Current Research in Pharmacology and Drug Discovery最新文献

Neuroprotective effects of naringenin on nicotine-induced anxiety and depression: Involvement of monoaminergic systems, oxidative stress, and neuroinflammation on male rats 柚皮素对尼古丁诱导的焦虑和抑郁的神经保护作用：雄性大鼠单胺能系统、氧化应激和神经炎症的参与

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-12-04 DOI: 10.1016/j.crphar.2025.100242

Murtaza Haidary , Yahya Samadi , Zakaria Rezai , Atiqullah Sadaqat , Mohammad Ali Ahmadi , Jamshid Gholami , Mohammad Mahdi Mohammadi , Mohammad Taqi Shojae

Introduction

Nicotine withdrawal during adolescence induces severe neurobehavioral disturbances and neurochemical alterations, including anxiety, depression, affective dysregulation, oxidative stress, and neuroinflammation. Current therapeutic options for managing nicotine dependence remain suboptimal. This study investigated the neuroprotective potential of naringenin (NG) in alleviating behavioral and biochemical sequelae of nicotine withdrawal in adolescent rats.

Materials and methods

Male adolescent Wistar rats were allocated into eight groups and subjected to nicotine exposure (1 mg/kg) and NG treatment (50 or 100 mg/kg) across nicotine exposure and withdrawal phases. Behavioral assays (OFT, EPM, FST) were employed to evaluate anxiety- and depression-like behaviors. Neurochemical assessments of dopamine, serotonin, their metabolites (DOPAC, 5-HIAA), MAO-A activity, oxidative stress markers (MDA, Nit), antioxidant enzymes (SOD, CAT, TT), and neuroinflammatory/neurodegenerative biomarkers (GFAP, IL-10, BDNF, NSE) were conducted in prefrontal cortex (PFC) homogenates.

Results

Nicotine withdrawal significantly induced anxiety- and depression-like behaviors, disrupted monoaminergic balance, elevated MAO-A activity, and triggered oxidative and neuroinflammatory responses in the PFC. NG administration, particularly at 100 mg/kg across both phases, significantly ameliorated behavioral impairments, restored neurotransmitter homeostasis, inhibited MAO-A, suppressed lipid peroxidation and nitrosative stress, enhanced antioxidant defenses, reduced GFAP and NSE expression, and restored IL-10 and BDNF levels.

Conclusion

NG exerts anxiolytic, antidepressant, antioxidant, and anti-inflammatory effects, likely via modulation of monoaminergic pathways and suppression of neuroinflammation and oxidative stress. These findings underscore the potential of NG as a promising candidate for mitigating neuropathological effects associated with nicotine withdrawal-induced neuropathology, particularly during adolescence.

青春期尼古丁戒断会引起严重的神经行为障碍和神经化学改变，包括焦虑、抑郁、情感失调、氧化应激和神经炎症。目前用于控制尼古丁依赖的治疗方案仍然不够理想。本研究探讨柚皮素（NG）在缓解青少年大鼠尼古丁戒断后行为和生化后遗症中的神经保护作用。材料与方法将成年Wistar大鼠分为8组，分别在尼古丁暴露和戒断阶段接受尼古丁暴露（1 mg/kg）和NG治疗（50或100 mg/kg）。行为测试（OFT， EPM， FST）用于评估焦虑和抑郁样行为。在前额皮质（PFC）匀浆中进行多巴胺、血清素及其代谢物（DOPAC、5-HIAA）、MAO-A活性、氧化应激标志物（MDA、Nit）、抗氧化酶（SOD、CAT、TT）和神经炎症/神经退行性生物标志物（GFAP、IL-10、BDNF、NSE）的神经化学评估。结果尼古丁戒断显著诱导焦虑和抑郁样行为，破坏单胺能平衡，提高MAO-A活性，并引发PFC. NG给药（特别是在两个阶段均为100 mg/kg时）的氧化和神经炎症反应，显著改善行为障碍，恢复神经递质稳态，抑制MAO-A，抑制脂质过氧化和亚硝酸盐应激，增强抗氧化防御。GFAP和NSE表达降低，IL-10和BDNF水平恢复。结论ng具有抗焦虑、抗抑郁、抗氧化和抗炎作用，可能通过调节单胺能通路和抑制神经炎症和氧化应激来实现。这些发现强调了NG作为缓解尼古丁戒断引起的神经病理相关神经病理效应的潜力，特别是在青少年时期。

