Biol. Pharm. Bull. [JOURNAL]
Sun
200 papers
Organ Crosstalk in CKD-Associated Frailty: Mechanistic Insights, Translational Opportunities, and Clinical Implications.
Watanabe H, Kitazato Y, Hirashima S … +7 more , Enoki Y, Kato H, Ochiai W, Maeda H, Tanaka M, Matsushita K, Maruyama T
Biol Pharm Bull · 2026 · PMID 42219324 · Publisher ↗
Frailty in chronic kidney disease (CKD) is increasingly recognized as a manifestation of accelerated biological aging, characterized by systemic impairments that extend beyond the musculoskeletal domain. A distinctive ye...
Frailty in chronic kidney disease (CKD) is increasingly recognized as a manifestation of accelerated biological aging, characterized by systemic impairments that extend beyond the musculoskeletal domain. A distinctive yet underappreciated feature of CKD-associated frailty is its triple burden-the co-existence of sarcopenia, bone fragility, and cognitive impairment. Rather than isolated phenomena, these deficits share convergent pathophysiological drivers, including uremic toxicity, oxidative stress, hormonal dysregulation, and chronic inflammation. Accumulating evidence highlights the role of organ crosstalk-particularly along the muscle-bone and muscle-brain axes-as a key integrative mechanism linking these outcomes. This review synthesizes current understanding of the epidemiology, diagnostic approaches, and mechanistic underpinnings of this multisystem condition, emphasizing skeletal muscle as a central node in a dynamic physiological network. Recent advances in biomarker development, imaging technologies, and therapeutic strategies point toward a shift from compartmentalized to network-informed care. By framing CKD-related frailty as a disorder of disrupted inter-organ communication resulting in a triple burden of decline, we propose a unified pathophysiological model to guide earlier recognition and personalized, multimodal interventions. Importantly, this perspective also calls for a critical re-evaluation of current treatment targets in CKD management to ensure alignment with the goals of frailty prevention and long-term functional preservation.
Fluvoxamine Exerts Anti-influenza A Virus Effects through Inhibiting Apoptosis Pathway.
Zhang Z, Liang H, Ren L … +1 more , Wei Z
Biol Pharm Bull · 2026 · PMID 42219288 · Publisher ↗
Influenza is a serious respiratory disease with high pathogenicity and mortality rates. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) antidepressant, has been shown to alleviate inflammation in sepsis anim...
Influenza is a serious respiratory disease with high pathogenicity and mortality rates. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) antidepressant, has been shown to alleviate inflammation in sepsis animal models and prevent severe complications caused by coronavirus disease 2019 (COVID-19). However, there are currently no reports on the potential anti-influenza effects of fluvoxamine. To investigate whether fluvoxamine has anti-influenza effects and elucidate the mechanisms of its action. This study evaluated the anti-influenza effects of fluvoxamine using H1N1-infected BALB/c mice and found that, compared to the H1N1 infection group, the survival rate of mice in the fluvoxamine intervention group increased by 30% (50 vs. 20%), with a decreased trend in body weight loss and improved lung tissue lesions. In vitro, fluvoxamine significantly increased the cell survival rate at nontoxic doses [(60.77 + 4.42) vs. (79.74 ± 5.43)%, p = 0.0028] and reduced cell damage caused by H1N1 infection. Furthermore, H1N1 infection in lung epithelial cells induces apoptosis, which can be prevented and reduced by fluvoxamine intervention. Fluvoxamine can significantly reduce Annexin V/PI cell ratio [(28.58 + 3.60) vs. (21.28 ± 4.01)%, p = 0.0273]. In vivo, the anti-apoptotic effect of fluvoxamine was confirmed, and it was shown that fluvoxamine can reduce the number of TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive) cells induced by H1N1 infection. Western blot analysis showed that fluvoxamine can significantly reduce the expression of cleaved caspase-3 and cleaved poly(ADP-ribose)polymerase. This study reveals that fluvoxamine has protective effects against influenza in vitro and in vivo for the first time, and reducing epithelial cell apoptosis may be one of the key mechanisms by which fluvoxamine exerts its anti-influenza effects.
Mitochondrial Membrane-Associated L-2-Hydroxyglutarate Dehydrogenase Catalyzes Electron Transport to Ubiquinone In Vitro.
Ito T, Yokoi T
Biol Pharm Bull · 2026 · PMID 42203459 · Publisher ↗
Mitochondrial L-2-hydroxyglutarate dehydrogenase (L2HGDH) is a FAD-containing membrane protein that oxidizes L-2-hydroxyglutarate (L-2-HG) to 2-oxoglutarate (2-OG). L2HGDH dysfunction is associated with human diseases, s...
