Pharmacological research最新文献_第6页

Advance in neuroprotective effects of proanthocyanidins (PCs): Structure, absorption, bioactivities, mechanism, and perspectives 原花青素神经保护作用的研究进展：结构、吸收、生物活性、机制及展望。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108082

Yudan Zhao , Hongyuan Lu , Xiaowen Jiang

With the global population growing and aging, along with increasing environmental, metabolic, and lifestyle-related risk factors, the worldwide incidence of stroke, Alzheimer's disease (AD) and other dementias, meningitis, and other neurological disorders-along with associated mortality-has risen significantly. Proanthocyanidins (PCs), which are oligomers and polymers of flavan-3-ols, are widely distributed across the plant kingdom, including in grape seeds, cinnamon, apples, cranberries, lotus seeds, and pine bark. They represent the second most abundant class of polyphenols in nature, after lignin. A substantial body of preclinical evidence indicates that PCs exert significant neuroprotective effects through multiple mechanisms. This review provides a systematic overview of the sources, structural characteristics, and bioavailability of PCs, with a focus on their pharmacological mechanisms in nervous system disease. Specifically, it examines their roles in regulating oxidative stress, neuroinflammation, protein homeostasis, apoptosis, autophagy, and key signaling pathways, including Nrf2/HO-1, CREB/BDNF, PI3K/Akt, MAPK, and NF-κB. Furthermore, this review systematically summarized the distinct structural forms of PCs, including monomers, dimers, trimers, and polymers, and explores their structure-activity relationships (SARs) in modulating the gut-brain axis. Additionally, recent advances in PCS-based nano-delivery systems and clinical studies related to neurological disorders are summarized. Growing evidence indicates that microbial metabolism in the gut serves as a key mechanism underlying their neuroprotective effects. Finally, the potential applications of PCs as promising dietary supplements or therapeutic agents for the prevention and treatment of nervous system diseases are discussed, along with existing challenges and future perspectives.

随着全球人口的增长和老龄化，以及环境、代谢和生活方式相关风险因素的增加，世界范围内中风、阿尔茨海默病（AD）和其他痴呆、脑膜炎和其他神经系统疾病的发病率以及相关死亡率显著上升。原花青素（PCs）是黄烷-3-醇的低聚物和聚合物，广泛分布于植物界，包括葡萄籽、肉桂、苹果、蔓越莓、莲子和松树皮。它们是自然界中含量第二丰富的多酚类物质，仅次于木质素。大量临床前证据表明，pc通过多种机制发挥重要的神经保护作用。本文综述了pc的来源、结构特点和生物利用度，重点介绍了其在神经系统疾病中的药理机制。具体来说，它研究了它们在调节氧化应激、神经炎症、蛋白质稳态、细胞凋亡、自噬和关键信号通路中的作用，包括Nrf2/HO-1、CREB/BDNF、PI3K/Akt、MAPK和NF-κB。此外，本文系统地总结了pc的不同结构形式，包括单体、二聚体、三聚体和聚合物，并探讨了它们在调节肠-脑轴中的构效关系（sar）。此外，总结了基于pc的纳米递送系统的最新进展以及与神经系统疾病相关的临床研究。越来越多的证据表明，肠道中的微生物代谢是其神经保护作用的关键机制。最后，讨论了pc作为有前途的膳食补充剂或治疗药物在预防和治疗神经系统疾病方面的潜在应用，以及存在的挑战和未来的展望。

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引用次数: 0

Targeting PGC-1α axis rescues aberrant development from thyroid hormone defect in brain organoids 靶向PGC-1α轴修复类脑器官甲状腺激素缺陷的异常发育。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108071

Emanuela Bottani , Francesca Ciarpella , Benedetta Lucidi , Giulia Pedrotti , Chiara Santanatoglia , Eros Rossi , Enrica Cappellozza , Elisa De Tomi , Sissi Dolci , Giovanni Malerba , Giorgio Malpeli , Ilaria Decimo

