Biol. Pharm. Bull. [JOURNAL]
Sun
200 papers
Identification of 3,5-Bis (2-Ethoxybenzylidene) Piperidin-4-one as a Monocarbonyl Curcumin Analog Inhibiting Cell-Intrinsic NF-κB Activity in 4T1 Breast Cancer Cells.
Jabbar S, Ucche S, Irshad FM … +5 more , Seephan S, Sasaki SI, Murwanti R, Ritmaleni, Hayakawa Y
Biol Pharm Bull · 2026 · PMID 42002900 · Publisher ↗
Although numerous biological properties of curcumin, a bioactive polyphenol from the rhizome of turmeric (Curcuma longa), have been documented, its poor bioavailability limits clinical application. Therefore, identifying...
Although numerous biological properties of curcumin, a bioactive polyphenol from the rhizome of turmeric (Curcuma longa), have been documented, its poor bioavailability limits clinical application. Therefore, identifying new analogs with improved pharmacokinetics and pharmacological properties is essential. Given that curcumin and its related compounds are known to inhibit cancer cell progression and metastasis through nuclear factor-kappaB (NF-κB) signaling inhibition, we investigated 58 newly synthesized, structurally diverse monocarbonyl curcumin analogs. Their inhibitory effects on intrinsic NF-κB activity were assessed in breast cancer cells using the 4T1 cell line expressing a luciferase NF-κB reporter. Among the 58 monocarbonyl curcumin analogs, 3,5-bis(2-ethoxybenzylidene)piperidin-4-one (E145) exhibited potent inhibition of NF-κB activity in 4T1 breast cancer cells. Based on the structure-activity relationship analysis, the central heterocyclic monocarbonyl linker structure of E145 contributed to its increased potency in NF-κB inhibition.
Localized Rectal Dextran Sulfate Sodium-Induced Colitis Is Associated with Small-Intestinal Shortening and Gut-Liver Axis-Related Alterations.
Mori M, Ishii M, Nakagawa R … +4 more , Morimoto K, Ise K, Nakamura Y, Tomita M
Biol Pharm Bull · 2026 · PMID 41987396 · Publisher ↗
Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by inflammation of the colon. Although various dextran sulfate sodium (DSS)-induced UC models are available, the traditional free-drinking model invo...
Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by inflammation of the colon. Although various dextran sulfate sodium (DSS)-induced UC models are available, the traditional free-drinking model involves oral administration, which complicates the assessment of extracolonic organs because of widespread intestinal exposure. This study aimed to create a localized UC model through rectal administration of DSS and evaluate whether this approach minimized direct DSS exposure to the small intestine and liver. Rats received 40% DSS rectally for 13 d. Changes in body weight, Disease Activity Index, and histological scores were monitored. The effects of 5-aminosalicylic acid treatment were examined, and small intestinal morphology, inflammatory markers, bile flow, and mRNA levels of hepatic bile salt export pump were analyzed. Rectal DSS induced localized inflammation in the distal colon and rectum, mimicking key features of UC such as weight loss, mucosal injury, and elevated disease activity. Some of these effects were partially alleviated by 5-aminosalicylic acid treatment. The small intestine shortened without infiltration of inflammatory cells or cytokine increase, indicating a non-inflammatory structural change. Bile flow and hepatic bile salt export pump expression significantly decreased in DSS-treated rats, suggesting hepatobiliary excretory dysfunction. Overall, the rectal DSS model offers a controlled and reproducible way to induce colon-specific inflammation, overcoming the limitations of the free-drinking model, which hinders extracolonic evaluation due to oral DSS exposure. This model may provide a research basis for further study of inter-organ interactions, particularly gut-liver axis dysfunction and intestinal barrier-related drug absorption in UC.
Ganoderic Acid A Derived from Reishi Mushroom Ganoderma lucidum Protects against Intestinal Immunity Reduction Due to Oxidative Stress in Rat.
Kubota A, Okamoto K, Yasuda G … +8 more , Narumi K, Suzuki Y, Ueda H, Mori A, Takahashi-Suzuki N, Satoh T, Iseki K, Kobayashi M
Biol Pharm Bull · 2026 · PMID 41987395 · Publisher ↗
Reishi (Ganoderma lucidum) is known to enhance intestinal immunity, with ganoderic acid A (GA-A) identified as one of its active constituents. However, the specific role of GA-A in regulating immune components such as im...
