Pharmacological research最新文献_第10页

Overcoming ELDR-mediated cancer cell survival in vitro and in vivo via sphingomyelin-driven TRPML1 inactivation and TFEB suppression through lysosomal HSP70 targeting 通过鞘磷脂驱动的TRPML1失活和通过溶酶体HSP70靶向抑制TFEB，克服eldr介导的癌细胞体外和体内存活

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108050

Hongyu Chen , Mengyuan Zhu , Ziying Zhao , Yuexin Jiang , Haidi Wang , Yu Liu , Yan Chen , Hui Li , Chen Xun , Hui Hui

Lysosomal adaptation through the endo-lysosomal damage response (ELDR) enables cancer cells to evade lysosome-targeted therapies. Here, we identified the flavonoid compound V8 as a first-in-class ELDR disruptor that eliminated cancer cells by sabotaging lysosomal resilience. Mechanistically, V8 bound lysosomal HSP70 via hydrogen bonding, destabilizing its interaction with bis(monoacylglycero)phosphate (BMP) and triggering pathological sphingomyelin (SM) accumulation. SM overload allosterically inhibited TRPML1, blocking calcineurin PPP3CB activation and subsequent TFEB dephosphorylation. This dual perturbation: enhanced lysophagy and failed TFEB-driven biogenesis drove catastrophic lysosomal bankruptcy. Crucially, V8 bypassed canonical ELDR activation: unlike lysosomotropic agent LLOMe, it induced global membrane remodeling rather than focal perforations, avoiding Ca²⁺-dependent endosomal sorting complexes required for transport (ESCRT) repair. Genetic validation using HSP70-knockout and point mutation models confirmed target specificity, while SM synthase inhibition rescued TRPML1 activity and mitigated apoptosis. Tumor-selective efficacy arose from malignant cells’ heightened SM dependency and lysosomal HSP70 reliance, sparing normal counterparts. Our work established HSP70-BMP-ASM axis disruption as a strategy to subvert lysosomal homeostasis, providing a blueprint for next-generation lysosome-targeting agents that exploit lipid-mediated channelopathy to sensitize cancer cells to lysosomal damage.

通过内溶酶体损伤反应（ELDR）的溶酶体适应使癌细胞逃避溶酶体靶向治疗。在这里，我们确定了类黄酮化合物V8作为一流的ELDR干扰物，通过破坏溶酶体的弹性来消除癌细胞。在机制上，V8通过氢键结合溶酶体HSP70，破坏其与BMP（单酰基甘油）磷酸（BMP）的相互作用，引发病理性鞘磷脂（SM）积累。SM超载变构性地抑制TRPML1，阻断钙调磷酸酶PPP3CB的激活和随后的TFEB去磷酸化。这种双重扰动：溶体吞噬增强和tfeb驱动的生物发生失败，导致了灾难性的溶酶体破产。关键是，V8绕过了典型的ELDR激活：与溶酶体增溶剂LLOMe不同，它诱导了全局膜重构，而不是局部穿孔，避免了运输（ESCRT）修复所需的Ca 2 +依赖的内体分选复合物。使用hsp70敲除和点突变模型进行的遗传验证证实了靶特异性，而SM合成酶抑制可挽救TRPML1活性并减轻细胞凋亡。肿瘤选择性疗效源于恶性细胞对SM的高度依赖和对溶酶体HSP70的依赖，而正常细胞则不受影响。我们的工作建立了HSP70-BMP-ASM轴破坏作为一种破坏溶酶体稳态的策略，为下一代溶酶体靶向药物提供了蓝图，这些药物利用脂质介导的通道病变使癌细胞对溶酶体损伤敏感。

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引用次数: 0

Selective HDAC6 inhibition by Mesinostat impairs tumor growth and stemness in triple-negative breast cancer Mesinostat选择性抑制HDAC6影响三阴性乳腺癌的肿瘤生长和干性

