Biol. Pharm. Bull. [JOURNAL]
Sun
200 papers
Qin Gui Huo Luo Oral Liquid Attenuates Blood-Brain Barrier Dysfunction after Cerebral Ischemia-Reperfusion Injury in Mice via the Regulation of the PI3K/AKT/FOXO3A Signaling Pathway.
Ling X, Bao L, Xu Y … +2 more , Gong S, Kou J
Biol Pharm Bull · 2025 · PMID 41161783 · Publisher ↗
Qin Gui Huo Luo oral liquid (QGHL) is a modern formulation derived from the Traditional Chinese Medicine (TCM) Daqinjiao Decoction. QGHL has been widely adopted in China's clinical settings as a therapeutic agent for mic...
Qin Gui Huo Luo oral liquid (QGHL) is a modern formulation derived from the Traditional Chinese Medicine (TCM) Daqinjiao Decoction. QGHL has been widely adopted in China's clinical settings as a therapeutic agent for microcirculatory dysfunction. However, the mechanistic interplay of QGHL in animal models for ischemic stroke (IS) treatment remains unexplored. This study aimed to investigate the impact of QGHL on blood-brain barrier (BBB) disruption induced by cerebral ischemia-reperfusion (I/R) injury. HPLC analysis was employed to identify the major chemical constituents of QGHL while maintaining stringent quality standards. Male C57BL/6J mice were subjected to 1-h right middle cerebral artery occlusion, followed by 24-h reperfusion to induce I/R injury. Subsequently, QGHL was administered intragastrically at 3 different doses (7.8, 15.6, and 31.2 g kg). QGHL treatment significantly attenuated cerebral I/R injury, as evidenced by reduced infarct volume, improved neurological scores, attenuated cerebral edema, and restored cerebral blood flow. Moreover, QGHL preserved BBB integrity by upregulating zonula occludens-1 (ZO-1) and occludin while suppressing matrix metalloproteinase (MMP)-2/9 expression. Network pharmacology revealed that phosphatidylinositol 3-kinase (PI3K)/AKT/FOXO3A axis served as a major signaling pathway mediating QGHL's therapeutic effects against IS, which was further confirmed by Western blot analysis. QGHL exerts neuroprotection against cerebral I/R injury in mice via modulation of the PI3K/AKT/FOXO3A signaling pathway, suggesting its potential as a novel therapeutic strategy for IS.
Multifactorial Alterations in Lacosamide Exposure in an Elderly Woman with Symptomatic Epilepsy and Tuberculous Pleurisy: A Case Report.
Takeda R, Matsuda S, Yokooji T … +5 more , Oda K, Takakura H, Mori N, Murakami T, Omoda K
Biol Pharm Bull · 2025 · PMID 41161772 · Publisher ↗
An elderly woman taking lacosamide (LCM) for epilepsy was diagnosed with tuberculous pleurisy. In the hospital, she received a four-drug combination therapy with rifampicin (RFP), isoniazid, pyrazinamide, and ethambutol...
An elderly woman taking lacosamide (LCM) for epilepsy was diagnosed with tuberculous pleurisy. In the hospital, she received a four-drug combination therapy with rifampicin (RFP), isoniazid, pyrazinamide, and ethambutol for tuberculous pleurisy, in addition to medications for symptomatic epilepsy. At admission, her renal function was mildly impaired but remained stable throughout hospitalization. Serum albumin levels were slightly below the normal range. C-reactive protein was markedly elevated on day 4 but returned to normal by the time of discharge. On day 4, therapeutic drug monitoring (TDM) was initiated for LCM, a substrate for CYP2C19 and P-glycoprotein, because RFP can induce multiple cytochrome P450s (CYPs) and P-glycoprotein. Initially, the doses of RFP and LCM were 450 and 100 mg/d, respectively, and the serum concentration of LCM was 9.5 μg/mL (day 4). On day 12, the serum concentration of LCM decreased to 4.1 μg/mL, and the dose of LCM was increased to 200 mg/d. The dose of LCM was further increased to 300 mg/d on day 60 to maintain the serum concentration of LCM at approximately 10 μg/mL. The estimated serum concentration (C) of LCM normalized by the dose (D) ratio, or C/D ratio, was 0.095 on day 4 and decreased to 0.03-0.04 after day 12. The LCM concentration during RFP co-administration may have been affected by the combined effects of RFP-mediated CYP2C19 and P-glycoprotein induction, the patient's inflammatory status, and concomitant anti-tuberculosis drugs. TDM is necessary to attain clinically effective serum concentrations of LCM when RFP is used concomitantly.
Effects of Resmetirom on Resistance to Thyroid Hormone Receptor Mutants: Potential Basis for Therapeutic Applications.
Mitsutani M, Hano H, Yokoyama M … +3 more , Matsushita M, Tagami T, Moriyama K
Biol Pharm Bull · 2025 · PMID 41161771 · Publisher ↗
Resistance to thyroid hormone-β (RTHβ) is caused by mutations in thyroid hormone receptors (TRs), with palpitations, tachycardia, and/or goiter being the most frequently reported clinical features. In recent years, sever...
Resistance to thyroid hormone-β (RTHβ) is caused by mutations in thyroid hormone receptors (TRs), with palpitations, tachycardia, and/or goiter being the most frequently reported clinical features. In recent years, several synthetic thyromimetics have been developed to target mutations associated with RTHβ. Resmetirom, which was granted an accelerated approval by the U.S. Food and Drug Administration, is a TRβ-agonist for the first line therapy for metabolic dysfunction-associated steatohepatitis. This study aimed to evaluate the potential mechanisms of action of resmetirom on RTHβ through co-factors and association with clinical manifestations. We selected cases from 13 clinical records based on recently reported domestic cases in Japan. Based on these clinical reports, we conducted screenings using clinical symptoms, laboratory findings, and mutation data. We attempted to unveil the interaction between 26 RTHβ mutants and resmetirom focusing on recruitment of co-factors. Among the 26 probands, dominant-negative effects (DNE) were identified in 12 mutant TRs (48.5 ± 11.8%). Resmetirom was involved in the recruitment of the co-activators, steroid receptor coactivator-1 and glucocorticoid receptor-interacting protein-1, as well as the co-repressors (CoRs), nuclear-CoR and silencing mediator of retinoic acid and TR. Co-factor recruitment by resmetirom was detected in all mutants. In eight patients with DNE, an association between transcriptional activity and clinical symptoms was observed, which were the reasons for clinical investigation. Notably, in the helix-12 mutant-P453, mild induction of DNE was associated with the recruitment of CoRs, suggesting that resmetirom may be effective in alleviating subjective symptoms in mutants with attenuated DNE located in helix-12.
Preferential Recognition of Drug-Induced Altered Self-Presentation on Tumor Cells, but Not Host Cells, by CD8 T Cells for Eliciting Anti-Tumor Immunity.
Susukida T, Aoki S, Hayakawa Y
Biol Pharm Bull · 2025 · PMID 41125346 · Publisher ↗
We previously reported that CD8 T cell activation via drug-induced altered self-presentation increases the tumor immunogenicity and cancer immunotherapy efficacy. Although the anti-human immunodeficiency virus drug abaca...
We previously reported that CD8 T cell activation via drug-induced altered self-presentation increases the tumor immunogenicity and cancer immunotherapy efficacy. Although the anti-human immunodeficiency virus drug abacavir (ABC) increases the tumor immunogenicity and induces CD8 T cell anti-tumor immune responses in mice inoculated with tumor cells ectopically expressing the human leukocyte antigen (HLA)-B*57:01, whether such anti-tumor immunity is also triggered in hosts with high HLA-B*57:01 expression levels remain unclear. To verify this, we investigated the anti-tumor effects of ABC on HLA-B*57:01-expressing tumor and normal host cells using HLA-B*57:01 transgenic (B*57:01-Tg) mice in this study. ABC suppressed the HLA-B*57:01-expressing B16F10 tumor growth and increased the CD8 T cell tumor infiltration in B*57:01-Tg mice. ABC also activated the tumor-infiltrating CD8 T cells to secrete interferon-γ but did not promote their proliferation in the tumors of B*57:01-Tg mice. Moreover, ABC did not increase the effector CD8 T cell proportions in the tumor-draining lymph nodes of B*57:01-Tg mice. Overall, CD8 T cells preferentially recognized the ABC-induced altered self-antigen-presenting HLA-B*57:01-expressing tumor cells, but not host cells, to elicit anti-tumor immunity.
The Involvement of HYBID in the Regulation of Intraocular Pressure and Extracellular Matrix Accumulation in the Trabecular Meshwork.
Takagi Y, Aoshima K, Kuse Y … +3 more , Nakamura S, Okada Y, Shimazawa M
Biol Pharm Bull · 2025 · PMID 41110947 · Publisher ↗
Increased accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) causes a rise in intraocular pressure (IOP), which is a primary risk factor for glaucoma. Hyaluronan (HA) is essential for forming the...
Increased accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) causes a rise in intraocular pressure (IOP), which is a primary risk factor for glaucoma. Hyaluronan (HA) is essential for forming the ECM network, but it is unclear whether HA metabolism plays a role in IOP control. In this study, we focused on the hyaluronan-binding protein involved in hyaluronan depolymerization (HYBID, also referred to as cell migration inducing hyaluronidase 1 (CEMIP)/KIAA1199), which is an HA-degrading enzyme. Hybid knockout (KO) mice exhibited IOP elevation [IOP on average +2.14 mmHg at 7 weeks old, +1.54 mmHg at 8 weeks old vs. IOP of wildtype (WT) mice]. In addition, fibronectin and HA accumulated in the TM of Hybid KO mice. In cultured human TM cells (HTMCs), HYBID knockdown with HYBID siRNA increased HA and fibronectin protein but the expression of fibronectin mRNA was not altered. In addition, in HYBID knockdown HTMCs, matrix metalloproteinase (MMP)-1 and tissue inhibitor of metalloproteinase (TIMP) 3 were increased and MMP-9 was decreased. These results indicated that HYBID knockdown did not contribute to fibronectin production but inhibited ECM degradation through decreased MMP-9 expression and increased TIMP3 expression, leading to reduced MMP-2 and MMP-9 activity. These findings may offer new perspectives on the underlying mechanisms of glaucoma associated with fibrosis and potentially contribute to the development of novel glaucoma therapeutics.
Anti-atrial Fibrillatory Effects of the TRPC3 Channel Inhibitor Pyrazole-3 in Rats with Atrial Enlargement Induced by Chronic Volume Overload.
Aimoto M, Nagasawa Y, Kusakabe T … +2 more , Kato K, Takahara A
Biol Pharm Bull · 2025 · PMID 41093584 · Publisher ↗
The effect of transient receptor potential canonical-3 (TRPC3) channel inhibitor pyrazole-3 (Pyr3) on the stability of atrial fibrillation (AF) was analyzed in a rat model of chronic volume overload. Male Wistar rats und...
The effect of transient receptor potential canonical-3 (TRPC3) channel inhibitor pyrazole-3 (Pyr3) on the stability of atrial fibrillation (AF) was analyzed in a rat model of chronic volume overload. Male Wistar rats underwent aorto-venocaval shunt (AVS) surgery and received Pyr3 treatment intraperitoneally for 12 weeks. Morphological and electrophysiological assessments were performed at the end of the treatment period. Longer P-wave duration, atrial conduction time, and AF duration, in addition to greater atrial tissue weight, were detected in AVS rats compared with sham rats. Chronic Pyr3 administration prevented AVS-induced prolongation of P-wave duration and atrial conduction time, partially prevented atrial weight increase, and abbreviated AVS-induced prolongation of AF duration to similar levels as those in sham rats, without affecting the atrial effective refractory period. These results suggest that the TRPC3 inhibitor Pyr3 can ameliorate sustained AF associated with chronic volume overload by improving atrial conduction defects in AVS rats. Pharmacological inhibition of TRPC3 channels by Pyr3 thus represents a promising therapeutic strategy for preventing AF development related to structural modeling.
Effect of Benzo[a]pyrene on Cellular Senescence in MCF7 Breast Cancer Cells.
Kitamoto N, Haga Y, Tsujii Y … +3 more , Kubo M, Higashisaka K, Tsutsumi Y
Biol Pharm Bull · 2025 · PMID 41093583 · Publisher ↗
Studies on the effect of environmental chemicals on cancer has primarily focused on the early stages, while the impact on later stages, particularly cancer progression, has been less explored. Cellular senescence, a resp...
Studies on the effect of environmental chemicals on cancer has primarily focused on the early stages, while the impact on later stages, particularly cancer progression, has been less explored. Cellular senescence, a response to stress such as DNA damage and oxidative stress, has been reported to play a crucial role in cancer progression. Environmental chemicals are suspected to promote cancer progression, yet it is unclear whether this is mediated through cellular senescence. Benzo[a]pyrene (BP) is known to induce DNA damage, a key trigger of senescence, but whether it directly induces senescence in cancer cells remains uncertain. This study aims to evaluate the senescence-inducing potential of BP in breast cancer cells to better understand its role in cancer progression. We examined the effects of BP, a polycyclic aromatic hydrocarbon primarily generated via incomplete combustion of organic matter and commonly found in water, soil, automobile exhaust, and tobacco smoke, on MCF7 breast cancer cells. BP enters the human body via inhalation, ingestion, and dermal contact. Here, as indicated by multiple senescence markers, including nuclear elongation, senescence-associated β-galactosidase activity, DNA damage, and increased p21 expression, BP induced cellular senescence in MCF7 cells. As cellular senescence is associated with malignant cell transformation, our results might suggest that BP contributes to cancer progression by inducing cellular senescence.
He-Wei-Decoction Ameliorates Chronic Atrophic Gastritis via Modulation of the TLR4/NF-κB Signaling Pathway.
Lin D, Wang G, Ge Y … +1 more , Yin J
Biol Pharm Bull · 2025 · PMID 41083380 · Publisher ↗
He-Wei-Decoction (HWD), a traditional Chinese medicine formula, emphasizes "strengthening the spleen and supplementing qi (Jianpi Yiqi)," and "resolving stasis and detoxifying (Huayu Jiedu)." This formula has been utiliz...
He-Wei-Decoction (HWD), a traditional Chinese medicine formula, emphasizes "strengthening the spleen and supplementing qi (Jianpi Yiqi)," and "resolving stasis and detoxifying (Huayu Jiedu)." This formula has been utilized in the treatment of chronic atrophic gastritis (CAG), however, its precise mechanisms of action remain to be elucidated. This study integrates network pharmacology with molecular dockings to identify the underlying mechanisms of HWD in the treatment of CAG. Then, immunohistochemistry assay analyzed the gastric mucosal lesions before and after treatment with HWD in CAG patients. The efficacy and mechanism of key active compounds in the treatment of CAG were validated using a 1-methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced GES-1 cell in vitro model. A total of 165 active compounds from HWD were identified, along with 169 targets associated with CAG. Gene oncology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Component-Target-Pathway network analysis revealed that the Toll-like receptor (TLRs) signaling pathway may play a role in HWD's regulation of inflammation in gastric mucosa. Molecular docking identified that luteolin, quercetin, and hederagenin potentially interact with key target proteins TLR4 and nuclear factor-kappaB (NF-κB). Experimental results validated that HWD significantly improved atrophic mucosa and inhibited the expression of TLR4, NF-κB, and cyclooxygenase 2 (COX2) proteins. The active compounds, luteolin, quercetin, and hederagenin, inhibit cell viability, migration and invasion, and reduce the expression of TLR4, NF-κB, and COX2. In summary, luteolin, quercetin, and hederagenin, the primary active components of HWD, can ameliorate the CAG by regulating the TLR4/NF-κB signaling pathway.
ROBO3 Drives Endometriosis Progression via Dual Wnt/β-Catenin Activation and M2 Macrophage Polarization.
Zhou X, Zhou W, Qu C … +3 more , Jiang Y, Liu W, Pei L
Biol Pharm Bull · 2025 · PMID 41083379 · Publisher ↗
Endometriosis, a prevalent gynecological disorder marked by ectopic growth of endometrial-like tissue, demonstrates malignant tumor-like properties including aggressive adhesion and invasiveness. Emerging evidence implic...
Endometriosis, a prevalent gynecological disorder marked by ectopic growth of endometrial-like tissue, demonstrates malignant tumor-like properties including aggressive adhesion and invasiveness. Emerging evidence implicates roundabout guidance receptor 3 (ROBO3) in cellular pathophysiology, yet its role in endometriosis remains unexplored. In this study, we first found abnormally high ROBO3 expression in endometriosis by bioinformatics analysis. Next, functional assays revealed that ROBO3 is a key regulator promoting the invasion and migration of endometriotic stromal cells (ESCs) in vitro. Mechanistically, ROBO3 activates the Wnt/β-catenin signaling pathway, evidenced by increased phosphorylation of glycogen synthase kinase 3β, nuclear β-catenin accumulation, and upregulated c-myc expression. Pharmacological inhibition of Wnt/β-catenin with MSAB (5 μM) reversed ROBO3-mediated pro-invasive and pro-migratory effects. Furthermore, we discovered that ROBO3 enhances the secretion of chemokines CCL2 and CCL5 in ESCs, which subsequently promote macrophage polarization toward the M2 phenotype, as indicated through elevated expression of interleukin-10 and Arg-1. Collectively, our findings elucidate a dual mechanism whereby ROBO3 drives endometriosis progression through both intrinsic activation of Wnt/β-catenin signaling and extrinsic modulation of tumor-associated macrophages, underscoring ROBO3 as a promising therapeutic target for endometriosis.
Association of Plasma Creatinine with Systemic Exposure to S-1 and Oxaliplatin in Two Types of Chronic Kidney Disease Animal Models.
Tanaka T, Tanaka A, Kobuchi S … +2 more , Ito Y, Sakaeda T
Biol Pharm Bull · 2025 · PMID 41083378 · Publisher ↗
Chronic kidney disease (CKD) is a serious chemotherapy-associated clinical condition. CKD complicates the pharmacokinetics of anticancer drugs, requiring personalized dosing strategies to minimize toxicity. S-1 and oxali...
Chronic kidney disease (CKD) is a serious chemotherapy-associated clinical condition. CKD complicates the pharmacokinetics of anticancer drugs, requiring personalized dosing strategies to minimize toxicity. S-1 and oxaliplatin (the SOX regimen) are widely used for gastrointestinal cancer treatment. However, the specific association between systemic drug exposure and renal biomarker levels in CKD remains unclear. This study evaluated the pharmacokinetics of S-1 and oxaliplatin in 2 CKD model rats (5/6 nephrectomy and adenine-induced) and examined their relationships with renal biomarkers. S-1 (2 mg/kg as tegafur) and oxaliplatin (5 mg/kg) were administered separately, and plasma levels of tegafur, 5-fluorouracil (5-FU), 5-chloro-2,4-dihydropyridine, oxaliplatin, and platinum were measured by LC-tandem MS. Systemic exposure to S-1 and oxaliplatin was higher in the CKD model rats than in the normal group, with 5-FU levels being particularly higher in the adenine-induced model than in the 5/6 nephrectomy model. The area under the curve values of 5-FU and platinum were strongly correlated with plasma creatinine (P) levels (r = 0.79 and 0.88, respectively). Population pharmacokinetic analysis identified P as a significant covariate of 5-FU clearance. A nomogram constructed using P-based simulations demonstrated the feasibility of individualized S-1 dosing. Overall, our findings suggest that P is a practical biomarker to guide S-1 dose optimization and highlight the importance of pharmacokinetics-based strategies for patients with cancer and CKD.
Mitochondrial Coenzyme Q Delivery Improves Energy Production in Rat Cardiac Myoblasts and Duchenne Muscular Dystrophy Model Rat Cardiomyocytes.
Sato I, Sasaki D, Abe J … +3 more , Yamanouchi K, Takeda A, Yamada Y
Biol Pharm Bull · 2025 · PMID 41083362 · Publisher ↗
Enhancing cardiomyocyte mitochondrial function has been reported as a potential therapeutic approach for various diseases. However, this is technically difficult, and its practical use has not been described. Although tr...
Enhancing cardiomyocyte mitochondrial function has been reported as a potential therapeutic approach for various diseases. However, this is technically difficult, and its practical use has not been described. Although treatments such as exon skipping for skeletal muscle have been established for Duchenne muscular dystrophy (DMD), no curative treatment has been developed for DMD cardiomyopathy, and only cardioprotective medications and symptomatic treatments are available. In this study, we attempted to activate cardiac myocyte mitochondria via direct drug delivery using lipid nanoparticles and investigated the application of this strategy to diseased cells. First, we delivered CoQ, a mitochondrial activator with cellular antioxidant capacity, into mitochondria in H9C2 cells using MITO-Porter, a mitochondria-directed nanoparticle. Cellular MITO-Porter uptake was measured using flow cytometry. Co-localization of mitochondria and MITO-Porter was confirmed using confocal laser microscopy. Mitochondrial respiratory capacity was measured using an extracellular flux analyzer. Furthermore, the concentration-response relationships of the amount of nanoparticles or CoQ with mitochondrial energy production capacity were confirmed. Next, we examined the possibility of improving mitochondrial energy production capacity in diseased cells. Cells were isolated from the myocardium of DMD model rats generated using the CRISPR-Cas9 system. Mitochondrial energy production capacity was lower in DMD primary cardiomyocytes than in wild-type primary cardiomyocytes. CoQ delivery to mitochondria in DMD primary cardiomyocytes using MITO-Porter improved mitochondrial energy production capacity. Thus, enhanced cardiomyocyte mitochondrial energy production might represent a potential treatment for cardiomyopathy.
Induction of Melanin Synthesis by Pueraria lobata Leaves in B16 Murine Melanoma Cells and Three-Dimensional Human Skin Equivalent.
Uto T, Ohta T, Kairada M … +5 more , Yoshitomi J, Nakagawa S, Tsuji Y, Kojima H, Hashimoto M
Biol Pharm Bull · 2025 · PMID 41083361 · Publisher ↗
Puerariae Radix, the root of Pueraria lobata (Willd.) Ohwi is primarily used as a traditional herbal medicine in East Asia. Although phytochemical and biological investigations of the roots have been well-reported, those...
Puerariae Radix, the root of Pueraria lobata (Willd.) Ohwi is primarily used as a traditional herbal medicine in East Asia. Although phytochemical and biological investigations of the roots have been well-reported, those of the leaves are limited. To explore the potential value of P. lobata leaves, this study aimed to evaluate their effect on melanin synthesis in B16-F1 murine melanoma cells and three-dimensional (3D) human skin equivalents and investigate the underlying molecular mechanism. The leaf extract increased the melanin content in B16-F1 cells, with stronger induction potency than that of the vine and root extracts. Among the 4 fractions prepared from the leaf extract, the hexane fraction significantly induced melanin synthesis. Both the leaf extract and hexane fraction also increased melanin content in a 3D human skin equivalent model. Of the 7 fractions separated from the hexane fraction, fraction 1 (fr. 1) strongly induces melanin synthesis and intracellular tyrosinase activity. Further analysis indicated that fr. 1 may induce melanin synthesis via cAMP-responsive element-binding protein (CREB) phosphorylation and microphthalmia-associated transcription factor (MITF) expression, leading to the expression of tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2. These results suggest that P. lobata leaves may be a useful medicinal resource for treating hypopigmentation.
Quercetin, a Natural Dietary Flavonoid, Emerges a Novel USP7 Inhibitor with Anti-colorectal Cancer Effects.
Li X, Li Q, Huang Y … +3 more , Zhou H, Yang Q, Kong L
Biol Pharm Bull · 2025 · PMID 41062308 · Publisher ↗
The human deubiquitinating enzyme ubiquitin-specific peptidase 7 (USP7) has emerged as a promising anti-tumor target, particularly in colorectal cancer, due to its regulation of the MDM2/p53 axis. Through a combination o...
The human deubiquitinating enzyme ubiquitin-specific peptidase 7 (USP7) has emerged as a promising anti-tumor target, particularly in colorectal cancer, due to its regulation of the MDM2/p53 axis. Through a combination of ubiquitin C-terminal 7-amido-4-methylcoumarin hydrolysis assay and ubiquitin-propargylamide protease profiling, we identified the natural dietary flavonoid quercetin as a potent USP7 inhibitor in both cell-free and cellular contexts. Cellular thermal shift and surface plasmon resonance analyses demonstrated that quercetin is directly bound to USP7. Consistent with USP7 target engagement in cells, quercetin decreased MDM2 levels and subsequently increased the levels of p53. Moreover, quercetin also suppressed colorectal cancer cell proliferation by inducing G2/M cell cycle arrest and inhibiting cell migration. Collectively, our study identified quercetin as a novel and effective USP7 inhibitor with potent anti-colorectal cancer activity, highlighting its therapeutic potential for targeting the USP7-MDM2-p53 axis and warranting further exploration as a promising therapeutic agent in colorectal cancer treatment.
Placental Extract Inhibits Melanogenesis by Inducing the Proteasome-Dependent Degradation of Tyrosinase and TRP-1.
Moriya M
Biol Pharm Bull · 2025 · PMID 41062307 · Publisher ↗
Placental extract (PE) is employed as a skin-whitening agent in Japan, where this material is used in cosmetics and dietary supplements. However, the mechanism of PE's anti-melanogenic activity remains poorly understood....
Placental extract (PE) is employed as a skin-whitening agent in Japan, where this material is used in cosmetics and dietary supplements. However, the mechanism of PE's anti-melanogenic activity remains poorly understood. The goal of the present study was to elucidate the mechanism of PE's inhibitory effect on melanogenesis in B16 murine melanoma cells. Specifically, the activity of equine PE (EPE) against tyrosinase and melanogenic proteins was evaluated. The effects of EPE on tyrosinase activity and melanin content were assessed spectrophotometrically. This analysis showed that EPE inhibits melanogenesis in melanoma cells in a dose-dependent manner without affecting cell proliferation. EPE did not directly inhibit the enzymatic activity of tyrosinase. Western blot analysis demonstrated that EPE exposure also led to decreases in the protein levels of tyrosinase and tyrosinase-related protein 1 (TRP-1) in melanoma cells, without affecting the levels of the mRNAs encoding these proteins. This analysis further demonstrated that the EPE-induced depletion of tyrosinase and TRP-1 resulted from the induction, by EPE, of proteasome-mediated proteolytic degradation. Notably, the EPE-induced depletion of tyrosinase and TRP-1 was prevented by joint exposure to EPE and the proteasome inhibitor MG132. Similar experiments showed that the exposure of melanoma cells to MG132 abrogates the inhibition of melanogenesis by EPE. Immunoprecipitation analysis further revealed that EPE induces the ubiquitination of tyrosinase and TRP-1. Taken together, these results suggested that EPE induces proteasomal degradation of tyrosinase and TRP-1 by enhancing the ubiquitination of these targets, leading to the depletion of these proteins and the inhibition of melanogenesis.
Disruption of Tight Junctions in Intestinal Epithelial Cells by Toxic Advanced Glycation End-Products.
Takeda R, Hori E, Natori M … +6 more , Yamada Y, Hashita T, Iwao T, Sakai-Sakasai A, Takeuchi M, Matsunaga T
Biol Pharm Bull · 2025 · PMID 41034037 · Publisher ↗
Intestinal epithelial cells (IECs) play a crucial role in forming a protective barrier and regulating the absorption of substances passing through the small intestine. Disrupting the epithelial barrier function can resul...
Intestinal epithelial cells (IECs) play a crucial role in forming a protective barrier and regulating the absorption of substances passing through the small intestine. Disrupting the epithelial barrier function can result in intestinal diseases such as inflammatory bowel disease. Glyceraldehyde (GA)-derived advanced glycation end-products (AGEs) (toxic AGEs, TAGE) are AGEs formed by the nonenzymatic Maillard reaction. Although AGEs have been implicated in intestinal barrier breakdown, the associated mechanism remains underexplored. In this study, the effects of accumulated TAGE in IECs were investigated by focusing on tight junctions using Caco-2 cells-a human colorectal epithelial adenocarcinoma cell line. While GA treatment induced the formation of intracellular TAGE in Caco-2 cells, resulting in cell death, the generated intracellular TAGE triggered increased paracellular permeability. In addition, immunofluorescence staining showed that GA treatment decreased the fluorescence intensities of ZO-1 and claudin-7, which are tight junction proteins attached to the plasma membrane. Furthermore, an evaluation of the mechanism behind intestinal barrier breakdown revealed excessive reactive oxygen species (ROS) production and increased expression of reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase subunit genes, a mechanism of ROS production, in the GA-treated group compared with the control group. Furthermore, GA treatment induced necrosis and caused cytotoxicity in this condition. Overall, these results suggest that TAGE induction can disrupt tight junctions in IECs via cell injury as a pathway.
Effect of 2-Hydroxypropyl-γ-cyclodextrin on Renal Inflammation in Alport Mouse Model.
Horizono J, Mizumoto K, Suico MA … +12 more , Shirakawa A, Kaseda S, Sannomiya Y, Tsuhako H, Owaki A, Sato R, Shiraga M, Kato R, Kumabe R, Shuto T, Ishitsuka Y, Kai H
Biol Pharm Bull · 2025 · PMID 41033979 · Publisher ↗
Cyclodextrins (CDs) are cyclic oligosaccharides that encapsulate hydrophobic molecules such as cholesterol. Hydroxypropyl-β-cyclodextrin (HP-β-CD), a cyclic heptasaccharide, has gained attention as a protective agent for...
Cyclodextrins (CDs) are cyclic oligosaccharides that encapsulate hydrophobic molecules such as cholesterol. Hydroxypropyl-β-cyclodextrin (HP-β-CD), a cyclic heptasaccharide, has gained attention as a protective agent for chronic kidney diseases, particularly the genetic kidney disease Alport syndrome, due to its anti-inflammatory property and the ability to reduce cholesterol content in Alport kidneys. However, HP-β-CD has side effects of hearing loss and kidney injury. These concerns are important issues for Alport syndrome patients who have pre-existing hearing abnormalities and kidney dysfunction. We previously revealed that 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), a cyclic octasaccharide, is less toxic than HP-β-CD. Here, we examined the dose-dependent effects of HP-γ-CD (0.71, 1.42, 2.85 mmol/kg, once a week) on the progressive disease phenotype in the Alport mouse model (Col4a5-G5X). HP-γ-CD at 0.71 mmol/kg suppressed the renal inflammation, glomerulosclerosis, and tubular injury in Alport mice, but did not prevent the decline in kidney function. Moreover, HP-γ-CD at 2.85 mmol/kg increased proteinuria and decreased the body weight of Alport mice. Interestingly, HP-γ-CD did not reduce the unesterified cholesterol (UC) content in Alport mouse kidneys, especially in the glomeruli. These results suggested that HP-γ-CD exerted its anti-inflammatory effect, but did not improve the progressive phenotype in the Col4a5 G5X Alport mouse model. Our findings add more information on the use and dosage effects of HP-γ-CD for experimental Alport syndrome.
Docosahexaenoic Acid Targets TRPC3/6 Channels to Suppress Noradrenaline-Induced Contraction in Rat Vas Deferens Smooth Muscle.
Obara K, Enomoto M, Furuta M … +11 more , Okura H, Kato A, Mouri T, Gohara M, Ura T, Nasu H, Yoshioka K, Kusakabe T, Takahashi K, Kato K, Tanaka Y
Biol Pharm Bull · 2025 · PMID 41033978 · Publisher ↗
We investigated the effects of docosahexaenoic acid (DHA) on noradrenaline (NA)-induced contractile responses in rat vas deferens smooth muscle (VDSM). DHA (3 × 10-3 × 10 M) significantly inhibited phasic contractions in...
We investigated the effects of docosahexaenoic acid (DHA) on noradrenaline (NA)-induced contractile responses in rat vas deferens smooth muscle (VDSM). DHA (3 × 10-3 × 10 M) significantly inhibited phasic contractions induced by NA (3 × 10 M) in a concentration-dependent manner. In contrast, under Ca-free conditions, DHA (3 × 10 M) slightly enhanced NA-induced contractile responses. DHA did not inhibit NA-induced contractile responses in the prostate, which are mediated by α-adrenoceptor stimulation, similar to those in VDSM. Although verapamil (10 M), an L-type Ca channel inhibitor, partially suppressed NA-induced contractile responses in VDSM, a substantial phasic component persisted. The residual phasic component was unaffected by LOE-908 (a receptor-operated Ca channel inhibitor, 3 × 10 M), but was markedly inhibited by SKF-96365 (an inhibitor of both receptor-operated and store-operated Ca channels, 3 × 10 M). Among inhibitors targeting store-operated Ca channel candidates with high mRNA expression in VDSM, GSK417651A (10 M) and Pyr10 (3 × 10 M)-both putative inhibitors of transient receptor potential canonical 3/6 (TRPC3/6) channels-effectively inhibited the contractile response, whereas inhibitors targeting Orai1, transient receptor potential vanilloid 4 (TRPV4), or TRPC1/4/5 did not exert inhibitory effects. Similarly, under combined treatment with verapamil and LOE-908, contractile responses induced by cyclopiazonic acid (3 × 10 M, a sarco/endoplasmic reticulum Ca-ATPase inhibitor) were reduced by DHA, SKF-96365, and putative TRPC3/6 inhibitors, but not by inhibitors of Orai1, TRPV4, or TRPC1/4/5. These findings indicate that DHA suppresses NA-induced contractile responses in VDSM, primarily through inhibition of TRPC3/6 channels.
Development of a Hyperglycemic Fish Model and Analysis of Bone Metabolism.
Kuroda K, Tabuchi Y, Takino H … +6 more , Maruyama Y, Honda M, Matsubara H, Hirayama J, Hattori A, Suzuki N
Biol Pharm Bull · 2025 · PMID 40993073 · Publisher ↗
The high plasma glucose induced in glucose metabolism disorders leads to secondary pathologies, including bone disease. Fish scales, similar to mammalian bone, are composed of osteoblasts, osteoclasts, and calcified bone...
The high plasma glucose induced in glucose metabolism disorders leads to secondary pathologies, including bone disease. Fish scales, similar to mammalian bone, are composed of osteoblasts, osteoclasts, and calcified bone matrix and have been used as a system to analyze hyperglycemia-induced bone abnormalities. Here, we developed a hyperglycemia model in fish to study abnormalities in bone metabolism linked to increased plasma glucose and to analyze the function of calcitonin, the suppressor of osteoclastic activity, while maintaining high glucose levels. Following a 1-d fast and exposure to 5% glucose, plasma glucose concentrations increased significantly. We then examined plasma calcium and osteoclast activity of scales related to bone metabolism in goldfish treated with glucose for 5 d after a 1-d fast. The results showed that glucose treatment significantly increased plasma calcium levels at 3 and 5 d with a decrease in calcium content in the scales of goldfish. Hyperglycemia in glucose-exposed goldfish induced osteoclastic activation in scales, as indicated by the ratio of the osteoclastic activating factor (rankl) to the osteoclast inhibiting factor (osteoprotegerin, opg). Plasma calcitonin was found to be increased in glucose-exposed goldfish, which appears to suppress bone resorption by regulating the rankl/opg ratio. This hyperglycemia model, capable of examining both glucose and bone metabolism, would be valuable for analyzing the mechanism underlying abnormal bone metabolism caused by hyperglycemia.
Effect of RANTES on Vascular Contractile and Relaxant Responses in Rat Carotid Arteries.
Matsumoto T, Nagano T, Tanaka-Totoribe N
Biol Pharm Bull · 2025 · PMID 40993072 · Publisher ↗
Although regulated-upon-activation normal T-cell expressed and secreted (RANTES), a chemokine originally identified as a T-cell-specific gene product, has been shown to influence various cellular processes, its effects o...
Although regulated-upon-activation normal T-cell expressed and secreted (RANTES), a chemokine originally identified as a T-cell-specific gene product, has been shown to influence various cellular processes, its effects on vascular reactivity remain unclear. Therefore, we investigated the direct effects of prolonged RANTES exposure on responses to various vasoactive agents in isolated rat carotid arteries. Contractile responses to serotonin, isotonic high K, noradrenaline, the thromboxane A analog U46619, and endothelin-1 were similar between the control and RANTES-treated groups (100 ng/mL for approximately 24 h). However, RANTES treatment impaired acetylcholine-induced relaxation, whereas relaxations induced by the nitric oxide donor sodium nitroprusside, the ATP-sensitive potassium channel activator cromakalim, and the large-conductance calcium-activated potassium channel activator NS19504 were unaffected. Acute incubation with the nitric oxide synthase inhibitor N-nitro-l-arginine abolished acetylcholine-induced relaxation and eliminated the differences between the control and RANTES-treated groups. Furthermore, the cyclooxygenase inhibitor indomethacin also abolished the differences in acetylcholine-induced relaxation between the 2 groups. Co-treatment with the antioxidant N-acetyl-l-cysteine enhanced acetylcholine-induced relaxation in the presence of RANTES, while co-treatment with the C-C motif chemokine receptor 5 antagonist maraviroc slightly improved the relaxation response. These findings suggest that RANTES impairs acetylcholine-induced relaxation, likely due to the reduction of nitric oxide bioavailability and the unmasking of vasoconstrictor prostanoids through increased reactive oxygen species.
Real-World Safety Characteristic of Iguratimod: A Pharmacovigilance Study Based on the Japanese Adverse Drug Event Report (JADER) Database.
Liu Y, Feng R
Biol Pharm Bull · 2025 · PMID 40976696 · Publisher ↗
The safety profiles of iguratimod in large cohorts are lacking. The clinical characteristics and time-to-onset of adverse events remain completely unclear. Our real-world study aims to provide more comprehensive data for...
The safety profiles of iguratimod in large cohorts are lacking. The clinical characteristics and time-to-onset of adverse events remain completely unclear. Our real-world study aims to provide more comprehensive data for the risk management of iguratimod in the actual application environment. All data of iguratimod were obtained from the Japanese Adverse Drug Event Report (JADER) database. Four disproportionality analysis methods were used to detect significant pharmacovigilance signals. The Weibull shape parameter test was used to analyze the time-to-onset of adverse events. In our study, a total of 1472 adverse events associated with iguratimod treatment were collected, which refers to 22 System Organ Class. Within the standardized MedDRA queries, 23 positive signals were detected; 55 preferred terms (PTs) were detected by all 4 disproportionality analysis methods; and 30 PTs associated with infection were gained. Fourteen PTs were not listed in the directions, including 5 potential tumor signals. The most-mentioned PT is interstitial lung disease. Close to half of the adverse events (48.74%) occurred in the first 3 months of iguratimod treatment. The Weibull shape parameter test results showed that all of the disproportionality signals had an early failure-type profile, but infective signals present a random failure profile. This pharmacovigilance study provides valuable information for risk monitor and management of iguratimod, which helps enhance the safety of the clinical application.
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