Thyroid hormone (T3) deficiency during central nervous system development leads to severe and often incurable human pathologies, including intellectual disability and motor dysfunction. Using murine dorsal forebrain organoids, we showed that T3 is required to activate mitochondrial β-oxidation and OXPHOS biogenesis to sustain neuronal development, while its absence caused profound neurodevelopmental defects such as defective maturation, astrogliosis, and reduced spontaneous activity. Mechanistically, we identified the transcriptional coactivator PGC-1α as a central mediator of the T3 effect. Pharmacological inhibition of β-oxidation in T3-supplemented organoids recapitulated the T3-deficient phenotype, whereas Ppargc1a gene augmentation rescued neuronal development under T3-deprived conditions. Most importantly, pharmacological stimulation of the PGC-1α axis with Nicotinamide Riboside or Bezafibrate rescues mitochondrial bioenergetics and neuronal development, effectively correcting aberrant brain organoid maturation despite T3 deficiency. These findings reveal for the first time the role of T3 in supporting neurodevelopment via activation of mitochondrial β-oxidation and OXPHOS biogenesis, and identify the PGC-1α axis as a promising therapeutic avenue for otherwise intractable disorders linked to thyroid hormone deficiency.

中枢神经系统发育过程中甲状腺激素（T3）缺乏导致严重且通常无法治愈的人类疾病，包括智力残疾和运动功能障碍。利用小鼠背前脑类器官，我们发现T3是激活线粒体β-氧化和OXPHOS生物发生以维持神经元发育所必需的，而缺乏T3会导致严重的神经发育缺陷，如成熟缺陷、星形胶质增生和自发活性降低。在机制上，我们确定了转录辅激活因子PGC-1α是T3效应的中心介质。在t3补充的类器官中，β-氧化的药理抑制再现了t3缺乏的表型，而Ppargc1a基因的增强则挽救了t3缺乏条件下的神经元发育。最重要的是，用烟酰胺核苷或贝扎菲特对PGC-1α轴进行药理学刺激，可以挽救线粒体生物能量和神经元发育，有效纠正T3缺乏时异常的脑类器官成熟。这些发现首次揭示了T3通过激活线粒体β-氧化和OXPHOS生物发生来支持神经发育的作用，并确定了PGC-1α轴是治疗甲状腺激素缺乏症相关顽固性疾病的有希望的治疗途径。

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引用次数: 0

Functional, synaptoproteomic and structural adaptations underlying sex-dependent traumatic stress susceptibility/resilience in the hippocampus 海马体中性别依赖性创伤应激易感性/恢复力的功能、突触蛋白质组学和结构适应。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108072

Sebastiano A. Torrisi , Maria Rosaria Tropea , Silvia Rizzo , Mattia Giovenzana , Chiara Magri , Alessandro Barbon , Jessica Mingardi , Clizia Chinello , Lisa Pagani , Isabella Piga , Loredana Leggio , Nunzio Iraci , Walter Gulisano , Filippo Drago , Daniela Puzzo , Laura Musazzi , Gian Marco Leggio

Although post-traumatic stress disorder (PTSD) occurs more in women than in men, how sex influences trauma susceptibility remains largely unknown. We developed the arousal-based individual screening (AIS) model, which identifies mice as susceptible/resilient to PTSD-like phenotypes, based on changes in startle reactivity induced by 24-hour-restraint. To test the hypothesis that sex drives trauma susceptibility/resilience, we applied a multidisciplinary approach involving electrophysiological, structural, and synaptoproteomic analyses of the hippocampus in susceptible and resilient mice of both sexes. Female mice were more susceptible to the trauma than male mice and exhibited long-lasting PTSD-like phenotypes. Long-term potentiation (LTP) was impaired in hippocampal slices of both male and female susceptible mice, whereas short-term presynaptic forms of plasticity and vesicle recycling remained unchanged. Increased apical dendritic length and augmented basal dendritic spine density of pyramidal neurons were found in CA1 of male susceptible mice, while decreased dendritic length of granule neurons was uncovered in the dentate gyrus of female resilient mice. Although minor synaptoproteomic changes were observed, bioinformatic analysis suggested sex- and susceptibility/resilience-dependent profiles. Notably, several pathways involving RHO Family GTPases were found to be upregulated exclusively in susceptible male mice. Accordingly, the Rac1/Rac3 GTPases inhibitor EHop-016 rescued the hippocampal LTP impairment in susceptible male mice but not in susceptible female mice. Our findings suggest that the AIS model mirrors sex differences in PTSD susceptibility/resilience highlighting associated functional, molecular and structural alterations. This model may represent a critical first step for studying sex-dependent pathophysiological mechanisms subserving PTSD susceptibility and for sex-tailored drug development.

