European journal of pharmacology最新文献_第10页

Comparative efficacy and safety of faricimab, aflibercept, conbercept, and ranibizumab for neovascular age-related macular degeneration: A systematic review and network meta-analysis faricimab, aflibercept， conberept和ranibizumab治疗新生血管性年龄相关性黄斑变性的比较疗效和安全性：一项系统评价和网络荟萃分析

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-11-25 DOI: 10.1016/j.ejphar.2025.178406

Shanduo Cen , Shixin Liu , Miaomiao Zhao , Lei Tang

Background

Existing meta-analyses of anti-vascular endothelial growth factor therapies for neovascular age-related macular degeneration focus mainly on ranibizumab and aflibercept, with limited data on newer agents (faricimab, conbercept). This network meta-analysis (NMA) comprehensively compares all four key agents.

Methods

We systematically searched multiple databases for randomized controlled trials. Bayesian random-effects network meta-analysis was conducted, with evidence certainty assessed using CINeMA (Confidence in Network Meta-Analysis).

Results

Thirty-nine randomized controlled trials involving 11,548 participants were included. For best-corrected visual acuity, agents showed comparable efficacy (high to moderate evidence); differences were neither statistically nor clinically significant. Choroidal neovascularization regression showed no important differences (mostly low certainty evidence). For retinal thickness, superior reductions versus ranibizumab 0.5 mg were observed with aflibercept 2 mg (MD: −14.27, 95 % CrI: −27.25, −1.75; high certainty), aflibercept 8 mg (MD: −32.43, 95 % CrI: −57.40, −7.75; high certainty), and conbercept 0.5 mg (MD: −10.26, 95 % CrI: −19.43, −0.98; moderate certainty). Faricimab required significantly fewer injections (high certainty evidence). Aflibercept 2 mg showed better ocular safety than faricimab 6 mg (OR: 0.58, 95 % CrI: 0.37, 0.90) and ranibizumab 0.5 mg (OR: 0.72, 95 % CrI: 0.53, 0.97; high certainty).

Conclusion

Aflibercept and conbercept may be preferred when anatomical outcomes are prioritized, whereas faricimab's extended dosing interval could benefit treatment-adherent populations. The superior safety profile of aflibercept 2 mg warrants consideration in risk averse patients. These differential effects support personalized therapeutic decision-making.

背景：现有的抗血管内皮生长因子治疗新血管性年龄相关性黄斑变性的荟萃分析主要集中在雷尼单抗和阿非利赛普，关于新药物（faricimab, concept）的数据有限。该网络荟萃分析（NMA）全面比较了所有四个关键因素。方法：系统地检索多个数据库进行随机对照试验。进行贝叶斯随机效应网络元分析，使用CINeMA（网络元分析置信度）评估证据确定性。结果：纳入39项随机对照试验，共11,548名受试者。对于最佳矫正视力，药物显示出相当的疗效（高到中等证据）；差异无统计学意义，也无临床意义。脉络膜新生血管的回归没有显示出重要的差异（主要是低确定性证据）。对于视网膜厚度，阿非利赛普2 mg （MD: -14.27, 95% CrI: -27.25, -1.75；高确定性）、阿非利赛普8 mg （MD: -32.43, 95% CrI: -57.40, -7.75；高确定性）和conberconcept 0.5 mg （MD: -10.26, 95% CrI: -19.43, -0.98；中等确定性）与雷尼单抗0.5 mg相比有更显著的降低。Faricimab的注射次数明显减少（高确定性证据）。afliberept 2mg的眼安全性优于faricimab 6mg （OR: 0.58, 95% CrI: 0.37, 0.90）和ranibizumab 0.5 mg （OR: 0.72, 95% CrI: 0.53, 0.97；高确定性）。结论：当解剖学结果优先考虑时，Aflibercept和conberept可能是首选，而faricimab延长的给药间隔可能有利于治疗依从性人群。阿伯西普2mg的优越安全性值得风险规避患者考虑。这些差异效应支持个性化治疗决策。

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引用次数: 0

Protective role of Oxyresveratrol against NaIO3-induced oxidative stress in RPE cells via targeting NRF2-mediated ferroptosis in vitro and in vivo 氧化白藜芦醇通过靶向nrf2介导的铁凋亡对naio2诱导的RPE细胞氧化应激的保护作用

