Journal of pharmacological sciences最新文献_第10页

Clarifying the mechanism of astaxanthin in the treatment of inflammation in ischemic stroke using integrated network analysis 应用综合网络分析阐明虾青素治疗缺血性脑卒中炎症的作用机制

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-04-08 DOI: 10.1016/j.jphs.2025.04.003

Jinwen Yao , Xu Wang , Dexi Zhao

Background and objective

Ischemic stroke is a disease with high incidence. Astaxanthin is a functional foods with protective effects against ischemic stroke. However, the integral mechanism of astaxanthin protect ischemic stroke is not clear. The aim of this study was to investigate the mechanism of astaxanthin protect ischemic stroke by integrated network analysis.

Methods

Middle cerebral artery occlusion model was used to establish ischemic stroke model, and ischemic stroke models were treated with 25, 45, 65 mg/kg astaxanthin for 7 days. The rats were killed 24 h after successful modeling. Integrated network analysis, molecular docking, molecular dynamics (MD) simulation, and Western blot were used to explore the astaxanthin and potential proteins related to inflammation and cell death.

Results

The results of integrated network analysis indicate that astaxanthin may protect ischemic stroke through Toll like receptor signaling pathway and apoptosis pathway. The main targets involved MMP9, IL1B, IL10, Bcl2 and among others. astaxanthin has a low binding score and compact complex with PARP1, AIF, Bax, IL10, MMP9, Bcl2. In addition, astaxanthin has reduced inflammation and cell death-related proteins such as PARP1, AIF, Bax, TLR4, MMP9, IL1β and increased anti-inflammation and anti-cell death-related proteins by Bcl2 and IL10.

Conclusions

Astaxanthin can improve anti-inflammatory, anti-cell death ability after ischemic stroke. Our study provides a theoretical basis for the subsequent experimental and clinical application of astaxanthin in the treatment of ischemic stroke.

背景和目的缺血性中风是一种发病率很高的疾病。虾青素是一种对缺血性中风有保护作用的功能性食品。然而，虾青素保护缺血性中风的整体机制尚不清楚。方法采用大脑中动脉闭塞模型建立缺血性脑卒中模型，用25、45、65 mg/kg虾青素治疗缺血性脑卒中模型7天。造模成功后24 h处死大鼠。结果综合网络分析结果表明，虾青素可通过Toll like受体信号通路和细胞凋亡通路保护缺血性中风。虾青素与PARP1、AIF、Bax、IL10、MMP9、Bcl2的结合得分较低，且复合紧密。此外，虾青素还减少了 PARP1、AIF、Bax、TLR4、MMP9、IL1β 等炎症和细胞死亡相关蛋白，增加了 Bcl2 和 IL10 等抗炎和抗细胞死亡相关蛋白。我们的研究为后续虾青素治疗缺血性脑卒中的实验和临床应用提供了理论依据。

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引用次数: 0

Hirsutine attenuated oxidative stress and autophagy in diabetic kidney disease through Keap1/Nrf2 pathway hirsutin通过Keap1/Nrf2通路减弱糖尿病肾病的氧化应激和自噬

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-04-07 DOI: 10.1016/j.jphs.2025.04.002

Yao Zhang , Bing Yang , Miao Tan, Jinchuan Tan

Objectives

To investigate the therapeutic potential and renal protective mechanisms of hirsutine in diabetic kidney disease (DKD).

Methods

A DKD model was induced in Sprague-Dawley rats using a high-fat diet (HFD) and streptozotocin (STZ). High glucose (HG)-stimulated HK-2 cells served as an in vitro model. Reactive oxygen species (ROS) levels in kidney tissues were measured using dihydroethidium (DHE) staining. ELISA was performed to measure MDA, SOD, and GSH in both rat tissues and HK-2 cells. Western blot and immunofluorescence analyses evaluated renal fibrosis, the Nrf2 signaling pathway, and autophagy-related proteins (Beclin 1, LC3I/II, P62).