尽管创伤后应激障碍（PTSD）在女性中的发病率高于男性，但性别如何影响创伤易感性在很大程度上仍然未知。我们开发了基于唤醒的个体筛选（AIS）模型，该模型基于24小时约束诱导的惊吓反应变化来识别小鼠对ptsd样表型的易感性/弹性。为了验证性别驱动创伤易感性/恢复力的假设，我们采用了一种多学科方法，包括电生理、结构和突触蛋白质组学分析了易感性和恢复力小鼠的海马。雌性小鼠比雄性小鼠更容易受到创伤，并表现出持久的ptsd样表型。雄性和雌性易感小鼠海马切片的长期增强（LTP）受损，而短期突触前形式的可塑性和囊泡循环保持不变。在雄性易感小鼠CA1中发现锥体神经元的顶端树突长度增加，基底树突棘密度增加，而在雌性弹性小鼠齿状回中发现颗粒神经元树突长度减少。虽然观察到轻微的突触蛋白质组学变化，但生物信息学分析表明性别和易感性/弹性依赖谱。值得注意的是，一些涉及RHO家族gtpase的途径被发现只在易感雄性小鼠中上调。因此，Rac1/Rac3 GTPases抑制剂Ehop-016对易感雄鼠海马LTP损伤有修复作用，而对易感雌鼠无修复作用。我们的研究结果表明，AIS模型反映了PTSD易感性/恢复力的性别差异，并强调了相关的功能、分子和结构改变。该模型可能是研究PTSD易感性的性别依赖病理生理机制和性别定制药物开发的关键的第一步。

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引用次数: 0

Plasma miR-150–5p as a biomarker for immunosuppressive therapy response in acetylcholine receptor positive myasthenia gravis: a long-term prospective longitudinal study 血浆miR-150-5p作为乙酰胆碱受体阳性重症肌无力免疫抑制治疗反应的生物标志物：一项长期前瞻性纵向研究

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108078

Nemanja Garai , Sanja Madic , Vukan Ivanovic , Aleksa Palibrk , Jovan Pesovic , Milos Brkusanin , Ivana Basta , Stojan Peric , Dusanka Savic-Pavicevic

Insufficient effectiveness and adverse effects of immunosuppressive therapy, seen in around 20 % of acetylcholine receptor (AChR) positive myasthenia gravis (MG) patients, highlight the need for new biomarkers. MicroRNAs (miRNAs), small regulatory non-coding RNAs with tissue-specific expression, have emerged as potential biomarkers due to their abundance and accessibility in body fluids. Several miRNAs involved in immune system and drug metabolism have been associated with improvement of neuromuscular status or response to immunosuppressive therapy in AChR-positive MG patients in cross-sectional studies. Here, we explored miRNAs as plasma biomarkers for immunosuppressive therapy response in a prospective longitudinal study of newly diagnosed, drug-naïve patients. Clinical examination and plasma sampling were performed at three time points: baseline (pre-treatment), 6-month, and 12-month follow-ups. MiRNA levels were quantified by qPCR. Three out of eight analyzed miRNAs (miR-150–5p, miR-27a–3p, and miR-21–5p) showed treatment-related changes. Among them, miR-150–5p level was negatively correlated with patient functionality (MG Activities of Daily Living score – MG-ADL; p = 0.007, ρ_s=−0.433), muscle strength and weakness (Quantitative MG score – QMG; p = 0.002, ρ_s=−0.355) and overall symptoms (MG Composite score – MGC; p = 7.814e-5, ρ_s=−0.457). Pre-treatment miR-150–5p levels showed excellent prognostic ability to discriminate responders from not-responders based on achieved minimal clinical expression (AUC=0.85, p = 0.0076) and MG-ADL (AUC=0.86, p = 0.016) at 12-month follow-up. Predictive performance was also acceptable based on QMG and MGC (AUC=0.74, p = 0.001 and AUC=0.73, p = 0.0002, respectively). Our findings imply plasma miR-150–5p as a potential biomarker for predicting immunosuppressive therapy response in AChR-positive MG, suggesting its further investigation for disease monitoring and a personalized medicine approach.

