Biol. Pharm. Bull. [JOURNAL]
Sun
200 papers
Comparison of Trough-Only and Peak-Trough Concentration Data for the Calculation of Vancomycin Area under the Concentration-Time Curve on Day 1 or Day 2.
Endo M, Niwa T, Yamada Y … +7 more , Goto-Fujibayashi A, Sumi K, Otsubo M, Ichihashi N, Hara K, Miyashita R, Suzuki A
Biol Pharm Bull · 2025 · PMID 41371636 · Publisher ↗
Area under the concentration-time curve (AUC)-guided vancomycin dosing is recommended to measure peak and trough concentrations. While recent studies have shown that AUC on Day 1 and Day 2 are associated with early clini...
Area under the concentration-time curve (AUC)-guided vancomycin dosing is recommended to measure peak and trough concentrations. While recent studies have shown that AUC on Day 1 and Day 2 are associated with early clinical response and nephrotoxicity, data confirming the accuracy of AUC estimation using trough-only data on Day 1 and Day 2 are scarce. The aim of this study was to evaluate the agreement of AUC calculated using trough-only data compared with 2-point sampling on Day 1 and Day 2 using the Bayesian-based, free web application PAT (Practical AUC-guided TDM for vancomycin). We conducted a single-center, cohort study to evaluate the agreement of AUC calculated using trough-only data compared to peak-trough sampling on Day 1 and Day 2. The ratios of trough/peak-trough AUC for AUC and AUC were within the acceptable range of 0.8-1.2. Furthermore, AUCs estimated using trough-only data and those estimated using peak-trough concentrations showed high agreement. In addition, multivariate ordinal logistic regression analysis showed that estimated glomerular filtration rate and serum albumin were significant factors affecting the deviation of trough/peak-trough AUC (p = 0.001 and p = 0.040, respectively). In conclusion, trough-only data may be sufficient for AUC estimation in AUC-guided dosing in patients identified as suitable candidates, even when obtained on Day 2. Further, renal function and serum albumin were found to be factors affecting the agreement rate of AUC on Day 2 when using trough-only data.
Polygalacin D Prevents Breast Cancer Progression through Proteasome-Mediated Degradation of HDAC1 and HDAC2.
Zhang X, Wang F, Dai Y … +2 more , Gao Z, He J
Biol Pharm Bull · 2025 · PMID 41371635 · Publisher ↗
Platycodon grandiflorum (P. grandiflorum), a traditional Chinese herbal medicine, possesses various biological activities. Among its constituents, polygalacin D (PGD) stands out as one of the principal compounds. This st...
Platycodon grandiflorum (P. grandiflorum), a traditional Chinese herbal medicine, possesses various biological activities. Among its constituents, polygalacin D (PGD) stands out as one of the principal compounds. This study determined the regulatory effect of PGD on breast cancer progression. Breast cancer cells MCF-7 and BT474 were treated with different concentrations of PGD. Colony formation assays, the detection of Ki67 expression, and cell cycle analysis were performed to verify the effect of PGD on the proliferation of breast cancer cells. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, flow cytometry, and examination of caspase-3 activity were conducted to assess the changes in apoptosis following PGD treatment. In addition, the co-treatment of PGD and cisplatin (DDP) on cells was performed to explore the effect of PGD on the chemosensitivity of DDP. Furthermore, bioinformation analysis suggested that histone deacetylase 1 (HDAC1) and HDAC2 were the downstream factors of PGD, and the effect of PGD on their expression was assessed. PGD inhibited breast cancer cell proliferation, as evidenced by reduced colony formation, downregulation of Ki67 expression, and induction of cell cycle arrest. Additionally, PGD treatment significantly increased caspase-3 activity and elevated the rate of cell apoptosis and TUNEL-positive cells. Furthermore, PGD was found to enhance the chemosensitivity to DDP. Mechanistically, PGD reduced the expression of HDAC1 and HDAC2 by promoting their protein degradation. Cell proliferation induced by HDAC1 or HDAC2 was also overcome by PGD. In conclusion, PGD was confirmed as an effective tumor inhibitor that suppressed the development of breast cancer by regulating HDAC1 and HDAC2.
Coagulation and Fibrinolysis Profiles in Mouse Breast Cancer 4T1 Tumor-Bearing Mice: A Characterization of Neutrophil-Associated Prothrombotic States.
Morimoto-Kamata R, Munakata L, Kageyama S … +4 more , Maruyama K, Suzuki R, Kamikubo Y, Ohkura N
Biol Pharm Bull · 2025 · PMID 41371634 · Publisher ↗
Cancer-associated thrombosis is the second leading cause of death in patients with cancer. The highly metastatic triple-negative mouse breast cancer cell line 4T1 induces thrombus formation that is dependent on neutrophi...