Reishi (Ganoderma lucidum) is known to enhance intestinal immunity, with ganoderic acid A (GA-A) identified as one of its active constituents. However, the specific role of GA-A in regulating immune components such as immunoglobulin A (IgA) from Peyer's patches (PPs) and α-defensin 5 from Paneth cells remains unclear. Additionally, the ability of Reishi to counteract oxidative stress-induced intestinal immune suppression has not been fully elucidated. Therefore, in this study, we aimed to examine the effects of Reishi and GA-A on intestinal immunity in a rat model of ischemia-reperfusion (I/R) injury. Oral administration of GA-A increased IgA secretion from PP cells isolated from rat small intestine and upregulated the mRNA expression of rat α-defensin 5 (RD-5) and toll-like receptor 4 (TLR4) in the ileum, similar to Reishi. In contrast, GA-A did not exhibit immunostimulatory effects in TLR4-deficient mice. In the I/R rat model, both Reishi and GA-A significantly restored IgA secretion and RD-5 mRNA expression, mitigating immune suppression. They were also associated with changes in superoxide dismutase 1 (SOD1) and SOD3 mRNA expression under I/R conditions and prevented villus shedding and Paneth cell loss, indicating protection against I/R-induced intestinal immune decline. These results were comparable to those observed with caffeic acid, the positive control. Overall, these findings suggest that Reishi mitigates intestinal immune suppression caused by I/R injury, with GA-A serving as a key active component mediating these protective effects.
Structure-Guided Evaluation of Thiol-Based Fluorescent Probes for Selective Detection and Inhibition of Metallo-β-Lactamases.
Kato K, Yamaguchi Y, Ichimaru Y … +10 more , Kajiyama M, Kato M, Nagatomo M, Jin W, Wachino JI, Arakawa Y, Fukuishi N, Fujita M, Otsuka M, Kurosaki H
Biol Pharm Bull · 2026 · PMID 41987394 · Publisher ↗
Metallo-β-lactamases (MBLs)-Zn-dependent β-lactamases that compromise the efficacy of most β-lactam antibiotics, including carbapenems-are difficult to monitor rapidly with broadly applicable small-molecule probes due to...
Metallo-β-lactamases (MBLs)-Zn-dependent β-lactamases that compromise the efficacy of most β-lactam antibiotics, including carbapenems-are difficult to monitor rapidly with broadly applicable small-molecule probes due to the structural diversity among the MBLs. Fluorescent thiol-based probes that bind to the dinuclear Zn active site would offer a mechanistically different approach for the selective detection and inhibition of MBLs compared to serine β-lactamases (SBLs); however, their performance across genetically divergent MBLs remains poorly defined. To clarify the structural determinants governing probe recognition across different MBLs, we examined the structure-activity relationships using a homologous series of dansyl-based thiol probes, DansylCSH (n = 2 and 4-6) toward BlaB, a class B MBL of Elizabethkingia meningoseptica, and compared their behavior with those of the clinically relevant MBLs imipenemase-1 (IMP-1) and Verona integron-encoded metallo-β-lactamase 2 (VIM-2). Consistent with the minimal differences in fluorescence enhancement among the series, BlaB inhibition exhibited only modest spacer-length dependence (IC = 29-51 μM; apparent inhibition constants (K) = 3600-5910 nM). In contrast, IMP-1 and VIM-2 showed markedly stronger fluorescence emission and inhibitory potencies (IMP-1: IC = 0.7-5.2 μM; K = 140-1100 nM; VIM-2: IC = 1.5-2.1 μM; K = 286-370 nM), reflecting their distinct active-site architectures. Docking analyses further revealed distinct binding orientations that explain their photophysical behaviors. No fluorescence enhancement or inhibition was observed with the class A SBL Guiana extended-spectrum β-lactamase-3 (GES-3), confirming the high selectivity and specificity of the DansylCSH series. These findings allow identifying key structural determinants governing selective activation and inhibition of fluorescence from each MBL.
Strain-Dependent and Site-Specific Differences in Irinotecan-Induced Skin Pigmentation in Mice.
Imai M, Hiramoto K, Ooi K
Biol Pharm Bull · 2026 · PMID 41987385 · Publisher ↗
Skin pigmentation induced by irinotecan-an anticancer drug-is clinically recognized; however, strain-dependent and skin site-specific differences in its manifestation have not been sufficiently investigated in mice. In t...
