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Gut microbiota-derived Metabolite, Shikimic Acid, inhibits vascular smooth muscle cell proliferation and migration 源自肠道微生物群的代谢物莽草酸能抑制血管平滑肌细胞的增殖和迁移
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-07 DOI: 10.1016/j.bcp.2024.116524
Sanjana Kumariya , Arturo Grano de Oro , Andrea L. Nestor-Kalinoski , Bina Joe , Islam Osman

Gut microbiota dysbiosis is linked to vascular wall disease, but the mechanisms by which gut microbiota cross-talk with the host vascular cells remain largely unknown. Shikimic acid (SA) is a biochemical intermediate synthesized in plants and microorganisms, but not mammals. Surprisingly, recent metabolomic profiling data demonstrate that SA is detectable in human and murine blood. In this study, analyzing data from germ-free rats, we provide evidence in support of SA as a bona fide gut microbiota-derived metabolite, emphasizing its biological relevance. Since vascular cells are the first cells exposed to circulating metabolites, in this study, we examined, for the first time, the effects and potential underlying molecular mechanisms of SA on vascular smooth muscle cell (VSMC) proliferation and migration, which play a key role in occlusive vascular diseases, such as post-angioplasty restenosis and atherosclerosis. We found that SA inhibits the proliferation and migration of human coronary artery SMCs. At the molecular level, unexpectedly, we found that SA activates, rather than inhibits, multiple pro-mitogenic signaling pathways in VSMCs, such as ERK1/2, AKT, and mTOR/p70S6K. Conversely, we found that SA activates the anti-proliferative AMP-activated protein kinase (AMPK) in VSMCs, a key cellular energy sensor and regulator. However, loss-of-function experiments demonstrate that AMPK does not mediate the inhibitory effects of SA on VSMC proliferation. In conclusion, these studies demonstrate that a microbiota-derived metabolite, SA, inhibits VSMC proliferation and migration in vitro and prompt further evaluation of the possible underlying molecular mechanisms and the potential protective role in VSMC-related vascular wall disease in vivo.

肠道微生物菌群失调与血管壁疾病有关,但肠道微生物菌群与宿主血管细胞的交叉对话机制在很大程度上仍然未知。莽草酸(SA)是一种在植物和微生物中合成的生化中间体,但在哺乳动物中并不存在。令人惊讶的是,最近的代谢组学分析数据表明,在人类和鼠类血液中可以检测到莽草酸。在本研究中,我们分析了无菌大鼠的数据,提供了支持 SA 成为真正的肠道微生物群衍生代谢物的证据,并强调了其生物学相关性。由于血管细胞是最先暴露于循环代谢物的细胞,在本研究中,我们首次考察了 SA 对血管平滑肌细胞(VSMC)增殖和迁移的影响及其潜在的分子机制。我们发现 SA 能抑制人冠状动脉 SMC 的增殖和迁移。在分子水平上,我们意外地发现 SA 能激活而不是抑制 VSMC 中的多种促有丝分裂信号通路,如 ERK1/2、AKT 和 mTOR/p70S6K。相反,我们发现 SA 能激活 VSMC 中的抗增殖 AMP 激活蛋白激酶(AMPK),这是一种关键的细胞能量传感器和调节器。然而,功能缺失实验表明,AMPK 并不介导 SA 对 VSMC 增殖的抑制作用。总之,这些研究证明了一种微生物群衍生代谢物 SA 在体外能抑制 VSMC 的增殖和迁移,并促使人们进一步评估其可能的潜在分子机制以及在体内 VSMC 相关血管壁疾病中的潜在保护作用。
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引用次数: 0
Cutting-edge advances in nano/biomedicine: A review on transforming thrombolytic therapy 纳米/生物医学的前沿进展:溶栓疗法变革综述
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-07 DOI: 10.1016/j.bcp.2024.116523
Chia-Hung Liu , Lekshmi Rethi , Pei-Wei Weng , Hieu Trung Nguyen , Andrew E.-Y. Chuang