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引用次数: 0

Synergistic effect of oxaliplatin and nanocurcumin in dendrosomal carrier to inhibits ovarian cancer cells invasion and metastasis through the long non-coding RNA MEG3 奥沙利铂和纳米姜黄素在树状体载体上通过长链非编码RNA MEG3抑制卵巢癌细胞侵袭转移的协同作用

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-12-02 DOI: 10.1016/j.crphar.2025.100243

Elahe Seyed Hosseini , Marziyeh Alizadeh Zarei , Zahra Shabani , Hamed Haddad Kashani , Hossein Nikzad

Background

Ovarian cancer (OC) remains one of the most lethal gynecological malignancies worldwide. The long non-coding RNA MEG3 (Maternally Expressed Gene 3), located on chromosome 14q32.3, has been identified as a tumor suppressor in various cancers. This study investigated the impact of siRNA-mediated MEG3 silencing in the context of dendrosomal nanocurcumin (DNC) and Oxaliplatin (OXA) treatments on ovarian cancer cell lines, focusing on the expression of genes associated with apoptosis and metastasis, including Bcl-2, BAX, MMP-2, and MMP-9.

Methods

Cell viability was assessed using the MTT assay; apoptosis and cell cycle progression were evaluated via flow cytometry and Annexin V-FLUOS staining. Cell migration and invasion were examined using the transwell assay, and gene expression levels were quantified by real-time PCR.

Results

MEG3 expression significantly increased in both cell lines upon DNC and OXA treatment in a time-dependent manner, with the most pronounced effect in OVCAR3 cells (P < 0.01–0.001). MEG3 silencing significantly attenuated the anticancer efficacy of both agents. Notably, MMP-2 expression increased in DNC (P < 0.01) and combination therapy (P < 0.001), while MMP-9 was upregulated following OXA treatment (P < 0.01) after MEG3 knockdown.

Conclusion

These results suggest that MEG3 knockdown impairs the anti-metastatic properties of DNC and OXA by modulating MMP-2 and MMP-9 expression. The combination of DNC and OXA holds promise as an effective therapeutic strategy in OC, and MEG3 may serve as a potential biomarker and therapeutic target, particularly in drug-resistant ovarian cancer.

卵巢癌（OC）仍然是世界范围内最致命的妇科恶性肿瘤之一。位于染色体14q32.3上的长链非编码RNA MEG3（母系表达基因3）已被确定为多种癌症的肿瘤抑制因子。本研究探讨了sirna介导的MEG3沉默在树状体纳米黄素（DNC）和奥沙利铂（OXA）治疗下对卵巢癌细胞系的影响，重点研究了与凋亡和转移相关的基因Bcl-2、BAX、MMP-2和MMP-9的表达。方法采用MTT法测定细胞活力；通过流式细胞术和Annexin V-FLUOS染色评价细胞凋亡和细胞周期进展。transwell法检测细胞迁移和侵袭，real-time PCR法检测基因表达水平。结果经DNC和OXA处理后，两种细胞系中meg3的表达均呈时间依赖性增加，其中OVCAR3细胞中meg3的表达最明显（P < 0.01-0.001）。MEG3沉默显著降低了两种药物的抗癌效果。值得注意的是，MMP-2在DNC和联合治疗中表达增加（P < 0.01），而在MEG3敲低后，OXA治疗后MMP-9表达上调（P < 0.01）。结论MEG3敲低可通过调节MMP-2和MMP-9的表达，从而影响DNC和OXA的抗转移特性。DNC和OXA的联合治疗有望成为卵巢癌的有效治疗策略，而MEG3可能作为潜在的生物标志物和治疗靶点，特别是在耐药卵巢癌中。

