Current Research in Pharmacology and Drug Discovery最新文献_第2页

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

Tissue distribution pharmacokinetics of intrathecal U1 adaptor oligonucleotide in mice 小鼠鞘内U1接头寡核苷酸的组织分布及药代动力学

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2025.100220

Medha Satti , Kavita Prasad , Yash Patel , Demi Poulathas , Lawrence Walker , Esha Paghdal , Samuel Gunderson , Lei Yu

U1 Adaptor is a novel gene-silencing technology, offering an innovative approach to target genes in the CNS for the treatment of diseases. Intrathecal delivery is a medically viable route of administration of CNS-bound nucleic acid drugs; therefore, it is important to investigate U1 Adaptor distribution after intrathecal drug delivery. We investigated the distribution patterns of U1 Adaptor upon intrathecal bolus administration in mice. It readily distributes to CNS tissues, including the lumbar and the cervical spinal cord, and the cerebellum. Over time, the U1 Adaptor also accumulates in the periphery, both in the liver and the kidneys, while plasma levels are undetectable. Our findings provide useful information for future in-depth pharmacokinetic modeling of U1 Adaptor distribution upon intrathecal administration.

U1 Adaptor是一种新型的基因沉默技术，为中枢神经系统中的靶基因治疗疾病提供了一种创新的方法。鞘内给药是医学上可行的给药途径；因此，研究鞘内给药后U1 Adaptor的分布是很重要的。我们研究了小鼠鞘内给药后U1 Adaptor的分布模式。它很容易分布到中枢神经系统组织，包括腰、颈脊髓和小脑。随着时间的推移，U1适配器也会在肝脏和肾脏的外周积聚，而血浆水平则无法检测到。我们的发现为未来深入建立鞘内给药U1 Adaptor分布的药代动力学模型提供了有用的信息。

引用次数: 0

Cyclodextrin-based therapeutics delivery systems: A review of current clinical trials 基于环糊精的治疗递送系统：当前临床试验综述

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2025.100232

Gjylije Hoti , Neha Bajwa , Fabrizio Caldera , Preet Amol Singh , Ibrahim Hussein , Claudio Cecone , Adrián Matencio , Rita Spagnolo , Monica Argenziano , Roberta Cavalli , Jitender Madan , Francesco Trotta

This review highlights the current status of cyclodextrin-based formulations tested in human participants, highlighting ongoing clinical research in this area. It provides a comprehensive link between the structure, properties, and clinical applications of these formulations, bridging the gap between medical theory and practical use. The aim of this work is to support the future commercialization of cyclodextrin-based therapies for patient care. Additionally, it emphasizes the need for expanded clinical investigations on cyclodextrin-based formulations, particularly cyclodextrin-based polymers, to pave the way for their successful introduction to the market. This is related to the potential of cyclodextrin-based polymers as advanced drug delivery systems, improving the therapeutic efficacy of numerous drugs. Expanding clinical trials will contribute to the optimization of cyclodextrin-based polymer synthesis, boosting their effectiveness as nanocarriers and facilitating the discovery of new disease treatments.

This review also explores the potential of artificial intelligence (AI) to support clinical and medical solutions.

这篇综述强调了环糊精为基础的配方在人类参与者中测试的现状，强调了这一领域正在进行的临床研究。它提供了这些配方的结构、性质和临床应用之间的全面联系，弥合了医学理论和实际应用之间的差距。这项工作的目的是支持环糊精为基础的治疗病人护理的未来商业化。此外，它强调需要扩大基于环糊精的配方的临床研究，特别是基于环糊精的聚合物，为其成功推向市场铺平道路。这与基于环糊精的聚合物作为先进药物递送系统的潜力有关，可以提高许多药物的治疗效果。扩大临床试验将有助于优化环糊精基聚合物的合成，提高其作为纳米载体的有效性，并促进发现新的疾病治疗方法。本文还探讨了人工智能（AI）在支持临床和医疗解决方案方面的潜力。

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引用次数: 0

Anti-inflammatory potential of quercetin: From chemistry and mechanistic insight to nanoformulations 槲皮素的抗炎潜能：从化学和机理洞察到纳米配方