大约20%的乙酰胆碱受体（AChR）阳性重症肌无力（MG）患者存在免疫抑制治疗的有效性不足和不良反应，这突出了对新的生物标志物的需求。MicroRNAs （miRNAs）是具有组织特异性表达的小调节非编码rna，由于其在体液中的丰度和可及性，已成为潜在的生物标志物。在横断面研究中，一些参与免疫系统和药物代谢的mirna与achr阳性MG患者神经肌肉状态的改善或对免疫抑制治疗的反应有关。在这里，我们在一项新诊断的drug-naïve患者的前瞻性纵向研究中探索了miRNAs作为免疫抑制治疗反应的血浆生物标志物。临床检查和血浆采样在三个时间点进行：基线（治疗前），6个月和12个月的随访。qPCR检测miRNA水平。8个分析的mirna中有3个（miR-150-5p， miR-27a-3p和miR-21-5p）显示出与治疗相关的变化。其中，miR-150-5p水平与患者功能（MG日常生活活动评分- MG- adl， p=0.007, ρs=-0.433）、肌肉力量和无力（MG定量评分- QMG， p=0.002, ρs=-0.355）、整体症状（MG综合评分- MGC， p= 7.814e-5, ρs=-0.457）呈负相关。根据12个月随访时达到的最小临床表达（AUC=0.85, p=0.0076）和MG-ADL (AUC=0.86, p=0.016)，治疗前miR-150-5p水平显示出区分应答者和无应答者的良好预后能力。基于QMG和MGC的预测性能也可以接受（AUC分别=0.74,p=0.001和AUC=0.73, p=0.0002）。我们的研究结果表明，血浆miR-150-5p是预测achr阳性MG患者免疫抑制治疗反应的潜在生物标志物，建议进一步研究其用于疾病监测和个性化医疗方法。

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引用次数: 0

Corrigendum to “Epigenetic regulation in calcific aortic valve disease: Mechanisms and therapeutic potential” [Pharmacol. Res. (2025) 223 108073] “钙化主动脉瓣疾病的表观遗传调控：机制和治疗潜力”的勘误表[Pharmacol]。Res.(2025) 223 108073]。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108083

Hanshen Luo, Yuehang Yang, Chiyang Xie, Chuli Shi, Siyuan Liu, Jiawei Shi

引用次数: 0

Corrigendum to “Tagitinin F has anti-inflammatory, anti-nociceptive and anti-matrix metalloproteinase properties: An in silico, in vitro and in vivo study” [Pharmacol. Res. 164 (2021) 105303] “他吉宁F具有抗炎、抗伤害和抗基质金属蛋白酶特性：一项硅、体外和体内研究”的勘误表[Pharmacol]。Res. 164(2021)[105303]。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108070

Laíla Pereira Silva , Eliziária Cardoso Santos , Bruno Arantes Borges , Marcia Paranho Veloso , Daniela Aparecida Chagas-Paula , Reggiani Vilela Gonçalves , Rômulo Dias Novaes

引用次数: 0

Mitochondrial pyruvate dehydrogenase kinase 1 drives bevacizumab resistance and malignant phenotype of TNBC by enhancing mitophagy 线粒体丙酮酸脱氢酶激酶1通过增强线粒体自噬驱动TNBC的贝伐单抗耐药和恶性表型。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-31 DOI: 10.1016/j.phrs.2025.108081