Results

Hirsutine treatment significantly improved metabolic and renal parameters in rats, enhancing renal function and reducing fibrosis, as shown by lower levels of Vimentin, Collagen-IV, and α-SMA. It alleviated oxidative stress, indicated by reduced ROS and MDA levels and increased SOD and GSH activity. Additionally, hirsutine enhanced autophagy, reflected by higher Beclin 1 and LC3I/II levels and decreased P62 expression. By disrupting the Keap1-Nrf2 interaction, hirsutine increased Nrf2 levels and upregulated antioxidative enzymes like NQO1, SOD-2, and HO-1.

Conclusion

Hirsutine exhibited renoprotective effects in DKD by modulating the Keap1/Nrf2 pathway, mitigating oxidative stress and promoting autophagy, making it a promising candidate for treatment.

目的探讨多毛素对糖尿病肾病（DKD）的治疗潜力及肾保护机制。方法采用高脂饲料（HFD）和链脲佐菌素（STZ）诱导sd大鼠DKD模型。高糖（HG）刺激的HK-2细胞作为体外模型。采用双氢乙啶（DHE）染色法测定肾组织中的活性氧（ROS）水平。ELISA法测定大鼠组织和HK-2细胞中MDA、SOD和GSH的含量。Western blot和免疫荧光分析评估肾纤维化、Nrf2信号通路和自噬相关蛋白（Beclin 1, LC3I/II, P62）。结果舒坦治疗可显著改善大鼠的代谢和肾脏参数，增强肾功能，减少纤维化，表现为降低Vimentin、Collagen-IV和α-SMA的水平。通过降低ROS和MDA水平，提高SOD和GSH活性来缓解氧化应激。此外，hirsutin增强了自噬，表现为Beclin 1和LC3I/II水平升高，P62表达降低。通过破坏Keap1-Nrf2相互作用，毛素增加了Nrf2水平，上调了NQO1、SOD-2和HO-1等抗氧化酶。结论毛茸素通过调节Keap1/Nrf2通路，减轻氧化应激，促进自噬，对DKD具有肾保护作用，是治疗DKD的理想药物。

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引用次数: 0

Ramelteon coordinates theta and gamma oscillations in the hippocampus for novel object recognition memory in mice Ramelteon在小鼠的新物体识别记忆中协调海马中的θ和γ振荡

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-04-01 DOI: 10.1016/j.jphs.2025.03.013

Kinjiro Takeda , Kisa Watanabe , Sena Iijima , Takeshi Nagahiro , Haruka Suzuki , Kano Izumo , Yuji Ikegaya , Nobuyoshi Matsumoto

Object recognition memory is an animal's ability to discriminate between novel and familiar items and is supported by neural activities in not only the perirhinal cortex but also the hippocampus and prefrontal cortex. Since we previously demonstrated that ramelteon enhanced object recognition memory in mice, we sought neural correlates of the memory improvement. We recorded neural activity in the hippocampus and prefrontal cortex of mice while they performed a novel object recognition task. We found that theta oscillations in the hippocampus were enhanced when ramelteon-treated mice explored both novel and familiar objects. Moreover, we showed high coherence in phases at low gamma frequencies between the hippocampus and prefrontal cortex. We assume that theta enhancement is indicative of increased cholinergic activity by melatonin receptor activation. High coherence of low gamma oscillations between the hippocampal and prefrontal network in ramelteon-treated mice sampling novel objects suggests better cognitive operations for discrimination between novelty and familiarity. The current study sheds light upon physiological consequences of melatonin receptor activation, further contributing improved cognitive functions.

物体识别记忆是动物区分新事物和熟悉事物的能力，它不仅受到周围皮层神经活动的支持，还受到海马和前额叶皮层神经活动的支持。由于我们之前证明了ramelteon增强了小鼠的物体识别记忆，我们寻找记忆改善的神经相关性。我们记录了小鼠在执行一项新的物体识别任务时海马和前额叶皮层的神经活动。我们发现，当服用ramelteon的小鼠探索新的和熟悉的物体时，海马区的θ波振荡增强。此外，我们在海马和前额叶皮层之间的低伽马频率的相位中显示出高度的一致性。我们假设theta增强表明褪黑激素受体激活增加了胆碱能活性。在接受ramelteon治疗的小鼠取样新物体时，海马和前额叶网络之间的低伽马振荡的高一致性表明在区分新事物和熟悉事物方面有更好的认知操作。目前的研究揭示了褪黑激素受体激活的生理后果，进一步促进了认知功能的改善。