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2025.100217

Diwakar Aggarwal , Mayank Chaudhary , Sachin Kumar Mandotra , Hardeep Singh Tuli , Ritu Chauhan , Naveen Chandra Joshi , Damandeep Kaur , Laurent Dufossé , Abhishek Chauhan

Flavonoids are hydroxylated polyphenols that are abundantly produced by plants as secondary metabolites. These flavonoids hold vast therapeutic potential as they possess numerous medicinal benefits encompassing anti-inflammatory, anti-oxidative, anticancer and antiviral properties. Flavonoids render anti-inflammatory effect either by activating antioxidant pathways or by inhibiting enzymatic secretions involved in inflammatory reactions. Flavonoids like quercetin targets inflammation by modulating expression of cytokines and pro-inflammatory molecules and by inhibiting pro-inflammatory enzymes. Mode of action, absorption and bioavailability of flavonoids greatly affect their biological activity. On-going research is focussing on isolation, synthesis of flavonoid analogs and effect of flavonoids on human health by manifestation of different techniques and animal models. Unravelling the anti-inflammatory potential of flavonoids can manifest better treatment options against variety of diseases and metabolic syndromes. Additionally, enhanced bioavailability of flavonoids can result in superior pharmaceutical activities.

黄酮类化合物是一种羟基化的多酚，是植物大量产生的次生代谢产物。这些类黄酮具有巨大的治疗潜力，因为它们具有多种药用价值，包括抗炎、抗氧化、抗癌和抗病毒特性。黄酮类化合物通过激活抗氧化途径或抑制参与炎症反应的酶分泌来发挥抗炎作用。类黄酮如槲皮素通过调节细胞因子和促炎分子的表达以及抑制促炎酶来靶向炎症。黄酮类化合物的作用方式、吸收和生物利用度对其生物活性有很大影响。目前正在进行的研究主要集中在类黄酮类似物的分离、合成和类黄酮对人体健康的影响，通过不同的技术和动物模型的表现。揭示类黄酮的抗炎潜能，可以为多种疾病和代谢综合征提供更好的治疗选择。此外，提高黄酮类化合物的生物利用度可以导致优越的药物活性。

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引用次数: 0

Pharmacogenetics association with long-term clinical evolution in a kidney transplant patients cohort 药物遗传学与肾移植患者长期临床演变的关系

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2025.100230

Luis Sendra , Gladys G. Olivera-Pasquini , Enrique G. Zucchet , Fabiana D.V. Genvigir , María Isabel Beneyto , Julio Hernández-Jaras , María José Herrero , Salvador F. Aliño

Background

Pharmacogenetic variability has been reported to influence the efficacy and safety of immunosuppressive therapies in early stages of kidney transplantation. This study investigates long-term associations between pharmacogene variants and clinical outcomes in a cohort of kidney transplant recipients over a 12-year follow-up.

Materials and methods

We analyzed 37 SNPs from 14 genes related to drug metabolism and transport in 79 kidney transplant patients. Clinical parameters, including survival, renal function, tumor occurrence, and pharmacokinetics of tacrolimus, were evaluated. Logistic regression and Kaplan-Meier analyses assessed associations between gene variants and clinical outcomes.

Results

Variants in metabolizer (CYP3A5, CYP2B6) and transporter genes (ABCB1, ABCC2) were associated with 12-year survival. Increased tumor risk correlated with ABCC2 variants in donors and decreased risk with CYP2B6 rs3745274 in recipients. Renal function was influenced by variants in ABCB1, ABCC2, CYP3A5, CYP3A4, and CYP2B6. Tacrolimus dose-dependent concentration was affected by variants in CYP3A4, CYP3A5, CYP2C19, ABCB1, and SLCO1B1. Increased nephrotoxicity risk was associated with CYP2C19 rs4244285 and reduced by SLCO1B1 rs2306283 AA and AG variants. Gene variant interactions between metabolizer and transporter genes were also associated with altered risk of events incidence.