Thrombotic blockages within blood vessels give rise to critical cardiovascular disorders, including ischemic stroke, venous thromboembolism, and myocardial infarction. The current approach to the therapy of thrombolysis involves administering Plasminogen Activators (PA), but it is hindered by fast drug elimination, narrow treatment window, and the potential for bleeding complications. Leveraging nanomedicine to encapsulate and deliver PA offers a solution by improving the efficacy of therapy, safeguarding the medicine from proteinase biodegradation, and reducing unwanted effects in in vivo trials. In this review, we delve into the underlying venous as well as arterial thrombus pathophysiology and provide an overview of clinically approved PA used to address acute thrombotic conditions. We explore the existing challenges and potential directions within recent pivotal research on a variety of targeted nanocarriers, such as lipid, polymeric, inorganic, and biological carriers, designed for precise delivery of PA to specific sites. We also discuss the promising role of microbubbles and ultrasound-assisted Sono thrombolysis, which have exhibited enhanced thrombolysis in clinical studies. Furthermore, our review delves into approaches for the strategic development of nano-based carriers tailored for targeting thrombolytic action and efficient encapsulation of PA, considering the intricate interaction in biology systems as well as nanomaterials. In conclusion, the field of nanomedicine offers a valuable method for the exact and effective therapy of severe thrombus conditions, presenting a pathway toward improved patient outcomes and reduced complications.

血管内的血栓堵塞会引发严重的心血管疾病,包括缺血性中风、静脉血栓栓塞症和心肌梗塞。目前的溶栓治疗方法包括使用血浆酶原激活剂(PA),但这种方法存在药物消除快、治疗窗口狭窄以及可能出现出血并发症等问题。利用纳米药物封装和递送 PA 可提高疗效,防止药物被蛋白酶生物降解,并减少体内试验中的不良反应,从而提供一种解决方案。在本综述中,我们深入探讨了静脉和动脉血栓的基本病理生理学,并概述了临床批准用于治疗急性血栓病症的 PA。我们探讨了近期对各种靶向纳米载体(如脂质、聚合物、无机和生物载体)进行关键性研究的现有挑战和潜在方向,这些载体旨在将 PA 精准地输送到特定部位。我们还讨论了微气泡和超声辅助索诺溶栓疗法的前景,这些疗法在临床研究中显示出更强的溶栓能力。此外,考虑到生物系统和纳米材料之间错综复杂的相互作用,我们的综述还深入探讨了纳米载体的战略开发方法,这些载体专为靶向溶栓作用和有效封装 PA 而量身定制。总之,纳米医学领域为准确有效地治疗严重血栓提供了一种宝贵的方法,为改善患者预后和减少并发症提供了一条途径。
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引用次数: 0
Roxadustat alleviates metabolic traits in letrozole-induced PCOS mice 罗沙司他能缓解来曲唑诱导的多囊卵巢综合症小鼠的代谢特征。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-06 DOI: 10.1016/j.bcp.2024.116522
Nikke Virtanen , Ulla Saarela , Mikko Karpale , Riikka K. Arffman , Kari A. Mäkelä , Karl-Heinz Herzig , Peppi Koivunen , Terhi Piltonen

Polycystic ovary syndrome (PCOS) is a highly prevalent disorder in women that is commonly accompanied by metabolic syndrome. Activation of the hypoxia-inducible factor (HIF) pathway is known to alleviate metabolic defects. Hence, this study utilized a preclinical PCOS mouse model to investigate the effects of chemically induced HIF activation on the metabolic traits of PCOS. Prepubertal letrozole treatment was used to generate a PCOS mouse model in the C57Bl6/J strain, and PCOS mice were orally treated with vehicle or roxadustat for six weeks from age 12 weeks onwards to induce HIF activation. Although the PCOS mice showed impaired glucose tolerance, increased insulin resistance, elevated blood lipids, and reduced muscle glycogen content, there was no difference in histological evaluations of white adipose tissue (WAT) or liver or in organ weights. Roxadustat treatment resulted in significant improvement in glucose tolerance (27 % reduction in area under the curve (AUC) values, p < 0.0001), fasting glucose levels (4.59 ± 0.83 mmol/l vs 3.05 ± 0.62 mmol/l, p < 0.0001) and insulin resistance (46 % reduction in homeostasis model assessment–insulin resistance (HOMA-IR) values, 6.76 ± 3.72 vs 3.64 ± 2.44, p = 0.019) compared to vehicle-treated mice without altering the body weight. Gene expression analyses with real-time quantitative polymerase chain reaction (RT-qPCR) and RNA sequencing revealed significant differences in gene expression in the tissues of PCOS mice compared to control mice, whereas the transcriptomic effects of roxadustat were mainly transient. However, immunohistochemistry revealed increased uncoupling protein 1 (UCP1) expression in WAT, which may indicate WAT browning related to HIF pathway activation.