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引用次数: 0

Receptor-mediated Gi-3 activation in mammalian and human brain membranes: Reestablishment method and its application to nociceptin/orphanin FQ opioid peptide (NOP) receptor/Gi-3 interaction 受体介导的Gi-3在哺乳动物和人类脑膜中的激活：重建方法及其在伤害肽/孤儿蛋白FQ阿片肽（NOP）受体/Gi-3相互作用中的应用

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-03-31 DOI: 10.1016/j.jphs.2025.03.014

Yuji Odagaki , Masakazu Kinoshita , Makoto Honda , J. Javier Meana , Luis F. Callado , Jesús A. García-Sevilla , Miklós Palkovits , Dasiel Oscar Borroto-Escuela , Kjell Fuxe

Functional activation of heterotrimeric guanine nucleotide-binding proteins (G-proteins) via G-protein-coupled receptors (GPCRs) has been extensively explored using guanosine-5′-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPγS) binding assay. However, the conventional method is primarily applicable to G_i/o family without discrimination among G-protein subtypes. Therefore, this study aims to reestablish a novel method termed “[³⁵S]GTPγS binding/immunoprecipitation assay” by identifying a most suitable anti-Gα_i-3 antibody instead of the previously utilized, now withdrawn antibody. In the initial screening of commercially available anti-Gα_i-3 antibodies, two were identified and one was selected for further investigations based on efficacy with adenosine—the most potent agonist in our previous research. After optimizing experimental conditions with rat and postmortem human brain membranes, the stimulatory effects of various agonists were evaluated. Some agonists, including nociceptin, exhibited sufficient stimulatory effects for further pharmacological characterization. Nociceptin increased [³⁵S]GTPγS binding to Gα_i-3 in a concentration-dependent manner, response that was insensitive to naloxone but potently inhibited using (±)-J-113397. The method described in this study provides a valuable strategy for determining the intrinsic efficacy of ligands at various GPCRs. This includes nociceptin/orphanin FQ opioid peptide (NOP) receptor selectively coupled to Gα_i-3, providing insights into the pharmacological concept of “functional selectivity.”

利用鸟苷-5′- o -（3-[35S]硫代）三磷酸（[35S]GTPγS）结合实验，广泛探讨了异三聚体鸟嘌呤核苷酸结合蛋白（g蛋白）通过g蛋白偶联受体（gpcr）的功能激活。而传统方法主要适用于Gi/o家族，对g蛋白亚型没有区别。因此，本研究旨在通过鉴定一种最合适的抗g αi-3抗体来替代先前使用的现已退出的抗体，从而重建一种称为“[35S]GTPγS结合/免疫沉淀法”的新方法。在对市售抗g αi-3抗体的初步筛选中，确定了两种抗体，并根据与腺苷（我们之前研究中最有效的激动剂）的疗效选择了一种抗体进行进一步研究。在优化大鼠和人死后脑膜的实验条件后，评估了各种激动剂的刺激作用。一些激动剂，包括诺西西汀，表现出足够的刺激作用，可以进一步进行药理学表征。Nociceptin以浓度依赖的方式增加[35S]GTPγS与Gαi-3的结合，该反应对纳洛酮不敏感，但（±）-J-113397有效抑制。本研究中描述的方法为确定各种gpcr配体的内在功效提供了有价值的策略。这包括痛觉肽/孤啡肽FQ阿片肽（NOP）受体选择性偶联Gαi-3，为“功能选择性”的药理学概念提供见解。

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引用次数: 0

Suppressing SPARC gene with siRNA exerts therapeutic effects and inhibits MMP-2/9 and ADAMTS1 overexpression in a murine model of ischemia/reperfusion-induced acute kidney injury 用siRNA抑制SPARC基因在小鼠缺血/再灌注急性肾损伤模型中发挥治疗作用，抑制MMP-2/9和ADAMTS1过表达

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-03-21 DOI: 10.1016/j.jphs.2025.03.010