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-11-25 DOI: 10.1016/j.ejphar.2025.178402

Chih-Chun Chuang , Yong-Syuan Chen , Wei-Yang Lu , Shih-Chi Su , Ting-Yu Liao , Shun-Fa Yang , Yi-Hsien Hsieh

Age-related macular degeneration (AMD) is a chronic retinal disorder that occurs when oxidative damages are gradually accumulated to the center of retina. Oxyresveratrol (OxyR), a naturally occurring stilbene found in many plants, has been reported to exhibit anti-inflammatory and anti-oxidative activities. To fill this gap, we explored the effect of OxyR on retinal pigment epithelial cells in response to oxidative stress and on a mouse model of AMD and further dissected the molecular mechanism underlying OxyR's actions. In this study, we demonstrated that OxyR efficiently impeded both apoptosis and ferroptosis of a human ARPE-19 cells induced by sodium iodate (NaIO₃). Such protective effect of OxyR on NaIO₃-induced ARPE-19 cells was accompanied with altered expression levels of NRF2, KEAP1, and several ferroptosis-related proteins. Moreover, OxyR treatment, coupled with silencing of NRF2, ferroptosis inhibitor (ferrostatin-1) or depletion of ROS, enhanced the protection of ARPE-19 cells from NaIO₃-induced damages. Consistently, oral gavage of OxyR restored the reduction of retinal thickness and attenuated the upregulation of NRF2 in retinal pigment epithelium layers of NaIO₃-treated mice. These results demonstrated that OxyR mitigates NaIO₃-induced ARPE19 cell death via targeting NRF2-ferroptosis signaling. Our findings provided potential avenues for the use of OxyR in controlling AMD.

年龄相关性黄斑变性（AMD）是一种慢性视网膜疾病，当氧化损伤逐渐累积到视网膜中心时发生。氧化白藜芦醇（Oxyresveratrol, OxyR）是一种天然存在于许多植物中的二苯乙烯，据报道具有抗炎和抗氧化活性。为了填补这一空白，我们探索了氧化应激对视网膜色素上皮细胞和AMD小鼠模型的影响，并进一步解剖了氧化应激作用的分子机制。在这项研究中，我们证明了OxyR有效地抑制了碘酸钠（NaIO3）诱导的人ARPE-19细胞的凋亡和铁下垂。这种对naio3诱导的ARPE-19细胞的保护作用伴随着NRF2、KEAP1和几种铁凋亡相关蛋白表达水平的改变。此外，OxyR处理，加上NRF2的沉默，ferroptosis抑制剂（ferrostatin-1）或ROS的消耗，增强了ARPE-19细胞对naio3诱导的损伤的保护。与此一致的是，口服氧合氧（OxyR）恢复了naio3处理小鼠视网膜色素上皮层中视网膜厚度的减少，并减弱了NRF2的上调。这些结果表明，OxyR通过靶向nrf2 -铁下垂信号通路减轻naio3诱导的ARPE19细胞死亡。我们的发现为使用OxyR控制AMD提供了潜在的途径。

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引用次数: 0

The immune thrombocytopenia therapeutic Avatrombopag alleviates osteoporosis by targeting NFATc1 signaling 免疫血小板减少治疗Avatrombopag通过靶向NFATc1信号通路缓解骨质疏松症

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-11-24 DOI: 10.1016/j.ejphar.2025.178377

Yangyang Hu , Zhixian Chen , Sitao Hu , Chengyu Zhou , Xiaojun Chen , Shiyao Wei , Ding Wang , Kaiyin Liang , Peng Wu , Lei Chen , Kai Chen , Lu Wang