Discussion

Our findings support that pharmacogene variants influence transplant outcomes. Notable associations include survival related to ABCB1 and ABCC2 variants, tumor occurrence linked to CYP2B6 rs3745274, and renal function affected by multiple pharmacogenes. Variants in CYP2C19 and SLCO1B1 significantly impacted tacrolimus pharmacokinetics and nephrotoxicity risk. These results underline the importance of pharmacogenetic testing for personalized management in kidney transplantation, although further validation in larger cohorts is necessary.

已有报道称药物遗传变异会影响肾移植早期免疫抑制治疗的有效性和安全性。本研究对一组肾移植受者进行了为期12年的随访，调查了药物基因变异与临床结果之间的长期关系。材料与方法对79例肾移植患者的14个药物代谢和转运相关基因的37个snp进行分析。临床参数包括生存、肾功能、肿瘤发生和他克莫司的药代动力学。逻辑回归和Kaplan-Meier分析评估了基因变异与临床结果之间的关系。结果代谢基因（CYP3A5、CYP2B6）和转运基因（ABCB1、ABCC2）变异与12年生存率相关。供体中ABCC2变异与肿瘤风险增加相关，受体中CYP2B6 rs3745274变异与肿瘤风险降低相关。肾功能受ABCB1、ABCC2、CYP3A5、CYP3A4和CYP2B6变异的影响。他克莫司剂量依赖性浓度受CYP3A4、CYP3A5、CYP2C19、ABCB1和SLCO1B1基因变异的影响。增加的肾毒性风险与CYP2C19 rs4244285相关，与SLCO1B1 rs2306283 AA和AG变体相关。代谢基因和转运基因之间的基因变异相互作用也与事件发生风险的改变有关。我们的研究结果支持药物基因变异影响移植结果。值得注意的关联包括与ABCB1和ABCC2变异相关的生存，与CYP2B6 rs3745274相关的肿瘤发生，以及受多种药物基因影响的肾功能。CYP2C19和SLCO1B1的变异显著影响他克莫司的药代动力学和肾毒性风险。这些结果强调了药物遗传学检测对肾移植个体化管理的重要性，尽管需要在更大的队列中进一步验证。

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引用次数: 0

Salvianolic acid B decreases oxidative stress and alleviates the tumor-promoting effects of arecoline in oral cancer 丹酚酸B在口腔癌中降低氧化应激，减轻槟榔碱的促瘤作用

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2025.100241

Hsuan-Yin Tung , Yi-Ling Ye , Chi-Maw Lin , Li-Shian Shi

Arecoline, which is a primary alkaloid in areca nuts, contributes in key ways to the development of oral submucous fibrosis and the subsequent oral cancer through the induction of oxidative stress, promotion of fibrosis, and activation of oncogenic signaling. Salvianolic acid B (SAB) is the most abundant water-soluble phenolic compound found in Salvia miltiorrhiza Bunge. SAB appears to have the potential to mitigate the effects of arecoline. However, the interaction between SAB and arecoline in oral cancer has been less frequently discussed. Therefore, we conducted this study in which SCC-4 tongue cancer cells were treated with arecoline alone or in combination with SAB. The effects on collagen contraction, cell migration, reactive oxygen species (ROS) production, and transcriptomic alterations were assessed. Arecoline increased collagen contraction, ROS accumulation, and the activation of tumor-promoting pathways, including TGF-β/Smad, EGFR, MAPK, and ferroptosis. In contrast, SAB effectively decreased collagen contraction, reduced cell migration, and attenuated oxidative stress in a dose-dependent manner. Moreover, in the presence of arecoline, SAB supplementation reversed fibrosis-related processes, modulated metabolic activity, and enhanced DNA repair mechanisms, thereby counteracting arecoline-induced oncogenic effects. Therefore, SAB, through its ability to reduce oxidative stress, fibrosis, and metabolic dysregulation, is a promising therapeutic candidate for mitigating arecoline-induced tumor progression. Our study offers novel insights into the role of SAB in protecting against the pathophysiology of oral cancer and highlights its potential as a natural compound for the prevention and treatment of this disease.