Hiroe Toba , Denan Jin , Shinji Takai

Secreted protein acidic and rich in cysteine (SPARC), a collagen-binding matricellular protein, is reported to facilitate inflammation and fibrosis in various tissues including the kidneys. Ischemia/reperfusion (I/R) is a major process of acute kidney injury. To investigate whether SPARC inhibition might attenuate renal I/R injury, we injected small interfering RNA (siRNA) targeting SPARC into male BALB/c mice one day before 45 min of renal ischemia followed by 72 h of reperfusion. Serum creatinine concentration, blood urea nitrogen, histological tubular damage, tubulointerstitial fibrosis, and expression of collagen I and transforming growth factor-β were increased after I/R. Expression of 4-hydroxy-2-nonenal, an oxidative stress marker, and the inflammatory cytokines monocyte chemoattractant protein-1 and tumor necrosis factor-α, were also upregulated in I/R kidneys. Overexpression of SPARC mRNA was observed after I/R, and immunohistochemistry revealed that SPARC was localized mainly in damaged tubuloepithelial cells. Additionally, a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1) expression colocalized with SPARC. Injection of siRNA targeting SPARC attenuated renal dysfunction, histological abnormalities, collagen deposition, oxidative stress, and renal inflammation. In addition, SPARC gene knockdown suppressed the I/R-induced increases in ADAMTS1 and matrix metalloproteinase-2/9 expression. In conclusion, I/R-induced SPARC could be a novel therapeutic target against acute kidney injury.

分泌蛋白酸性和富含半胱氨酸（SPARC），胶原结合基质细胞蛋白，据报道，促进炎症和纤维化在各种组织，包括肾脏。缺血再灌注（I/R）是急性肾损伤的一个重要过程。为了研究抑制SPARC是否可以减轻肾I/R损伤，我们在雄性BALB/c小鼠肾缺血45 min前1天注射靶向SPARC的小干扰RNA (siRNA)，然后再灌注72 h。I/R后血清肌酐浓度、血尿素氮、组织学小管损伤、小管间质纤维化、I型胶原和转化生长因子-β表达升高。氧化应激标志物4-羟基-2-壬烯醛、炎症细胞因子单核细胞趋化蛋白-1和肿瘤坏死因子-α的表达也在I/R肾脏中上调。I/R后观察到SPARC mRNA过表达，免疫组化显示SPARC主要定位于受损的小管上皮细胞。此外，具有血小板反应蛋白1型基序的崩解素和金属蛋白酶（ADAMTS1）表达与SPARC共定位。注射靶向SPARC的siRNA可减轻肾功能障碍、组织学异常、胶原沉积、氧化应激和肾脏炎症。此外，SPARC基因敲低抑制了I/ r诱导的ADAMTS1和基质金属蛋白酶2/9表达的增加。综上所述，I/ r诱导的SPARC可能是治疗急性肾损伤的新靶点。

{"title":"Suppressing SPARC gene with siRNA exerts therapeutic effects and inhibits MMP-2/9 and ADAMTS1 overexpression in a murine model of ischemia/reperfusion-induced acute kidney injury","authors":"Hiroe Toba , Denan Jin , Shinji Takai","doi":"10.1016/j.jphs.2025.03.010","DOIUrl":"10.1016/j.jphs.2025.03.010","url":null,"abstract":"<div><div>Secreted protein acidic and rich in cysteine (SPARC), a collagen-binding matricellular protein, is reported to facilitate inflammation and fibrosis in various tissues including the kidneys. Ischemia/reperfusion (I/R) is a major process of acute kidney injury. To investigate whether SPARC inhibition might attenuate renal I/R injury, we injected small interfering RNA (siRNA) targeting SPARC into male BALB/c mice one day before 45 min of renal ischemia followed by 72 h of reperfusion. Serum creatinine concentration, blood urea nitrogen, histological tubular damage, tubulointerstitial fibrosis, and expression of collagen I and transforming growth factor-β were increased after I/R. Expression of 4-hydroxy-2-nonenal, an oxidative stress marker, and the inflammatory cytokines monocyte chemoattractant protein-1 and tumor necrosis factor-α, were also upregulated in I/R kidneys. Overexpression of SPARC mRNA was observed after I/R, and immunohistochemistry revealed that SPARC was localized mainly in damaged tubuloepithelial cells. Additionally, a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1) expression colocalized with SPARC. Injection of siRNA targeting SPARC attenuated renal dysfunction, histological abnormalities, collagen deposition, oxidative stress, and renal inflammation. In addition, SPARC gene knockdown suppressed the I/R-induced increases in ADAMTS1 and matrix metalloproteinase-2/9 expression. In conclusion, I/R-induced SPARC could be a novel therapeutic target against acute kidney injury.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 2","pages":"Pages 103-112"},"PeriodicalIF":3.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gadoxetic acid-enhanced magnetic resonance imaging predicts early nab-paclitaxel-induced peripheral neuropathy during pancreatic cancer treatment: A pilot study 加多西酸增强磁共振成像预测胰腺癌治疗期间早期nab-紫杉醇诱导的周围神经病变：一项初步研究