Osteoporosis is a systemic skeletal disorder characterized by increased osteoclast activity and bone loss, for which the clinical management remains an unmet need. Here, through in silico drug screening of an FDA-approved drug library, we identified Avatrombopag (Ava) — a thrombopoietin (TPO) receptor agonist approved for immune thrombocytopenia (ITP) — as a potent inhibitor of nuclear factor of activated T cells c1 (NFATc1), the master transcriptional regulator of osteoclastogenesis. Indeed, Ava significantly inhibited osteoclastogenesis in vitro, with significant inhibitory effects starting at a low concentration. Molecular docking analysis revealed that Ava binds with high affinity to NFATc1, forming hydrogen bonds with residues GLN-419 and ASP-417. This interaction was further validated by drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA). Moreover, Ava suppressed the expression of osteoclast marker genes (Nfatc1, Fos, Ctsk, Acp5) and inhibited resorptive function. To evaluate its therapeutic potential in vivo, Ava was administrated to ovariectomized (OVX)-induced osteoporotic mice. Micro-CT and histological analyses (H&E and TRAP staining) revealed that Ava protected against bone loss, accompanied by reduced osteoclast formation. Immunohistochemistry and qPCR assays of bone tissues further confirmed that Ava effectively downregulated NFATc1 expression. Collectively, our findings demonstrate that the ITP drug Ava may serve as a therapeutic option for osteoclast-related bone loss and potentially for ITP patients who also suffer from osteoporosis.

骨质疏松症是一种以破骨细胞活性增加和骨质流失为特征的全身性骨骼疾病，其临床管理仍然是一个未满足的需求。在这里，通过fda批准的药物文库的计算机药物筛选，我们确定了Avatrombopag (Ava) -一种被批准用于免疫性血小板减少症（ITP）的血小板生成素（TPO）受体激动剂-作为活化T细胞核因子c1 （NFATc1）的有效抑制剂，NFATc1是破骨细胞发生的主要转录调节因子。事实上，Ava在体外显著抑制破骨细胞的形成，从低浓度开始就有显著的抑制作用。分子对接分析显示，Ava与NFATc1结合具有高亲和力，与残基GLN-419和ASP-417形成氢键。通过药物亲和力反应靶稳定性（dart）和细胞热移测定（CETSA）进一步验证了这种相互作用。此外，Ava抑制破骨细胞标记基因（Nfatc1、Fos、Ctsk、Acp5）的表达，抑制骨吸收功能。为了评估其在体内的治疗潜力，Ava被给予卵巢切除（OVX）诱导的骨质疏松小鼠。显微ct和组织学分析（H&；E和TRAP染色）显示Ava可防止骨质流失，并伴有破骨细胞形成减少。骨组织免疫组化和qPCR检测进一步证实Ava有效下调NFATc1表达。总的来说，我们的研究结果表明，ITP药物Ava可能作为破骨细胞相关骨质流失的治疗选择，并可能用于同时患有骨质疏松症的ITP患者。

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引用次数: 0

Spinal microglial membrane glucocorticoid receptors regulate anti-hypersensitivity by stimulating dynorphin A expression 脊髓小胶质膜糖皮质激素受体通过刺激肌啡肽A的表达调节抗超敏反应。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-11-21 DOI: 10.1016/j.ejphar.2025.178362

Le Ma , Jinbao Wei , Meng-Yan Deng , Khalil Ali Ahmad , Jinlu Huang , Meng-Jing Zhao , Xinyan Li , Yemeng Mao , Yong-Xiang Wang , Jinghong Chen

Previous studies have speculated the existence of a specific expression of the glucocorticoid receptor (GR) that is independent of the nuclear transcription mechanism, this type of receptor may play a decisive role in analgesic effects. The effects were determined by behavioral assessment, whole-cell recording, immunofluorescence staining, and quantitative PCR. A single intrathecal agonism of dexamethasone (DEX) and membrane-impermeable DEX-BSA exerted time-dependent anti-hypersensitivity effects and regulated spinal functional connectivities in formalin and neuropathic rats, respectively. Both DEX and DEX-BSA significantly reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) in a dosage-dependent manner. Pharmacological inhibition of GRs, dynorphin A, kappa-opioid receptors (KORs), and microglia effectively reversed the inhibitory effects of DEX and DEX-BSA on mEPSCs. Protopanaxadiol (PPD), an analogue of DEX, exhibited similar inhibitory effects on mEPSCs, without affecting the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Molecular docking analysis indicated an effective binding of DEX and PPD to GRs. GRs were mainly colocalized with the nuclear biomarker DAPI in the spinal cord. Importantly, scatter GRs, particularly in the substantia gelatinosa, were colocalized with microglia. Pharmacological stimulation of GR expression in neuronal nuclei did not alter the frequency and amplitude of mEPSCs in neuropathic rats. In addition, intrathecal DEX, DEX-BSA, and PPD also suppressed pain in female rats. DEX exerts antinociceptive effects by activating spinal microglial membrane GRs and dynorphin A release, thereby stimulating KORs-mediated inhibition of glutamatergic transmission.