Cancer-associated thrombosis is the second leading cause of death in patients with cancer. The highly metastatic triple-negative mouse breast cancer cell line 4T1 induces thrombus formation that is dependent on neutrophil extracellular traps (NETs) in transplanted mice when exposed to certain stimuli, such as lipopolysaccharide (LPS) injection. These findings suggest that 4T1 transplantation into mice increases the susceptibility to NET release, followed by thrombus formation in response to external stimuli. However, the blood levels of coagulation-associated factors in 4T1-bearing mice that are in a primed state without any stimulation remain unknown. In this study, we analyzed coagulation and fibrinolytic factors in the plasma of mice orthotopically transplanted with 4T1 cells. In 4T1-bearing mice, a NET marker, citrullinated histone H3, was detected in the tumor tissues and lungs, but not in the plasma. The presence of fibrin(ogen)-containing Ly6G-positive cell clusters in the lung vasculature suggested that NET release and NET-induced microthrombus formation occurred in the lungs. In plasma, increased levels of tissue factor and active and total plasminogen activator inhibitor-1 (PAI-1) suggested enhanced procoagulant activity and suppressed fibrinolysis. However, plasma thrombin-antithrombin complex levels, which reflect overt thrombin activation that forms fibrin clots, were similar in 4T1-bearing and non-transplanted mice. These findings indicate that 4T1 cell growth and metastasis in mice establish a pre-thrombotic state characterized by NET release and procoagulant potential, which requires a secondary trigger, such as LPS, to develop into pathological thrombosis. Therefore, 4T1-bearing mice may be useful as an in vivo model for exploring secondary triggers of pathological thrombosis.
Oncolytic Reovirus-Induced Prostaglandin E2 Production in Human Tumor Cells.
Ishigami I, Shimada H, Ihara A … +3 more , Kawase A, Mizuguchi H, Sakurai F
Biol Pharm Bull · 2025 · PMID 41354424 · Publisher ↗
Oncolytic viruses, which kill tumor cells by tumor cell-specific replication, elicit superior antitumor immunity by efficiently activating the innate immune system. However, innate immunity-mediated inflammation is an un...
Oncolytic viruses, which kill tumor cells by tumor cell-specific replication, elicit superior antitumor immunity by efficiently activating the innate immune system. However, innate immunity-mediated inflammation is an undesirable consequence that often induces cellular production of immunosuppressive cellular factors. Among various immunosuppressive cellular factors, much attention has recently been focused on prostaglandin E2 (PGE2). In this study, we examined PGE2 production in human tumor cells following treatment with the mammalian orthoreovirus type 3 Dearing strain (hereafter reovirus), which has been used as an oncolytic virus in preclinical and clinical studies. Reovirus significantly induced PGE2 secretion from several types of human tumor cells in a virus titer-dependent manner. A nuclear factor-kappa B (NF-κB) inhibitor, BAY11-7082, and a cyclooxygenase 2 (COX2) inhibitor, celecoxib, significantly inhibited PGE2 secretion, indicating that NF-κB and COX2 played a crucial role in reovirus-induced PGE2 production. Moreover, UV-irradiated reovirus (UV-Reo), which lost virus replication ability, did not increase PGE2 secretion. In addition, inhibitors of cathepsins B and L, cysteine lysosomal proteases crucial for reovirus replication, significantly reduced PGE2 secretion. These results indicate that reovirus replication in tumor cells is important for reovirus-induced PGE2 production. Attention should be paid to possible PGE2 production in tumors following reovirus treatment.
Inhibition of Cell Proliferation by Euphorbia Factors L1 and L3 from Euphorbia lathyris through the ATF4-CHOP.
Yun YS, Niimura S, Kawai K … +6 more , Shimamura M, Takeshita A, Fuchino H, Kawahara N, Takahashi Y, Inoue H
Biol Pharm Bull · 2025 · PMID 41354423 · Publisher ↗
A luciferase reporter gene assay demonstrates that a methanol extract of the aerial parts of Euphorbia lathyris L. activates reporter gene expression mediated by CCAAT-enhancer-binding protein homologous protein (CHOP) t...