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-03-19 DOI: 10.1016/j.jphs.2025.03.009

Yusuke Takasaki , Hironao Okubo , Yuka Fukuo , Muneo Ikemura , Hitoshi Ando , Hiroyuki Isayama

Nab-paclitaxel (nab-PTX) is transported by organic anion-transporting polypeptide (OATP)1B1 and OATP1B3. Chemotherapy-induced peripheral neuropathy (CIPN) is a representative adverse event associated with gemcitabine plus nab-PTX (GnP) in patients with pancreatic cancer. Gadoxetic acid is also transported by OATP1B1 and OATP1B3. We aimed to assess whether the enhancement effect of gadoxetic acid-enhanced magnetic resonance (MR) imaging could predict the development of CIPN for GnP. This study evaluated 27 patients with pancreatic cancer who underwent gadoxetic acid-enhanced MR imaging prior to GnP treatment. The contrast enhancement index (CEI), a measure of liver enhancement on hepato-biliary images, was measured. Plasma concentrations of paclitaxel at 0.5, 6, and 24 h after first administration were also determined in 13 patients. Sixteen of the twenty-seven patients (59.3 %) developed ≥ grade 1 CIPN during the first 8 weeks. We found a negative relationship between the CEI and area under the plasma concentration curve of PTX (r = −0.729, p = 0.003). In multivariate analysis, a CEI <1.84 and concomitant diabetes mellitus were independent predictors of CIPN development (hazard ratio, 5.37, p = 0.027; hazard ratio, 3.68, p = 0.012, respectively). Gadoxetic acid-enhanced MR imaging could be useful in predicting the development of CIPN during GnP therapy.

nab-紫杉醇（nab-PTX）通过有机阴离子转运多肽（OATP）1B1和OATP1B3进行转运。化疗诱导的周围神经病变（CIPN）是胰腺癌患者吉西他滨联合nab-PTX （GnP）相关的典型不良事件。Gadoxetic酸也通过OATP1B1和OATP1B3进行运输。我们的目的是评估gadoxetic酸增强磁共振（MR）成像的增强效果是否可以预测GnP的CIPN发展。本研究评估了27例胰腺癌患者，他们在接受胰腺癌治疗前接受了加多己酸增强磁共振成像。对比增强指数（CEI）是衡量肝胆图像上肝脏增强的指标。还测定了13例患者首次给药后0.5、6和24 h的血浆紫杉醇浓度。27例患者中有16例（59.3%）在前8周发生 ≥ 1级CIPN。我们发现CEI与PTX血药浓度曲线下面积呈负相关（r = −0.729,p = 0.003）。在多因素分析中，CEI <；1.84和合并糖尿病是CIPN发生的独立预测因素(危险比5.37,p = 0.027；风险比为3.68,p = 0.012)。Gadoxetic酸增强MR成像可用于预测在GnP治疗期间CIPN的发展。