以往的研究推测存在一种独立于核转录机制的糖皮质激素受体（GR）的特异性表达，这类受体可能在镇痛作用中起决定性作用。通过行为评估、全细胞记录、免疫荧光染色和定量PCR来确定效果。地塞米松（DEX）和膜不渗透性DEX- bsa的单鞘内激动作用分别在福尔马林和神经性病变大鼠中发挥时间依赖性抗超敏反应作用并调节脊髓功能连接。DEX和DEX- bsa均以剂量依赖性的方式显著降低了微型兴奋性突触后电流（mEPSCs）的频率。药理抑制GRs、dynorphin A、kappa-阿片受体（KORs）和小胶质细胞可有效逆转DEX和DEX- bsa对mEPSCs的抑制作用。Protopanaxadiol （PPD）是DEX的类似物，对mEPSCs具有类似的抑制作用，但不影响微型抑止突触后电流（mIPSCs）的频率和幅度。分子对接分析表明，DEX和PPD与GRs有效结合。GRs主要与脊髓中的核生物标志物DAPI共定位。重要的是，分散的GRs，特别是在明胶质中，与小胶质细胞共定位。神经病变大鼠神经细胞核GR表达的药物刺激未改变mepsc的频率和振幅。此外，鞘内DEX、DEX- bsa和PPD也能抑制雌性大鼠的疼痛。DEX通过激活脊髓小胶质膜GRs和dynorphin A的释放，从而刺激kors介导的谷氨酸能传递抑制，发挥抗感知作用。

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引用次数: 0

Sulodexide can ameliorates renal interstitial fibrosis in adenine-induced kidney injury rats 舒洛地特可改善腺嘌呤所致肾损伤大鼠肾间质纤维化。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-11-21 DOI: 10.1016/j.ejphar.2025.178354

Minghui Xing , Liming Liang , Qun Wang , Shuqi Xu , Yifei Zhang , Lin Li , Xianglei Kong , Huiyan Xu , Wenbin Li

Objective

To investigate the effect and mechanisms of sulodexide(SDX) on adenine-induced kidney injury (KI) in rats.

Methods

Thirty female Sprague-Dawley rats were randomized into 3 groups: rats were fed on a normal diet (control group), rats received 0.75 % adenine diet for 4 weeks and 0.9 % saline intraperitoneally for 8 weeks (KI group) and rats received 0.75 % adenine diet for 4 weeks and sulodexide (15 mg/kg/day) intraperitoneally for 8 weeks (KI + SDX group). After the treatments of 8 weeks, the blood and kidney tissue specimens were obtained. Biochemical index and pathological staining were used to assess renal injury and fibrosis. Immunohistochemistry and Western blot were used to detect fibrosis-related proteins and signaling pathways.

Results

Compared with the control group, the KI group showed higher blood creatinine and urea nitrogen levels, lower total protein levels, and increased renal injury, with significantly higher expression of α-SMA (p < 0.01) and FN (p < 0.01) and increased expression of the Wnt/β-catenin signaling pathway proteins Wnt3a (p < 0.05) and β-catenin (p < 0.01). After sulodexide treatment, biochemical indexes and renal pathological manifestations were improved, and the expression of α-SMA (p < 0.01) and FN (p < 0.01) were significantly reduced, and the expression of Wnt/β-catenin signaling pathway proteins Wnt3a (p < 0.01) and β-catenin (p < 0.05) was decreased.

Conclusions

The study demonstrated that SDX can delay renal interstitial fibrosis in adenine-induced kidney injury rats, which may be related to the inhibition of Wnt/β-catenin signaling pathway.

