenesis. Mitochondria, which are essential for maintaining energy homeostasis within cells, can be targeted by drug delivery to regulate energy metabolism. However, there is a lack of research comparing how mitochondria control energy metabolism in different cell types derived from the neural crest. Understanding the effects of berberine (BBR), a compound that acts on mitochondria, on energy metabolism in neural crest-derived cells is important. This study reports how MITO-Porter, a mitochondria-targeted liposome, affects neuroblasts (Neuro2a cells) and normal human epidermal melanocytes (NHEMs) when loaded with BBR. We found that treatment with MITO-Porter containing BBR reduced mitochondrial respiration in Neuro2a cells, while it caused a slight increase in NHEMs. Additionally, the treatment shifted the ATP production pathway in Neuro2a cells to rely more on glycolysis, while in NHEMs, there was a slight decrease in the reliance on glycolysis. We also observed a significant decrease in ATP production in Neuro2a cells, while NHEMs showed a tendency to increase ATP production. Importantly, on the basis of the results of the Premix WST-1 assay, the study found that BBR treatment was not toxic to either cell type. It is important to take note of the varied effects of BBR treatment on different cell types derived from the neural crest. These findings necessitate attention when utilizing NHEMs as a cell model in the development of therapeutic strategies for neurodegenerative diseases, including the use of BBR for metabolic control.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 10","pages":"1726-1733"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494569","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":"Cloperastine Reduces IL-6 Expression via Akt/GSK3/Nrf2 Signaling in Monocytes/Macrophages and Ameliorates Symptoms in a Mouse Sepsis Model Induced by Lipopolysaccharide.","authors":"Ayumi Kawamura, Atsushi Sawamoto, Satoshi Okuyama, Mitsunari Nakajima","doi":"10.1248/bpb.b24-00472","DOIUrl":"https://doi.org/10.1248/bpb.b24-00472","url":null,"abstract":"<p><p>Cloperastine (CLP) is a drug with a central antitussive effect that is used to treat bronchitis. Therefore, we have attempted to examine the anti-inflammatory effects of CLP. CLP reduced the secretion of interleukin (IL)-6, a pro-inflammatory cytokine, from RAW264.7 monocyte/macrophage-linage cells treated with lipopolysaccharide (LPS). IL-6 is a biomarker of sepsis and has been suggested to exacerbate its symptoms. We found that the intraperitoneal administration of CLP reduced IL-6 levels in the lungs and also improved hypothermia in mice with LPS-induced sepsis. CLP ameliorated kidney pathologies such as congestion and increased the survival rate of mice administered with a lethal dose of LPS. To reveal the mechanisms underlying the anti-inflammatory function of CLP, we analysed the intracellular signaling in LPS-treated RAW264.7 cells. CLP induced the phosphorylation of protein kinase B (Akt) and glycogen synthase kinase 3 (GSK3) and also increased the amount of nuclear factor erythroid-2-related factor 2 (Nrf2) in RAW264.7 cells with/without LPS. Wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K), reduced the upregulated phosphorylation levels of Akt and GSK3 and the increased amount of Nrf2. It also halted the reduction of IL-6 secretion caused by CLP. These results suggest that CLP has an anti-inflammatory function via Akt/GSK3/Nrf2 signaling and could be a candidate drug for the treatment of inflammatory diseases, including sepsis.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 10","pages":"1699-1707"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494497","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":"Impact of Interventions by Certified Pharmacists for Outpatients with Cancer Pain on Hospital Admission after the Introduction of Opioid Analgesics.","authors":"Masami Yamada, Tomoyoshi Miyamoto, Yumi Jimaru, Sari Torii, Naoko Mitsuba, Yuichi Muraki, Kazushige Takahashi","doi":"10.1248/bpb.b24-00358","DOIUrl":"https://doi.org/10.1248/bpb.b24-00358","url":null,"abstract":"<p><p>The treatment of patients with cancer in an outpatient setting is important for maintaining patients' QOL and reducing the social burden of therapy, thus requiring extensive intervention by pharmacists in the outpatient setting. Japan has a system to certify pharmacists with specialized knowledge and skills in palliative care. However, few studies have investigated the impact of certified pharmacists' activities and of pharmacists' interventions on hospitalization and outpatient visits. Therefore, in this study, we retrospectively investigated the effects of interventions by certified pharmacists during the period from the introduction of opioid analgesics to hospitalization for pain management and the duration of outpatient visits at a single acute care hospital. Analysis using the Cox proportional hazards model showed that interventions by certified pharmacists significantly reduced hospitalizations for pain management (p = 0.014). Further, the results of the log-rank test showed that interventions by certified pharmacists significantly prolonged the period from the introduction of opioid analgesics to hospitalization compared with the absence of such interventions (p = 0.013). Additionally, interventions by certified pharmacists significantly increased the duration of outpatient visits compared with the absence of such interventions (p < 0.001). These results suggest that active and careful interventions by pharmacists, including certified pharmacists, contribute to the maintenance of the patients' QOL and healthcare economics by extending the period from the introduction of opioid analgesics to hospitalization for pain management and the duration of outpatient visits.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 10","pages":"1746-1750"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543447","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":"Notice of Addendum for Biological and Pharmaceutical Bulletin.","authors":"","doi":"10.1248/bpb.b24-e4710","DOIUrl":"https://doi.org/10.1248/bpb.b24-e4710","url":null,"abstract":"","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"47 10","pages":"1796"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543450","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}