多囊卵巢综合征(PCOS)是一种女性高发疾病,通常伴有代谢综合征。众所周知,激活低氧诱导因子(HIF)通路可以缓解代谢缺陷。因此,本研究利用临床前多囊卵巢综合征小鼠模型来研究化学诱导的 HIF 激活对多囊卵巢综合征代谢特征的影响。本研究利用青春期前来曲唑治疗在 C57Bl6/J 品系中产生 PCOS 小鼠模型,并从 PCOS 小鼠 12 周龄起连续六周口服载体或罗沙司他以诱导 HIF 激活。虽然多囊卵巢综合征小鼠表现出糖耐量受损、胰岛素抵抗增加、血脂升高和肌糖原含量降低,但白色脂肪组织(WAT)或肝脏的组织学评估或器官重量却没有差异。罗沙司他治疗可显著改善葡萄糖耐量(曲线下面积(AUC)值降低 27%,P<0.05)。
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引用次数: 0
Identification of human-specific amino acid residues governing atenolol transport via organic cation transporter 2 鉴定通过有机阳离子转运体 2 转运阿替洛尔的人类特异性氨基酸残基。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-03 DOI: 10.1016/j.bcp.2024.116514
Akira Hosooka, Tomoya Yasujima, Ayano Murata, Takahiro Yamashiro, Hiroaki Yuasa

Organic cation transporter 2 (OCT2/SLC22A2) is predominantly localized on the basolateral membranes of renal tubular epithelial cells and plays a crucial role in the renal secretion of various cationic drugs. Although variations in substrate selectivity among renal organic cation transport systems across species have been reported, the characteristics of OCT2 remain unclear. In this study, we demonstrated that atenolol, a β1-selective adrenergic antagonist, is transported almost exclusively by human OCT2, contrasting with OCT2s from other selected species. Using chimeric constructs between human OCT2 (hOCT2) and the highly homologous monkey OCT2 (monOCT2), along with site-directed mutagenesis, we identified non-conserved amino acids Val8, Ala31, Ala34, Tyr222, Tyr245, Ala270, Ile394, and Leu503 as pivotal for hOCT2-mediated atenolol transport. Kinetic analysis revealed that atenolol was transported by hOCT2 with a 12-fold lower affinity than MPP+, a typical OCT2 substrate. The inhibitory effect of atenolol on MPP+ transport was 6200-fold lower than that observed for MPP+ on atenolol transport. Additionally, we observed weaker inhibitory effects on MPP+ transport compared to atenolol transport with ten different OCT2 substrates. Altogether, this study suggests that eight hOCT2-specific amino acids constitute the low-affinity recognition site for atenolol transport, indicating differences in OCT2-mediated drug elimination between humans and highly homologous monkeys. Our findings underscore the importance of understanding species-specific differences in drug transport mechanisms, shedding light on potential variations in drug disposition and aiding in drug development.

有机阳离子转运体 2(OCT2/SLC22A2)主要定位于肾小管上皮细胞的基底侧膜上,在肾脏分泌各种阳离子药物的过程中起着至关重要的作用。虽然有报道称不同物种的肾脏有机阳离子转运系统对底物的选择性存在差异,但 OCT2 的特性仍不清楚。在这项研究中,我们证明了β1选择性肾上腺素能拮抗剂阿替洛尔几乎完全由人类OCT2转运,这与其他物种的OCT2形成了鲜明对比。利用人 OCT2(hOCT2)和高度同源的猴 OCT2(monOCT2)之间的嵌合构建物以及定点突变,我们确定了 Val8、Ala31、Ala34、Tyr222、Tyr245、Ala270、Ile394 和 Leu503 等非保守氨基酸是 hOCT2 介导阿替洛尔转运的关键氨基酸。动力学分析表明,hOCT2转运阿替洛尔的亲和力比典型的OCT2底物MPP+低12倍。阿替洛尔对 MPP+ 转运的抑制作用比 MPP+ 对阿替洛尔转运的抑制作用低 6200 倍。此外,与阿替洛尔转运相比,我们观察到十种不同的 OCT2 底物对 MPP+ 转运的抑制作用较弱。总之,这项研究表明,八个 hOCT2 特异性氨基酸构成了阿替洛尔转运的低亲和力识别位点,表明 OCT2 介导的药物清除在人类和高度同源的猴子之间存在差异。我们的发现强调了了解药物转运机制物种特异性差异的重要性,揭示了药物处置的潜在差异,有助于药物开发。
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引用次数: 0
Eicosatrienoic acid inhibits estradiol synthesis through the CD36/FOXO1/CYP19A1 signaling pathway to improve PCOS in mice 二十碳三烯酸通过 CD36/FOXO1/CYP19A1 信号途径抑制雌二醇的合成,从而改善小鼠的多囊卵巢综合症。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-03 DOI: 10.1016/j.bcp.2024.116517
Jun Zhu , Jun-Xia Wang , Zheng-Yun Jin , Dongxu Li , Shaobo Qi , Sheng-Zhong Han , Shuang-Yan Chang , Jin Yan , Jin-Dan Kang , Lin-Hu Quan

Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder characterized by abnormal elevation in hormone levels, with currently lacking effective treatment options. N-3 polyunsaturated fatty acids (PUFA) have broad pharmacological activity and play a beneficial role in the development of PCOS. In this study, we observed that n-3 PUFA-eicosatrienoic acid (ETA) improves the estrous cycle and ovarian morphology in dehydroepiandrosterone (DHEA)-induced PCOS mice, particularly serum hormone levels. Additionally, it suppresses the expression of CYP19A1 and E2 synthesis in human granulosa-like tumor cell line (KGN) cells. Further investigation revealed that ETA significantly upregulates the expression of CD36, cAMP, P-PKA, and FOXO1 in KGN cells and mouse ovaries to lower E2 levels. This conclusion was supported by inhibiting CD36 and FOXO1 at both the mouse and cellular levels. Additionally, ETA treatment decreased the expression of ESR1, Kiss1, Gnrh in the hypothalamus, and GnRHR, Lhβ, Egr1, Pitx1, Sf1 in the pituitary of PCOS mice. No differences were observed after ETA treatment in the CD36 and FOXO1 inhibitor groups, indicating that ETA improves PCOS mice by regulating the hypothalamic-pituitary axis through E2 synthesis inhibition. In summary, we have elucidated for the first time the mechanism by which CD36 regulates E2 synthesis in ovarian granulosa cells and demonstrated that ETA activates the CD36 receptor to inhibit E2 synthesis through the cAMP/PKA/FOXO1/CYP19A1 signaling pathway, thereby improving hormonal imbalance and treating PCOS. This provides a new strategy for the effective prevention and treatment of PCOS.

多囊卵巢综合征(PCOS)是一种常见的代谢和内分泌疾病,其特点是激素水平异常升高,目前缺乏有效的治疗方法。N-3 多不饱和脂肪酸(PUFA)具有广泛的药理活性,在多囊卵巢综合征的发病过程中发挥着有益的作用。在这项研究中,我们观察到 n-3 PUFA-二十碳三烯酸(ETA)能改善脱氢表雄酮(DHEA)诱导的多囊卵巢综合征小鼠的发情周期和卵巢形态,尤其是血清激素水平。此外,它还能抑制 CYP19A1 的表达和人肉芽肿样肿瘤细胞系(KGN)细胞中 E2 的合成。进一步研究发现,ETA 能明显上调 KGN 细胞和小鼠卵巢中 CD36、cAMP、P-PKA 和 FOXO1 的表达,从而降低 E2 水平。在小鼠和细胞水平上抑制 CD36 和 FOXO1 也支持这一结论。此外,ETA 治疗降低了 ESR1、Kiss1 和 Gnrh 在 PCOS 小鼠下丘脑中的表达,以及 GnRHR、Lhβ、Egr1、Pitx1 和 Sf1 在垂体中的表达。ETA治疗后,CD36组和FOXO1抑制剂组没有观察到差异,这表明ETA通过抑制E2的合成来调节下丘脑-垂体轴,从而改善PCOS小鼠的状况。综上所述,我们首次阐明了CD36调控卵巢颗粒细胞E2合成的机制,证明了ETA可激活CD36受体,通过cAMP/PKA/FOXO1/CYP19A1信号通路抑制E2合成,从而改善内分泌失调,治疗多囊卵巢综合征。这为有效预防和治疗多囊卵巢综合症提供了一种新策略。
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引用次数: 0
USP10-mediated deubiquitination of NR3C1 regulates bone homeostasis by controlling CST3 expression USP10 介导的 NR3C1 泛素化通过控制 CST3 的表达调节骨稳态。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-03 DOI: 10.1016/j.bcp.2024.116519
Long Zhou , Shuai Mu , Yiqi Zhang , Hanyi Song