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108055

Ivana Bello , Simona Barone , Anna Guadagni, Camilla Esposito, Morena D’Ariano, Martina Smimmo, Giuseppe Cirino, Vincenzo Summa, Margherita Brindisi , Elisabetta Panza

Triple-negative breast cancer (TNBC) remains the most aggressive breast cancer subtype, accounting for over half of breast cancer-related deaths. In the era of precision oncology, epigenetic dysregulation has emerged as a key driver of breast tumorigenesis. Among epigenetic targets, histone deacetylase 6 (HDAC6) has attracted increasing attention due to its cytoplasmic localization and regulation of non-histone substrates such as Hsp90, α-tubulin, and cortactin. We recently identified a novel class of spirocyclic molecules as potent and selective HDAC6 inhibitors. Here, we investigated the pharmacological profile of Mesinostat, one of the most selective compounds of this series, in human TNBC cell lines, 3D spheroids, and patient-derived organoids (PDOs) from lymph node metastases. In TNBC cells, using western blot analysis, we demonstrated that Mesinostat (1–30 µM) selectively inhibited HDAC6 by increasing acetylated α-tubulin levels, with no effect on the histone H3 acetylation. Yet, Mesinostat markedly reduced cell proliferation through apoptosis, cell cycle arrest, and autophagy. Furthermore, it inhibited epithelial-mesenchymal transition, decreased cell migration, and disrupted spheroid integrity. Treatment of PDOs led to a dose-dependent reduction in viability and clonogenic capacity, accompanied by downregulation of stemness and proliferation markers. Overall, these findings demonstrate that selective HDAC6 inhibition by Mesinostat modulates key oncogenic pathways in TNBC, supporting its potential as a promising therapeutic approach for HDAC6-overexpressing breast cancers.

三阴性乳腺癌（TNBC）仍然是最具侵袭性的乳腺癌亚型，占乳腺癌相关死亡人数的一半以上。在精准肿瘤学时代，表观遗传失调已成为乳腺肿瘤发生的关键驱动因素。在表观遗传靶点中，组蛋白去乙酰化酶6 （HDAC6）因其细胞质定位和调控非组蛋白底物如Hsp90、α-微管蛋白和内联蛋白而受到越来越多的关注。我们最近发现了一类新的螺旋环分子作为有效的和选择性的HDAC6抑制剂。在这里，我们研究了Mesinostat（该系列中最具选择性的化合物之一）在人类TNBC细胞系、3D球体和来自淋巴结转移的患者源性类器官（PDOs）中的药理学特征。在TNBC细胞中，使用western blot分析，我们证明Mesinostat（1-30µM）通过增加乙酰化α-微管蛋白水平选择性抑制HDAC6，而对组蛋白H3乙酰化没有影响。然而，Mesinostat通过凋亡、细胞周期阻滞和自噬显著降低细胞增殖。此外，它抑制上皮-间质转化，减少细胞迁移，破坏球体完整性。PDOs的治疗导致细胞活力和克隆生成能力的剂量依赖性降低，并伴有干性和增殖标志物的下调。总的来说，这些发现表明，Mesinostat选择性抑制HDAC6可调节TNBC中关键的致癌途径，支持其作为HDAC6过表达乳腺癌治疗方法的潜力。

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引用次数: 0

Proteolysis targeting chimera degraders target pseudokinases to treat metabolic dysfunction-associated steatohepatitis and fibrosis: Mechanisms and therapeutic insights 靶向嵌合体降解物的蛋白水解靶向假激酶治疗代谢功能障碍相关的脂肪性肝炎和纤维化：机制和治疗见解。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108054