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引用次数: 0

Targeting telomere dynamics with plant-derived compounds: Molecular strategies against aging 用植物源性化合物靶向端粒动力学：抗衰老的分子策略

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2025.100238

Raushanara Akter, Adwiza Chakraborty Bishakha, Raisha Rajib, Asef Raj, Mashwiyat Samrin Roja, Fouzia Noor

Telomeres, the repetitive DNA–protein complexes capping eukaryotic chromosomes, preserve genomic stability and regulate cellular replicative capacity. Progressive telomere shortening, coupled with diminished telomerase activity, is a hallmark of aging and contributes to cellular senescence, tissue degeneration, and the onset of age-related diseases. Conversely, telomerase overactivation in malignant cells enables uncontrolled proliferation, positioning telomere biology as a dual therapeutic target in longevity and oncology. Plant-derived compounds possess diverse structural classes such as polyphenols, flavonoids, triterpenoid saponins, polysaccharides, lignans, alkaloids, carotenoids, amino acids, and fatty acids that can modulate telomere length and telomerase activity via multiple molecular pathways. These include antioxidant and anti-inflammatory actions, regulation of key genes such as hTERT, SIRT1, and c-Myc, modulation of PI3K/Akt, JAK/STAT, and ERK signaling, and stabilization or destabilization of G-quadruplex DNA structures. Compounds such as resveratrol, epigallocatechin gallate, astragaloside IV, cycloastragenol, and ginsenoside Rg1 have demonstrated telomerase activation or inhibition in a context-dependent manner, influenced by concentration, cell type, and disease state. This review categorizes plant-derived positive and negative telomere/telomerase modulators, detailing their sources, mechanisms of action, experimental evidence, and the formulation challenges that hinder clinical translation, such as low bioavailability, instability, and variability in phytochemical content. By integrating molecular insights with pharmacological perspectives, this review highlights the potential of plant-derived agents as multi-target interventions in aging and cancer. Advancing this field will require rigorous pharmacokinetic profiling, standardized preparations, and longitudinal clinical studies to bridge the gap between laboratory findings and real-world therapeutic outcomes.

端粒是覆盖在真核生物染色体上的重复dna -蛋白质复合物，它保持基因组的稳定性并调节细胞的复制能力。进行性端粒缩短，加上端粒酶活性降低，是衰老的标志，并有助于细胞衰老，组织变性和年龄相关疾病的发病。相反，端粒酶在恶性细胞中的过度激活会导致不受控制的增殖，使端粒生物学成为长寿和肿瘤的双重治疗靶点。植物源性化合物具有多种结构类别，如多酚、类黄酮、三萜皂苷、多糖、木脂素、生物碱、类胡萝卜素、氨基酸和脂肪酸，它们可以通过多种分子途径调节端粒长度和端粒酶活性。这些包括抗氧化和抗炎作用，关键基因如hTERT、SIRT1和c-Myc的调节，PI3K/Akt、JAK/STAT和ERK信号的调节，以及g -四重体DNA结构的稳定或不稳定。诸如白藜芦醇、表没食子儿茶素没食子酸酯、黄芪甲苷IV、环黄芪醇和人参皂苷Rg1等化合物已经证明端粒酶的激活或抑制以依赖于环境的方式进行，受浓度、细胞类型和疾病状态的影响。本文对植物源性端粒/端粒酶阳性和阴性调节剂进行了分类，详细介绍了它们的来源、作用机制、实验证据以及阻碍临床转化的配方挑战，如低生物利用度、不稳定性和植物化学含量的可变性。通过结合分子和药理学的观点，本综述强调了植物源性药物作为多靶点干预衰老和癌症的潜力。推进这一领域将需要严格的药代动力学分析、标准化的制剂和纵向临床研究，以弥合实验室发现和现实世界治疗结果之间的差距。

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引用次数: 0

Corrigendum to “Metabolic and clinical effect of alpha-lipoic acid administration in schizophrenic subjects stabilized with atypical antipsychotics: A 12-week, open-label, uncontrolled study” [Curr. Res. Pharmacol. Drug Discov. 3 (2022) 100116] “非典型抗精神病药物稳定的精神分裂症患者服用α硫辛酸的代谢和临床效果：一项为期12周、开放标签、非对照研究”的更正[Curr。研究》杂志。药物发现，3 (2022)100116]