Dysregulated bone homeostasis contributes to multiple diseases including osteoporosis (OP). In this study, osteoporotic mice were successfully generated using ovariectomy to investigate the role of nuclear receptor subfamily 3 group C member 1 (NR3C1) in OP. NR3C1, identified as a significantly upregulated gene in OP using bioinformatic tools, was artificially downregulated in osteoporotic mice. NR3C1 expression was significantly elevated in the femoral tissues of osteoporotic patients, and downregulation of NR3C1 alleviated bone loss and restored bone homeostasis in osteoporotic mice, as manifested by increased ALP- and OCN-positive cells and reduced RANKL/OPG ratio. Downregulation of NR3C1 inhibited osteoclastic differentiation of RAW264.7 cells and mouse bone marrow-derived macrophages (BMDM) and promoted osteogenic differentiation of MC3T3-E1 cells. The transcription factor NR3C1 bound to the cystatin-3 (CST3) promoter to repress its transcription in both RAW264.7 and MC3T3-E1 cells. The downregulation of CST3 reversed the protective effect of NR3C1 downregulation against OP. Ubiquitin-specific-processing protease 10 (USP10)-mediated deubiquitination of NR3C1 improved NR3C1 stability. Downregulation of USP10 inhibited osteoclastic differentiation of RAW264.7 cells and BMDM while promoting osteogenic differentiation of MC3T3-E1 cells. Taken together, USP10-mediated deubiquitination of NR3C1 regulates bone homeostasis by controlling CST3 transcription, providing an attractive therapeutic strategy to alleviate OP.

骨平衡失调是包括骨质疏松症(OP)在内的多种疾病的诱因。本研究利用卵巢切除术成功培育了骨质疏松症小鼠,以研究核受体 3 亚家族 C 组 1(NR3C1)在 OP 中的作用。利用生物信息学工具确定 NR3C1 是 OP 中显著上调的基因,并在骨质疏松症小鼠中人为下调了 NR3C1 的表达。骨质疏松症患者股骨组织中的 NR3C1 表达明显升高,下调 NR3C1 能缓解骨质疏松症小鼠的骨质流失并恢复骨平衡,表现为 ALP 和 OCN 阳性细胞增加,RANKL/OPG 比值降低。下调 NR3C1 可抑制 RAW264.7 细胞和小鼠骨髓源性巨噬细胞(BMDM)的破骨分化,促进 MC3T3-E1 细胞的成骨分化。转录因子 NR3C1 与胱抑素-3(CST3)启动子结合,抑制其在 RAW264.7 和 MC3T3-E1 细胞中的转录。CST3的下调逆转了NR3C1下调对OP的保护作用。泛素特异性加工蛋白酶 10(USP10)介导的 NR3C1 泛素化提高了 NR3C1 的稳定性。下调 USP10 可抑制 RAW264.7 细胞和 BMDM 的破骨分化,同时促进 MC3T3-E1 细胞的成骨分化。综上所述,USP10 介导的 NR3C1 泛素化通过控制 CST3 转录调节骨稳态,为缓解 OP 提供了一种光学治疗策略。
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引用次数: 0
Piperlongumine, a natural alkaloid from Piper longum L. ameliorates metabolic-associated fatty liver disease by antagonizing the thromboxane A2 receptor 胡椒龙葵碱是从胡椒龙葵中提取的一种天然生物碱,它能通过拮抗血栓素 A2 受体改善代谢相关性脂肪肝。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-03 DOI: 10.1016/j.bcp.2024.116518
Yufeng Dai , Jinxiang Chen , Jialong Fang , Shuxiao Liang , Hao Zhang , Haitao Li , Wei Chen

Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, including hyperglycemia, hepatic steatosis, and insulin resistance. Piperlongumine (PL), a natural amide alkaloid extracted from the fruits of Piper longum L., exhibited hepatoprotective effects in zebrafish and liver injury mice. This study aimed to investigate the therapeutic potential of PL on MAFLD and its underlying mechanisms. The findings demonstrate that PL effectively combats MAFLD induced by a high-fat diet (HFD) and improves metabolic characteristics in mice. Additionally, our results suggest that the anti-MAFLD effect of PL is attributed to the suppression of excessive hepatic gluconeogenesis, inhibition of de novo lipogenesis, and alleviation of insulin resistance. Importantly, the results indicate that, on the one hand, the hypoglycemic effect of PL is closely associated with CREB-regulated transcriptional coactivators (CRTC2)-dependent cyclic AMP response element binding protein (CREB) phosphorylation; on the other hand, the lipid-lowering effect of PL is attributed to reducing the nuclear localization of sterol regulatory element-binding proteins 1c (Srebp-1c). Mechanistically, PL could alleviate insulin resistance induced by endoplasmic reticulum stress by antagonizing the thromboxane A2 receptor (TP)/Ca2+ signaling, and the TP receptor serves as the potential target for PL in the treatment of MAFLD. Therefore, our results suggested PL effectively improved the major hallmarks of MAFLD induced by HFD, highlighting a potential therapeutic strategy for MAFLD.

代谢功能障碍相关性脂肪肝(MAFLD)包括一系列肝脏疾病,包括高血糖、肝脂肪变性和胰岛素抵抗。胡椒龙葵碱(Piperlongumine,PL)是从胡椒龙葵果实中提取的一种天然酰胺类生物碱,对斑马鱼和肝损伤小鼠具有保肝作用。本研究旨在探讨胡椒龙葵碱对 MAFLD 的治疗潜力及其内在机制。研究结果表明,PL 能有效对抗高脂饮食(HFD)诱导的 MAFLD,并改善小鼠的代谢特征。此外,我们的研究结果表明,PL 的抗 MAFLD 作用可归因于抑制过多的肝糖生成、抑制新脂肪生成和缓解胰岛素抵抗。重要的是,研究结果表明,一方面,聚乳酸的降血糖作用与CREB调控转录辅激活因子(CRTC2)依赖的环磷酸腺苷反应元件结合蛋白(CREB)磷酸化密切相关;另一方面,聚乳酸的降血脂作用归因于减少甾醇调控元件结合蛋白1c(Srebp-1c)的核定位。从机理上讲,PL 可通过拮抗血栓素 A2 受体(TP)/Ca2+ 信号转导来缓解内质网应激诱导的胰岛素抵抗,而 TP 受体是 PL 治疗 MAFLD 的潜在靶点。因此,我们的研究结果表明,PL能有效改善HFD诱导的MAFLD的主要特征,为MAFLD提供了一种潜在的治疗策略。
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引用次数: 0
An inducible sphingosine kinase 1 in hepatic stellate cells potentiates liver fibrosis 肝星状细胞中的诱导性鞘氨醇激酶 1 能促进肝纤维化。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-03 DOI: 10.1016/j.bcp.2024.116520
Jin Sol Baek , Ji Hyun Lee , Ji Hye Kim , Sam Seok Cho , Yun Seok Kim , Ji Hye Yang , Eun Jin Shin , Hyeon-Gu Kang , Seok-Jun Kim , Sang-Gun Ahn , Eun Young Park , Dong Jae Baek , Sung-Kun Yim , Keon Wook Kang , Sung Hwan Ki , Kyu Min Kim

Hepatic stellate cells (HSCs) play a role in hepatic fibrosis and sphingosine kinase (SphK) is involved in biological processes. As studies on the regulatory mechanisms and functions of SphK in HSCs during liver fibrosis are currently limited, this study aimed to elucidate the regulatory mechanism and connected pathways of SphK upon HSC activation. The expression of SphK1 was higher in HSCs than in hepatocytes, and upregulated in activated primary HSCs. SphK1 was also increased in liver homogenates of carbon tetrachloride-treated or bile duct ligated mice and in transforming growth factor-β (TGF-β)-treated LX-2 cells. TGF-β-mediated SphK1 induction was due to Smad3 signaling in LX-2 cells. SphK1 modulation altered the expression of liver fibrogenesis-related genes. This SphK1-mediated profibrogenic effect was dependent on SphK1/sphingosine-1-phosphate/sphingosine-1-phosphate receptor signaling through ERK. Epigallocatechin gallate blocked TGF-β-induced SphK1 expression and hepatic fibrogenesis by attenuating Smad and MAPK activation. SphK1 induced by TGF-β facilitates HSC activation and liver fibrogenesis, which is reversed by epigallocatechin gallate. Accordingly, SphK1 and related signal transduction may be utilized to treat liver fibrosis.