Mitochondrial L-2-hydroxyglutarate dehydrogenase (L2HGDH) is a FAD-containing membrane protein that oxidizes L-2-hydroxyglutarate (L-2-HG) to 2-oxoglutarate (2-OG). L2HGDH dysfunction is associated with human diseases, such as neurometabolic disorders and cancer. Recently, the first crystal structure of Drosophila melanogaster L2HGDH (DmL2HGDH) bound with FAD and 2-OG was reported. Structural analysis, together with mutagenesis and activity measurements, revealed the oxidation mechanism of L-2-HG. However, the physiologically relevant electron acceptor has not yet been elucidated. While bacterial L2HGDH has been proposed to reduce ubiquinone, this remains controversial. To understand the full reaction mechanism of L2HGDH, identification of the electron acceptor and characterization of its interaction with the enzyme are necessary. In this study, we demonstrate that DmL2HGDH transfers electrons from L-2-HG to decylubiquinone, a ubiquinone analog that is sparingly soluble in aqueous buffers and used for in vitro studies. The reaction was moderately inhibited by ferulenol, which inhibits some quinone reductases, including the homologous enzyme malate-quinone oxidoreductase (MQO). Interestingly, the observed kinetic behavior differs from that of MQO. Using AlphaFold3 and molecular dynamics, we provide insights into the interaction between DmL2HGDH and ubiquinone and propose a mechanism for ubiquinone reduction.
Aromatic-Turmerone Analogs Activate Chaperone-Mediated Autophagy and Ameliorate Dendritic Shrinkage in Purkinje Cell Models of Spinocerebellar Ataxia.
Motomura K, Ueda-Ishizaka E, Boateng A … +10 more , Sugiura M, Konno A, Yabuki Y, Hitora-Imamura N, Kurauchi Y, Shioda N, Masuda S, Hirai H, Katsuki H, Seki T
Biol Pharm Bull · 2026 · PMID 42203458 · Publisher ↗
We recently demonstrated that aromatic (ar)-turmerone analogs ((E)-5-methyl-1-(p-tolyl)hexa-1,4-dien-3-one [A2] and (E)-1-(4-methoxyphenyl)-5-methylhexa-1,4-dien-3-one [A4]) activate chaperone-mediated autophagy (CMA), a...
We recently demonstrated that aromatic (ar)-turmerone analogs ((E)-5-methyl-1-(p-tolyl)hexa-1,4-dien-3-one [A2] and (E)-1-(4-methoxyphenyl)-5-methylhexa-1,4-dien-3-one [A4]) activate chaperone-mediated autophagy (CMA), a pathway in the autophagy-lysosome protein degradation system, in SH-SY5Y cells. Our previous studies revealed that the impairment of CMA and microautophagy (mA), another autophagy-related pathway, and dendritic shrinkage were observed in primary cultured Purkinje cells (PCs) expressing causal proteins of spinocerebellar ataxia (SCA), an autosomal dominant neurodegenerative disease. In the present study, we first investigated the effects of A2 and A4 on lysosomal protein degradation and dendritic morphology in cerebellar primary cultured PCs. Both compounds enhanced dendritic development and activated CMA in cultured PCs. These effects were significantly suppressed by the inhibitors of nuclear factor erythroid 2-related factor 2 and p38. We next examined the effects of A2 and A4 on PCs expressing several types of SCA-causing proteins (SCA model PCs). Both chemicals ameliorated the dendritic shrinkage and restored the decreased CMA/mA activity in several SCA model PCs. These findings suggest that the ar-turmerone analogs A2 and A4 improve the in vitro phenotype of SCA model PCs through CMA activation, highlighting the therapeutic potential of these analogs for various types of SCAs.
Modeling Hypertrophic Cardiomyopathy-Related MYH7 Variants: Insights into Structural Changes and Cardiovascular Drug-Binding Affinities.
Widjaja N, Dermawan D, Tan S … +3 more , Simatupang ST, Yulandi A, Tjandrawinata RR
Biol Pharm Bull · 2026 · PMID 42203436 · Publisher ↗
Mutations in the MYH7 gene, which encodes β-myosin heavy chain (β-MHC), are a significant cause of hypertrophic cardiomyopathy (HCM). These variants may lead to variable clinical outcomes, thereby influencing responsiven...
Mutations in the MYH7 gene, which encodes β-myosin heavy chain (β-MHC), are a significant cause of hypertrophic cardiomyopathy (HCM). These variants may lead to variable clinical outcomes, thereby influencing responsiveness to targeted therapies such as mavacamten, a cardiac myosin inhibitor. In this study, we employed AlphaFold modeling to construct structural models of both wild-type (WT) and mutant β-MHC associated with HCM. We performed molecular docking to evaluate the binding affinity of mavacamten for 22 MYH7 mutant proteins. A subset of variants was further analyzed using molecular dynamics (MD) simulations and molecular mechanics with Poisson-Boltzmann and surface area (MM/PBSA) binding free energy calculations. Our results provide preliminary evidence that the Arg719Trp and Arg723Gly mutations enhance mavacamten binding, whereas the Gly741Trp mutation disrupts binding affinity. Interestingly, variants such as Arg453Cys and Thr1377Met, although exhibiting increased structural flexibility, maintained favorable interaction profiles. These findings provide insights into how specific mutations affect drug-binding behavior and may inform future efforts toward genotype-tailored treatment strategies for HCM.