目的：探讨舒洛地特（SDX）对腺嘌呤所致大鼠肾损伤的作用及机制。方法：雌性Sprague-Dawley大鼠30只，随机分为3组：正常饮食（对照组），0.75%腺嘌呤饮食4周，0.9%生理盐水腹腔注射8周（KI组），0.75%腺嘌呤饮食4周，舒洛地特（15 mg/Kg/d）腹腔注射8周（KI+SDX组）。治疗8周后，取血、肾组织标本。采用生化指标及病理染色评价肾损伤及纤维化程度。免疫组织化学和Western blot检测纤维化相关蛋白和信号通路。结果：与对照组相比，KI组血肌酐、尿素氮水平升高，总蛋白水平降低，肾损伤加重，α-SMA表达显著升高(p)。结论：本研究表明SDX可延缓腺嘌呤所致肾损伤大鼠肾间质纤维化，其作用机制可能与抑制Wnt/β-catenin信号通路有关。

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引用次数: 0

Gypenoside XVII regulates apoptosis and fear extinction deficits mediated by post-traumatic stress disorder through the PERK/CHOP signaling pathway 绞绳皂苷XVII通过PERK/CHOP信号通路调节创伤后应激障碍介导的细胞凋亡和恐惧消退缺陷。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-11-21 DOI: 10.1016/j.ejphar.2025.178391

Yitai Yang , Jingjing Wang , Shuying Wang , Yueyang Chen , Zemeng Li , Huimin Zhang , Pengbo Zhou , Wei Li , Dangli Ren , Hongtao Sun

Objective

Post-traumatic stress disorder (PTSD) leads to apoptosis in the medial prefrontal cortex (mPFC). Although studies have demonstrated the neuroprotective effects of Gypenoside XVII(GP-17), the potential mechanisms of GP-17 for the treatment of PTSD remain to be elucidated. This study aimed to investigate the inhibitory effect of GP-17 on the fear state of PTSD through the PERK/CHOP pathway.

Materials and methods

Establishment of a Single Prolonged Stress (SPS) model using Sprague Dawley (SD) rats, combined with behavioral assessments, TUNEL staining, Western blot analysis, Immunofluorescence staining, and Flow cytometry analyses of a primary microglia model. This study aims to evaluate the effects of GP-17 treatment on fear and anxiety states, as well as the role of the endoplasmic reticulum (ER) stress signaling pathway, specifically protein kinase RNA (PKR)-like ER kinase (PERK), in regulating apoptosis in rats.

Results

Research shows that GP-17 significantly reduces apoptosis in the prefrontal cortical microglia of SPS rats by modulating the PERK-C/EBP-homologous protein (CHOP) signaling pathway. This modulation helps improve fear extinction deficits and reduces anxiety-like behavior. Additionally, GP-17 intervention effectively inhibits neuroinflammation and oxidative stress. In vitro experiments further demonstrate that GP-17 prevents tunicamycin (Tu)-induced apoptosis related to PERK-mediated ER stress in primary rat microglia.

Conclusion

GP-17 demonstrates therapeutic potential for PTSD by modulating fear and anxiety in SPS rats through the PERK/CHOP pathway, positioning it as a promising candidate for PTSD treatment via the endoplasmic reticulum stress pathway.

目的：创伤后应激障碍（PTSD）导致内侧前额叶皮层（mPFC）细胞凋亡。虽然研究已经证明绞股皂苷XVII（GP-17）具有神经保护作用，但GP-17治疗PTSD的潜在机制仍有待阐明。本研究旨在探讨GP-17通过PERK/CHOP通路对PTSD恐惧状态的抑制作用。材料与方法：建立SD大鼠单次延长应激（SPS）模型，结合行为学评估、TUNEL染色、Western blot分析、免疫荧光染色、流式细胞术等方法对初代小胶质细胞模型进行分析。本研究旨在评估GP-17治疗对大鼠恐惧和焦虑状态的影响，以及内质网（ER）应激信号通路，特别是蛋白激酶RNA （PKR）样ER激酶（PERK）在调节细胞凋亡中的作用。结果：研究表明GP-17通过调节PERK-C/ ebp同源蛋白（CHOP）信号通路，显著减少SPS大鼠前额皮质小胶质细胞凋亡。这种调节有助于改善恐惧消除缺陷，减少类似焦虑的行为。此外，GP-17干预有效抑制神经炎症和氧化应激。体外实验进一步证明，GP-17可阻止tunicamycin （Tu）诱导的与perk介导的内质网应激相关的大鼠原代小胶质细胞凋亡。结论：GP-17通过PERK/CHOP通路调节SPS大鼠的恐惧和焦虑，具有治疗PTSD的潜力，是内质网应激通路治疗PTSD的有希望的候选物质。