Skin pigmentation induced by irinotecan-an anticancer drug-is clinically recognized; however, strain-dependent and skin site-specific differences in its manifestation have not been sufficiently investigated in mice. In this study, we compared melanocyte activation in plantar and genital skin following repeated irinotecan administration in three mouse strains: ICR (Slc:ICR), C57BL/6 (C57BL/6JmsSlc), and C3H (C3H/HeSlc). Melanocyte activation was assessed by 3,4-dihydroxyphenylalanine (DOPA) staining and immunofluorescence staining for microphthalmia-associated transcription factor (MITF). Although no obvious macroscopic pigmentation was observed in any strain or skin site, DOPA staining revealed an increased number of DOPA-positive cells in the plantar skin of all three mouse strains. By contrast, marked strain-dependent differences were observed in the genital skin: DOPA-positive cells were detected in ICR (Slc:ICR) and C57BL/6 (C57BL/6JmsSlc) mice but not in C3H (C3H/HeSlc) mice. MITF immunofluorescence staining results were consistent with the DOPA staining findings, demonstrating enhanced MITF signals in skin sites exhibiting melanocyte activation. Notably, the induction of DOPA-positive cells in the genital skin of albino ICR mice was an unexpected finding, suggesting that drug-induced melanocyte activation may occur independently of intrinsic melanin-producing capacity and instead involve upstream regulatory pathways. Collectively, these findings demonstrate clear strain-dependent and skin site-specific differences in irinotecan-induced melanocyte responses and provide important insights into the heterogeneity of drug-induced skin pigmentation.
Integration of Pharmacists' Knowledge into a Predictive Model for Teicoplanin Dose Planning.
Matsuzaki T, Nakai T, Kato Y … +2 more , Yamada K, Yagi T
Biol Pharm Bull · 2026 · PMID 41967963 · Publisher ↗
Teicoplanin is an important antibiotic for methicillin-resistant Staphylococcus aureus infections. To enhance its clinical effectiveness while preventing adverse effects, therapeutic drug monitoring (TDM) of teicoplanin...
Teicoplanin is an important antibiotic for methicillin-resistant Staphylococcus aureus infections. To enhance its clinical effectiveness while preventing adverse effects, therapeutic drug monitoring (TDM) of teicoplanin trough concentration is recommended. Given the importance of the early attainment of therapeutic concentrations for treatment success, initial dosing regimens, including loading and maintenance doses, are deliberately designed based on patient information. However, initial dose planning for teicoplanin strongly relies on clinician expertise. This study aimed to use a machine learning (ML) approach to integrate clinicians' knowledge into a predictive model for initial teicoplanin dose planning. First, we confirmed that dose planning by pharmacists specialized in TDM (TDM pharmacists) significantly improved early therapeutic target attainment for patients who were not admitted to intensive or high care units. Subsequently, we used a dataset of initial teicoplanin dose plans created by TDM pharmacists to train the model that emulates their dosing decision-making process. Although the prediction accuracies of the ML model were modest (45.8 and 66.7% for the loading and maintenance doses, respectively), the model successfully learned the basic policy of dose planning, suggesting that ML approaches have potential utility in supporting appropriate initial teicoplanin treatment.
PCV13/PPSV23 Co-vaccination versus PPSV23 Monotherapy for the Prevention of Pneumococcal Infections: A Systematic Review and Meta-analysis.
Matsumoto Y, Mihara T, Okamoto Y … +11 more , Tsubouchi A, Ikegami S, Takahashi M, Nakabayashi K, Nishimoto N, Mizukami Y, Muraishi T, Igarashi Y, Enoki Y, Taguchi K, Matsumoto K
Biol Pharm Bull · 2026 · PMID 41967962 · Publisher ↗
The 23-valent pneumococcal polysaccharide (PPSV23) and 13-valent pneumococcal conjugate (PCV13) vaccines are available for the prevention of infections caused by Streptococcus pneumoniae. This systematic review and meta-...
The 23-valent pneumococcal polysaccharide (PPSV23) and 13-valent pneumococcal conjugate (PCV13) vaccines are available for the prevention of infections caused by Streptococcus pneumoniae. This systematic review and meta-analysis evaluated the immunogenicity and safety of PPSV23 and PCV13 co-vaccination (PCV13/PPSV23) compared with PPSV23 monotherapy in adult populations. PubMed, Cochrane Library, Web of Science, and ClinicalTrials.gov were systematically searched for randomized controlled trials (RCTs) comparing PCV13/PPSV23 co-vaccination with PPSV23 monotherapy published until September 15, 2023. Immunogenicity was assessed using the geometric mean titer ratio (GMTR) of opsonophagocytic activity (OPA), which reflects bactericidal activity against each serotype. The safety outcomes included local and systemic adverse events. The risk ratios and 95% confidence intervals were calculated using the inverse variance-weighted method. The meta-analysis included 4 RCTs involving 2739 participants. The OPA GMTRs for 11 of the 13 evaluated serotypes were significantly higher in the PCV13/PPSV23 group than those in the PPSV23 group. The safety analysis showed no statistically significant differences in the incidence of adverse events between the 2 groups across all assessed outcomes. PCV13/PPSV23 showed significantly higher immunogenicity against the pneumococcal serotypes and maintained a safety profile comparable to that of PPSV23. These results support the potential utility of PCV13/PPSV23 as an effective strategy for preventing pneumococcal diseases in older adults.
Associations between Anticholinergic Use and Dementia Risk in a Prevalent-User Cohort: Analysis of Japanese Medication Histories as Real-World Data.