Rutin Protects Ischemic Stroke-Induced Astrocytic Injury by Activating PRDX1.
Said A, Liu S, Cao R … +2 more , Zhou X, Zhang H
Biol Pharm Bull · 2026 · PMID 42161532 · Publisher ↗
Ischemic stroke is a highly destructive disease with extremely high mortality and disability rates. So far, there have been few available neuroprotective drugs. Rutin, a natural plant alkaloid derived from the flavonoid...
Ischemic stroke is a highly destructive disease with extremely high mortality and disability rates. So far, there have been few available neuroprotective drugs. Rutin, a natural plant alkaloid derived from the flavonoid class of natural compounds, has been proven to have protective effects against ischemic stroke-induced brain injury via its antioxidant and anti-inflammatory pharmacological effects. However, the mechanisms of rutin's antioxidative and anti-inflammatory effects remain largely unknown. The results showed that rutin alleviated ischemia/reperfusion-induced brain injury, including reduced infarct volume, improved neurological deficits, and decreased glial scar thickness. Rutin also alleviated oxygen-glucose deprivation/reoxygenation (OGD/Re)-induced oxidative stress-related indicators, such as reactive oxygen species, lipid peroxidation levels, 4-hydroxynonenal, and malondialdehyde, as well as pro-inflammatory factors such as interleukin-6, interleukin-1β, and tumor necrosis factor-α in astrocytes, thereby ultimately reducing astrocytic injury and inhibiting the activation of reactive astrocytes. The underlying mechanism is that rutin enhances the enzymatic activity of peroxiredoxin-1 (PRDX1). Knockdown of PRDX1 weakened the pharmacological effects of rutin in inhibiting oxidative stress and inflammatory responses. Finally, rutin could indirectly protect neurons by reducing OGD/Re-induced astrocytic damage and directly reduce OGD/Re-induced damage to primary neurons. Therefore, rutin alleviates ischemic stroke-induced oxidative stress and inflammatory responses in astrocytes, at least partially, by activating PRDX1, thereby inhibiting glial scar formation and exerting neuroprotective effects.
Magnesium Deficiency Disrupts Blood Glucose Homeostasis in a Time-of-Day-Dependent Manner.
Inoue S, Uemura M, Ikegaya Y … +2 more , Matsumoto N, Kashima T
Biol Pharm Bull · 2026 · PMID 42161485 · Publisher ↗
Magnesium deficiency (MgD) disrupts numerous physiological processes, yet its specific impact on in vivo glucose homeostasis remains unclear. This study investigated the longitudinal effects of MgD on blood glucose dynam...
Magnesium deficiency (MgD) disrupts numerous physiological processes, yet its specific impact on in vivo glucose homeostasis remains unclear. This study investigated the longitudinal effects of MgD on blood glucose dynamics in freely moving rats using continuous glucose monitoring. Animals were maintained on a 2-3-week MgD or Control diet under two conditions: access to standard drinking water or a 10% glucose solution. Under standard drinking water conditions, MgD rats exhibited significantly lower mean blood glucose levels specifically during the quiescent day phase, although nonlinear fluctuation patterns remained comparable to those of controls. Conversely, when provided with the glucose solution, MgD rats increased fluid intake, exhibiting a behavioral compensation that normalized mean glucose levels despite the hypoglycemic tendency. However, detailed time-series analysis utilizing recurrence plots revealed that this compensation coincided with altered dynamics; MgD rats exhibited significant impairment in the periodicity of glucose fluctuations during the day phase under the glucose-challenge condition, indicating disrupted blood glucose homeostasis. These findings suggest that chronic MgD lowers baseline glucose levels, potentially via enhanced insulin secretion, thereby further compromising glucose stability under metabolic challenge. This study highlights the important role of magnesium (Mg) in maintaining circadian glucose rhythmicity and pancreatic functional integrity. Consequently, we propose the synergistic application of Mg assays and continuous glucose monitoring as biomarkers for metabolic disorders.
Protective Effects of the Phytocannabinoid Cannabidiol on Disuse-Induced Muscle Atrophy through Modulation of Proteolysis and Mitochondrial Regulation.
Kato H, Uratsuji I, Nakadai Y … +1 more , Ochiai W
Biol Pharm Bull · 2026 · PMID 42161484 · Publisher ↗
Muscle atrophy induced by prolonged inactivity (disuse), including denervation-induced atrophy, is accompanied by oxidative stress, inflammation, and dysregulated protein turnover, yet no effective pharmacological therap...
Muscle atrophy induced by prolonged inactivity (disuse), including denervation-induced atrophy, is accompanied by oxidative stress, inflammation, and dysregulated protein turnover, yet no effective pharmacological therapy is currently available. Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has been reported to exhibit anti-inflammatory and antioxidant properties; however, its potential involvement in disuse-related muscle atrophy has not been fully characterized. In this study, to evaluate the potential effects of CBD on disuse-related muscle atrophy, we employed both in vivo and in vitro models. A mouse model of sciatic nerve resection-induced muscle atrophy was used for the in vivo experiments, while C2C12 myotubes were utilized for the in vitro analyses. In the denervated mouse model, CBD attenuated the decrease in muscle mass in the tibialis anterior and gastrocnemius muscles, as well as the decline in treadmill running performance. CBD also reduced oxidative stress and suppressed the denervation-induced upregulation of Atrogin-1 and muscle RING-finger 1 (MuRF1) proteins, as well as tumor necrosis factor-α (TNF-α) mRNA. Furthermore, CBD partially restored the decreased mitochondrial markers observed following denervation. In vitro, CBD similarly suppressed MuRF1 and Atrogin-1 protein levels and TNF-α mRNA expression in C2C12 myotubes. These findings suggest that CBD is associated with protective effects against disuse-related muscle atrophy, accompanied by reductions in oxidative stress markers, alterations in proteolytic pathways, and changes in mitochondrial-related markers. This study highlights a previously underexplored biological effect of a natural phytocannabinoid and supports further investigation of CBD as a potential supportive strategy for disuse-related muscle wasting.
Acetic Acid-Induced Writhing Is Temporally Dissociated from Gastrointestinal Motility in Freely Moving Rats.
Kuroyanagi H, Kusakabe H, Ikegaya Y … +1 more , Matsumoto N
Biol Pharm Bull · 2026 · PMID 42144371 · Publisher ↗
The acetic acid-induced writhing test is a standard model for visceral pain and analgesic screening. While writhing behavior may have been implicitly assumed to be associated with gastrointestinal motor activity, whether...
The acetic acid-induced writhing test is a standard model for visceral pain and analgesic screening. While writhing behavior may have been implicitly assumed to be associated with gastrointestinal motor activity, whether gastrointestinal motility directly triggers writhing behavior has remained untested. We simultaneously recorded antral and duodenal motility using strain gauge transducers in freely moving rats during acetic acid-induced writhing events. Our analysis, employing a hidden Markov model, found no evidence that antral or duodenal motility exhibited time-locked changes relative to writhing events. Furthermore, writhing behavior persisted even when gastrointestinal motility was pharmacologically suppressed with scopolamine butylbromide, providing direct evidence that writhing occurs independently of gut motor activity. Thus, acetic acid-induced writhing is temporally dissociated from gastrointestinal contraction, indicating that writhing reflects visceral nociceptive signaling distinct from gut motility.
Economic Burden of Cachexia in Japanese Lung Cancer Patients: A Retrospective Claims Database Analysis.
Kashiwa M
Biol Pharm Bull · 2026 · PMID 42128873 · Publisher ↗
Cancer cachexia is associated with poor clinical outcomes in lung cancer patients; however, its economic impact in Japan remains largely uncharacterized. This study quantified the incremental healthcare costs associated...
Cancer cachexia is associated with poor clinical outcomes in lung cancer patients; however, its economic impact in Japan remains largely uncharacterized. This study quantified the incremental healthcare costs associated with cachexia in Japanese lung cancer patients using nationwide claims data. We conducted a retrospective cohort study using the Japan Medical Data Center Claims Database. Deceased lung cancer patients were classified into cachexia (n = 447) and control (n = 10464) groups based on International Classification of Diseases, 10th Revision diagnosis codes. Between-group cost differences were assessed using generalized linear models with a gamma distribution, adjusting for survival time, demographics, histology, metastasis, and comorbidities. Within-patient cost changes were analyzed using fixed-effects regression, comparing 6-month periods before and after cachexia diagnosis. Cachexia was independently associated with 13.5% higher total medical costs (rate ratio: 1.14, 95% confidence interval [CI]: 1.06-1.21, p < 0.001). Within-patient analysis demonstrated a 57.9% cost increase in the month of diagnosis (from ¥371360 to ¥586405), with costs remaining 21.7% elevated post-diagnosis. Cost composition shifted from procedures (1.3 vs. 5.4%) toward home care (8.6 vs. 5.7%) in cachexia patients. Median survival following cachexia diagnosis was only 1.0 month, with 71% of patients dying within 3 months. Anamorelin use increased from 2.4 to 29.8% post-diagnosis, although 70.2% of patients did not receive this therapy. Cachexia diagnosis in lung cancer patients is associated with substantial cost increases in Japan. The extremely short survival after diagnosis and the shift toward supportive care highlight the need for earlier recognition and intervention. These findings provide essential data for the economic evaluation of cachexia therapies.
An Oligodeoxynucleotide from Lactic Acid Bacteria Promotes the Differentiation of Endothelial Cells from Induced Pluripotent Stem Cells.
Yamaguchi-Shibano T, Nishijima M, Takaya T … +1 more , Kawabata K
Biol Pharm Bull · 2026 · PMID 42128872 · Publisher ↗
Bacterial genome-derived oligodeoxynucleotides (ODNs) are recognized as pathogen-associated molecular patterns by Toll-like receptors. They induce inflammatory responses by activating the innate immune response. Recently...
Bacterial genome-derived oligodeoxynucleotides (ODNs) are recognized as pathogen-associated molecular patterns by Toll-like receptors. They induce inflammatory responses by activating the innate immune response. Recently, ODNs reported to regulate stem cell differentiation have garnered attention owing to the discovery of new functions. In this study, we aimed to investigate the effects of a myogenic ODN (iSN04), derived from the Lactobacillus genome sequence and reported to enhance myoblast differentiation, on the differentiation of vascular endothelial cells and other mesodermal lineages derived from the human induced pluripotent stem cell lines iMR90-4 and 201B7. The addition of iSN04 to the differentiation induction medium increased the proportion of CD31CD144 endothelial cells in the cell population. Furthermore, quantitative RT-PCR showed that the addition of iSN04 increased the gene expression of vascular endothelial cell markers such as von Willebrand factor. Analysis of cells on Day 3 after the addition of iSN04 revealed an increase in the expression of Brachyury-T, a marker of the mesoderm. These results suggest that iSN04 may improve the differentiation efficiency of cells, such as vascular endothelial cells, into other mesodermal cells by promoting mesoderm differentiation.
Tramadol Eye Drop Reduces Ocular Nocifensive Behavior Not Primarily Mediated by μ-Opioid Receptor Activation in a Rat Dry Eye Model.
Nagaoka S, Takai Y, Kiyoi T … +1 more , Masuoka T
Biol Pharm Bull · 2026 · PMID 42128871 · Publisher ↗
This study aimed to explore the possibility of using a novel eye drop for ocular pain in dry eyes by examining the effect of tramadol eye drops on nocifensive behavior in normal and dry eye rats. Dry eye model rats were...
This study aimed to explore the possibility of using a novel eye drop for ocular pain in dry eyes by examining the effect of tramadol eye drops on nocifensive behavior in normal and dry eye rats. Dry eye model rats were generated by the unilateral surgical excision of the extraorbital lacrimal glands. The effect of tramadol eye drops on ocular pain in normal and dry eye model rats was assessed using the eye closure time induced by a hyperosmolar (5 M NaCl) solution and the transient receptor potential vanilloid 1 (TRPV1) agonist (1 mM capsaicin). The current response induced by 1 μM capsaicin in the primary sensory neurons was measured by whole-cell recording using cultured trigeminal ganglion neurons. Extraorbital lacrimal gland excision (LGE) significantly enhanced the ocular nocifensive response induced by a 5 M NaCl solution. Pretreatment with tramadol eye drops transiently suppressed nocifensive behavior on the ocular surface in sham-operated and dry eye rats. The suppressive effect of tramadol was only effective on the ipsilateral eye and was not canceled by a μ-opioid receptor antagonist. Furthermore, the capsaicin-induced nocifensive behavior and current responses in primary sensory neurons were suppressed by tramadol treatment. Tramadol eye drops have been shown to temporarily relieve ocular pain in normal and hyperalgesic conditions, such as dry eye. The underlying mechanism may be a decrease in TRPV1-mediated responses at the peripheral sensory nerves on the ocular surface, not primarily mediated by μ-opioid receptor activation.
Plasma Mid-Regional Pro-adrenomedullin as a Prognostic Biomarker in Hematopoietic Stem Cell Transplant Recipients with Febrile Neutropenia.
Iwao M, Tanaka R, Shiraiwa K … +6 more , Sueshige Y, Suzuki Y, Takano K, Tatsuta R, Ogata M, Itoh H
Biol Pharm Bull · 2026 · PMID 42128870 · Publisher ↗
This study aimed to elucidate the association between mid-regional pro-adrenomedullin (MR-proADM) levels at the onset of febrile neutropenia (FN) and clinical outcomes in patients with hematological malignancy undergoing...
This study aimed to elucidate the association between mid-regional pro-adrenomedullin (MR-proADM) levels at the onset of febrile neutropenia (FN) and clinical outcomes in patients with hematological malignancy undergoing hematopoietic stem cell transplantation (HSCT), and the prognostic performance of MR-proADM compared with established infection-related biomarkers comprising presepsin (P-SEP), procalcitonin (PCT), and C-reactive protein (CRP). We analyzed 26 patients (28 FN episodes) who underwent HSCT for hematological malignancy at Oita University Hospital. For each patient, time-dependent profiles of MR-proADM, P-SEP, PCT, and CRP from FN onset until clinical stabilization were evaluated. Correlation analysis was conducted among the four biomarkers. Multivariate analyses were performed to examine associations between peak biomarker levels and clinical outcomes. MR-proADM exhibited an early increase after FN onset, similar to other biomarkers. However, correlation analyses revealed no significant association between MR-proADM and P-SEP (r = 0.087, p = 0.290), PCT (r = 0.026, p = 0.791), or CRP (r = 0.073, p = 0.332). Multivariate analysis identified MR-proADM (p = 0.049) as a significant predictor of fever duration, while CRP (p = 0.032) was significantly associated with the number of organs affected by acute graft-versus-host disease (aGVHD). This study is the first to evaluate MR-proADM at FN onset in HSCT recipients. Elevated MR-proADM may predict prolonged fever, whereas CRP may reflect the severity of aGVHD. These findings suggest that these biomarkers may serve as complementary biomarkers for predicting different clinical outcomes.
Disturbed Flow-Induced ATP Release Upregulates COX-2 Expression via P2Y Receptor in bEnd.3 Endothelial Cells.
Yoshida K, Ikezaki M, Kayakabe M … +2 more , Ito MA, Matsuoka I
Biol Pharm Bull · 2026 · PMID 42128830 · Publisher ↗
Shear stress (SS) generated by blood flow elicits endothelial cell (EC) responses through mechanotransduction pathways. In particular, ATP released by SS is instrumental in regulating vascular dynamics. Cyclooxygenase-2...
Shear stress (SS) generated by blood flow elicits endothelial cell (EC) responses through mechanotransduction pathways. In particular, ATP released by SS is instrumental in regulating vascular dynamics. Cyclooxygenase-2 (COX-2), typically induced by inflammatory responses, is also constitutively expressed in vascular ECs under SS and exerts antithrombotic and vasodilatory effects. However, the mechanism whereby SS-induced ATP release regulates COX-2 expression remains incompletely understood. In this study, we investigated whether extracellular ATP released by SS under disturbed flow conditions promotes COX-2 expression in the mouse brain microvascular EC line bEnd.3. SS applied by disturbed flow via orbital shaking triggered ATP release and upregulated COX-2 expression. Moreover, stimulation by exogenous ATP and uridine 5'-triphosphate (UTP) increased COX-2 expression, which was suppressed by the P2Y receptor antagonist AR-C118925XX. Disturbed flow-induced COX-2 expression was consistently attenuated by AR-C118925XX. Mechanistically, P2Y receptor-mediated upregulation of COX-2 was dependent on the Gq/protein kinase C/extracellular signal-regulated kinases 1/2 signaling cascade. These findings suggest that SS-induced ATP released from ECs contributes to maintaining the expression of endothelial COX-2, highlighting the role of P2Y receptor signaling in endothelial mechanotransduction.
Impact of Deprescribing Medications on Muscle Strength and Muscle Mass in Older Patients with Sarcopenia after Stroke.
Kose E, Matsumoto A, Yoshimura Y
Biol Pharm Bull · 2026 · PMID 42128829 · Publisher ↗
Polypharmacy is prevalent among older adults with sarcopenia and may negatively impact clinical outcomes. Although sarcopenia is associated with polypharmacy, the effect of deprescribing on muscle health in hospitalized...
Polypharmacy is prevalent among older adults with sarcopenia and may negatively impact clinical outcomes. Although sarcopenia is associated with polypharmacy, the effect of deprescribing on muscle health in hospitalized patients with sarcopenia remains poorly understood. This study aimed to investigate the association between deprescribing during hospitalization and muscle strength and mass at discharge in sarcopenic patients after stroke. This study retrospectively analyzed data from a cohort of sarcopenic patients aged ≥65 years admitted to a convalescent rehabilitation ward after stroke. Sarcopenia was diagnosed using the Asian Working Group for Sarcopenia 2019 criteria. Deprescribing was defined as a reduction in the number of medications during hospitalization. The primary outcome was handgrip strength at discharge, and the secondary outcome was skeletal muscle mass index (SMI) at discharge. Multiple linear regression analyses were performed to examine the association between deprescribing and outcomes, adjusting for potential confounders. Of the 970 patients enrolled, 217 older patients, with a mean age of 81.8 years (males, 45.6%), were diagnosed with sarcopenia and included in the analysis. The median number of medications at admission was 5 (interquartile range 3-8), and 23.0% of patients experienced deprescribing during hospitalization. Deprescribing during hospitalization was independently associated with higher handgrip strength (β = 0.122, p = 0.009) and SMI (β = 0.138, p = 0.009) at discharge. Deprescribing was positively associated with improved muscle strength and mass at discharge in sarcopenic patients after stroke. These findings suggest that medication review and deprescribing may be beneficial strategies in the rehabilitation of sarcopenic stroke patients.
The Dual Role of Saikosaponins in Liver Disease Treatment: A Comprehensive Review of Pharmacological Activities and Toxicological Characteristics.
Zhu S, Hao D, Mao B … +4 more , Hua Y, Wang B, Wang P, Yuan W
Biol Pharm Bull · 2026 · PMID 42091451 · Publisher ↗
Liver diseases, including viral hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), remain major global health burdens due to their high prevalence and limited therapeutic options. The need for safer and...
Liver diseases, including viral hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), remain major global health burdens due to their high prevalence and limited therapeutic options. The need for safer and more effective hepatoprotective agents has renewed interest in traditional herbal medicines such as Radix Bupleuri. Its major bioactive constituents, saikosaponins (SSs), exhibit diverse pharmacological activities. This review synthesizes recent advances in the pharmacodynamics, molecular mechanisms, and toxicological characteristics of SSs, emphasizing their dual hepatoprotective and hepatotoxic properties. Relevant literature published from 2000 to 2025 was systematically retrieved from major scientific databases, including PubMed, Web of Science, Google Scholar, and other sources as appropriate, with emphasis on mechanistic studies and in vitro/in vivo evidence. SSs exert hepatoprotective effects through multiple mechanisms, including inhibition of nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling pathways, activation of nuclear receptors, induction of hepatic stellate cell apoptosis and autophagy, and modulation of lipid metabolism via peroxisome proliferator-activated receptor α (PPARα)/sterol regulatory element-binding protein 1c (SREBP1c) signaling. SSs in HCC inhibit Cyclooxygenase-2 and STAT3, promote apoptosis and ferroptosis, suppress angiogenesis, and enhance chemotherapy and radiotherapy sensitivity. However, accumulating evidence indicates that SSs may induce dose-dependent hepatotoxicity through oxidative stress, apoptosis and autophagy injury. These dual pharmacological effects are influenced by CYP regulation, bioavailability, and potential drug-drug interactions. Overall, SSs represent promising yet complex therapeutic candidates. Optimization of dosing strategies, clarification of mechanistic determinants, and development of advanced delivery systems are essential for their safe clinical translation. Future research should incorporate multi-omics approaches, physiologically relevant liver models, and rigorously designed clinical trials to establish standardized Saikosaponin-based therapies for liver diseases.
Establishment of a Rat Model for Renal Anemia Based on 5/6 Nephrectomized Rats.
Nakayama Y, Kamikawa S, Masuda S
Biol Pharm Bull · 2026 · PMID 42021107 · Publisher ↗
Chronic kidney disease (CKD) progresses to renal fibrosis and anemia, ultimately leading to chronic renal failure (CRF). Renal anemia, primarily caused by impaired erythropoietin (EPO) production and dysregulated iron me...
Chronic kidney disease (CKD) progresses to renal fibrosis and anemia, ultimately leading to chronic renal failure (CRF). Renal anemia, primarily caused by impaired erythropoietin (EPO) production and dysregulated iron metabolism, reduces QOL and increases cardiovascular risk. To establish an experimental model of CRF-associated anemia, male Wistar rats underwent 5/6 nephrectomy (Nx). In a subset of Nx rats, tacrolimus (TAC, 1 mg/kg, subcutaneously every other day for two weeks starting at week 4) was administered to exacerbate renal injury. Renal function, hematological parameters, iron-related indices, and fibrotic changes were evaluated at defined postoperative time points. The Nx rats developed progressive renal dysfunction and interstitial fibrosis, accompanied by declining hematocrit and reduced plasma EPO levels and attenuation of renal hypoxia-inducible factor-2α expression. TAC administration further aggravated renal injury and anemia and resulted in a lower hematocrit despite detectable circulating EPO levels. This pattern may suggest a relative inadequacy of erythropoietic response under aggravated renal injury conditions rather than absolute EPO deficiency. These findings indicate that the Nx model reproducibly recapitulates key features of CKD-associated anemia. The addition of TAC accelerates pathological progression within this established model and facilitates the induction of advanced renal injury. This experimental system provides a practical preclinical platform for investigating the molecular mechanisms underlying CKD/CRF-related anemia and for evaluating therapeutic strategies targeting fibrosis, iron metabolism, or impaired erythropoietic response.
Claims-Based Identification of Urinary Tract Infections among Patients in Long-Term Care Wards: A Retrospective Validation Study.
Kumagai K, Inose R, Kimura A … +1 more , Muraki Y
Biol Pharm Bull · 2026 · PMID 42021106 · Publisher ↗
Claims data can be a resource for epidemiological evaluations in long-term care patients at increased risk of urinary tract infections (UTI) from antimicrobial-resistant bacteria. However, as claims data are primarily co...
Claims data can be a resource for epidemiological evaluations in long-term care patients at increased risk of urinary tract infections (UTI) from antimicrobial-resistant bacteria. However, as claims data are primarily collected for administrative purposes, validating diagnostic accuracy is required. This study evaluated the validity of claims-based UTI identification in this patient population. This retrospective study included patients in long-term care wards between January 2023 and December 2024. Using diagnoses from electronic medical records as the gold standard, we evaluated the positive predictive value (PPV) of claims-based identification of UTI and catheter-associated UTI (CAUTI). Diagnoses were identified using International Classification of Diseases, 10th Revision (ICD-10) codes or urinalysis with microscopy, urine culture, antibiotic prescriptions, or indwelling bladder catheter procedures. Sensitivity analysis excluding suspected diagnoses was performed. Among 523 patients, 200 with at least one ICD-10 code for UTI were randomly selected. The PPV for identifying UTI using ICD-10 codes improved from 66.0 to 77.8% when additional codes were combined, and that for CAUTI improved from 45.5 to 86.8% with indwelling bladder catheter procedures. Excluding suspected diagnoses further improved the accuracy. Integrating ICD-10 codes, urinalysis with microscopy, urine culture, antibiotic prescriptions, and, when relevant, indwelling bladder catheter procedures while excluding suspected diagnoses enhances the validity of claims-based UTI identification and may be applicable to database studies using claims data.
Factors Influencing Induced Abortion in Women Aged 18-45 Years: A Nationwide Web-Based Questionnaire Survey in Japan.
Isozaki H, Hattori H, Kusunoki Y … +10 more , Tagawa N, Oshima Y, Moriya K, Takita H, Morohoshi H, Ryu K, Hida N, Sambe T, Shirato N, Momo K
Biol Pharm Bull · 2026 · PMID 42021022 · Publisher ↗
Abortion remains a significant public health concern and often results from unintended pregnancies. Although abortion rates have declined, approximately 40% are still due to unplanned pregnancies. We conducted a subanaly...
Abortion remains a significant public health concern and often results from unintended pregnancies. Although abortion rates have declined, approximately 40% are still due to unplanned pregnancies. We conducted a subanalysis of the FIKA study, a survey on sexuality among Japanese women aged 18-45 years, to examine factors correlated with abortion. We analyzed responses obtained from 3228 sexually experienced women, who were categorized based on abortion history. Sources of knowledge about intercourse and contraceptives were assessed using a standardized questionnaire. A decision tree analysis was performed to identify associated risk factors. Among the participants, 410 women (12.7%) had undergone an abortion. Women who had undergone an abortion were significantly more likely to rely on friends as a source of contraceptive information than women who had not had an abortion (p = 0.0024). Participants with abortion experience showed greater variation in knowledge about contraceptive scores, with most of them being in the lowest knowledge group. Decision tree analysis revealed two key factors: sexual debut before the age of 17 years and only compulsory education. The abortion rate was 39.5% among women with both factors, compared to 7.9% among those with none. Early sexual initiation and limited education were strongly associated with abortion experience. Reliance on informal sources may also contribute to a poor understanding of reproductive health. These findings underscore the need for early, comprehensive, and formal sex education to improve sexual literacy and reduce unintended pregnancies.
Immunohistochemical Localization of Sotorasib-Protein Conjugates in the Rat Gastrointestinal Tract.
Saita T, Teramoto M
Biol Pharm Bull · 2026 · PMID 42002901 · Publisher ↗
Sotorasib is a molecularly targeted drug that exerts antitumor effects by selectively binding to KRAS G12C through a Michael addition reaction, irreversibly inhibiting KRAS. However, the frequent occurrence of adverse ev...
Sotorasib is a molecularly targeted drug that exerts antitumor effects by selectively binding to KRAS G12C through a Michael addition reaction, irreversibly inhibiting KRAS. However, the frequent occurrence of adverse events, such as gastrointestinal and hepatic disorders, has raised major concerns. These toxicities are thought to arise from interactions between sotorasib and proteins other than KRAS in normal cells. In this study, we generated a specific antibody against sotorasib and established an immunohistochemical method capable of detecting sotorasib-protein conjugates. Using this technique, we clarified the localization of sotorasib-protein conjugates in the digestive tract of rats, including the duodenum, jejunum, ileum, and colon. Sotorasib-protein conjugates were strongly localized to the villous epithelial cells of the small intestine but were scarcely detected in the colon, highlighting regional differences. This study elucidates the localization of sotorasib-protein conjugates in the gastrointestinal tract of rats and provides important insights into the mechanisms underlying sotorasib-induced gastrointestinal disorders.
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