槟榔碱是槟榔果中的一种主要生物碱，通过诱导氧化应激、促进纤维化和激活致癌信号，在口腔粘膜下纤维化和随后的口腔癌的发展中起着关键作用。丹参酚酸B （Salvianolic acid B， SAB）是丹参中含量最多的水溶性酚类化合物。SAB似乎有可能减轻槟榔碱的影响。然而，SAB和槟榔碱在口腔癌中的相互作用却很少被讨论。因此，我们进行了这项研究，用槟榔碱单独或联合SAB治疗SCC-4舌癌细胞。对胶原收缩、细胞迁移、活性氧（ROS）产生和转录组改变的影响进行了评估。槟油碱增加胶原收缩、ROS积累和肿瘤促进通路的激活，包括TGF-β/Smad、EGFR、MAPK和铁下垂。相反，SAB有效地减少胶原收缩，减少细胞迁移，并以剂量依赖的方式减轻氧化应激。此外，在槟榔碱存在的情况下，SAB补充逆转了纤维化相关过程，调节了代谢活性，增强了DNA修复机制，从而抵消了槟榔碱诱导的致癌作用。因此，SAB通过其减少氧化应激、纤维化和代谢失调的能力，是缓解槟碱诱导的肿瘤进展的有希望的治疗候选药物。我们的研究为SAB在预防口腔癌病理生理方面的作用提供了新的见解，并强调了其作为预防和治疗口腔癌的天然化合物的潜力。

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引用次数: 0

MAO-B inhibition by selegiline blunts cardiac functions improved by high-fat diet: Role of inflammation, apoptosis, and calcium-handling selegiline抑制MAO-B使高脂肪饮食改善的心功能钝化：炎症、细胞凋亡和钙处理的作用

Q2 Agricultural and Biological Sciences

Current Research in Pharmacology and Drug Discovery

Pub Date : 2025-01-01 DOI: 10.1016/j.crphar.2025.100237

Szabolcs Hambalkó , Csilla Pelyhe , Csenger Kovácsházi , Bence Kenyeres , Bernadett Kiss , Bence Ágg , Tamás G. Gergely , Bennet Y. Weber , András Makkos , Gábor B. Brenner , Tímea Komlódi , László Tretter , Csaba Horváth , Izabela Jarabicová , Adriana Adameová , Anikó Görbe , Paola Poggi , Alexandros Chatgilialoglu , Ildikó Horváth , Domokos Máthé , Zoltán Giricz

Background

Obesity is a major risk factor for the development of cardiovascular disease. However, recent research shows that moderate obesity reduces the risk of developing cardiovascular disease. We evidenced before that MAO-B inhibitor selegiline reduced visceral adiposity.

Aim

Therefore, our aim was to investigate cardiac effects of selegiline in moderate obesity in rats treated with a high-fat diet (HFD).

Key findings

We demonstrated that HFD improved cardiac contractility parameters, which were reversed by selegiline. Enhanced contractility might be attributed to an increased sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA2a) expression and phospholamban pentamerization. Selegiline reduced SERCA2a expression in HFD. HFD increased Tumor necrosis factor and Nuclear factor-kappa B expression which were not affected by selegiline. HFD induced proapoptotic processes, which were restored by selegiline.

Conclusion

In conclusion, moderate obesity improves cardiac function through Ca²⁺ homeostasis and inflammatory processes and MAO-B inhibition reverses these effects.

背景：肥胖是心血管疾病发生的主要危险因素。然而，最近的研究表明，适度肥胖可以降低患心血管疾病的风险。我们之前证实MAO-B抑制剂selegiline可以减少内脏脂肪。因此，我们的目的是研究selegiline对高脂肪饮食（HFD）治疗的中度肥胖大鼠的心脏影响。我们证明HFD改善了心脏收缩性参数，而selegiline逆转了这一点。收缩力的增强可能归因于肌浆/内质网Ca2+- atp酶（SERCA2a）表达和磷蛋白五聚化的增加。Selegiline降低HFD中SERCA2a的表达。HFD增加了肿瘤坏死因子和核因子κ B的表达，而selegiline对其没有影响。HFD诱导细胞凋亡前过程，经selegiline恢复。结论适度肥胖可通过Ca2+稳态和炎症过程改善心功能，抑制MAO-B可逆转这些作用。

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引用次数: 0