Iwai H, Tanaka S, Nakatani E … +5 more , Miyata S, Yamato J, Kogawa M, Yamori T, Okura T
Biol Pharm Bull · 2026 · PMID 41951407 · Publisher ↗
Medication history from Japanese pharmacies is potentially rich in useful information regarding drug-related events in diverse populations; however, this information has rarely been utilized as real-world data. This stud...
Medication history from Japanese pharmacies is potentially rich in useful information regarding drug-related events in diverse populations; however, this information has rarely been utilized as real-world data. This study aimed to evaluate the feasibility of using medication history as real-world data to assess associations between anticholinergic medications for overactive bladder (OAB) and increased risk of dementia. A retrospective prevalent-user cohort study was performed to analyze medication history using a logistic regression model. The primary exposure was anticholinergic drug use for OAB (vs. beta-3 agonists only). The risk associated with each specific anticholinergic drug was also analyzed. Adjustments included age, sex, comorbidities (diabetes, hyperlipidemia, and hypertension), and psychotropic drug use. OAB anticholinergics and age were significant predictors. The adjusted odds ratio (OR) and 95% confidence interval (CI) for OAB anticholinergics were 1.53 (95% CI: 1.10-2.14, p = 0.0110), and those for age were 1.07 (95% CI: 1.04-1.09, p < 0.0001). Among individual OAB anticholinergics, the ORs for oxybutynin (4.53; 95% CI: 2.18-9.42, p < 0.0001) and tolterodine (5.64; 95% CI: 2.42-13.17, p < 0.0001) were significant, whereas ORs for other OAB anticholinergics were not. These findings suggest the potential to identify agents with lower dementia risk. In conclusion, analysis in this prevalent-user cohort study using medication history data showed a significant association between OAB anticholinergic use and increased dementia risk, with variation by drug. These results support the feasibility of utilizing medication history as real-world data for pharmacovigilance.
Aniseed, Caraway, and Cumin: Appetite-Enhancing Effects and Identification of Active Compounds.
Ogawa K, Naruo K, Ihara M … +3 more , Nomura M, Koga R, Morinaga O
Biol Pharm Bull · 2026 · PMID 41951376 · Publisher ↗
Apiaceae plants are widely utilized as spices across the globe. Fennel, a prominent member of this family, has been previously shown to possess appetite-enhancing properties, suggesting that other Apiaceae spices may exh...
Apiaceae plants are widely utilized as spices across the globe. Fennel, a prominent member of this family, has been previously shown to possess appetite-enhancing properties, suggesting that other Apiaceae spices may exhibit similar effects. Herein, we investigated the appetite-enhancing effects of essential oils extracted from aniseed, caraway seeds, and cumin seeds. All three essential oils significantly increased food intake in mice. Analysis revealed that the major active compounds were (i) trans-anethole and pseudoisoeugenyl 2-methylbutyrate in aniseed oil, (ii) d-limonene and d-carvone in caraway oil, and (iii) cuminaldehyde in cumin oil. Intriguingly, the effective doses of d-carvone and trans-anethole were elevated when administered in combination with d-limonene and pseudoisoeugenyl 2-methylbutyrate, respectively. This newly identified modulatory effect, driven by co-occurring compounds, suggests a complex interaction between the constituents. Furthermore, the side chain structures of terpenoids were found to influence the effects analogously to those of phenylpropanoids, thereby suggesting the existence of common or similar sites of action within the mice olfactory system.
Schisandrin A Suppresses Guinea Pig Ileal Longitudinal Smooth Muscle Contraction through Functional Inhibition of L-Type Ca Channels.
Hong Q, Ohta T, Otsuki K … +7 more , Kinami W, Sato T, Kikuchi T, Li W, Yoshioka K, Obara K, Tanaka Y
Biol Pharm Bull · 2026 · PMID 41951375 · Publisher ↗
Schisandrin A (SA), a major lignan isolated from the fruits of Schisandra chinensis, has been reported to modulate smooth muscle (SM) function in several tissues; however, its direct effects on intestinal SM have not bee...