A luciferase reporter gene assay demonstrates that a methanol extract of the aerial parts of Euphorbia lathyris L. activates reporter gene expression mediated by CCAAT-enhancer-binding protein homologous protein (CHOP) transcriptional activity in the human pancreatic cancer cell line MIA PaCa-2. We isolated 2 lathyrane-type diterpenoids, euphorbia factor L1 (EFL1) and L3 (EFL3), from the extracts. This is the first report of their isolation from aerial parts of this plant. Treatment of the MIA PaCa-2 with EFL1 or EFL3 increased the levels of phosphorylated inositol-requiring enzyme 1 alpha (IRE1α), activating transcription factor 4 (ATF4) and CHOP, involved in the endoplasmic reticulum (ER) stress pathway and cleaved poly (ADP-ribose) polymerase protein (PARP), as apoptotic markers, and inhibited cell proliferation. Thus, EFL1 and EFL3 may be useful in the development of treatments for pancreatic cancer.
Effectiveness of Outpatient Pharmaceutical Clinics in the Overseeing of Self-Injectable Biologic Prescriptions for Inflammatory Immune Diseases and the Cost-Effectiveness of Pharmacological Management.
Oba H, Hirata I, Inoue M … +4 more , Ogura C, Mori K, Rokutanda R, Funakoshi R
Biol Pharm Bull · 2025 · PMID 41354422 · Publisher ↗
Pharmacists provide pharmacological management prior to a physician visit, which is effective for the smooth introduction of biologics and the avoidance of serious side effects. However, pharmacists face challenges in im...
Pharmacists provide pharmacological management prior to a physician visit, which is effective for the smooth introduction of biologics and the avoidance of serious side effects. However, pharmacists face challenges in implementing pharmacological management through dispensing alone. Furthermore, reports on the high risk of side effects associated with biologics remain limited. In this study, we investigated the cost-effectiveness and clinical impact of pharmaceutical management in outpatient pharmaceutical clinics for inflammatory immune diseases, from before the introduction of biologics until 52 weeks after introduction. The number of pharmacological management cases and their associated cost-effectiveness were compared between dispensing and outpatient pharmaceutical clinic groups. Patients aged ≥18 years with an autoimmune disease who were instructed to self-inject biologics between April 2018 and March 2023 were included. The primary outcome was the number of pharmacological management cases performed at the time of biologic introduction. A total of 264 eligible patients were identified, of whom 54 were excluded. After propensity score matching, patients were assigned to 2 groups (n = 67 each). Pharmacological management was significantly more common in the outpatient pharmaceutical clinic group (p < 0.05) than in the dispensing group. In the outpatient clinic group, 10 patients (14.9%) avoided severe adverse events, whereas avoidance was not observed in the dispensing group. The financial benefits of pharmacological management were 915000 and 26091000 yen in the dispensing and outpatient pharmaceutical clinic groups, respectively. Overall, this study demonstrated that pharmacist-led outpatient clinics targeting inflammatory autoimmune diseases can help prevent serious adverse drug reactions and are significantly cost-effective.
The Combination of Phytic Acid and Inositol Alleviates Metastasis of Colorectal Cancer in Mice by Inhibiting PI3K/AKT Pathway and M2 Macrophage Polarization.
Yan S, Lan T, Wang H … +7 more , Wang N, Hou Q, Luan Y, Shi Y, Hu S, Gong X, Song Y
Biol Pharm Bull · 2025 · PMID 41339008 · Publisher ↗
This study established an orthotopic mouse model of colorectal cancer (CRC) liver metastasis to investigate the inhibitory effects of combined phytic acid (IP6) and inositol (INS) at different ratios on CRC liver metasta...
This study established an orthotopic mouse model of colorectal cancer (CRC) liver metastasis to investigate the inhibitory effects of combined phytic acid (IP6) and inositol (INS) at different ratios on CRC liver metastasis, as well as their impact on the phosphatidylinositol 3-kinase/serine/threonine protein kinase (PI3K/AKT) signaling pathway and macrophage polarization. Combined treatment with varying ratios of IP6 and INS significantly enhanced survival rates and reduced both cecal tumor weight and the incidence of liver metastasis. Flow cytometry indicated an increased CD4/CD8 T cell ratio and a decrease in regulatory T cells, with the 1 : 3 group showing the most pronounced effects (p < 0.05). Cytokine levels were modulated after treatment with varying IP6-to-INS ratios, with a significant reduction in CCL20, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) (p < 0.05), and an increase in IL-10 and transforming growth factor-β (TGF-β) (p < 0.05). Western blot analysis confirmed a significant downregulation of PI3K/AKT pathway proteins, including PI3K, phosphorylated (p)-PI3K, AKT, p-AKT, and mammalian target of rapamycin (p < 0.05), with the 1 : 3 group exhibiting the greatest effect. Additionally, the expression of M2 macrophage polarization-related proteins CD163 and CD206 was downregulated (p < 0.05). Our findings suggest that the combination of IP6 and INS alleviates CRC metastasis by downregulating the PI3K/AKT pathway and influencing macrophage polarization, with the most significant inhibitory effect observed at an IP6-to-INS ratio of 1 : 3.