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2025.100215

Fiammetta Iannuzzo , Gianpaolo Antonio Basile , Domenica Campolo , Giovanni Genovese , Gianluca Pandolfo , Loretta Giunta , Domenica Ruggeri , Antonino Di Benedetto , Antonio Bruno

引用次数: 0

Therapeutic effects of vitamin D and omega-3 supplementation on HFHS diet-induced endothelial dysfunction in Wistar rats 补充维生素D和omega-3对HFHS饮食诱导的Wistar大鼠内皮功能障碍的治疗作用

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2025.100240

Dylan Le Jan , Sandrine Destrumelle , Chantal Thorin , Jean-Claude Desfontis , Eric Betti , Mohamed Yassine Mallem

Background

Obesity impairs cardiovascular health through endothelial dysfunction, which is exacerbated by high-fat high-sugar (HFHS) diets through mechanisms involving chronic inflammation, oxidative stress, and insulin resistance. Nutritional interventions, specifically vitamin D (VD) and omega-3 fatty acids (ω3), have emerged as potential therapies to improve endothelial function and mitigate cardiovascular risks associated with obesity.

Objective

This study investigated the effects of VD, ω3 and their combination on endothelial dysfunction induced by an HFHS diet in Wistar rats.

Methods

Sixty-four male Wistar rats were fed either a Standard (S) or HFHS diet for 26 weeks. After 13 weeks, rats were supplemented with VD (600 IU/kg/day), ω3 (300 mg/kg/day), both (VD/ω3), or a control (C) for an additional 13 weeks. Endothelial function was assessed using aortic ring assays, focusing on acetylcholine (ACh)-mediated endothelium-dependent vasorelaxation, phenylephrine (Phe)-mediated vasoconstriction, and insulin responsiveness.

Results

VD and/or ω3 supplementation effectively improved ACh-mediated vasorelaxation and counteracted HFHS-induced endothelial dysfunction. VD enhanced insulin-mediated vasorelaxation, while ω3 showed a non-significant trend towards improved Phe-mediated vasoconstriction.

Conclusion

VD and ω3 supplementation, alone or in combination, significantly improved endothelial function and mitigated the adverse effects of an HFHS diet. The combination did not show clear additive effects. These findings suggest their potential as therapeutic strategies for managing obesity-related cardiovascular issues.

背景：肥胖通过内皮功能障碍损害心血管健康，而高脂高糖（HFHS）饮食通过慢性炎症、氧化应激和胰岛素抵抗等机制加剧了内皮功能障碍。营养干预，特别是维生素D （VD）和ω -3脂肪酸（ω3），已经成为改善内皮功能和减轻与肥胖相关的心血管风险的潜在疗法。目的探讨VD、ω3及其联用对HFHS致Wistar大鼠内皮功能障碍的影响。方法雄性Wistar大鼠64只，分别饲喂标准(S)和HFHS两种饲料，饲养26周。13周后，大鼠再补充VD （600 IU/kg/day）、ω3 （300 mg/kg/day）、两者（VD/ω3）或对照组(C) 13周。通过主动脉环检测评估内皮功能，重点关注乙酰胆碱（ACh）介导的内皮依赖性血管舒张、苯肾上腺素（Phe）介导的血管收缩和胰岛素反应性。结果补充vd和/或ω3可有效改善乙酰胆碱介导的血管松弛，抵消hfhs诱导的内皮功能障碍。VD增强了胰岛素介导的血管舒张，而ω3对ph介导的血管收缩的改善趋势不显著。结论单独或联合补充vd和ω3可显著改善HFHS饮食的内皮功能，减轻其不良反应。联合用药未显示明显的加性效应。这些发现表明，它们有可能作为治疗肥胖相关心血管问题的治疗策略。