Yan Ye , Qian Zeng , Zuli Ou , Xiaoqian Ju , Qingyu Liao , Canling Li , Dian Zhang , Yu Wei , Xiang Zhang , Kejia Wu , Tingmei Chen

Bevacizumab is an anti-angiogenic agent widely used in neoadjuvant chemotherapy for advanced triple-negative breast cancer (TNBC). TNBC patients frequently acquire resistance to bevacizumab due to the hypoxic tumor microenvironment, yet the underlying molecular mechanism remains unclear. Here, we demonstrate that mitochondrial reprogramming under hypoxia is crucial for resistance to bevacizumab. Mechanically, prolonged hypoxia causes the glycolytic pathway enzyme PDK1 to accumulate inside mitochondria. In mitochondria, PDK1 exerts its non-canonical function to phosphorylate mitochondrial protein Prohibitin 2 (PHB2) at Ser190. Phosphorylation at Ser190 stabilizes PHB2 and enhances its binding with LC3, thereby initiating mitophagy. Functionally, mitochondrial PDK1 (mito-PDK1) initiates mitophagy in response to hypoxia-induced mitochondrial damage and promotes the malignant phenotype of TNBC cells. In xenograft tumors, inhibiting the function of mito-PDK1 enhances the sensitivity to bevacizumab. Collectively, our findings identify the crucial function and mechanism of mito-PDK1 in TNBC. Targeting mito-PDK1 function may emerge as a novel therapeutic strategy to address acquired resistance to bevacizumab.

贝伐单抗是一种抗血管生成药物，广泛用于晚期三阴性乳腺癌（TNBC）的新辅助化疗。由于肿瘤微环境缺氧，TNBC患者经常获得对贝伐单抗的耐药，但其潜在的分子机制尚不清楚。在这里，我们证明了缺氧条件下线粒体重编程对贝伐单抗耐药性至关重要。机械上，长时间的缺氧导致糖酵解途径酶PDK1在线粒体内积聚。在线粒体中，PDK1发挥其非规范功能，使线粒体蛋白禁止蛋白2 （PHB2）在Ser190位点磷酸化。Ser190磷酸化稳定PHB2并增强其与LC3的结合，从而启动有丝分裂。在功能上，线粒体PDK1 （mito-PDK1）启动线粒体自噬以应对缺氧诱导的线粒体损伤，并促进TNBC细胞的恶性表型。在异种移植物肿瘤中，抑制mitto - pdk1的功能可增强对贝伐单抗的敏感性。总的来说，我们的研究结果确定了mito-PDK1在TNBC中的关键功能和机制。靶向mitto - pdk1功能可能成为解决贝伐单抗获得性耐药的新治疗策略。

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引用次数: 0

Low, non-psychedelic doses of psilocybin as a novel treatment for MASLD, obesity and type 2 diabetes via 5-HT2B receptor-dependent mechanisms 低剂量、非致幻剂裸盖菇素通过5-HT2B受体依赖机制作为MASLD、肥胖和2型糖尿病的新治疗方法。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-29 DOI: 10.1016/j.phrs.2025.108080

Martina Colognesi , Daniela Gabbia , Anna Signor , Miles Sarill , Lucia Centofanti , Andrea Rinaldi , Luciano Cascione , Sara Nunziata , Marco Banzato , Andrea Mattarei , Giovanna Finzi , Sonia Sonda , Diana Pendin , Ilaria Zanotto , Stefano Comai , Gianfranco Pasut , Abdullah Alajati , Miriam Saponaro , Loredana Bucciarelli , Maria Elena Lunati , Sara De Martin