A Novel RORγ-Selective Agonist Facilitates the Infiltration of Effector T Cells and Innate Immune Cells into Tumor Tissue, Demonstrating Antitumor Efficacy.
Terawaki T, Suzukawa A, Tanimoto M … +2 more , Fukuda S, Yamaguchi T
Biol Pharm Bull · 2025 · PMID 41338992 · Publisher ↗
Retinoic acid receptor-related orphan receptor gamma (RORγ) is a key transcriptional factor that plays a crucial role in the differentiation and activation of Type 17 cells, such as interleukin-17 (IL-17)-producing CD4 T...
Retinoic acid receptor-related orphan receptor gamma (RORγ) is a key transcriptional factor that plays a crucial role in the differentiation and activation of Type 17 cells, such as interleukin-17 (IL-17)-producing CD4 T (Th17) cells and CD8 T (Tc17) cells, which are known to boost antitumor responses. Although a RORγ agonist (LYC-55716) has been under clinical evaluation, the precise effects of RORγ agonists on immune cells within tumor environments remain unclear. In our study, we investigated the role of tumor-infiltrating immune cells in the MC38 syngeneic mouse model of colorectal cancer using Compound-34, a novel orally available RORγ-selective agonist we discovered. Our findings revealed that Compound-34 exerts its antitumor efficacy by modulating immune cell activity rather than directly targeting tumor cells. Specifically, Compound-34 increased the infiltration of effector T cells, including Th17 and Tc1 (interferon [IFN]-γ CD8 T) cells, as well as innate immune cells like natural killer (NK) and natural killer T (NKT) cells, within the MC38 tumor tissue. Following the administration of Compound-34, there was an increase in IFNγ and Granzyme B within the MC38 tumor tissue, accompanied by an increase in the infiltration of cytotoxic immune cells. Moreover, the addition of Th17-derived cytokines to MC38 cells stimulated the release of CXCL10, a chemokine crucial for immune cell recruitment. These results offer valuable insights into the immunomodulatory and therapeutic potential of RORγ agonists in cancer immunotherapy, highlighting their role in enhancing immune cell infiltration and activity within tumors.
Comparative Study of Histone Deacetylase Inhibitors for Radiation Protection Using Survival Outcomes in a Mouse Model.
Kurokawa Y, Watanabe S, Yano T … +3 more , Hidaka N, Yamaguchi T, Tanaka M
Biol Pharm Bull · 2025 · PMID 41320313 · Publisher ↗
Histone deacetylases (HDACs) regulate chromatin structure and gene expression, and their inhibition has been proposed as a radioprotective strategy. However, few studies have compared multiple HDAC inhibitors (HDACis) un...
Histone deacetylases (HDACs) regulate chromatin structure and gene expression, and their inhibition has been proposed as a radioprotective strategy. However, few studies have compared multiple HDAC inhibitors (HDACis) under identical conditions. This study evaluated the efficacy of seven HDACis in a mouse total body irradiation (TBI) model. Male ICR mice received 7.5 Gy TBI followed by a single administration of valproic acid (VPA; 300 or 600 mg/kg), sodium butyrate (NaB; 500 or 1000 mg/kg), trichostatin A (TSA; 0.5 or 1.0 mg/kg), vorinostat (10 or 50 mg/kg), panobinostat (25 or 50 mg/kg), givinostat (5 or 10 mg/kg), or entinostat (25 or 50 mg/kg). Survival was monitored for 20 d. Only VPA at 600 mg/kg significantly improved survival compared with vehicle (overall p = 0.00241; p = 0.0039 vs. vehicle), while all other HDACis showed no significant benefit. VPA's efficacy may reflect a combination of effects on DNA repair, inflammation, and redox regulation rather than HDAC inhibition alone. These findings suggest VPA to be a promising candidate for radioprotection and emphasize the need for further studies to optimize dosing and explore underlying mechanisms.
Incidence of Hepatobiliary Injury in Patients Undergoing Dai-kenchu-to Administration Following Gastrectomy: A Retrospective Cohort Study Using Japanese Diagnosis Procedure Combination Data.
Wada Y, Watanabe S, Nagata J … +3 more , Asakawa T, Hirata K, Fujino Y
Biol Pharm Bull · 2025 · PMID 41320312 · Publisher ↗
Dai-kenchu-to is used to prevent and relieve ileus post-gastrectomy; however, it has been reported to cause hepatobiliary injury in 0.3% of patients, and knowledge regarding its risk in this context is limited. In this s...