{"title":"Gadoxetic acid-enhanced magnetic resonance imaging predicts early nab-paclitaxel-induced peripheral neuropathy during pancreatic cancer treatment: A pilot study","authors":"Yusuke Takasaki , Hironao Okubo , Yuka Fukuo , Muneo Ikemura , Hitoshi Ando , Hiroyuki Isayama","doi":"10.1016/j.jphs.2025.03.009","DOIUrl":"10.1016/j.jphs.2025.03.009","url":null,"abstract":"<div><div>Nab-paclitaxel (nab-PTX) is transported by organic anion-transporting polypeptide (OATP)1B1 and OATP1B3. Chemotherapy-induced peripheral neuropathy (CIPN) is a representative adverse event associated with gemcitabine plus nab-PTX (GnP) in patients with pancreatic cancer. Gadoxetic acid is also transported by OATP1B1 and OATP1B3. We aimed to assess whether the enhancement effect of gadoxetic acid-enhanced magnetic resonance (MR) imaging could predict the development of CIPN for GnP. This study evaluated 27 patients with pancreatic cancer who underwent gadoxetic acid-enhanced MR imaging prior to GnP treatment. The contrast enhancement index (CEI), a measure of liver enhancement on hepato-biliary images, was measured. Plasma concentrations of paclitaxel at 0.5, 6, and 24 h after first administration were also determined in 13 patients. Sixteen of the twenty-seven patients (59.3 %) developed ≥ grade 1 CIPN during the first 8 weeks. We found a negative relationship between the CEI and area under the plasma concentration curve of PTX (r = −0.729, <em>p</em> = 0.003). In multivariate analysis, a CEI <1.84 and concomitant diabetes mellitus were independent predictors of CIPN development (hazard ratio, 5.37, <em>p</em> = 0.027; hazard ratio, 3.68, <em>p</em> = 0.012, respectively). Gadoxetic acid-enhanced MR imaging could be useful in predicting the development of CIPN during GnP therapy.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 2","pages":"Pages 113-120"},"PeriodicalIF":3.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The citrus flavonoid nobiletin prevents the development of doxorubicin-induced heart failure by inhibiting apoptosis 柑橘类黄酮皂素通过抑制细胞凋亡来防止阿霉素诱导的心力衰竭的发生

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-03-19 DOI: 10.1016/j.jphs.2025.03.011

Yoichi Sunagawa , Sonoka Iwashimizu , Masaya Ono , Saho Mochizuki , Kenshiro Iwashita , Rina Sato , Satoshi Shimizu , Masafumi Funamoto , Kana Shimizu , Toshihide Hamabe-Horiike , Yasufumi Katanasaka , Akira Murakami , Tomohiro Asakawa , Makoto Inai , Toshiyuki Kan , Maki Komiyama , Philip Hawke , Kiyoshi Mori , Yoshiki Arakawa , Koji Hasegawa , Tatsuya Morimoto

Background

The anthracycline anticancer drug doxorubicin (DOX) induces myocardial cell death and heart failure. The aim of the present study was to investigate whether nobiletin (NOB), a natural flavonoid isolated from citrus peel, has a protective effect against DOX-induced cardiotoxicity.

Methods and results

H9C2 cells were pretreated with 100 μM NOB and then treated with 1 μM DOX. An MTT assay revealed that NOB improved the decreased cell viability induced by DOX. A TUNEL assay showed that NOB treatment improved DOX-induced apoptosis in H9C2 cells. Western blotting indicated that DOX-induced increases in cleaved caspase-3 and -9 expression were significantly suppressed by NOB treatment. Motion field imaging of human iPS cell-derived cardiomyocyte sheets showed that NOB significantly suppressed a DOX-induced reduction of their contractile function. Next, to investigate the effect of NOB in vivo, DOX was intraperitoneally administered to mice. Echocardiography showed that oral administration of NOB reduced DOX-induced left ventricular systolic dysfunction, and a TUNEL assay showed that oral administration also inhibited apoptosis in the mouse heart.

Conclusions

These results indicate that NOB treatment suppressed DOX-induced cardiotoxicity by reducing apoptosis. Further study of the mechanism of this effect may lead to the development of a novel therapy for DOX-induced heart failure.