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引用次数: 0

The suppression of the SPHK1/S1P/S1PR3 signaling pathway diminishes EGFR activation and increases the sensitivity of non-small cell lung cancer to gefitinib 抑制SPHK1/S1P/S1PR3信号通路可降低EGFR激活，增加非小细胞肺癌对吉非替尼的敏感性。

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2024.100212

Jing Zhang , Zequn Wang , Xihua Wei , Mengyuan Han , Ribai Yan , Lijie Ma , Yan Pan

Non-small-cell lung cancer (NSCLC) represents a predominant histological subtype of lung cancer, characterized by high incidence and mortality rates. Despite significant advancements in therapeutic strategies and a deeper understanding of targeted therapies in recent years, tumor resistance remains an inevitable challenge, leading to poor prognostic outcomes. Several studies have indicated that sphingosine kinase 1 (SPHK1) plays a regulatory role in epidermal growth factor receptor (EGFR) signaling, and its elevated expression may be associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Furthermore, the catalytic product of SPHK1, sphingosine 1-phosphate (S1P), along with its receptor, sphingosine 1-phosphate receptor 3 (S1PR3), plays a regulatory role in the function of the EGFR. However, the specific effects of the SPHK1/S1P/S1PR3 axis on EGFR in NSCLC, as well as the combined effects of SPHK1/S1P/S1PR3 inhibitors with the EGFR-TKI gefitinib, remain to be elucidated. In the present study, we investigated the correlation between SPHK1 expression levels and the survival rates of NSCLC patients, the relationship between SPHK1 or S1PR3 and EGFR, and the impact of SPHK1 expression on the half-maximal inhibitory concentration (IC₅₀) of gefitinib in NSCLC. In A549 cells, the phosphorylation of EGFR was significantly reduced following SPHK1 knockdown. Utilizing SPHK1/S1P/S1PR3 inhibitors, namely PF543, TY52156, and FTY720, we established that the SPHK1/S1P/S1PR3 axis modulates EGFR activation in NSCLC. Furthermore, these signaling inhibitors enhanced the anti-proliferative efficacy of the EGFR-TKI gefitinib. RNA sequencing analysis revealed substantial alterations in 85 differentially expressed genes in NSCLC cells treated with the combination of FTY720 and gefitinib. These genes were predominantly associated with pathways such as axon guidance, microRNAs in cancer, and the JAK-STAT signaling pathway, among others. Overall, targeting the SPHK1/S1P/S1PR3 signaling pathway represents a promising therapeutic strategy to enhance gefitinib sensitivity in NSCLC.

非小细胞肺癌（NSCLC）是肺癌的主要组织学亚型，其特点是发病率和死亡率高。尽管近年来治疗策略取得了重大进展，并且对靶向治疗有了更深入的了解，但肿瘤耐药性仍然是一个不可避免的挑战，导致预后不良。多项研究表明，鞘氨酸激酶1 （SPHK1）在表皮生长因子受体（EGFR）信号传导中起调节作用，其表达升高可能与对EGFR酪氨酸激酶抑制剂（EGFR- tkis）的耐药有关。此外，SPHK1的催化产物sphingosin 1-phosphate （S1P）及其受体sphingosin 1-phosphate receptor 3 （S1PR3）在EGFR的功能中起调节作用。然而，SPHK1/S1P/S1PR3轴对NSCLC中EGFR的特异性作用，以及SPHK1/S1P/S1PR3抑制剂与EGFR- tki吉非替尼的联合作用仍有待阐明。在本研究中，我们探讨了SPHK1表达水平与NSCLC患者生存率的相关性，SPHK1或S1PR3与EGFR的关系，以及SPHK1表达对吉非替尼在NSCLC中的半最大抑制浓度（IC50）的影响。在A549细胞中，SPHK1敲除后，EGFR的磷酸化显著降低。利用SPHK1/S1P/S1PR3抑制剂，即PF543、TY52156和FTY720，我们确定了SPHK1/S1P/S1PR3轴调节NSCLC中EGFR的激活。此外，这些信号抑制剂增强了EGFR-TKI吉非替尼的抗增殖功效。RNA测序分析显示，在FTY720和吉非替尼联合治疗的NSCLC细胞中，85个差异表达基因发生了实质性变化。这些基因主要与轴突引导、癌症中的microrna和JAK-STAT信号通路等途径相关。总的来说，靶向SPHK1/S1P/S1PR3信号通路是一种很有前景的治疗策略，可以增强吉非替尼对非小细胞肺癌的敏感性。