Dai-kenchu-to is used to prevent and relieve ileus post-gastrectomy; however, it has been reported to cause hepatobiliary injury in 0.3% of patients, and knowledge regarding its risk in this context is limited. In this study, we aimed to evaluate the effect of dai-kenchu-to, a representative traditional Japanese herbal medicine, on the risk of hepatobiliary injury in patients with gastric cancer who underwent gastrectomy, using real-world data from acute care hospitals. The diagnosis procedure combination data of patients admitted with gastric cancer who underwent gastrectomy between April 2008 and May 2019 were analyzed. The collected data included sex, age, comorbid injuries and illnesses at admission, medication records during hospitalization, and tumor node metastasis classifications. The primary outcome, occurrence of hepatobiliary injury, was identified using records of the use of hepatoprotective agents or cholagogues. The odds ratios of dai-kenchu-to for predisposition to hepatobiliary injury after gastrectomy were estimated using multivariate logistic regression analysis. Herein, 33137 gastric cancer patients who underwent gastrectomy were included in the analysis. The incidences of hepatobiliary injury among patients in the dai-kenchu-to-exposed and non-exposed groups were both 5.9%. The multivariate odds ratio of dai-kenchu-to exposure for hepatobiliary injury was 0.97 (95% confidence interval, 0.73-1.29; p = 0.847). In this study, no risk of moderate-to-severe hepatobiliary injury due to the postoperative administration of dai-kenchu-to was noted in patients with gastric cancer who had undergone gastrectomy. These results provide information regarding the safety of dai-kenchu-to use after gastrectomy in patients with gastric cancer.
Propofol Alleviates LPS-Induced Acute Lung Injury by Inhibiting Pulmonary Alveolar Epithelium Pyroptosis.
Zhang X, Tian X, Wang J … +1 more , Zhuang Y
Biol Pharm Bull · 2025 · PMID 41320311 · Publisher ↗
This study established experimental models of acute lung injury (ALI) both in vitro, using human alveolar epithelial cells, and in vivo, using murine models, with ALI induced by lipopolysaccharide (LPS). Propofol was adm...
This study established experimental models of acute lung injury (ALI) both in vitro, using human alveolar epithelial cells, and in vivo, using murine models, with ALI induced by lipopolysaccharide (LPS). Propofol was administered to the animal models, and its effects on alveolar epithelial cell damage, lung tissue pathology, and inflammatory mediator levels were evaluated to assess its potential protective role against lung injury. The results showed that LPS-induced reactive oxygen species (ROS) played a central role in the development of ALI in both the cell and animal models, triggering pyroptosis of alveolar epithelial cells. This, in turn, led to the release of pro-inflammatory cytokines, exacerbating the lung injury. Importantly, propofol was found to reduce LPS-induced ALI by inhibiting ROS production and modulating key proteins involved in the pyroptosis pathway. These findings offer new insights into the mechanisms underlying ALI, providing a basis for the development of clinical treatments and suggesting promising therapeutic strategies for ALI patients.
Protective Effects of Maternal Administration of a Standardized Extract of Cultured Lentinula edodes Mycelia against Radiation-Induced Fetal Morphological Abnormalities.
Adachi S, Tougan T, Kimura C … +4 more , Takanari J, Wakame K, Aoshi T, Nomura T
Biol Pharm Bull · 2025 · PMID 41320310 · Publisher ↗
Exposure to ionizing radiation during early pregnancy poses serious risks to fetal development, particularly during organogenesis. In this study, we evaluated the protective effects of AHCC, a standardized extract of Len...
Exposure to ionizing radiation during early pregnancy poses serious risks to fetal development, particularly during organogenesis. In this study, we evaluated the protective effects of AHCC, a standardized extract of Lentinula edodes mycelia with known immunomodulatory and metabolic properties, using an ICR mouse model. Intraperitoneal administration of AHCC prior to 1.4-Gy γ-irradiation on gestational day 9 significantly reduced the incidence of tail malformations and diaphragmatic hernias, without affecting implantation or fetal survival. Additionally, lifelong AHCC ingestion across three generations did not alter reproductive parameters, namely, gestation length and litter size, supporting its safety during pregnancy. These findings suggest that AHCC may mitigate radiation-induced teratogenic effects through maternal immune modulation, without compromising reproductive outcomes.
Visualization and Optical Manipulation of the Erectile Tissue, Penile Corpus Cavernous.