蒽环类抗癌药物多柔比星（DOX）可诱导心肌细胞死亡和心力衰竭。本研究的目的是研究从柑橘皮中分离的天然类黄酮nobiletin （NOB）是否对dox诱导的心脏毒性具有保护作用。方法与结果用100 μM NOB预处理sh9c2细胞，再用1 μM DOX处理sh9c2细胞。MTT实验显示，NOB改善了DOX诱导的细胞活力下降。TUNEL实验显示，NOB处理可改善dox诱导的H9C2细胞凋亡。Western blotting结果显示，NOB处理可显著抑制dox诱导的cleaved - caspase-3和-9表达的增加。人类iPS细胞衍生的心肌细胞片的运动场成像显示，NOB显著抑制dox诱导的收缩功能的降低。接下来，为了研究NOB在体内的作用，小鼠腹腔注射DOX。超声心动图显示口服NOB可减轻dox诱导的左心室收缩功能障碍，TUNEL实验显示口服NOB还可抑制小鼠心脏细胞凋亡。结论NOB可通过减少细胞凋亡抑制dox诱导的心脏毒性。对这种作用机制的进一步研究可能会导致dox诱导心力衰竭的新疗法的发展。

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引用次数: 0

Acute curcumin administration enhances delta oscillations in the hippocampus underlying object memory improvement 急性姜黄素管理增强了海马体的delta振荡，从而改善了对象记忆

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-03-15 DOI: 10.1016/j.jphs.2025.03.007

Sena Iijima , Kinjiro Takeda , Takeshi Nagahiro , Kisa Watanabe , Yuji Ikegaya , Nobuyoshi Matsumoto

Curcumin mitigates memory deficits or improves memory when it is chronically administered to animals. Due to limited bioavailability of curcumin, it remains almost unknown whether acutely treated curcumin influences cognitive function and underlying neural activity. To address this question, we monitored behavior and neural activity in the hippocampus and medial prefrontal cortex of mice treated with vehicle or curcumin while they were engaged in a novel object recognition task. Object recognition memory performance in the novel object recognition task was increased in curcumin-treated mice. Moreover, delta oscillations in the hippocampus were enhanced in the curcumin-administered mice in the test trial. Altogether, acute curcumin treatment boosts delta oscillations for memory recognition possibly by neuromodulation.

长期服用姜黄素可以减轻动物的记忆缺陷或改善记忆。由于姜黄素的生物利用度有限，急性姜黄素治疗是否会影响认知功能和潜在的神经活动仍然几乎未知。为了解决这个问题，我们监测了接受载体或姜黄素治疗的小鼠在从事一项新的物体识别任务时海马和内侧前额叶皮层的行为和神经活动。姜黄素处理的小鼠在新的目标识别任务中的目标识别记忆性能有所提高。此外，在试验中，姜黄素组小鼠海马区的δ波振荡增强。总之，急性姜黄素治疗可能通过神经调节促进记忆识别的δ波振荡。

引用次数: 0

Efficacy and safety of daprodustat versus darbepoetin alfa in the treatment of anemia in chronic renal failure: Systematic review and meta-analysis of randomized controlled trials 达必达与达贝泊汀治疗慢性肾功能衰竭贫血的疗效和安全性：随机对照试验的系统评价和荟萃分析

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-03-15 DOI: 10.1016/j.jphs.2025.03.006

Shuyue Pang , Zhongtian Wang , Yanyan Fu , Xu Huang

Objectives

To compare the efficacy and safety of daprodustat (DPD) versus darbepoetin alfa (DBPA) in patients with anemia in chronic renal failure.

Materials and methods

Randomized controlled trials (RCTs) of DPD and DBPA in anemia were retrieved from PubMed, Embase, Cochrane library, and Web of Science from inception to August 1, 2023. The collected data were analyzed using Stata 15.0.

Results

Four RCTs involving 7419 patients (3717 in the DPD group and 3702 in the DBPA group) were included in the study. Meta-analysis revealed that there were no significant differences in the change in hemoglobin level [Standardized Mean Difference (SMD) = 3.23, 95 % CI (−0.25, 6.70)], transferrin saturation [SMD = −0.07, 95 % CI (−0.31, 0.17)], total iron [SMD = 0.24, 95 % CI (−0.05, 0.53))], and incidence of adverse events [ RR = 1.02, 95 % CI (0.98, 1.06)] between the two groups. However, DPD was superior in lowering ferritin level [SMD = −0.05, 95 % CI (−0.10, −0.01)] and improving total iron-binding capacity [SMD = 0.57, 95 % CI (0.46, 0.68)] than DBPA.