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引用次数: 0

Angiotensin II-induced fibrosis is mediated by activation of FGFR1 pathway in renal epithelial cells: Attenuation by chimeric peptide 血管紧张素ii诱导的纤维化是由肾上皮细胞中FGFR1通路的激活介导的：嵌合肽的衰减。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-11-20 DOI: 10.1016/j.ejphar.2025.178390

Jegadheeswari Venkadakrishnan , Audesh Bhat , Kirtikumar B. Jadhav , Arti Dhar

Renal fibrosis is a prominent pathophysiologic change seen with the progression of chronic kidney disease. Angiotensin II (Ang II), the central peptide of the renin-angiotensin aldosterone system (RAAS), is known to cause fibrosis under various disease conditions. Fibroblast growth factor receptor-1 (FGFR1) plays a critical role in epithelial to mesenchymal transition and tubulointerstitial fibrosis, but its role in Ang II-induced fibrosis in renal epithelial cells (RECs) and renal fibroblasts (RFbs) remains poorly understood. Our study aimed to investigate the role of FGFR1 in Ang II-induced fibrosis in both REC, RFbs and explore the potential of chimeric peptide (CP) in attenuating it. We developed a time-dependent in vitro fibrosis model using REC exposed to Ang II and analyzed the expression of FGFR1 and fibrotic markers by qPCR. Oxidative stress and profibrotic markers were measured using confocal imaging and flow cytometry. In RFbs, we also examined fibrotic cell proliferation and collagen deposition using proliferation assays and Sirius red staining. Our findings show that Ang II significantly increases FGFR1, AT₁ receptor, and oxidative stress markers through the ERK/MAPK pathway. Simultaneously, it downregulates MAS1 and pGC-A expression, protective pathways of the RAAS system. However, co-treatment with CP, which targets MAS1 and pGC-A, reversed the harmful changes caused by Ang II. In conclusion, our study suggests that Ang II-induced fibrosis is mediated through FGFR1, AT₁ receptor activation, and CP can more effectively counteract these effects than individual peptides by dual activation of the protective pathways of the RAAS system.

肾纤维化是慢性肾脏疾病进展过程中显著的病理生理变化。血管紧张素II （Ang II）是肾素-血管紧张素醛固酮系统（RAAS）的中心肽，已知在各种疾病条件下引起纤维化。成纤维细胞生长因子受体-1 （FGFR1）在上皮细胞向间质转化和小管间质纤维化中起关键作用，但其在Ang ii诱导的肾上皮细胞（RECs）和肾成纤维细胞（RFbs）纤维化中的作用尚不清楚。我们的研究旨在探讨FGFR1在REC和RFbs中Ang ii诱导的纤维化中的作用，并探索嵌合肽（CP）减轻其作用的潜力。我们利用暴露于Ang II的REC建立了一个时间依赖性的体外纤维化模型，并通过qPCR分析了FGFR1和纤维化标志物的表达。采用共聚焦成像和流式细胞术检测氧化应激和纤维化标志物。在RFbs中，我们还使用增殖试验和天狼星红染色检测了纤维化细胞增殖和胶原沉积。我们的研究结果表明，Ang II通过ERK/MAPK途径显著增加FGFR1、AT1受体和氧化应激标志物。同时下调RAAS系统的保护通路MAS1和pGC-A的表达。然而，与靶向MAS1和pGC-A的CP共处理，逆转了Ang II引起的有害变化。总之，我们的研究表明，Ang ii诱导的纤维化是通过FGFR1、AT1受体激活介导的，而CP可以通过双重激活RAAS系统的保护途径，比单个肽更有效地抵消这些影响。

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引用次数: 0

From cells to systems: A comprehensive perspective on In-Vitro, In-Vivo, and 3D culture models of heart failure 从细胞到系统：对心力衰竭的体外，体内和3D培养模型的综合观点。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-11-20 DOI: 10.1016/j.ejphar.2025.178356