Schisandrin A (SA), a major lignan isolated from the fruits of Schisandra chinensis, has been reported to modulate smooth muscle (SM) function in several tissues; however, its direct effects on intestinal SM have not been fully characterized. In the present study, we investigated the effects of SA on contractile responses in guinea pig (GP) ileal longitudinal smooth muscle (ILSM) and examined the involvement of L-type voltage-dependent Ca channels (VDCCs). SA (1-100 µM) concentration-dependently inhibited contractions induced by acetylcholine (1 µM), histamine (1 µM), and prostaglandin F (10 µM). These agonist-induced contractions were completely suppressed by the L-type VDCC inhibitor diltiazem (10 µM). SA also attenuated depolarization-induced contractions evoked by high-KCl (80 mM), which were similarly sensitive to diltiazem. In A7r5 vascular SM cells, high-KCl (100 mM) elicited marked increases in intracellular Ca concentration ([Ca]), and these responses were substantially inhibited by SA (30 µM) as well as by diltiazem (30 µM). Furthermore, molecular docking simulations using the Ca1.2 channel structure (PDB ID: 8HMA) suggested that SA may interact with the tetrandrine-binding pocket, potentially forming a hydrogen bond with Tyr1508. Taken together, these findings indicate that SA suppresses intestinal SM contraction primarily by inhibiting Ca influx through L-type VDCCs, likely via direct interaction with Ca1.2. This mechanism may partly underlie the traditional use of S. chinensis fruits in the treatment of gastrointestinal disorders such as diarrhea.
Diterpenes in Aralia cordata Rhizomes Suppress the Expression of Proinflammatory and Extracellular Matrix Degradation-Related Genes in ATDC5 Cells.
Tanaka R, Fujii A, Nishidono Y … +4 more , Okazaki A, Kawamura T, Ikeya Y, Nishizawa M
Biol Pharm Bull · 2026 · PMID 41936451 · Publisher ↗
Aralia cordata Thunberg (Araliaceae) is a perennial plant that grows in East Asia, including Japan. Its rhizome, called Dokukatsu in Japanese, is used as a crude drug in traditional Japanese (Kampo) medicines. Aralia rhi...
Aralia cordata Thunberg (Araliaceae) is a perennial plant that grows in East Asia, including Japan. Its rhizome, called Dokukatsu in Japanese, is used as a crude drug in traditional Japanese (Kampo) medicines. Aralia rhizomes are included in several Kampo formulae, such as Dokkatsuto, which is prescribed for patients with osteoarthritis-related arthralgia, due to its analgesic and anti-inflammatory properties. However, the specific compounds responsible for these effects remain unexplored. In this study, we aimed to evaluate the anti-inflammatory properties of Aralia rhizome constituents by monitoring the production of the proinflammatory mediator nitric oxide (NO) in primary cultured rat hepatocytes. An ethyl acetate (EtOAc)-soluble fraction from an Aralia rhizome extract significantly suppressed interleukin (IL)-1β-induced NO production in rat hepatocytes. Within this fraction, we identified diterpenes, such as pimaradienoic acid (most abundant), kaurenoic acid, and pimaric acid. Among these, pimaradienoic acid markedly inhibited NO production in hepatocytes. We further investigated the effects of the EtOAc-soluble fraction on mouse chondrogenic cell line ATDC5-which produces NO in response to IL-1β and bacterial lipopolysaccharide (LPS)-and found that it inhibited NO production in ATDC5 cells treated with IL-1β and LPS. Moreover, pimaradienoic acid suppressed IL-1β-induced expression of the inducible nitric oxide synthase gene and downregulated genes involved in extracellular matrix (ECM) degradation in cartilage, specifically matrix metalloproteinase-13 (Mmp13) and a disintegrin and metalloproteinase with thrombospondin motifs-5 (Adamts5) genes. These findings suggest that pimaradienoic acid contributes to the anti-inflammatory effects of Aralia rhizomes by inhibiting NO-mediated inflammation and matrix degradation in articular cartilage during osteoarthritis.
Evaluation of the Perceptions and Acceptability of Checklist for Assessing Achievement in Hospital Practical Training for Pharmacy School Students: A Prospective Questionnaire-Based Survey.
Asai Y, Kato H, Hiramatsu SI … +1 more , Iwamoto T
Biol Pharm Bull · 2026 · PMID 41922275 · Publisher ↗
To enhance the learning motivation of pharmacy school students undergoing hospital practical training, it would be important to establish tools that facilitate the clarification of learning items and the sharing of progr...
To enhance the learning motivation of pharmacy school students undergoing hospital practical training, it would be important to establish tools that facilitate the clarification of learning items and the sharing of progress between students and pharmacists. To address this, Mie University Hospital developed the "Checklist for Assessing Achievement in Hospital Practical Training (checklist)." This study aimed to evaluate the perceptions and acceptability of the checklist in facilitating smooth operations and fostering student initiative. A prospective, single-center, questionnaire-based survey was conducted with 23 students and 48 preceptor pharmacists participating in practical training. Checklist completion rates were calculated by counting the number of items checked by each student and pharmacist across all sections. Separate questionnaires were created for students and pharmacists, and customer satisfaction (CS) analyses were performed across seven pharmacy sections. In addition, responses related to perceived benefits in students' initiatives during training were evaluated. Valid response rates were 95.7% for students and 68.8% for pharmacists. Checklist completion exceeded 80% for all six pharmacy sections. While no items were identified as specific areas of priority improvement in the student CS graph, the pharmacist CS graph identified four items that required priority improvement. Regarding whether the introduction of the checklist enhanced students' initiative, 77% of students responded "agree" and 23% "somewhat agree," while 36% of pharmacists responded "agree" and 32% "somewhat agree." This study revealed that the checklist may support the smooth operation of practical hospital training and has a positive impact on students' initiatives for practical training.