The therapeutic potential of low, non-psychedelic doses of psilocybin, a fungal tryptamine alkaloid, was investigated in metabolic disorders including obesity, type 2 diabetes mellitus (T2DM), and liver steatosis. Mice fed a high-fat/high-fructose diet received chronic treatment with psilocybin (0.05 mg/kg) for 12 weeks. Body weight, liver histology, insulin sensitivity, and skeletal muscle function were assessed, and hepatic and muscle tissues underwent transcriptomic and lipidomic analyses. The role of three serotonin receptors (5-HT2A, 5-HT2B, and 5-HT2C) in psilocybin-induced metabolic effects was examined in human cell lines using pharmacological and CRISPR/Cas9-based genetic approaches. Low-dose psilocybin reduced body-weight gain, liver steatosis, hyperglycaemia, and insulin resistance without eliciting central nervous system effects. Multi-omics analyses revealed near-complete normalization of disrupted hepatic lipid and carbohydrate metabolism pathways. Psilocybin also improved muscle strength and function, potentially through restoration of leptin sensitivity. Mechanistic studies demonstrated that these metabolic benefits were independent of the canonical psychedelic target 5-HT2A and instead resulted from antagonism of the serotonin 5-HT2B receptor in the liver. Overall, chronic low-dose psilocybin exerts broad metabolic benefits via a hepatic 5-HT2B-dependent mechanism, distinct from its psychedelic effects, supporting its potential as a novel therapeutic strategy for liver steatosis, obesity, T2DM, and sarcopenia.

低剂量的非致幻剂裸盖菇素（一种真菌色胺生物碱）治疗代谢紊乱包括肥胖、2型糖尿病（T2DM）和肝脂肪变性的潜力进行了研究。饲喂高脂肪/高果糖饮食的小鼠给予裸盖菇素（0.05mg/kg）慢性治疗12周。评估体重、肝脏组织学、胰岛素敏感性和骨骼肌功能，并对肝脏和肌肉组织进行转录组学和脂质组学分析。在人类细胞系中，使用药理学和基于CRISPR/ cas9的遗传方法检测了三种5-羟色胺受体（5-HT2A、5-HT2B和5-HT2C）在裸盖菇素诱导的代谢效应中的作用。低剂量裸盖菇素可减少体重增加、肝脂肪变性、高血糖和胰岛素抵抗，而不会引起中枢神经系统的影响。多组学分析显示，肝脏脂质和碳水化合物代谢途径几乎完全正常化。裸盖菇素还能改善肌肉力量和功能，可能是通过恢复瘦素敏感性来实现的。机制研究表明，这些代谢益处与典型的迷幻靶点5-HT2A无关，而是由肝脏中5-HT2B受体的5-羟色胺的拮抗作用引起的。总的来说，慢性低剂量裸盖菇素通过肝脏5- ht2b依赖机制发挥广泛的代谢益处，不同于其迷幻作用，支持其作为肝脏脂肪变性、肥胖、2型糖尿病和肌肉减少症的新治疗策略的潜力。

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引用次数: 0

PHGDH as a therapeutic node: Natural modulators from TCM, degradation pathways, and emerging TPD strategies PHGDH作为治疗节点：来自中医的天然调节剂、降解途径和新兴的TPD策略。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-23 DOI: 10.1016/j.phrs.2025.108079

Song-Song Shi , Yu-Dan Du , Si-Yi Chen , Wen Zhang , Guo-Wu Rao , Quan Zheng

Phosphoglycerate dehydrogenase (PHGDH) has emerged as a promising therapeutic target due to its critical roles in the pathogenesis of cancer and neurological disorders. Targeting PHGDH holds significant theoretical and translational potential for cancer therapy and the amelioration of cognitive impairments. However, currently available PHGDH inhibitors are limited in number and primarily function through inhibition of the enzyme's catalytic activity. This review systematically summarizes PHGDH modulators identified from traditional Chinese medicine, including both inhibitors and activators, and presents a detailed analysis of their structure–activity relationships (SAR) and mechanisms of action. It also comprehensively outlines the signaling pathways that regulate PHGDH degradation through the ubiquitin–proteasome system and autophagy–lysosome pathway. Importantly, it also discusses emerging targeted protein degradation (TPD) technologies, including PROTACs, LYTACs, AUTACs, and ATTECs. The development of these frontier technologies has opened new pathways for mitigating the limitations of existing inhibitors.