肝星状细胞(HSCs)在肝纤维化中发挥作用,而鞘磷脂激酶(SphK)参与了肝纤维化的生物学过程。由于目前对肝纤维化过程中造血干细胞中SphK的调控机制和功能的研究有限,本研究旨在阐明造血干细胞活化时SphK的调控机制和相关途径。SphK1在造血干细胞中的表达高于肝细胞,并在活化的原代造血干细胞中上调。SphK1在四氯化碳处理或胆管结扎小鼠的肝匀浆中以及在转化生长因子-β(TGF-β)处理的LX-2细胞中也有所增加。TGF-β介导的SphK1诱导是由于LX-2细胞中的Smad3信号传导。SphK1的调节改变了肝纤维化相关基因的表达。SphK1介导的促纤维化效应依赖于SphK1/鞘氨醇-1-磷酸/鞘氨醇-1-磷酸受体通过ERK发出信号。EGCG通过抑制Smad和MAPK的活化,阻断了TGF-β诱导的SphK1表达和肝纤维化。TGF-β 诱导的 SphK1 可促进造血干细胞活化和肝纤维化,而 EGCG 可逆转这种作用。因此,SphK1和相关的信号转导可用于治疗肝纤维化。
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引用次数: 0
Dasatinib interferes with HIV-1 proviral integration and the inflammatory potential of monocyte-derived macrophages from people with HIV 达沙替尼干扰HIV-1前病毒整合和HIV感染者单核细胞衍生巨噬细胞的炎症潜能。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-01 DOI: 10.1016/j.bcp.2024.116512
Sara Rodríguez-Mora , Clara Sánchez-Menéndez , Guiomar Bautista-Carrascosa , Elena Mateos , Lucia Moreno-Serna , Diego Megías , Juan Cantón , Valentín García-Gutiérrez , María Aránzazu Murciano-Antón , Miguel Cervero , Adam Spivak , Vicente Planelles , Mayte Coiras

HIV-1 infection is efficiently controlled by the antiretroviral treatment (ART) but viral persistence in long-lived reservoirs formed by CD4 + T cells and macrophages impedes viral eradication and creates a chronic inflammatory environment. Dasatinib is a tyrosine kinase inhibitor clinically used against chronic myeloid leukemia (CML) that has also showed an anti-inflammatory potential. We previously reported that dasatinib is very efficient at interfering with HIV-1 infection of CD4 + T cells by preserving the antiviral activity of SAMHD1, an innate immune factor that blocks T-cell activation and proliferation and that is inactivated by phosphorylation at T592 (pSAMHD1). We observed that short-term treatment in vitro with dasatinib significantly reduced pSAMHD1 in monocyte-derived macrophages (MDMs) isolated from people with HIV (PWH) and healthy donors, interfering with HIV-1 infection. This inhibition was based on low levels of 2-LTR circles and proviral integration, while viral reverse transcription was not affected. MDMs isolated from people with CML on long-term treatment with dasatinib also showed low levels of pSAMHD1 and were resistant to HIV-1 infection. In addition, dasatinib decreased the inflammatory potential of MDMs by reducing the release of M1-related cytokines like TNFα, IL-1β, IL-6, CXCL8, and CXCL9, but preserving the antiviral activity through normal levels of IL-12 and IFNγ. Due to the production of M2-related anti-inflammatory cytokines like IL-1RA and IL-10 was also impaired, dasatinib appeared to interfere with MDMs differentiation. The use of dasatinib along with ART could be used against HIV-1 reservoir in CD4 and macrophages and to alleviate the chronic inflammation characteristic of PWH.