Mechanisms of Skin Aging and the Interventional Effects of Plant Polysaccharides: A Review Based on Signaling Pathways.
Hou X, Chen Z, Wang J … +5 more , Yu H, Liu B, Zhang Y, Shao H, Liu F
Biol Pharm Bull · 2026 · PMID 41922266 · Publisher ↗
Skin aging is a complex physiological process driven by both endogenous and exogenous factors, involving various mechanisms such as oxidative stress, inflammatory responses, and cellular senescence. As natural bioactive...
Skin aging is a complex physiological process driven by both endogenous and exogenous factors, involving various mechanisms such as oxidative stress, inflammatory responses, and cellular senescence. As natural bioactive macromolecules, plant polysaccharides possess properties including antioxidant, anti-inflammatory, and free radical scavenging abilities, and have recently shown significant potential in anti-skin aging research. This article systematically reviews the molecular mechanisms of skin aging, with a focus on elucidating how plant polysaccharides exert anti-aging effects by regulating key signaling pathways. Additionally, it summarizes strategies for the extraction, purification, and structural modification of plant polysaccharides, as well as their structure-activity relationships. The aim is to provide a theoretical foundation and research directions for both fundamental studies and product development of plant polysaccharides in the field of anti-skin aging.
Roles of Temperature and Reactive Oxygen Species in Circadian Rhythms and Thermosensitivity.
Miyake T
Biol Pharm Bull · 2026 · PMID 41922265 · Publisher ↗
Noxious temperature changes and high levels of reactive oxygen species (ROS) have traditionally been regarded as harmful stimuli. However, there is now substantial evidence for the importance of small-to-moderate changes...
Noxious temperature changes and high levels of reactive oxygen species (ROS) have traditionally been regarded as harmful stimuli. However, there is now substantial evidence for the importance of small-to-moderate changes in temperature and ROS levels-well below the thresholds that induce cell death or physiological dysfunction-as fundamental signaling cues that regulate a wide range of physiological functions in mammals. In this review, I summarize our recent findings on the regulatory roles of slight fluctuations in temperature and intracellular ROS in biological processes. In particular, this review focuses on two key examples: (A) the effects of subtle changes in physiological circadian body temperature fluctuations on the translational efficiency of the core clock gene Period2 and (B) the role of non-toxic levels of ROS as essential intracellular signals that modulate transient receptor potential ion channel activity and cold sensitivity. Our findings challenge longstanding assumptions that circadian clocks are governed solely by transcriptional and post-translational mechanisms and that the temperature sensitivity of ion channels arises exclusively from direct thermal gating. We demonstrated the pivotal roles of the translational control of mRNA and mitochondrial responses in the temperature-mediated maintenance of circadian clock function and ion channel activity. These insights provide conceptual advances relevant to chronobiology, neuroscience, and pharmacology.
Transporters for Creatine and Related Guanidino Compounds: Their Relevance to Brain Health and Disorders.
Tachikawa M
Biol Pharm Bull · 2026 · PMID 41922264 · Publisher ↗
Creatine, α-N-methyl-guanidino-acetic acid, plays a fundamental role in the storage and regeneration of high-energy phosphate in the brain. Defects in the creatine transporter gene (CRT/SLC6A8) result in a significant re...
Creatine, α-N-methyl-guanidino-acetic acid, plays a fundamental role in the storage and regeneration of high-energy phosphate in the brain. Defects in the creatine transporter gene (CRT/SLC6A8) result in a significant reduction in brain creatine levels and severe neurological symptoms such as intellectual disability. Clarifying creatine dynamics in the brain is essential to increase our understanding of CRT deficiency syndrome (CRTD) pathology and the development of CRTD therapeutics. This review comprehensively summarizes the pathophysiological roles of transporters in dynamics of creatine and related guanidine compounds in the brain barriers and brain parenchyma. Brain creatine dynamics are regulated by the cooperative actions of various influx and efflux transporters of creatine, guanidinoacetate, creatinine, and creatine biosynthetic enzymes. These transporters include CRT/SLC6A8 as a creatine/guanidinoacetate/creatinine influx transporter, MCT12/SLC16A12, and SLC22A15 for creatine efflux transport, TauT/SLC6A6, GAT2/SLC6A13, and GAT3/SLC6A11 for guanidinoacetate influx transport, and OCT3/SLC22A3 for creatinine influx transport. Transporters and creatine biosynthetic enzymes, such as arginine-glycine amidinotransferase and guanidinoacetate N-methyltransferase, exhibit cell-type specific spatio-temporal expression at the brain barrier and in neurons, astrocytes, and oligodendrocytes. To date, no effective therapeutics have been developed for the treatment of CRTD. The link between low brain creatine level and the mechanism of neurological dysfunction remains unclear. Creatine prodrugs, molecular chaperones, and adeno-associated virus-based gene therapies are potential therapeutic options for CRTD. Advanced technologies, such as omics and genetic engineering, will open new avenues for CRTD therapeutics.