磷酸甘油酸脱氢酶（Phosphoglycerate dehydrogenase， PHGDH）由于在癌症和神经系统疾病的发病机制中起着关键作用而成为一个有希望的治疗靶点。靶向PHGDH在癌症治疗和改善认知障碍方面具有重要的理论和转化潜力。然而，目前可用的PHGDH抑制剂数量有限，主要通过抑制酶的催化活性起作用。本文系统综述了中药中发现的PHGDH调节剂，包括抑制剂和激活剂，并详细分析了它们的构效关系（SAR）和作用机制。它还全面概述了通过泛素-蛋白酶体系统和自噬-溶酶体途径调节PHGDH降解的信号通路。重要的是，它还讨论了新兴的靶向蛋白降解（TPD）技术，包括PROTACs， lytac， autac和attec。这些前沿技术的发展为减轻现有抑制剂的局限性开辟了新的途径。

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引用次数: 0

Multi-target neuroprotective effects of notoginsenoside R1 in neurodegenerative diseases: From pharmacokinetics to translational prospects 三七皂苷R1在神经退行性疾病中的多靶点神经保护作用：从药代动力学到转化前景。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-18 DOI: 10.1016/j.phrs.2025.108074

Hao-wen Lin , Shi-pian Li , Jia-xin Wen , Jia-xuan Zhang , Bi-meng Zhang , Yong-jun Wang , Xue-jun Cui , Min Yao

Neurodegenerative diseases impose a heavy social and economic burden, and effective therapeutic strategies are essential for slowing disease progression and improving patient quality of life. Notoginsenoside R1 (NGR1), a key saponin derived from Panax notoginseng (Burk. F.H. Chen), has been widely studied in experimental models of neurodegenerative diseases, such as stroke and Alzheimer’s disease (AD). Based on a rigorous literature screening and a meta-analysis of animal studies, we confirmed that NGR1 significantly reduces infarct volumes in cerebral ischemia-reperfusion models and improves escape latency in AD mice. Mechanistically, NGR1 confers neuroprotection by attenuating oxidative stress, suppressing neuroinflammation, inhibiting apoptosis, and preserving the neurovascular unit. Furthermore, using network pharmacology, reverse virtual screening, and molecular docking, we preliminarily identified potential targets and signaling pathways, providing a theoretical basis for future studies. However, clinical translation of NGR1 remains limited due to poor oral bioavailability and restricted permeability across the blood-brain and blood-spinal cord barriers. To address these challenges, we summarized delivery strategies, including nanoparticle-based carriers, intranasal administration, and permeability enhancers, to facilitate NGR1 entry into the central nervous system. We also discussed additional potential approaches, such as structural modification and targeted delivery, analyzing their respective advantages and limitations. Collectively, these findings highlight NGR1 as a promising candidate for the prevention and treatment of neurodegenerative diseases.

神经退行性疾病造成沉重的社会和经济负担，有效的治疗策略对于减缓疾病进展和改善患者生活质量至关重要。三七皂苷R1 （NGR1）是一种从三七中提取的关键皂苷。在神经退行性疾病，如中风和阿尔茨海默病（AD）的实验模型中得到了广泛的研究。基于严格的文献筛选和动物研究的荟萃分析，我们证实NGR1显著减少脑缺血再灌注模型中的梗死体积，并改善AD小鼠的逃避潜伏期。从机制上讲，NGR1通过减轻氧化应激、抑制神经炎症、抑制细胞凋亡和保存神经血管单位来提供神经保护。通过网络药理学、反向虚拟筛选、分子对接等手段，初步确定了潜在靶点和信号通路，为后续研究提供理论基础。然而，由于口服生物利用度差以及血脑和血脊髓屏障的渗透性有限，NGR1的临床转化仍然有限。为了解决这些挑战，我们总结了递送策略，包括纳米颗粒载体、鼻内给药和渗透性增强剂，以促进NGR1进入中枢神经系统。我们还讨论了其他可能的方法，如结构改造和定向输送，分析了各自的优势和局限性。总的来说，这些发现突出了NGR1作为预防和治疗神经退行性疾病的有希望的候选者。

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引用次数: 0