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引用次数: 0

ABCC1 and ABCC10 as predictive biomarkers of docetaxel treatment response in prostate cancer ABCC1和ABCC10作为多西他赛治疗前列腺癌反应的预测性生物标志物

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2025.100216

Nandi Ngesi , Beynon Abrahams , Aubrey Shoko , Mamello Sekhoacha

Prostate cancer (PCa) is a leading global health burden, with a particularly high prevalence in South Africa. Despite therapeutic advancements, chemoresistance remains a major challenge, limiting the efficacy of docetaxel and contributing to treatment failure and disease progression. Multidrug resistance (MDR), primarily mediated by ATP-binding cassette (ABC) transporters such as ABCC1 and ABCC10, has been implicated in reduced chemotherapy effectiveness. This study aimed to evaluate the association between ABCC1 and ABCC10 expression levels and docetaxel treatment response in PCa patients. A retrospective case-control study was conducted using pre-treated formalin-fixed paraffin-embedded (FFPE) tissue biopsies from PCa patients. Patients were classified into good responders (cases) and poor responders (cases) based on treatment outcomes. For each patient, tumour and adjacent normal sections were excised from FFPE samples, with normal sections serving as the control group. RNA was extracted and subjected to quantitative real-time PCR (qRT-PCR) to assess ABCC1 and ABCC10 expression levels. ABCC1 and ABCC10 were significantly upregulated in tumour sections of poor responders, whereas good responders exhibited downregulated expression in tumour sections. Importantly, normal tissue sections (controls) displayed significantly lower expression levels of both transporter genes compared to tumour sections. The overexpression of ABCC1 and ABCC10 in tumour tissues, particularly in poor responders, suggests their potential role in mediating docetaxel resistance. These findings highlight ABCC1 and ABCC10 as potential predictive biomarkers for docetaxel treatment response in PCa, warranting further investigation in prospective clinical studies.

前列腺癌（PCa）是全球主要的健康负担，在南非的发病率尤其高。尽管在治疗方面取得了进展，但化疗耐药性仍然是一项重大挑战，它限制了多西他赛的疗效，并导致治疗失败和疾病进展。多药耐药性（MDR）主要由ATP结合盒（ABC）转运体（如ABCC1和ABCC10）介导，与化疗效果下降有关。本研究旨在评估PCa患者中ABCC1和ABCC10表达水平与多西他赛治疗反应之间的关系。研究采用PCa患者预先处理过的福尔马林固定石蜡包埋（FFPE）组织活检样本，进行了一项回顾性病例对照研究。根据治疗结果将患者分为反应良好者（病例）和反应不佳者（病例）。每名患者都从 FFPE 样品中切除肿瘤和邻近的正常切片，正常切片作为对照组。提取 RNA 并进行定量实时 PCR（qRT-PCR），以评估 ABCC1 和 ABCC10 的表达水平。反应差者的肿瘤切片中 ABCC1 和 ABCC10 表达明显上调，而反应良好者的肿瘤切片中 ABCC1 和 ABCC10 表达下调。重要的是，与肿瘤切片相比，正常组织切片（对照组）中这两种转运体基因的表达水平明显较低。ABCC1和ABCC10在肿瘤组织中的过表达，尤其是在反应差的患者中，表明它们在介导多西他赛耐药性方面可能起着重要作用。这些发现突出表明，ABCC1和ABCC10是多西他赛治疗PCa反应的潜在预测性生物标志物，值得在前瞻性临床研究中进一步研究。