Multifaceted MRVI1 Serves as a Tumor Suppressor in HCT116 Colorectal Cancer Cells.
Higashi K, Cho Y, Aoyama K
Biol Pharm Bull · 2026 · PMID 41905951 · Publisher ↗
MRVI1 is a multifaceted gene whose functions in cancer vary across tissue types, acting either as a tumor-promoting or tumor-suppressive factor. In colorectal cancer, MRVI1 functions downstream of p53, and its loss enhan...
MRVI1 is a multifaceted gene whose functions in cancer vary across tissue types, acting either as a tumor-promoting or tumor-suppressive factor. In colorectal cancer, MRVI1 functions downstream of p53, and its loss enhances malignant phenotypes; however, the effects of MRVI1 overexpression have remained unclear. In this study, we established HCT116 colorectal cancer cells stably overexpressing MRVI1 to examine its functional impact. Western blot analysis confirmed robust expression of the V5-TurboID-MRVI1 fusion protein in the established cell line. Cell proliferation assays showed that MRVI1 overexpression markedly reduced cell growth compared with control cells under standard culture conditions. Trypan blue staining demonstrated that MRVI1 overexpression did not increase cell death, indicating that the reduction in cell number reflects a cytostatic rather than cytotoxic effect. These findings provide direct evidence that MRVI1 suppresses the proliferation of colorectal cancer cells when overexpressed. Combined with previous reports demonstrating that MRVI1 knockdown promotes proliferation and invasive behavior in colorectal cancer cells, our results support the view that MRVI1 contributes to p53-associated growth control in this tumor lineage. These observations further reinforce the concept that MRVI1 is a context-dependent, multifaceted cancer-associated gene.
Effect of Cytochrome P450 3A4 Genetic Polymorphisms on Heme Recognition by Using Molecular Dynamics Simulations.
Mizuno A, Nakayoshi T, Mizutani E … +3 more , Hiratsuka M, Kato K, Oda A
Biol Pharm Bull · 2026 · PMID 41905950 · Publisher ↗
CYP3A4 is a drug-metabolizing enzyme involved in the metabolism of numerous drugs, and genetic polymorphisms of CYP3A4 can influence individual differences in drug toxicity and efficacy. For some variants, it has been re...
CYP3A4 is a drug-metabolizing enzyme involved in the metabolism of numerous drugs, and genetic polymorphisms of CYP3A4 can influence individual differences in drug toxicity and efficacy. For some variants, it has been reported that not only were the enzymatic activities reduced, but also the 450 nm absorption spectra in the presence of CO were lost. In this study, molecular dynamics simulations of CYP3A4.1, CYP3A4.8, CYP3A4.12, and CYP3A4.17 for which 450 nm absorption spectra were not observed were performed to predict the three-dimensional (3D) structures and evaluate the effects of amino acid mutations on such structures. By comparing the 3D structures of these variants with the wild-type CYP3A4.1, the impact of the mutations on heme recognition within CYP3A4 was clarified. Analysis of structural flexibility and hydrogen bond networks revealed significant changes in active site interactions and conformation, suggesting these alterations likely affected heme recognition. Furthermore, not only the direct interactions between the mutation site and heme but also the effects of the mutations on the surrounding structure were estimated.
Establishment of Irinotecan-Induced Oral Mucositis Hamster Model and Evaluation of Therapeutic Agents.
Watanabe S, Mori N, Toyooka S … +4 more , Utsunomiya K, Kurokawa Y, Nakagami Y, Yamaguchi T
Biol Pharm Bull · 2026 · PMID 41905949 · Publisher ↗
Chemotherapy-induced oral mucositis is a frequent and debilitating adverse effect that impairs nutritional status and interrupts cancer therapy. Although 5-fluorouracil-induced animal models of oral mucositis are well es...
Chemotherapy-induced oral mucositis is a frequent and debilitating adverse effect that impairs nutritional status and interrupts cancer therapy. Although 5-fluorouracil-induced animal models of oral mucositis are well established, irinotecan, widely used for colorectal, lung, and pancreatic cancers, has also been associated with oral mucosal injury; however, no standardized preclinical model exists. This study aimed to establish a reproducible hamster model of irinotecan-induced oral mucositis and evaluate the prophylactic and therapeutic efficacy of topical hangeshashinto (HST) compared with dexamethasone. Male Syrian hamsters received intraperitoneal irinotecan (100, 150, or 200 mg/kg) on Day 0, followed by localized mucosal injury induced by 50% acetic acid. Ulcer area, body weight, histopathology, peripheral blood count, and myeloperoxidase (MPO) activity were evaluated. HST (10% aqueous solution) or dexamethasone (0.01% elixir) was administered topically once daily either prophylactically (Days -3 to 0) or therapeutically (from Day 0 onward). Ulcer area increased in a dose-dependent manner, peaking on Day 4. The 200 mg/kg dose yielded consistent lesion formation with transient weight loss. Histopathological examination revealed dense neutrophilic infiltration and epithelial disruption. MPO activity was significantly elevated on Days 4 and 7. Prophylactic HST significantly reduced the peak and cumulative ulcer areas, whereas dexamethasone delayed healing. The 200 mg/kg irinotecan plus acetic acid hamster model thus provides a reliable platform for investigating oral mucositis. HST, particularly when administered prophylactically, exhibited better efficacy than dexamethasone, potentially through modulation of inflammatory responses and attenuation of oxidative stress. This model may facilitate further mechanistic studies and the development of preventive strategies for chemotherapy-induced oral mucositis.
Investigation of the Effects of Calcium Alginate on Blood Sodium Concentration and the Suppression of Blood Pressure Elevation in Rats.
Namiki Y, Ida K, Homma Y … +5 more , Tomimori N, Sato K, Kakinuma C, Tachiki H, Ogihara T
Biol Pharm Bull · 2026 · PMID 41882823 · Publisher ↗
The effects of calcium alginate (Ca-Alg) on the suppression of blood sodium (Na) concentration and blood pressure elevation in rats were investigated. In a single-dose administration test, oral administration of a 0.3% s...
The effects of calcium alginate (Ca-Alg) on the suppression of blood sodium (Na) concentration and blood pressure elevation in rats were investigated. In a single-dose administration test, oral administration of a 0.3% sodium chloride (NaCl) solution (5 mg/kg) resulted in a significant increase in the difference in the area under the blood Na concentration-time curve (ΔAUC). When the finest Ca-Alg particles (8 mg/body, 270 mesh) were simultaneously administered orally under the same conditions, a significant decrease in ΔAUC and a tendency for a decrease in the maximum blood concentration difference (ΔC) were observed. In a repeated administration test, rats were allowed to freely ingest a 3.0% Ca-Alg-containing feed for 5 weeks, and an increase in Na excretion in feces was observed. Furthermore, in spontaneously hypertensive rats (SHR), when the same Ca-Alg-containing feed was freely consumed for 15 weeks, a significant inhibition of blood pressure elevation was observed after 10 weeks. Additionally, blood biochemical tests and renal histopathological examination of these rats confirmed the safety of Ca-Alg. Based on these results, it was concluded that Ca-Alg suppresses Na absorption and blood pressure elevation in rats.
Rapid Screening for Detecting Genetically Modified Wheat by Loop-Mediated Isothermal Amplification.
Kimata S, Daimon T, Takahashi M … +4 more , Miyatake K, Ishida Y, Iijima K, Takabatake R
Biol Pharm Bull · 2026 · PMID 41882822 · Publisher ↗
We developed a loop-mediated isothermal amplification (LAMP)-based detection method for screening glyphosate-tolerant genetically modified (GM) wheat by targeting nucleotide sequences of the cauliflower mosaic virus 35S...
We developed a loop-mediated isothermal amplification (LAMP)-based detection method for screening glyphosate-tolerant genetically modified (GM) wheat by targeting nucleotide sequences of the cauliflower mosaic virus 35S promoter (P35S) and 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) from Agrobacterium tumefaciens strain CP4. LAMP products were detected using a Genie II real-time fluorometer. The limit of detection (LOD) was found to be ≤0.05% corresponding to 14 copies of target DNA. We also designed primer sets for detecting the endogenous reference sequences of wheat, proline-rich protein (PRP), and Waxy-D1. The combination of two LAMP primer sets targeting the PRP and Waxy-D1 sequences was useful for distinguishing common wheat from durum wheat. Single-stranded tag hybridization (STH) on a chromatography printed-array strip (C-PAS) system, a lateral-flow DNA chromatography technology, was used to improve efficiency. LAMP amplification was clearly detected by the STH C-PAS system at the LOD level, and duplex detection of P35S and PRP, and EPSPS and PRP was successfully achieved. This simple and quick method for screening GM wheat will be useful for preventing food and environmental contamination by unauthorized GM crops.
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