抗逆转录病毒疗法(ART)可有效控制 HIV-1 感染,但病毒在 CD4 + T 细胞和巨噬细胞形成的长效储库中的持续存在阻碍了病毒的根除,并造成了慢性炎症环境。达沙替尼是一种酪氨酸激酶抑制剂,临床上用于治疗慢性髓性白血病(CML),它也具有抗炎潜力。我们以前曾报道,达沙替尼通过保留 SAMHD1 的抗病毒活性,能非常有效地干扰 CD4 + T 细胞的 HIV-1 感染。SAMHD1 是一种先天性免疫因子,能阻止 T 细胞的活化和增殖,并通过 T592 处的磷酸化(pSAMHD1)而失活。我们观察到,用达沙替尼进行体外短期治疗可显著降低从艾滋病病毒感染者(PWH)和健康供体中分离出来的单核细胞衍生巨噬细胞(MDMs)中的pSAMHD1,从而干扰HIV-1感染。这种抑制作用基于低水平的 2-LTR 圈和前病毒整合,而病毒反转录不受影响。从长期接受达沙替尼治疗的慢性骨髓性白血病患者体内分离出的MDMs也显示出较低水平的pSAMHD1,并对HIV-1感染具有抵抗力。此外,达沙替尼通过减少M1相关细胞因子如TNFα、IL-1β、IL-6、CXCL8和CXCL9的释放,降低了MDMs的炎症潜能,但通过正常水平的IL-12和IFNγ保持了抗病毒活性。由于 IL-1RA 和 IL-10 等 M2 相关抗炎细胞因子的产生也受到影响,达沙替尼似乎干扰了 MDMs 的分化。达沙替尼与抗逆转录病毒疗法(ART)一起使用,可用于对抗CD4和巨噬细胞中的HIV-1储库,并缓解PWH特有的慢性炎症。
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引用次数: 0
Functional significance of CYP2B6 gene rare allelic variants identified in Japanese individuals 在日本人中发现的 CYP2B6 基因罕见等位基因变异的功能意义。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-31 DOI: 10.1016/j.bcp.2024.116515
Shuki Yamazaki , Eiji Hishinuma , Yuma Suzuki , Akiko Ueda , Caroline Kijogi , Tomoki Nakayoshi , Akifumi Oda , Sakae Saito , Shu Tadaka , Kengo Kinoshita , Masamitsu Maekawa , Yu Sato , Masaki Kumondai , Nariyasu Mano , Noriyasu Hirasawa , Masahiro Hiratsuka

Cytochrome P450 2B6 (CYP2B6) catalyzes the metabolism of many drugs, including efavirenz and propofol. Genetic polymorphisms in CYP2B6 alter its enzymatic activity and substantially affect its pharmacokinetics. High-frequency variants, such as CYP2B6*6, are associated with the risk of developing side effects due to reduced CYP2B6 activity. However, the impact of rare alterations on enzyme function remains unknown, and some of these variants may significantly decrease the CYP2B6 activity. Therefore, in this study, we evaluated in vitro the functional alterations in 29 missense variants of the CYP2B6 gene identified in 8,380 Japanese individuals. Wild-type CYP2B6 and 29 rare CYP2B6 variants were transiently expressed in mammalian cells. The expression levels of variant CYP2B6 proteins in the microsomal fractions extracted from 293FT cells were assessed using western blotting and reduced-carbon monoxide difference spectroscopy, and a specific peak at 450 nm was detected in the wild-type and 19 variants. Furthermore, kinetic parameters were determined by assaying the reactions with efavirenz and propofol and quantifying the metabolite concentrations. We found that 12 variants had significantly lower or abolished enzymatic activity with both the substrates. In silico three-dimensional docking and molecular-dynamics simulations suggested that these functional changes were due to conformational changes in essential regions, such as the heme-binding site and ligand channels involved in transporting substrates to the active site. These findings have implications for predicting the plasma concentrations of CYP2B6 substrates and controlling their side effects.

细胞色素 P450 2B6 (CYP2B6) 催化许多药物的代谢,包括依非韦伦和异丙酚。CYP2B6 的遗传多态性会改变其酶活性,并对其药代动力学产生重大影响。高频变异,如 CYP2B6*6,与因 CYP2B6 活性降低而产生副作用的风险有关。然而,罕见变异对酶功能的影响仍然未知,其中一些变异可能会显著降低 CYP2B6 的活性。因此,在本研究中,我们在体外评估了在 8380 名日本人中发现的 29 个 CYP2B6 基因错义变异的功能改变。野生型 CYP2B6 和 29 个罕见的 CYP2B6 变体在哺乳动物细胞中进行了瞬时表达。使用 Western 印迹法和还原一氧化碳差异光谱法评估了从 293FT 细胞提取的微粒体组分中变体 CYP2B6 蛋白的表达水平,在 450 纳米波长处检测到野生型和 19 个变体的特异峰。此外,还通过测定与依非韦伦和异丙酚的反应并量化代谢物浓度来确定动力学参数。我们发现,12 个变体对两种底物的酶活性明显降低或消失。硅学三维对接和分子动力学模拟表明,这些功能变化是由于重要区域的构象变化造成的,如血红素结合位点和将底物运输到活性位点的配体通道。这些发现对预测 CYP2B6 底物的血浆浓度和控制其副作用具有重要意义。
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引用次数: 0
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Biochemical pharmacology
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