Yibing Wang , Jiajing Peng

Metabolic dysfunction-associated steatohepatitis (MASH, previously NASH) is the severe type of metabolic dysfunction-associated steatotic liver disease (MASLD, previously NAFLD), the most common liver condition. The excessive hepatic lipid accumulation triggers apoptosis of hepatocytes and lobular inflammation, which are the key features of MASH. MASH may develop into liver fibrosis, while current therapeutics exhibit limited responses in patients. Identification of novel upstream regulators for both hepatic inflammation and fibrosis holds great promise to treat MASH and liver fibrosis. Pseudokinases, which contain the pseudokinase domains without kinase activity, are hub genes that integrate the signaling pathways of cell death, inflammation and fibrosis in the liver. We critically analyze the STAT and other signaling pathways through which JAK1, JAK2 (kinases with pseudokinase domains), TRIB2, MLKL and IRAK-M regulate the progression of MASH and liver fibrosis. Collectively, pseudokinases are potential therapeutic targets for treating MASH and liver fibrosis. Although the pseudokinase inhibitors show effectively treat inflammatory diseases, specific and safe pseudokinase inhibitors are understudied. Proteolysis targeting chimeras (PROTACs) are rapidly evolved bifunctional molecules that efficiently bind to and catalytically degrade the target proteins via recruiting E3 ubiquitin ligases. We discuss the design, selectivity, and limitations of pseudokinase PROTACs, and present the most active lead PROTACs that may treat MASH and liver fibrosis at distinct stages. Furthermore, innovative strategies enhance PROTACs’ efficacy through addressing the main translational hurdles, especially the low bioavailability and cellular uptake. It facilitates the development of PROTACs to probe in vivo function of pseudokinases and to combat MASH and liver fibrosis.

代谢功能障碍相关脂肪性肝炎（MASH，以前称为NASH）是代谢功能障碍相关脂肪性肝病（MASLD，以前称为NAFLD）的严重类型，是最常见的肝脏疾病。过度的肝脂质积累引发肝细胞凋亡和小叶炎症，这是MASH的主要特征。MASH可能发展为肝纤维化，而目前的治疗方法对患者的反应有限。鉴定出肝脏炎症和纤维化的新型上游调节因子对治疗MASH和肝纤维化具有很大的希望。假激酶是整合肝脏细胞死亡、炎症和纤维化信号通路的枢纽基因，它包含无激酶活性的假激酶结构域。我们批判性地分析了STAT和其他JAK1， JAK2（具有假激酶结构域的激酶），TRIB2， MLKL和IRAK-M调节MASH和肝纤维化进展的信号通路。总的来说，假激酶是治疗MASH和肝纤维化的潜在治疗靶点。虽然假激酶抑制剂能有效治疗炎症性疾病，但特异性和安全性的假激酶抑制剂还有待研究。蛋白水解靶向嵌合体（Proteolysis targeting chimeras, PROTACs）是一种快速进化的双功能分子，通过招募E3泛素连接酶有效结合并催化降解靶蛋白。我们讨论了假激酶PROTACs的设计、选择性和局限性，并提出了可能在不同阶段治疗MASH和肝纤维化的最活跃的PROTACs导联。此外，创新策略通过解决主要的转化障碍，特别是低生物利用度和细胞摄取来提高PROTACs的功效。它促进了PROTACs的发展，以探测假激酶的体内功能，并对抗MASH和肝纤维化。

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引用次数: 0

Effect of esketamine on postoperative depression and anxiety in patients undergoing cardiac valve surgery: A randomised, placebo-controlled, double-blinded clinical trial 艾氯胺酮对心脏瓣膜手术患者术后抑郁和焦虑的影响：一项随机、安慰剂对照、双盲临床试验

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108047

Zhuo-Ning Zhang , Xin-Yu Hao , Chen Cai , Li Sun , Zi-Yi Zhang , Miao Wang , Yi-Shuang Wu , Ying Wang , Jiang-Bei Cao , Yan-Hong Liu , Jing-Sheng Lou , Qiang Fu , Sheng-Li Jiang , Ru-Quan Han , Wei-Dong Mi , Li Tong