Hashimoto D, Yamada G, Fujimoto K … +6 more , Nakata M, Noda M, Suzuki K, Asamura S, Kawakami Y, Hotta Y
Biol Pharm Bull · 2025 · PMID 41320274 · Publisher ↗
Erectile responses in reproduction have not been analyzed extensively because of the limitation of their visualization analyses of inner penile structure and its dynamic changes. In addition, the complex and rapid change...
Erectile responses in reproduction have not been analyzed extensively because of the limitation of their visualization analyses of inner penile structure and its dynamic changes. In addition, the complex and rapid changes of erectile responses require new manipulation techniques suitable to regulate erected and flaccid status. The current review describes novel strategies for the above visualization of erection and regulation of the erectile responses.
Protein Posttranslational Modifications in Glioma Stem Cells.
Hinoi E
Biol Pharm Bull · 2025 · PMID 41320273 · Publisher ↗
Glioblastoma (GBM) is the most malignant form of glioma. Glioma stem cells (GSCs) contribute to the initiation, progression, and recurrence of GBM via their self-renewal potential and tumorigenicity. This review presents...
Glioblastoma (GBM) is the most malignant form of glioma. Glioma stem cells (GSCs) contribute to the initiation, progression, and recurrence of GBM via their self-renewal potential and tumorigenicity. This review presents a brief overview of the influences of two protein posttranslational modifications in GSCs on the properties of GSCs and malignancy of GBM: (I) the ubiquitination of transforming growth factor (TGF)-β receptor (TGFBR) by SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) and (II) the phosphorylation of extracellular signal-regulated kinase 5 (ERK5) by mitogen-activated protein kinase/ERK kinase 5 (MEK5). The phosphorylation state of SMURF2Thr249 regulates the stemness and tumorigenicity of GSCs via the ubiquitin-dependent modification of the TGFBR-SMAD-SOX axis, along with the downregulation of SMURF2Thr249 phosphorylation in patients with GBM. MEK5 controls the self-renewal and tumorigenic potential of GSCs by phosphorylating the ERK5-signal transducer and activator of transcription 3 (STAT3) axis concomitant with high expression and activity of ERK5 in GSCs. These findings contributed to our understanding of the molecular mechanisms underlying the maintenance of the stemness and tumorigenicity of GSCs through protein posttranslational modifications. We propose that these two protein posttranslational modifications in GSCs might be explored as an effective therapeutic approach against various cancers whose malignancies are associated with the stemness of cancer stem cells.
Assessment of μ-Opioid Receptor Signaling Responses for Fentanyl Analogs Using Luciferase Complementation Assay.
Ono Y, Tayama K, Makino K … +4 more , Sakamoto M, Suzuki J, Takahashi H, Inomata A
Biol Pharm Bull · 2025 · PMID 41260693 · Publisher ↗
To study the toxicity of fentanyl analogs that damage the liver and kidneys in rats, these analogs were evaluated by examining two types of μ-opioid receptor (MOR) signaling responses using HEK293 cells. The results indi...
To study the toxicity of fentanyl analogs that damage the liver and kidneys in rats, these analogs were evaluated by examining two types of μ-opioid receptor (MOR) signaling responses using HEK293 cells. The results indicated that, in the MOR-mini-Gi recruitment assay, the 50% effective concentration (EC) ranked as iBF < DAMGO ≈ 4F-iBF < 4Cl-iBF, and the maximum response (E) ranked as iBF ≈ DAMGO > 4F-iBF > 4Cl-iBF. In the MOR-β-arrestin 2 recruitment assay, the EC ranking was DAMGO < iBF < 4F-iBF < 4Cl-iBF, and the E ranking was DAMGO > iBF > 4F-iBF. In addition, each of the desphenethylated metabolites, likely the major metabolites of these analogs, showed no MOR signaling responses.
Feeding Time-Dependent Changes in the Preventive Effect of Empagliflozin on the Development of Peripheral Neuropathic Pain in Diabetic Model Mice.
Sato A, Iwanaka N, Yamauchi T … +3 more , Tsuruta A, Ohdo S, Koyanagi S
Biol Pharm Bull · 2025 · PMID 41260692 · Publisher ↗
It is known that the daily feeding cycle affects the dosing time-dependent changes in the pharmacodynamics and pharmacokinetics of many drugs. Our previous study demonstrated that administration of empagliflozin (EMPA),...