Kushal Vesmaker, Jegadheeswari Venkadakrishnan, Arti Dhar

Heart failure (HF) is a cardiovascular condition with varying etiology, in which the heart ceases to pump sufficient blood to the body. It is a major cause of death worldwide, with prevalence increasing continuously over the years. Despite tremendous progress in understanding HF pathophysiology, creating effective therapy strategies remains challenging, with high mortality rates and translating experimental findings into an effective therapeutic. Drug testing for HF utilizes in-vitro and in-vivo models to examine prospective treatments as well as therapeutic efficacy. In-vivo murine models of HF are frequently employed to recreate human disease phenotypes and identify their underlying mechanisms. It has significantly improved our understanding of the mechanisms underlying HF, paving the way for successful treatments. These models provide numerous information about cardiac functionality, but species-specific genetic differences may restrict their translational utility. In-vitro models, such as 2D cell cultures, offer a controlled environment for studying cellular responses to therapeutic interventions. However, standard 2D cultures fail to reproduce the 3D architecture and the cell-cell interaction in complex organ-level systems. Introducing 3D in-vitro models provides a physiologically realistic platform for an accurate replication of the in-vivo cardiac milieu, which is critical for accurate preclinical drug testing. Combining in-vitro and in-vivo techniques is crucial for developing HF therapeutics, as each model carries intrinsic advantages and limitations in representing the complexity of the disease. This review focuses on in-vitro and in-vivo HF models, highlighting animal models, 2D cultures, and emerging trends in 3D in-vitro models, offering potential for streamlining the drug discovery process.

心力衰竭（HF）是一种有多种病因的心血管疾病，其中心脏停止向身体泵送足够的血液。它是世界范围内死亡的一个主要原因，多年来患病率不断上升。尽管在了解心衰病理生理方面取得了巨大进展，但创造有效的治疗策略仍然具有挑战性，死亡率高，并将实验结果转化为有效的治疗方法。心衰的药物测试利用体外和体内模型来检查未来的治疗方法以及治疗效果。体内小鼠心衰模型经常用于重建人类疾病表型并确定其潜在机制。它大大提高了我们对心衰机制的理解，为成功的治疗铺平了道路。这些模型提供了许多关于心脏功能的信息，但物种特异性的遗传差异可能限制了它们的翻译效用。体外模型，如二维细胞培养，为研究细胞对治疗干预的反应提供了一个可控的环境。然而，标准的2D培养不能在复杂的器官水平系统中再现3D结构和细胞-细胞相互作用。引入3D体外模型为准确复制体内心脏环境提供了生理上真实的平台，这对于准确的临床前药物测试至关重要。结合体外和体内技术对于开发HF治疗方法至关重要，因为每种模型在代表疾病的复杂性方面都具有固有的优势和局限性。本文综述了体外和体内HF模型，重点介绍了动物模型、2D培养和3D体外模型的新趋势，为简化药物发现过程提供了可能。

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引用次数: 0

Anti-diabetic drug target perturbation modulates susceptibility to aortic aneurysm 抗糖尿病药物靶扰动调节主动脉瘤易感性。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-11-19 DOI: 10.1016/j.ejphar.2025.178386

Ranran Kong , Zhihui Kuang , Xia Wu , Huilei Zhou , Yilin Zhou , Jianping Bin , Guojun Chen , Shifei Wang

Background

Aortic aneurysms (AAs), including abdominal AA (AAA) and thoracic AA (TAA), are life-threatening conditions for which effective preventive therapies are lacking. Despite the promising results of anti-diabetic drugs in treating AAs, conclusive evidence supporting their efficacy remains lacking. Identifying effective anti-diabetic drugs for AAs is of considerable clinical importance.

Methods

Herein, we performed drug-target Mendelian randomisation (MR) using summary statistics from the largest genome-wide meta-analyses of AAA/TAA (FinnGen R10 and UK Biobank) and gene expression data from the eQTLGen consortium. Analyses included inverse-variance weighted MR, mediation MR (common risk factors), colocalisation, phenome-wide MR and animal experiment to validate causality and pleiotropy of the genes.