Conclusions

DPD is not inferior to DBPA in the treatment of anemia in chronic renal failure.

目的比较达生产司他（DPD）与达贝泊汀（DBPA）治疗慢性肾功能衰竭贫血患者的疗效和安全性。材料与方法从PubMed、Embase、Cochrane图书馆和Web of Science检索至2023年8月1日，DPD和DBPA在贫血中的随机对照试验（RCTs）。收集的数据使用Stata 15.0进行分析。结果共纳入4项随机对照试验，共7419例患者（DPD组3717例，DBPA组3702例）。meta分析显示，两组患者血红蛋白水平[标准化平均差(SMD) = 3.23, 95% CI(- 0.25, 6.70)]、转铁蛋白饱和度[SMD = - 0.07, 95% CI(- 0.31, 0.17)]、总铁[SMD = 0.24, 95% CI(- 0.05, 0.53))]、不良事件发生率[RR = 1.02, 95% CI(0.98, 1.06)]的变化无显著差异。但DPD在降低铁蛋白水平[SMD = - 0.05, 95% CI(- 0.10, - 0.01)]和提高总铁结合能力[SMD = 0.57, 95% CI(0.46, 0.68)]方面优于DBPA。结论sdpd治疗慢性肾功能衰竭贫血的疗效不逊于DBPA。

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引用次数: 0

Ca2+ microdomains in vascular smooth muscle cells: Roles in vascular tone regulation and hypertension 血管平滑肌细胞中的Ca2+微结构域：在血管张力调节和高血压中的作用

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-03-14 DOI: 10.1016/j.jphs.2025.03.008

Yoshiaki Suzuki

Vascular smooth muscle cells (VSMCs) modulate blood pressure by adjusting vascular contractility. Specific families of ion channels that are expressed in VSMCs regulate membrane potential and intracellular Ca²⁺ concentration ([Ca²⁺]_cyt). Subsets of them are known to form molecular complexes with Ca²⁺-sensitive molecules via scaffolding proteins such as caveolin and junctophilin. This enables localized and molecular complex-specific signal transduction to regulate vascular contractility. This intracellular region is referred to as a Ca²⁺ microdomain. When hypertensive stimuli are applied to blood vessels, gene expression of ion channels and scaffold proteins in vascular cells changes dramatically, often leading to membrane depolarization and increased [Ca²⁺]_cyt. As a result, blood vessels undergo functional remodeling characterized by enhanced contractility. In addition, the transcription of inflammatory genes in vascular cells is also upregulated. This induces leukocyte infiltration into the vascular wall and structural remodeling mediated by VSMC proliferation and extracellular matrix remodeling. This functional and structural remodeling perpetuates the hypertensive state, leading to progressive damage to systemic organs. This review summarizes recent findings on the mechanisms by which Ca²⁺ microdomains in VSMCs regulate contractility. In addition, the changes in Ca²⁺ microdomains due to hypertensive stimuli and their contributions to both functional and structural remodeling are summarized.

血管平滑肌细胞（VSMCs）通过调节血管收缩来调节血压。VSMCs中表达的特定离子通道家族调节膜电位和细胞内Ca2+浓度（[Ca2+]cyt）。已知它们的子集通过支架蛋白（如caveolin和junctophilin）与Ca2+敏感分子形成分子复合物。这使得局部和分子复合物特异性信号转导能够调节血管收缩性。这个细胞内区域被称为Ca2+微域。当高血压刺激作用于血管时，血管细胞中离子通道和支架蛋白的基因表达发生显著变化，往往导致膜去极化和[Ca2+]cyt增加。结果，血管经历以收缩性增强为特征的功能性重塑。此外，血管细胞中炎症基因的转录也上调。这诱导白细胞浸润到血管壁，并通过VSMC增殖和细胞外基质重塑介导结构重塑。这种功能和结构的重塑使高血压状态永久化，导致对全身器官的进行性损害。本文综述了VSMCs中Ca2+微域调控收缩性的机制。此外，本文还总结了高血压刺激引起的Ca2+微域的变化及其对功能和结构重塑的贡献。

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