It is known that the daily feeding cycle affects the dosing time-dependent changes in the pharmacodynamics and pharmacokinetics of many drugs. Our previous study demonstrated that administration of empagliflozin (EMPA), sodium-glucose cotransporter 2 (SGLT2) inhibitor, at the beginning of daily feeding cycle (active phase) effectively prevents the development of neuropathic pain in streptozotocin (STZ)-induced diabetic mice. Although the blood glucose levels are closely related to feeding, the relationship between the daily feeding cycle and the optimal dosing time of EMPA remains unclear. In this study, we used STZ-induced diabetic mice and implemented a daily time-restricted feeding (TRF) regimen to investigate whether the dosing time-dependent preventive effect of EMPA on the diabetic neuropathy is modulated by TRF. Animals were housed under a 12-h light/dark cycle, and were assigned to either light-phase TRF (feeding during the light phase) or dark-phase TRF (feeding during the dark phase). The hypoglycemic effect of EMPA was enhanced when the drug was administrated at the beginning of both TRF conditions. A similar influence of the daily feeding cycle on the dosing time-dependent hypoglycemic effect of EMPA was also observed in its preventive effect on the development of diabetic neuropathic pain. Further analysis revealed that dosing time-dependent variations in both the hypoglycemic effect of EMPA and its preventive effect on diabetes-induced pain hypersensitivity were attributable to corresponding changes in urinary glucose excretion. Our results support the notion that the administration of EMPA at the onset of daily feeding cycle effectively suppresses the development of diabetic peripheral neuropathy.
Pinpoint Insertion of a Single Amino Acid into a Framework Region Enhanced the Affinity of an Anti-cortisol Antibody to Enable Sensitive Immunoassays.
Kiguchi Y, Morita I, Kobayashi N … +1 more , Takegami S
Biol Pharm Bull · 2025 · PMID 41260691 · Publisher ↗
"Antibody engineering" is a promising strategy for generating high-affinity antibodies required for developing sensitive immunoassays. Therein, the variable domains (V and V) of the parental antibody are genetically rand...
"Antibody engineering" is a promising strategy for generating high-affinity antibodies required for developing sensitive immunoassays. Therein, the variable domains (V and V) of the parental antibody are genetically randomized and combined to produce diverse single-chain Fv fragment (scFv) molecules. Subsequently, high-affinity scFv mutants are selectively isolated. In the randomization process, mutations have conventionally been targeted to the complementarity-determining regions (CDRs) in the variable domains, which often interact directly with antigens. However, we previously discovered that, pinpoint insertion of only a single amino acid (leucine, asparagine, aspartic acid, proline, glutamine, arginine, or histidine) between positions 6 and 7 in the framework region 1 (FR1) of the V, which is unlikely to interact with antigens, enhanced the affinity of an anti-cortisol scFv (original K, 3.6 × 10 M) up to 17-61-fold. These findings prompted us to conduct a comprehensive study of this affinity-enhancement phenomenon involving the remaining amino acids. Thus, we generated the necessary 13 scFv mutants and compared their K values. Remarkably, all mutants showed enhanced affinities, similar to those of the previous 7 mutants. Among the 20 mutants, the leucine-inserted scFv showed the largest K (2.2 × 10 M) and consequently enabled a 75-fold more sensitive enzyme-linked immunosorbent assay (midpoint, 9.86 pg/assay) compared to the assay using the parental scFv (midpoint, 744 pg/assay). In silico modeling suggested that, regardless of the amino acid inserted, elongated FR1 can alter the conformation of the CDR3 in V to facilitate a favorable interaction with cortisol.
A Multicenter Retrospective Observational Study on Drug-Drug Interactions between Opioid Analgesics and Immune Checkpoint Inhibitors in Cancer Patients.
Miyasato A, Hidaka N, Funato M … +5 more , Nakamura K, Ouchi R, Awaji K, Aoyama T, Kokubun H
Biol Pharm Bull · 2025 · PMID 41260678 · Publisher ↗
Opioid analgesics are indispensable therapeutic agents for patients experiencing cancer pain. Recently, immune checkpoint inhibitors (ICIs) have made substantial progress in cancer treatment, and the range of cancer type...
Opioid analgesics are indispensable therapeutic agents for patients experiencing cancer pain. Recently, immune checkpoint inhibitors (ICIs) have made substantial progress in cancer treatment, and the range of cancer types for which they are applicable has expanded. Consequently, the combined use of ICIs with other drugs has also increased. However, it has been pointed out that ICIs may interfere with opioid nociception and weaken the analgesic effects of opioids. Therefore, in this study, we investigated the drug-drug interactions between opioid analgesics and ICIs in patients with cancer, especially their influence on analgesic effects. A multicenter collaborative study was conducted to investigate changes in pain intensity in patients with cancer pain who were prescribed opioid analgesics and ICIs. As a result, when opioids were administered to patients receiving ICIs, the median pain intensity, measured using the Numerical Rating Scale (NRS), significantly decreased from 4.5 at baseline to 3.0 on Day 1 and 2.5 on Day 7, demonstrating favorable analgesic effects. Similarly, when ICIs were administered to patients receiving opioids, the median pain intensity (NRS) significantly decreased from 3.0 at baseline to 2.0 on Day 1 and 2.75 on Day 7. These results suggest that opioids provided effective analgesia when administered alongside ICIs.