Results

Among the 10 anti-diabetic drug targets analysed, PRKAB1 (metformin target) showed protective effects against AAA (discovery OR = 0.92, 95 % CI: 0.88–0.97, P = 0.003; meta-OR = 0.93, 95 % CI: 0.89–0.97, P < 0.001) and TAA (discovery OR = 0.90, 95 % CI: 0.86–0.94, P < 0.001; meta-OR = 0.92, 95 % CI: 0.88–0.96, P = 0.002). Mediation MR demonstrated that 15.3 % (P = 0.021) and 11.7 % (P = 0.038) of the effects of PRKAB1 were mediated by elevated concentrations of high-density lipoprotein and reduced levels of triglycerides, respectively; insulin receptor reduced TAA risk (discovery OR = 0.86, 95 % CI: 0.75–0.99, P = 0.037; replication OR = 0.54, 95 % CI: 0.36–0.80, P = 0.002; meta-OR = 0.82, 95 % CI: 0.72–0.93, P = 0.012).

Conclusions

These results highlight the pivotal role of PRKAB1 in preventing AA formation, particularly by regulating lipid levels. Additionally, the insulin receptor may have a role in reducing TAA incidence. Our findings provide valuable early-stage evidence for developing targeted AA therapies based on anti-diabetic drug target perturbation.

背景：主动脉瘤（AAs），包括腹主动脉瘤（AAA）和胸主动脉瘤（TAA）是危及生命的疾病，缺乏有效的预防治疗。尽管抗糖尿病药物在治疗AAs方面取得了令人鼓舞的结果，但仍缺乏支持其疗效的确凿证据。寻找有效的抗糖尿病药物治疗AAs具有重要的临床意义。方法：本文采用AAA/TAA （FinnGen R10和UK Biobank）最大全基因组荟萃分析的汇总统计数据和来自eQTLGen联盟的基因表达数据，进行药物靶向孟德尔随机化（MR）。分析包括反方差加权MR、中介MR（共同风险因素）、共定位、全现象MR和动物实验，以验证基因的因果关系和多效性。结果：在分析的10个降糖药物靶点中，PRKAB1（二甲双胍靶点）对AAA具有保护作用（发现OR=0.92, 95% CI: 0.88-0.97， P=0.003; meta-OR=0.93, 95% CI: 0.89-0.97， P）。结论：这些结果突出了PRKAB1在预防AA形成中的关键作用，特别是通过调节脂质水平。此外，胰岛素受体可能在降低TAA发生率方面发挥作用。我们的发现为开发基于抗糖尿病药物靶标扰动的靶向AA治疗提供了有价值的早期证据。

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引用次数: 0

The growing landscape of lysine lactylation links to immunosuppressive microenvironment 赖氨酸乳酸化与免疫抑制微环境有关。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2025-11-19 DOI: 10.1016/j.ejphar.2025.178378

Chao Huang , Wei Zhu , Li Sun

Lysine lactylation (Kla) has emerged as an epigenetic-metabolic regulatory mechanism linking post-translational modification (PTM) to immunosuppressive TME formation. Evidence supports its complex role in TME by modulating immune state transitions and augmenting tumor malignancy. However, the existence of specialized lactyltransferases and multiple crosstalk mechanisms remain debated. This review summarizes upstream and downstream regulatory factors influencing lactylation modification, comparing differential substrate modification patterns that diverge in their requirements for Lactyl-CoA biosynthesis, which contributes to gene expression or protein function. Furthermore, we explore the mechanism that the lactate-Kla axis drives tumor progression by orchestrating metabolic reprogramming, fostering therapy resistance, and suppressing T-cell cytotoxicity. Finally, we summarize the burgeoning field of anti-lactylation pharmacology, evaluating prospective therapeutic strategies from preclinical and clinical studies.

赖氨酸乳酸化（Kla）已成为一种表观遗传代谢调节机制，将翻译后修饰（PTM）与免疫抑制TME的形成联系起来。证据支持其在TME中的复杂作用，通过调节免疫状态转变和增强肿瘤恶性。然而，是否存在特化的乳酸转移酶和多种串扰机制仍存在争议。本文综述了影响乳酸化修饰的上游和下游调控因素，比较了不同底物修饰模式对Lactyl-CoA生物合成的不同要求，这有助于基因表达或蛋白质功能。此外，我们探索了乳酸- kla轴通过协调代谢重编程、促进治疗抵抗和抑制t细胞毒性来驱动肿瘤进展的机制。最后，我们总结了抗乳酸化药理学的新兴领域，从临床前和临床研究中评估了前瞻性的治疗策略。

引用次数: 0