This randomized, double-blind, parallel-group trial evaluated the efficacy of a single intravenous dose of esketamine (0.3 mg/kg) administered at anesthesia induction in reducing postoperative depression and anxiety among patients undergoing cardiac valve surgery. A total of 142 patients from three centers were randomly assigned to receive esketamine or saline. The primary outcomes were the prevalence of depression and anxiety at postoperative day (POD) 7, assessed by the Hospital Anxiety and Depression Scale (HADS). Key secondary outcomes included delirium incidence, pain and insomnia scores, and quality of recovery. Results showed that the esketamine group had significantly lower rates of depression (7.0 % vs. 31.0 %; P < 0.001) and anxiety (11.3 % vs. 35.2 %; P < 0.001) at POD 7, along with reduced delirium incidence (9.8 % vs. 22.5 %; P = 0.040). Improvements were also observed in pain, sleep, and recovery quality. Mechanistic analyses revealed that esketamine reduced inflammatory markers (IL-6, CRP) and neuronal injury marker (S100β), while increasing brain-derived neurotrophic factor (BDNF). No significant differences in adverse events were observed. In conclusion, a single low dose of esketamine during induction effectively alleviates early postoperative depression and anxiety, possibly through modulating neuroinflammation and promoting neurotrophic signaling. (Clinicaltrials.gov, ID Number: NCT06608030).

这项随机、双盲、平行组试验评估了麻醉诱导时单次静脉注射艾氯胺酮（0.3mg/kg）减轻心脏瓣膜手术患者术后抑郁和焦虑的疗效。来自三个中心的142名患者被随机分配接受艾氯胺酮或生理盐水治疗。主要结局是术后当天抑郁和焦虑的发生率（POD） 7，由医院焦虑和抑郁量表（HADS）评估。主要的次要结局包括谵妄发生率、疼痛和失眠评分以及恢复质量。结果显示，艾氯胺酮组抑郁发生率明显低于对照组(7.0% vs. 31.0%

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引用次数: 0

A broad-spectrum anti-angiogenic tetrapeptide regresses diabetic retinopathy through β-arrestin-1 binding and prevention of Akt phosphorylation 广谱抗血管生成四肽通过β-arrestin-1结合和预防Akt磷酸化来逆转糖尿病视网膜病变

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-11-20 DOI: 10.1016/j.phrs.2025.108042

Alberto Zani , Antonella Bugatti , Eleonora Maceroni , Melissa Duheric , Matteo Uggeri , Ekta Manocha , Marta Bertelli , Michele d'Angelo , Annamaria Cimini , Francesca Caccuri , Arnaldo Caruso

Proliferative diabetic retinopathy (DR) is characterized by neovascularization which can lead to neovascular glaucoma, retinal detachment and blindness. To date, the treatment of DR consists in the intravitreal injection of anti-VEGF antibody (Ab), the only drug currently approved for DR therapy. U94, the latency protein of the human herpesvirus type 6, is endowed with anti-angiogenic activity on human endothelial cells. Here, we identify the tetrapeptide KDKY as the U94 functional epitope. It displays a broad-spectrum anti-angiogenic activity by binding to the intracellular protein β-arrestin-1 and preventing Akt phosphorylation, thus impairing activation of the main pro-angiogenic pathway. A single intravitreal administration of the KDKY peptide showed therapeutic efficacy against DR in a streptozotocin-induced diabetes mouse model. The KDKY in vivo potency was similar to that exerted by anti-VEGF Ab. Overall, our data highlight the possible use of KDKY as a minimalist drug in developing promising new DR therapeutic strategies.

增殖性糖尿病视网膜病变（DR）以新生血管形成为特征，可导致新生血管性青光眼、视网膜脱离和失明。迄今为止，DR的治疗包括玻璃体内注射抗vegf抗体（Ab），这是目前唯一被批准用于DR治疗的药物。人6型疱疹病毒的潜伏期蛋白U94对人内皮细胞具有抗血管生成活性。在这里，我们确定了四肽KDKY作为U94的功能表位。它通过与细胞内蛋白β-arrestin-1结合并阻止Akt磷酸化，从而损害主要促血管生成途径的激活，从而显示出广谱的抗血管生成活性。在链脲佐菌素诱导的糖尿病小鼠模型中，单次玻璃体内注射KDKY肽显示出对DR的治疗效果。KDKY在体内的效力与抗vegf抗体相似。总的来说，我们的数据强调了KDKY作为一种极简药物在开发有前景的新DR治疗策略中的可能性。

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引用次数: 0

Pyrazolone-based ERO1 inhibitors in ERO1-driven triple-negative breast cancer and SEPN1-related myopathy: Structure–activity relationship and therapeutic potential 吡唑啉酮类ERO1抑制剂在ERO1驱动的三阴性乳腺癌和sepn1相关肌病中的作用：结构-活性关系和治疗潜力

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-11-19 DOI: 10.1016/j.phrs.2025.108037

Michele Retini , Alessandro Cherubini , Alice Marrazza , Ersilia Varone , Serena Germani , Giorgia Maria Renna , Adriano Recchia , Andrea Guidarelli , Stefano Fumagalli , Chiara Grasselli , Michele Mari , Giovanni Piersanti , Giovanni Bottegoni , Roberto Tonelli , Marco Gobbi , Bo-Ram Jin , Jaehyung Cho , Orazio Cantoni , Ester Zito

Endoplasmic reticulum oxidoreductin 1 alpha (ERO1A) is a disulfide oxidase that facilitates oxidative protein folding by reoxidizing protein disulfide isomerase (PDI), a process essential for maintaining endoplasmic reticulum (ER) homeostasis. Under ER stress, ERO1A expression is upregulated via the unfolded protein response (UPR), promoting cell survival. However, sustained ERO1A activity can impair proteostasis and contribute to disease. Notably, ERO1A is overexpressed in triple-negative breast cancer (TNBC), where it supports tumor growth and adaptation to hypoxia, and in SEPN1-related myopathy, a rare congenital muscle disorder linked to ER and oxidative stress. To investigate ERO1A as a therapeutic target, we conducted a structure–activity relationship (SAR) study of EN460-based pyrazolone inhibitors. Forty derivatives and three EN460 salts were synthesized to optimize potency and solubility. In vitro and cell-based assays revealed that effective inhibition required covalent binding to Cys397, interactions with Arg287 and Trp200, and distortion of the phenyl ring. While sulfonic acid substitution improved solubility, it abolished activity by disrupting key interactions. The most potent compound, I29, featuring a mono ortho-fluorine substitution, demonstrated improved inhibitory activity (IC₅₀ = 2.6 µM) and efficacy in preclinical models of TNBC and SEPN1-related myopathy. These findings highlight ERO1A’s pathological role in cancer and congenital muscle disease and support its inhibition as a promising therapeutic strategy for conditions characterized by chronic ER and oxidative stress.

内质网氧化还原蛋白1 α (ERO1A)是一种二硫氧化酶，通过氧化蛋白二硫异构酶（PDI）来促进氧化蛋白折叠，这是维持内质网（ER）稳态所必需的过程。在内质网应激下，ERO1A的表达通过未折叠蛋白反应（UPR）上调，促进细胞存活。然而，持续的ERO1A活性会损害蛋白质平衡并导致疾病。值得注意的是，ERO1A在三阴性乳腺癌（TNBC）和sepn1相关的肌病（一种与内质网和氧化应激相关的罕见先天性肌肉疾病）中过表达，其中它支持肿瘤生长和对缺氧的适应。为了研究ERO1A作为治疗靶点，我们对基于en460的吡唑酮抑制剂进行了构效关系（SAR）研究。合成了40种衍生物和3种EN460盐，以优化其效价和溶解度。体外和细胞实验表明，有效抑制需要与Cys397共价结合，与Arg287和Trp200相互作用，以及苯环扭曲。虽然磺酸取代提高了溶解度，但它通过破坏关键的相互作用而取消了活性。最有效的化合物I29具有单正氟取代，在TNBC和sepn1相关肌病的临床前模型中表现出更好的抑制活性（IC₅₀= 2.6µM）和功效。这些发现强调了ERO1A在癌症和先天性肌肉疾病中的病理作用，并支持其抑制作为一种有希望的治疗策略，以慢性内质网和氧化应激为特征。

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引用次数: 0

Adaptive immunity in osteoarthritis: Mechanisms and opportunities for regulatory T-cell–targeted therapy 骨关节炎的适应性免疫：调节性t细胞靶向治疗的机制和机会。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-11-19 DOI: 10.1016/j.phrs.2025.108041

Xueyou Zhang , Mingde Cao , Bruma Sai-Chuen FU , Jian-Quan Wang , Michael Tim-Yun Ong , Patrick Shu-Hang Yung

Osteoarthritis (OA) affects over 500 million individuals globally and currently lacks effective disease-modifying therapies. Although chronic synovial inflammation is recognized as a central driver of joint damage, clinical trials targeting IL-1β, TNF, and related inflammatory pathways have shown limited benefit, suggesting that immune dysregulation in OA extends beyond innate mechanisms. Emerging evidence highlights a role for adaptive immunity, particularly regulatory T (T_reg) cells, as potential targets for immunomodulation. This review critically examines the contribution of adaptive immune responses to OA, emphasizing synovial T_reg cells and their therapeutic potential. Clinical, experimental, and genetic studies consistently reveal infiltration of antigen-experienced T and B lymphocytes, evidence of clonal expansion, autoantibody generation, and robust local antigen-presenting activity in OA joints. Synovial T_reg cells are detectable throughout the disease course, exhibiting tissue-resident and activated phenotypes. Clinical observations and Mendelian randomization analyses further indicate a protective role for CD25⁺ T_reg cells. However, critical questions remain regarding their functional stability, antigen specificity, and immunoregulatory capabilities within OA joints. Insights from other inflammatory diseases point to several mechanistic avenues through which T_reg cells could mediate therapeutic benefit, offering substantial yet untested opportunities for translation into the OA context. In conclusion, accumulating evidence underscores a significant role for sustained adaptive immune activity in OA pathogenesis. Despite the consistent presence of synovial T_reg cells, their precise immunological functions remain unresolved. Defining the antigen specificity, suppressive capacity, and functional stability of these cells is essential for evaluating their therapeutic potential as targets for innovative immune-based disease-modifying strategies in OA.

骨关节炎（OA）影响全球超过5亿人，目前缺乏有效的疾病改善疗法。尽管慢性滑膜炎症被认为是关节损伤的主要驱动因素，但针对IL-1β、TNF和相关炎症途径的临床试验显示益处有限，这表明OA中的免疫失调超出了先天机制。新出现的证据强调了适应性免疫，特别是调节性T （Treg）细胞作为免疫调节的潜在靶标的作用。这篇综述批判性地探讨了适应性免疫反应对OA的贡献，强调了滑膜Treg细胞及其治疗潜力。临床、实验和遗传学研究一致表明，OA关节中存在抗原经历的T淋巴细胞和B淋巴细胞浸润、克隆扩增、自身抗体产生和强大的局部抗原呈递活性。滑膜Treg细胞在整个疾病过程中都可检测到，表现出组织驻留和活化表型。临床观察和孟德尔随机化分析进一步表明CD25 + Treg细胞具有保护作用。然而，关于它们在OA关节中的功能稳定性、抗原特异性和免疫调节能力的关键问题仍然存在。来自其他炎症性疾病的见解指出了Treg细胞介导治疗益处的几种机制途径，为将其转化为OA提供了大量尚未经过测试的机会。总之，越来越多的证据强调了持续的适应性免疫活性在OA发病机制中的重要作用。尽管始终存在滑膜Treg细胞，但其精确的免疫功能仍未解决。确定这些细胞的抗原特异性、抑制能力和功能稳定性对于评估它们作为OA创新免疫疾病修饰策略靶点的治疗潜力至关重要。

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引用次数: 0

Feeding difficulties, eating disorders and therapeutic approaches in autism spectrum disorder: An overview 自闭症谱系障碍的进食困难、进食障碍和治疗方法综述。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-11-17 DOI: 10.1016/j.phrs.2025.108040

Martina Siracusano , Lucrezia Arturi , Assia Riccioni , Alessandro Medoro , Rosa Savino , Giovanni Scapagnini , Sergio Davinelli , Luigi Mazzone

Feeding problems are highly prevalent in individuals with autism spectrum disorder (ASD) from early developmental stages. Difficulties during the transition to solid foods, limited dietary variety, and reluctance to try new foods since infancy, combined with gastrointestinal disorders, represent significant concerns for both parents and clinicians from diagnostic and, more importantly, therapeutic perspectives. The primary clinical link between atypical eating behaviors and core autistic symptoms lies in aberrant sensory processing and an insistence on sameness, which have important implications for intervention strategies. Additionally, the increased risk of gastrointestinal disorders and altered gut microbiome composition in individuals with ASD constitute another critical factor, opening avenues for novel therapeutic approaches. Therefore, the aim of this review is to summarize the existing literature on therapeutic approaches for feeding problems in ASD, with a focus on evidence-based practices across pharmacological, psychological, and nutritional domains.

进食问题在自闭症谱系障碍（ASD）的早期发育阶段非常普遍。从诊断和更重要的是，从治疗的角度来看，过渡到固体食物的困难，有限的饮食种类，以及自婴儿期以来不愿尝试新食物，都是父母和临床医生非常关注的问题。非典型饮食行为与核心自闭症症状之间的主要临床联系在于异常的感觉加工和对一致性的坚持，这对干预策略具有重要意义。此外，ASD患者胃肠道疾病风险的增加和肠道微生物组成的改变是另一个关键因素，为新的治疗方法开辟了道路。因此，本综述的目的是总结ASD喂养问题治疗方法的现有文献，重点关注药理学，心理学和营养领域的循证实践。

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引用次数: 0

PXR activation ameliorates hyperuricemic nephropathy via NRF2 signaling PXR激活通过NRF2信号改善高尿酸血症肾病。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-11-17 DOI: 10.1016/j.phrs.2025.108039

Ting Wu , Lu Li , Yongjun Chen , Wenjie Ye , Zitao Guo , Fengting Liang , Wenhong Zhou , Zichao Yang , Fengxin Zheng , Hui Liao , Guofang Bi , Xiao Yang , Shicheng Fan , Jian-Hong Fang , Jianxin Pang , Huichang Bi

Long-term hyperuricemia (HUA) constitutes a major determinant of HUA-induced nephropathy (HN), yet current uricosuric drugs often exhibit limited efficacy and may pose a risk of kidney damage. Pregnane X receptor (PXR) plays a key role in xenobiotic and endobiotic metabolism homeostasis and has demonstrated anti-inflammatory, anti-fibrotic, and renoprotective properties. However, the role of PXR in regulating uric acid homeostasis and mitigating HN remains unclear. This study reveals PXR activation modulates uric acid homeostasis through dual suppression of xanthine oxidase (XOD) activity and enhanced ATP-binding cassette sub-family G member 2 (ABCG2) expression, thereby reducing uric acid accumulation and ameliorating renal injury. Mechanistically, PXR could interact with nuclear factor erythroid 2-related factor 2 (NRF2) to facilitate its nuclear translocation. Furthermore, we found that PXR activation inhibited K48-linked ubiquitination of NRF2 and promoted phosphorylation of NRF2 at S40, thereby activating NRF2 signaling and upregulating downstream target genes. This study elucidates PXR's dual role in regulating uric acid metabolism and attenuating HN, providing potential novel therapeutic targets for HN management.

长期高尿酸血症（HUA）是HUA所致肾病（HN）的主要决定因素，但目前的降尿药物往往疗效有限，并可能造成肾损害的风险。妊娠烷X受体（PXR）在外源和内源代谢稳态中起关键作用，具有抗炎、抗纤维化和肾保护作用。然而，PXR在调节尿酸稳态和减轻HN中的作用尚不清楚。本研究揭示PXR激活通过双重抑制黄嘌呤氧化酶（XOD）活性和增强atp结合盒亚家族G成员2 （ABCG2）表达来调节尿酸稳态，从而减少尿酸积累，改善肾损伤。机制上，PXR可与核因子红系2相关因子2 （NRF2）相互作用，促进其核易位。此外，我们发现PXR激活抑制k48相关的NRF2泛素化，促进NRF2在S40位点的磷酸化，从而激活NRF2信号，上调下游靶基因。本研究阐明了PXR在调节尿酸代谢和减轻HN中的双重作用，为HN治疗提供了潜在的新靶点。

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引用次数: 0

Advances in anthocyanin nanoparticle delivery systems in anti-inflammatory therapies 纳米花青素传递系统在抗炎治疗中的研究进展。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-11-17 DOI: 10.1016/j.phrs.2025.108038

Hanchi Zhang , Xinrui Qi , Lin Yang , Panpan Xia , Jitao Ling , Xuehong Zheng , Jianqi Liang , Pingping Yang , Yixuan Chen , Xiao Liu , Deju Zhang , Yaqi Rong , Caiwei Chen , Jing Zhang , Peng Yu , Yiming Gan

Chronic inflammation, a major global health burden, is a significant contributor to various diseases, including liver and kidney failure, inflammatory bowel disease, myocardial dysfunction, rheumatoid arthritis, diabetes, sepsis, and even cancer. Anthocyanins (ACNs), natural pigments widely distributed in diverse angiosperms, are renowned for their biological properties, such as anti-inflammatory, antioxidant, anti-tumor, and antibacterial effects. They have been demonstrated to play a pivotal role in modulating inflammation and treating a broad spectrum of inflammatory disorders. However, low bioavailability, instability, and uncontrollable distribution and excretion of ACNs have significantly restricted their applications. Encapsulation of ACNs into nanomaterials has therefore emerged as a viable strategy to overcome these limitations. Despite growing interest in this field, no comprehensive reviews has yet systematically examined the anti-inflammatory activity of ACN-loaded nanoparticles (NPs). In this review, we provide an in-depth summary of the preparation techniques, physicochemical properties, and functional characteristics of ACNs-loaded NPs based on polysaccharides, proteins, lipids, and metal NPs, and critically evaluate their direct and indirect anti-inflammatory effects. Furthermore, we discuss the therapeutic potential and underlying regulatory mechanisms of ACNs-loaded NPs in inflammatory diseases, including colitis, neuritis, and wound inflammation. This review aims to offer a comprehensive reference for the development of function-enhanced novel ACNs-loaded NPs and paves the way for their future clinical application.

慢性炎症是全球主要的健康负担，是各种疾病的重要因素，包括肝肾衰竭、炎症性肠病、心肌功能障碍、类风湿关节炎、糖尿病、败血症，甚至癌症。花青素（Anthocyanins, ACNs）是广泛存在于被子植物中的天然色素，具有抗炎、抗氧化、抗肿瘤和抗菌等生物学特性。它们已被证明在调节炎症和治疗广泛的炎症性疾病中发挥关键作用。然而，acn的低生物利用度、不稳定性和不可控的分布和排泄严重限制了其应用。因此，将acn封装到纳米材料中已成为克服这些限制的可行策略。尽管对这一领域的兴趣日益浓厚，但尚未有全面的综述系统地研究负载acn的纳米颗粒（NPs）的抗炎活性。本文综述了基于多糖、蛋白质、脂质和金属的acns负载NPs的制备技术、理化性质和功能特点，并对其直接和间接抗炎作用进行了批判性评价。此外，我们还讨论了acns负载NPs在炎性疾病（包括结肠炎、神经炎和伤口炎症）中的治疗潜力和潜在的调节机制。本文旨在为功能增强的新型acns负载NPs的开发提供综合参考，并为其未来的临床应用铺平道路。

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