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引用次数: 0

Fragment-based drug discovery: A graphical review 基于片段的药物发现：图形回顾

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2025.100233

Dana F. AlKharboush , Frank Kozielski , Geoffrey Wells , Exequiel O.J. Porta

Three decades after its introduction, fragment-based drug (or lead) discovery (FBDD or FBLD) has become a mature and powerful strategy for generating novel leads, offering distinct advantages for challenging or previously “undruggable” targets where traditional screening (e.g., high throughput screening) often fails. The FBDD approach identifies low molecular weight fragments (MW < 300 Da) that bind weakly to a target; these interactions are detected using highly sensitive biophysical methods such as NMR, X-ray crystallography, and SPR. These initial hits are then optimised into potent leads through structure-guided strategies, including fragment growing, linking, or merging. This graphical review illustrates the modern FBDD workflow, highlighting the critical integration of experimental and computational methods. We discuss how innovations in library design, hybrid screening platforms, and the application of AI/ML are accelerating discovery cycles and improving hit validation. The power of this approach is demonstrated through case studies of FDA-approved drugs, including Vemurafenib and Venetoclax, which progressed from simple fragments to transformative medicines. Finally, we provide an outlook on the future of FBDD as it continues to evolve with emerging technologies to push the boundaries of drug discovery.

在引入三十年后，基于片段的药物（或先导物）发现（FBDD或FBLD）已成为产生新型先导物的成熟而强大的策略，为具有挑战性或以前“不可药物”的靶标提供了独特的优势，而传统筛选（例如高通量筛选）往往失败。FBDD方法识别与靶标结合较弱的低分子量片段（MW < 300 Da）；这些相互作用是使用高灵敏度的生物物理方法，如核磁共振、x射线晶体学和SPR来检测的。然后通过结构导向策略（包括片段增长、链接或合并）将这些初始命中优化为有效的线索。这张图表说明了现代FBDD工作流程，突出了实验和计算方法的关键集成。我们讨论了图书馆设计、混合筛选平台和AI/ML应用的创新如何加速发现周期和改进命中验证。这种方法的力量通过fda批准的药物的案例研究得到了证明，包括Vemurafenib和Venetoclax，这些药物从简单的片段发展到变革性药物。最后，我们展望了FBDD的未来，因为它将随着新兴技术的发展而不断发展，以推动药物发现的界限。

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引用次数: 0

Melatonin combined with antineoplastic drugs or natural products for cancer treatment: An update 褪黑素与抗肿瘤药物或天然产品联合用于癌症治疗：最新进展

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2025.100239

Cristina Trejo-Solís , Irma Susana Rojas-Tomé , Helgi Jung-Cook , Francisca Palomares-Alonso

Drug combinations have shown promise in suppressing drug resistance, improving drug efficacy, and reducing side effects in anticancer therapy. Considering that the anticancer activity of melatonin may be due to its antiproliferative, antioxidant, and immunomodulatory activities, the combined administration of this endogenous indoleamine with anticancer drugs has been extensively explored. This review provides an overview of the advances in the last five years in the anticancer activity of melatonin in combination with synthetic drugs and natural products. Papers on this topic were searched in PubMed, Google Scholar, Cochrane, and Scopus within the period 2018–2024. A total of 47 papers were retrieved showing a synergistic antitumor effect of melatonin combined with different drugs in the treatment of breast, colorectal, prostate, gastric, thyroid, and pancreatic cancer, as well as in head and neck squamous cell carcinoma, melanoma, and glioblastoma. The evidence gathered in this review will contribute to our knowledge of the use of melatonin. In addition, it may allow us to develop novel approaches to the treatment of cancer to be evaluated in preclinical and/or clinical trials.