Downregulation of HepaRG Cell CYP Genes by Hypoxia Inducible Factor Prolyl Hydroxylase (HIF-PH) Inhibitor.
Murata H, Kobayashi S, Nomura Y … +1 more , Iwanaga K
Biol Pharm Bull · 2025 · PMID 41260677 · Publisher ↗
Metabolic enzymes are occasionally downregulated in in vitro induction studies. Recently, HepaRG cells have been used for CYP induction assays instead of human hepatocytes in the early drug discovery stage; however, ther...
Metabolic enzymes are occasionally downregulated in in vitro induction studies. Recently, HepaRG cells have been used for CYP induction assays instead of human hepatocytes in the early drug discovery stage; however, there is limited information on CYP downregulation by drug stimulation. In this study, we evaluated the effect of hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, which downregulate CYP in human hepatocytes, on CYP gene expression in HepaRG cells. Microarray analysis to determine the expression levels of pharmacokinetics-related enzymes and RT-PCR to determine the expression levels of CYP3A4, CYP2B6, CYP1A2, and their nuclear receptor mRNA were conducted in HepaRG cells treated with HIF-PH inhibitors. Treatment of HepaRG cells with HIF-PH inhibitors decreased the expression of several pharmacokinetics-related metabolic enzymes, whereas Erythropoietin (EPO) and Pyruvate Dehydrogenase Kinase1 (PDK1) genes were induced. The expression of CYP3A4 and CYP2B6 in HepaRG cells showed concentration- and time-dependent downregulation following treatment with the HIF-PH inhibitor. The downregulation of these enzymes was correlated with the decrease of PXR/RXRα and CAR/RXRα, respectively. CYP1A2 decreased transiently, but recovered with continued HIF-PH inhibitor treatment. CYP3A4 and CYP2B6 were downregulated by HIF-PH inhibitors in HepaRG cells and human hepatocytes. In contrast, CYP1A2 in HepaRG cells responded differently to HIF-PH inhibitors than in human hepatocytes. Since CYP downregulation is commonly observed with HIF-PH inhibitors, along with the induction of EPO and PDK1 genes, stabilizing HIF may be one of the factors involved in CYP downregulation.
Grandifloridin D: A Potent Antiausterity Agent Targeting Pancreatic Cancer Cells via Akt/mTOR and Autophagy Inhibition.
Nguyen HH, Maneenet J, Fujii T … +3 more , Caggiano L, Lewis SE, Awale S
Biol Pharm Bull · 2025 · PMID 41260676 · Publisher ↗
The hypovascular nature of pancreatic tumors creates a nutrient-scarce, hypoxic microenvironment, yet pancreatic cancer cells adapt by altering their metabolism to thrive under austere conditions-a phenomenon known as "a...
The hypovascular nature of pancreatic tumors creates a nutrient-scarce, hypoxic microenvironment, yet pancreatic cancer cells adapt by altering their metabolism to thrive under austere conditions-a phenomenon known as "austerity." Targeting this adaptation offers a promising strategy for next-generation therapeutics that selectively impair pancreatic cancer cell viability in nutrient-deprived states without toxicity under nutrient-rich conditions. Here, we evaluated the anti-pancreatic cancer properties of grandifloridin D, a synthetic derivative of (+)-grandifloracin. In vitro antiausterity assays demonstrated that grandifloridin D potently and preferentially reduced the viability of MIA PaCa-2 pancreatic cancer cells under nutrient deprivation at a PC concentration of 0.14 μM. Live-cell imaging and ethidium bromide/acridine orange (EB/AO) dual staining confirmed that grandifloridin D induces cell death by disrupting membrane integrity. Under nutrient-rich conditions, grandifloridin D exhibited antimetastatic activity, significantly inhibiting MIA PaCa-2 cell migration in real-time assays and suppressing colony formation and spheroid formation. Western blot analysis revealed that grandifloridin D is a potent inhibitor of the protein kinase B (Akt) and mammalian target of rapamycin (mTOR) signaling pathway while also suppressing the autophagy-related proteins microtubule-associated protein 1 light chain 3 (LC3). These results suggest that grandifloridin D is a promising antiausterity agent for pancreatic cancer drug development.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe