Biological & pharmaceutical bulletin最新文献

{"title":"TRPC3 Mediates Neurological Dysfunction after Intracerebral Hemorrhage in Mice.","authors":"Kosei Tamada, Shota Tobori, Nozomi Kato, Kazuki Nagayasu, Hisashi Shirakawa","doi":"10.1248/bpb.b26-00276","DOIUrl":"https://doi.org/10.1248/bpb.b26-00276","url":null,"abstract":"<p><p>Intracerebral hemorrhage (ICH) is a lethal stroke subtype characterized by secondary injury resulting from pathological intracellular Ca²⁺ signaling. Bioactive molecules such as ATP and thrombin activate multiple receptor subtypes. Thus, targeting a common downstream molecular mechanism may be more effective than inhibiting individual receptors. One potential candidate is transient receptor potential canonical 3 (TRPC3), a Ca²⁺-permeable nonselective cation channel activated via Gq/phospholipase C signaling. However, its role in ICH remains unclear. Thus, this study aimed to investigate the role of TRPC3 in neurological dysfunction after ICH by using TRPC3 knockout (KO) mice and astrocyte-specific knockdown approaches. The TRPC3-KO mice exhibited significantly lower neurological deficit scores and performed better on the rotarod test than the wild-type mice at 1 and 3 d after ICH, suggesting that TRPC3 plays a critical role in functional impairment. However, the astrocyte-specific knockdown of TRPC3 using an adeno-associated virus vector did not significantly improve neurological dysfunction. These results indicate that TRPC3 contributes to neurological dysfunction after ICH, but that its pathological role cannot be explained by astrocytic TRPC3 alone, indicating the involvement of multiple cell types. In conclusion, TRPC3 is a key channel involved in neurological dysfunction after ICH, suggesting that targeting TRPC3 may provide a new therapeutic strategy for attenuation of neurological dysfunction after ICH.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"49 7","pages":"1093-1096"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disturbed Flow-Induced ATP Release Upregulates COX-2 Expression via P2Y₂ Receptor in bEnd.3 Endothelial Cells.","authors":"Kazuki Yoshida, Miyu Ikezaki, Masaki Kayakabe, Masa-Aki Ito, Isao Matsuoka","doi":"10.1248/bpb.b26-00028","DOIUrl":"10.1248/bpb.b26-00028","url":null,"abstract":"<p><p>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 P2Y₂ receptor antagonist AR-C118925XX. Disturbed flow-induced COX-2 expression was consistently attenuated by AR-C118925XX. Mechanistically, P2Y₂ 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 P2Y₂ receptor signaling in endothelial mechanotransduction.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"49 5","pages":"778-784"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rutin Protects Ischemic Stroke-Induced Astrocytic Injury by Activating PRDX1.","authors":"Ali Said, Shuai Liu, Ruiqi Cao, Xianyong Zhou, Huiling Zhang","doi":"10.1248/bpb.b25-00790","DOIUrl":"10.1248/bpb.b25-00790","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"49 5","pages":"841-851"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147979761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluvoxamine Exerts Anti-influenza A Virus Effects through Inhibiting Apoptosis Pathway.","authors":"Zhaoyan Zhang, Huan Liang, Lei Ren, Zhenqiao Wei","doi":"10.1248/bpb.b25-00792","DOIUrl":"10.1248/bpb.b25-00792","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"49 5","pages":"888-895"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148136417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vladimiria souliei Ameliorated Aspirin-Induced Gastric Mucosal Injury by Activation Nrf2 and Inhibition RIP1 Signaling Pathways.","authors":"Binjing Zhao, Xinyi Jiang, Xiaojing Wei, Lunli Lan, Rui Wang, Yuanyuan Li","doi":"10.1248/bpb.b25-00808","DOIUrl":"10.1248/bpb.b25-00808","url":null,"abstract":"<p><p>Prolonged or high-dose administration of nonsteroidal anti-inflammatory drugs (NSAIDs) can induce gastric mucosal injury (GMI), potentially progressing to gastric ulcer (GU). Studies have shown that oxidative stress and necroptosis were closely associated with GU. Vladimiria souliei, a traditional Chinese herb, has been used to treat digestive disorders, particularly GU, but its pharmacological mechanisms remain unidentified. This study aimed to investigate the pharmacological mechanisms of GMI treatment in this herb. Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to analyze blood-enterable components. Aspirin (ASP) was orally administered to induce GMI in mice. After intervention with Vladimiria souliei extract (VSE), the morphology of gastric tissues was observed, and the levels of pepsin and prostaglandin E2 (PGE2) were detected. Further therapeutic evaluation of VSE in GMI was performed using hematoxylin and eosin (H&E) and periodic acid-schif (PAS) staining. Serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) were measured, while immunohistochemistry and Western blot were used to assess nuclear factor erythroid 2-related factor 2 (Nrf2) and receptor interacting protein kinase 1 (RIP1)-related signaling. Six prototype components were identified in the drug-containing serum of the VSE. Moreover, VSE mitigated ASP-induced GMI with shrunken areas of ulcers and promoted gastric mucin secretion, increased the levels of SOD and PGE2, and decreased the levels of pepsin, MDA, IL-1β, IL-6, and TNF-α. Pharmacological studies revealed that VSE upregulated the expression of Nrf2, NAD (P) H quinone dehydrogenase 1 (NQO1), and heme oxygenase-1 (HO-1) and down-regulated the expression of kelch-like ECH-associated protein-1 (Keap1), RIP1, RIP3, mixed lineage kinase domain-like protein (MLKL), phosphoglycerate mutase 5 (PGAM5), and dynamin-related protein 1 (Drp1) in the gastric mucosa. Therefore, VSE alleviated oxidative stress and necroptosis by regulating Nrf2 and RIP1 signaling in ASP-induced GMI mice, providing a theoretical basis for GU treatment and for the development of medicinal resources with this herb.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"49 7","pages":"1108-1118"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preventive Effects of Non-sedating and Sedating Histamine H₁ Receptor Antagonists Premedication for Subcutaneous Daratumumab-Associated Infusion-Related Reactions: A Prospective Observational Study.","authors":"Mayu Yakumaru-Suzukawa, Tohru Aomori, Norifumi Suzuki, Koichi Ohata, Maiko Abumiya, Yukiyoshi Fujita, Tomoe Yoshizawa, Kaori Matsumoto, Akira Kudo, Naoya Suehiro, Shiori Hishida-Sadaka, Haruka Igarashi, Chinami Inoue, Tomoko Yamazaki, Junichiro Wakatsuki, Hiroomi Sakurai, Serika Banno-Matsuoka, Yayoi Fukushi, Hirotoshi Iihara, Masafumi Kikuchi, Hitoshi Kawazoe, Hisakazu Ohtani","doi":"10.1248/bpb.b26-00011","DOIUrl":"10.1248/bpb.b26-00011","url":null,"abstract":"<p><p>The optimal choice between sedating histamine H₁ antagonists (sAHs) and non-sedating histamine H₁ antagonists (nsAHs) for preventing infusion-related reactions (IRRs) during daratumumab subcutaneous (DARA-SC) therapy remains unclear. Here, we aimed to compare the efficacy and safety of nsAH and sAH as premedication for DARA-SC therapy. Patients with multiple myeloma or light-chain amyloidosis who received DARA-SC therapy at eight hospitals were enrolled in this prospective, multicenter, observational study. Patients were categorized into nsAH and sAH groups based on their premedication. IRRs and drowsiness were assessed using patient-reported questionnaires, including the Stanford Sleepiness Scale (SSS) and the Japanese Epworth Sleepiness Scale (JESS), at baseline, post-administration (Q2), and before bedtime (Q3). Overall, 104 patients (nsAH, n = 49; sAH, n = 55) were analyzed. No significant differences were observed in the IRR incidence between the nsAH and sAH groups at Q2 (8.2 vs. 9.1%) or Q3 (13 vs. 17%). Conversely, the incidence of new-onset drowsiness at Q2 was significantly lower in the nsAH group (13%) than in the sAH group (32%, p < 0.05). Additionally, the increase in SSS from baseline to Q2 was significantly lower in the nsAH group than in the sAH group (p < 0.05). No significant differences were observed in JESS scores. Thus, nsAH was associated with reduced early post-administration drowsiness and there were no statistically significant differences in IRR preventive effects compared to that for sAH, suggesting that nsAH may reduce sedation without a significant increase in the incidence of IRRs; however, these hypothesis-generating findings warrant verification through future prospective comparative trials.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"49 7","pages":"1153-1160"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of Drug-Induced Kidney Injury by Primary Culture of Rat Kidney Tissue Slices Using Oxygen-Permeable Polyolefin Plate with Low Drug Adsorption.","authors":"Moeno Kadoguchi, Kohei Matsushita, Katsuhiro Esashika, Jingjing Yang, Jun Takahashi, Ikumi Tamai, Hiroshi Arakawa","doi":"10.1248/bpb.b25-00572","DOIUrl":"10.1248/bpb.b25-00572","url":null,"abstract":"<p><p>Rat kidney tissue slices are expected to be useful for an in vitro evaluation of drug-induced kidney injury (DIKI). We previously established a primary culture of rat kidney tissue slices using gas-permeable plates. However, polydimethylsiloxane (PDMS) exhibits a significant adsorption of lipophilic drugs, leading to limitations in DIKI evaluation. The aim of the present study was to evaluate a gas-permeable InnoCell™ non-treated plate made of polyolefin with low adsorption of lipophilic compounds for the primary culture of rat kidney tissue slices as an in vitro DIKI evaluation system. Drug concentrations in the medium were measured 24 h after the addition of 9 drugs to PDMS plates and InnoCell™ non-treated plates. Intra-tissue ATP levels and histopathology of rat kidney tissue slices were examined on Day 3 of culture. As a result, the InnoCell™ non-treated plates exhibited lower adsorption rates for sunitinib, cyclosporine A, and alectinib than the PDMS plates. Intra-tissue ATP levels were maintained, and immunohistochemical staining of megalin and aquaporin 1 was observed for up to 3 d. Furthermore, exposure to nephrotoxic lipophilic drugs reduced the ATP content in slices compared to that in non-treated slices. These results suggest that the primary culture of rat kidney tissue slices using InnoCell™ non-treated plates is useful for the DIKI evaluation of lipophilic drugs compared with conventional PDMS plates.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"49 1","pages":"122-129"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Inhibitors for eIF5A2-Dependent Translation Elongation by Monitoring the Translational Efficiency of Polyproline Motif in Mitochondrial Fission Regulator 1.","authors":"Masato Suzuki, Masahiro Komeno, Ryosuke Yasumura, Ayuna Miwa, Misaki Enomoto, Hitoshi Kotani, Ken Matsumoto, Kazunori Akimoto, Chiaki Takahashi, Kazuei Igarashi, Kyohei Higashi","doi":"10.1248/bpb.b25-00720","DOIUrl":"10.1248/bpb.b25-00720","url":null,"abstract":"<p><p>We previously reported that eukaryotic translation initiation factor 5A2 (eIF5A2), rather than eIF5A1, is important for the proliferation of HeLa S3 and MDA-MB-231 cells, despite the 84% amino acid sequence identity between eIF5A1 and eIF5A2. In addition, individual upregulated genes, including mitochondrial fission regulator 1 (MTFR1), which has a proline-rich motif, by eIF5A2 were different from those in eIF5A1. Thus, eIF5A2-dependent translational elongation is a promising target for cancer treatment with minimal side effects. In this study, we constructed a high-throughput screening system to identify eIF5A2-dependent translation elongation inhibitors by monitoring the translation efficiency of the MTFR1-luciferase fusion protein in HeLa S3 cells. Orlistat and andrographolide (AGP) were suggested as inhibitors of eIF5A2-dependent translation elongation among 1744 compounds from libraries. In addition to the findings related to AGP, the present study revealed that orlistat and the silencing of eIF5A2 suppressed the invasive activity of MDA-MB-231 cells. Downregulation of heparanase 1 expression, but not of matrix metalloproteinase-2 (MMP2) and MMP9, by eIF5A2 silencing was similar to that by treatment with orlistat and AGP, suggesting that orlistat and AGP were, at least in part, capable of attenuating eIF5A2-dependent translation elongation through the repression of eIF5A2 expression. Based on these observations, monitoring the translational efficiency of MTFR1 synthesis may be useful for identifying new eIF5A2 inhibitors.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"49 2","pages":"355-363"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147275629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Toxicodynamic Modeling of the Acute Kidney Injury-to-Chronic Kidney Disease Transition Following Repeated Cisplatin Administration in Rats.","authors":"Takumi Hotta, Hirohito Muroi, Haruno Oku, Keizo Fukushima, Nobuyuki Sugioka","doi":"10.1248/bpb.b26-00117","DOIUrl":"https://doi.org/10.1248/bpb.b26-00117","url":null,"abstract":"<p><p>Cisplatin (cis-diammineplatinum (II) dichloride [CDDP]) induces acute kidney injury (AKI), and repeated dosing may lead to incomplete recovery and progression to chronic kidney disease (CKD). However, the quantitative dynamics underlying the AKI-to-CKD transition remain unclear. This study aimed to develop a mathematical model to characterize the CDDP-induced AKI-to-CKD transition during repeated administration. Rats received three cycles of CDDP at 21-d intervals under different dosing regimens, but with an identical cumulative dose (9 mg/kg). Plasma creatinine (Cr) was measured longitudinally as a marker of renal function, and values from Days 15 to 21 after each dosing cycle were used to evaluate the extent of recovery following AKI. A toxicodynamic model based on Cr mass balance was developed. The model incorporated a Hill-type function to describe CDDP-induced toxic effects and evaluated alternative structural assumptions in which toxicity progression across cycles was modeled as either additive or multiplicative. Renal function progressively decreased in a dose-dependent manner across cycles. Although Cr profiles differed among regimens during individual cycles, Cr levels converged by the end of the third cycle. The additive toxicity model, in which CDDP accumulates in a virtual kidney compartment and the toxic signal decays slowly (half-life: 79 d), best described the data (CDDP dose per body weight producing 50% inhibition: 5.11 mg/kg). To our knowledge, this study presents the first mathematical model describing the dynamics of the AKI-to-CKD transition following repeated CDDP administration. The proposed modeling approach may facilitate prediction of the AKI-to-CKD transition and support the optimization of safer CDDP treatment strategies.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"49 7","pages":"1125-1131"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition and Knockdown of Monocarboxylate Transporter 1 Induce L-Lactate Accumulation in T-Cell Acute Lymphoblastic Leukemia Cells.","authors":"Yudai Suganuma, Yuto Mukai, Noriyuki Matsumoto, Atsushi Yamaguchi, Hinata Ueda, Keisuke Okamoto, Katsuya Narumi, Masaki Kobayashi","doi":"10.1248/bpb.b26-00267","DOIUrl":"https://doi.org/10.1248/bpb.b26-00267","url":null,"abstract":"<p><p>Tumors exhibit the Warburg effect, characterized by elevated glucose metabolism through both oxidative phosphorylation and glycolysis to produce energy. To maintain intracellular pH and metabolic homeostasis, cancer cells depend on monocarboxylate transporters (MCTs) to export the glycolytic end product, l-lactate. Similar to other cancers, glucose metabolism is enhanced in T-cell acute lymphoblastic leukemia (T-ALL), supporting rapid cell proliferation. Although MCT1 expression and its sensitivity to inhibition have been reported in certain T-ALL models, the relative contributions of other co-expressed MCT isoforms (MCT2 and MCT4) to l-lactate transport are unclear. This study aimed to evaluate the functional contribution of MCT isoforms to l-lactate transport in human T-ALL cell lines. We examined the expression and function of MCTs in Jurkat E6-1 and MOLT-3 cells. RT-PCR and Western blot analyses confirmed mRNA and protein expression of MCT1, MCT2, and MCT4 in both cell lines. Treatment with AZD3965, an MCT1 and MCT2 inhibitor, significantly increased intracellular l-lactate levels in T-ALL cells. In contrast, selective inhibition of MCT2 with atorvastatin or MCT4 with AZD0095 and VB124 did not alter intracellular l-lactate levels. Consistent with these pharmacological findings, MCT1 knockdown using small interfering RNA led to significant intracellular l-lactate accumulation. Collectively, these findings indicate that MCT1 is the principal transporter responsible for l-lactate transport in T-ALL cell lines, despite the co-expression of MCT2 and MCT4. Of all the multiple co-expressed isoforms, MCT1 is the primary mediator of l-lactate transport and is a promising therapeutic target for T-ALL treatment.</p>","PeriodicalId":8955,"journal":{"name":"Biological & pharmaceutical bulletin","volume":"49 10","pages":"1616-1622"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}