在抗癌治疗中，药物组合在抑制耐药性、提高药物疗效和减少副作用方面显示出前景。考虑到褪黑素的抗癌活性可能是由于其抗增殖、抗氧化和免疫调节的活性，这种内源性吲哚胺与抗癌药物的联合用药已被广泛探索。本文综述了近五年来褪黑素与合成药物和天然产物联合抗肿瘤活性的研究进展。在2018-2024年期间在PubMed， b谷歌Scholar， Cochrane和Scopus中检索了有关该主题的论文。共检索到47篇论文，显示褪黑素与不同药物联合治疗乳腺癌、结直肠癌、前列腺癌、胃癌、甲状腺癌、胰腺癌以及头颈部鳞状细胞癌、黑色素瘤、胶质母细胞瘤的协同抗肿瘤作用。本综述收集的证据将有助于我们了解褪黑激素的使用。此外，它可能使我们能够开发新的方法来治疗癌症，在临床前和/或临床试验中进行评估。

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引用次数: 0

Metformin's impact on asprosin and FBN1 expression: Potential mechanisms beyond insulin sensitivity in type 2 diabetes in rats 二甲双胍对asprosin和FBN1表达的影响：2型糖尿病大鼠胰岛素敏感性之外的潜在机制

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2024.100207

Ali Dashtkar , Mansour Karajibani , Mohsen Saravani , Roya zanganeh , Hamed Fanaei

Background

Asprosin, a novel adipokine released under fasting conditions, may play a significant role in the pathophysiology of type 2 diabetes mellitus (T2DM). The objective of this study is to investigate the effects of metformin on serum asprosin levels and FBN1 gene expression in white adipose tissue in male rats.

Methods

Thirty-two male Wistar rats were randomly and equally divided into four groups (n = 8): 1. Control Group (CON): Received standard food; 2. Non-Diabetic Metformin Group (CON + MET): Received standard food and were treated with metformin (400 mg/kg/day) for four weeks; 3. Diabetic Group (DM): Induced with T2DM; and 4. Diabetic Metformin Group (DM + MET): Induced with T2DM and treated with metformin (400 mg/kg/day) for four weeks. Finally, serum asprosin levels, lipid profiles, fasting glucose, and insulin concentrations were measured. The expression level of the FBN1 gene in white adipose tissue was quantified using quantitative real-time polymerase chain reaction (qRT-PCR).

Results

Serum asprosin levels were significantly higher in the DM group compared to both the CON and CON + MET groups (P < 0.0001). However, serum asprosin levels were significantly lower in the DM + MET group than in the DM group (P = 0.0003). Additionally, the FBN1 gene expression level in white adipose tissue was significantly higher in the DM group compared to the CON group (P = 0.0053), while FBN1 gene expression was significantly lower in the DM + MET group than in the DM group (P < 0.0001). Furthermore, lipid profile, insulin resistance, and fasting blood sugar improved in the CON + MET and DM + MET groups compared to the CON and DM groups, respectively.

Discussion

Our findings in diabetic male rats reveal that metformin treatment significantly downregulates FBN1 gene expression and reduces serum asprosin levels, suggesting a potential mechanism for its therapeutic benefits beyond improving insulin sensitivity.

背景：阿司匹林是一种在空腹条件下释放的新型脂肪因子，可能在2型糖尿病（T2DM）的病理生理学中发挥重要作用。本研究的目的是探讨二甲双胍对雄性大鼠血清阿司匹林水平和白色脂肪组织中 FBN1 基因表达的影响：将 32 只雄性 Wistar 大鼠随机平均分为四组（n = 8）：1.对照组（CON）：2. 非糖尿病二甲双胍组（CON + MET）：2.非糖尿病二甲双胍组（CON + MET）：摄入标准食物，并接受二甲双胍（400 毫克/千克/天）治疗四周；3.糖尿病组（DM）：诱发 T2DM；和 4.糖尿病二甲双胍组（DM + MET）：诱发 T2DM 并接受二甲双胍（400 毫克/千克/天）治疗四周。最后，测定血清天冬氨酸水平、血脂概况、空腹血糖和胰岛素浓度。使用实时定量聚合酶链式反应（qRT-PCR）对白色脂肪组织中 FBN1 基因的表达水平进行了量化：结果：与 CON 组和 CON + MET 组相比，DM 组的血清天冬氨酸水平明显升高（P 讨论）：我们对糖尿病雄性大鼠的研究结果表明，二甲双胍治疗可显著下调 FBN1 基因的表达，并降低血清中的酪氨酸水平，这表明二甲双胍的潜在治疗机制不仅仅是改善胰岛素敏感性。

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引用次数: 0