Aspects of molecular medicine最新文献_第2页

Exploring new Frontiers in dry eye Disease: Treatments, mechanisms, and diagnostic innovations a comprehensive review 探索干眼病的新领域：治疗、机制和诊断创新的综合综述

Aspects of molecular medicine

Pub Date : 2025-06-01 DOI: 10.1016/j.amolm.2025.100090

K. Narendra , Sonali K. Singh , C.K. Deepa , S. Meghana , K.R. Akanth , M. Manjushree , D. Raajasubramaniyan , S. Srinivasan , R. Murali , H.N. Sowbhagya

Dry Eye Disease (DED) significantly impacts quality of life through tear film instability and ocular surface inflammation. This review highlights advancements in treatments, mechanisms, and diagnostics. Emerging pharmacological therapies, including novel anti-inflammatory agents, secretagogues, corticosteroids, and autologous serum eye drops, alongside innovative devices like punctal plugs, thermal pulsation devices, and meibomian gland expression techniques. Lifestyle modifications and nutritional supplements, such as omega-3 fatty acids and antioxidants, are also explored.

Mechanistic insights cover tear film instability, inflammatory pathways, neuropathic pain, and meibomian gland dysfunction, emphasizing recent findings on the ocular surface microbiome, genetic and epigenetic factors, and chronic inflammation. Diagnostic innovations include AI and machine learning integration, advanced imaging techniques, tear film analysis, and functional tests, enhancing early detection and monitoring.

Emerging research on gene therapy, stem cell therapy, ocular surface microbiota, and gene editing technologies like CRISPR is examined for future treatment potential. Personalized medicine approaches, incorporating genomic and proteomic profiling and patient-reported outcomes, are emphasized for tailored therapies.

Environmental and lifestyle factors, including pollution, climate change, diet, and behavioral modifications, are considered for their impact on DED management. Integrating these advancements into clinical practice aims to improve patient outcomes and quality of life, highlighting the future potential of cutting-edge research and innovations.

干眼病（DED）通过泪膜不稳定和眼表炎症显著影响生活质量。本文综述了在治疗、机制和诊断方面的进展。新兴的药物疗法，包括新型抗炎剂、分泌剂、皮质类固醇和自体血清滴眼液，以及创新的设备，如点塞、热搏动装置和睑板腺表达技术。生活方式的改变和营养补充，如ω -3脂肪酸和抗氧化剂，也在探索中。机制方面的见解包括泪膜不稳定性、炎症途径、神经性疼痛和睑板腺功能障碍，强调了最近在眼表微生物组、遗传和表观遗传因素以及慢性炎症方面的发现。诊断创新包括人工智能和机器学习的集成、先进的成像技术、泪膜分析和功能测试，加强了早期发现和监测。对基因治疗、干细胞治疗、眼表微生物群和基因编辑技术（如CRISPR）等新兴研究进行了研究，以探索未来的治疗潜力。个性化医疗方法，结合基因组和蛋白质组学分析和患者报告的结果，强调量身定制的治疗。环境和生活方式因素，包括污染、气候变化、饮食和行为改变，被认为是对DED管理的影响。将这些进步整合到临床实践中，旨在改善患者的治疗效果和生活质量，突出前沿研究和创新的未来潜力。

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引用次数: 0

Statin therapy for NAFLD: Molecular underpinnings of myopathic consequences and treatment strategies 他汀类药物治疗NAFLD：肌病后果和治疗策略的分子基础

Aspects of molecular medicine

Pub Date : 2025-06-01 DOI: 10.1016/j.amolm.2025.100091

Pratiksha Nanepag , Shubhada Mangrulkar , Aarti Shriwas , Mayur Kale , Sapana Kushwaha , Nitu Wankhede , Brijesh Taksande , Milind Umekar

Non-alcoholic fatty liver disease (NAFLD) encompasses a range of hepatic disorders characterized by excessive lipid accumulation in hepatocytes and is closely linked to metabolic syndrome. Statins, which are potent lipid-lowering agents, have emerged as potential therapeutic options for managing NAFLD. Recent meta-analyses have demonstrated the efficacy of statins in reducing liver enzymes, improving histological features, and attenuating disease progression in patients with NAFLD. Mechanistically, statins exert their beneficial effects by inhibiting cholesterol synthesis, modulating lipid metabolism, and exhibiting anti-inflammatory and antifibrotic properties. They target key pathogenic pathways in NAFLD, including the inhibition of sterol regulatory element-binding proteins (SREBPs), activation of peroxisome proliferator-activated receptor-alpha (PPAR-α), and enhancement of fatty acid β-oxidation. Additionally, statins mitigate hepatic inflammation by reducing pro-inflammatory cytokines and oxidative stress, while promoting fibrosis regression through the inhibition of RhoA/Rho kinase signaling and transforming growth factor-beta (TGF-β) pathways. However, statin-associated muscle symptoms (SAMS) remain a significant concern, often leading to treatment non-adherence or discontinuation. The molecular mechanisms underlying statin-induced myopathy involve the inhibition of the mevalonate pathway, coenzyme Q10 depletion, mitochondrial dysfunction, and disruption of the ubiquitin-proteasome system. Strategies to prevent and manage SAMS include alternative dosing regimens, statin switching, and the use of complementary therapies such as coenzyme Q10 and vitamin D supplementation. Novel approaches, including PCSK9 inhibitors and nutraceuticals, have also shown promise in mitigating statin-related muscle adverse effects. In conclusion, statins offer a promising therapeutic avenue for NAFLD management, particularly in patients with elevated cardiovascular risk. This review updated the statins' therapeutic potential in NAFLD, their molecular mechanisms, statin-induced myopathy, extra-hepatic effects, and preventive strategies for future research.

非酒精性脂肪性肝病（NAFLD）包括一系列以肝细胞脂质过度积累为特征的肝脏疾病，并与代谢综合征密切相关。他汀类药物是一种有效的降脂药物，已成为治疗NAFLD的潜在治疗选择。最近的荟萃分析表明，他汀类药物在NAFLD患者中具有降低肝酶、改善组织学特征和减缓疾病进展的功效。从机制上讲，他汀类药物通过抑制胆固醇合成，调节脂质代谢，并表现出抗炎和抗纤维化的特性来发挥其有益作用。它们靶向NAFLD的关键致病途径，包括抑制甾醇调节元件结合蛋白（SREBPs）、激活过氧化物酶体增殖因子激活受体α (PPAR-α)和增强脂肪酸β-氧化。此外，他汀类药物通过降低促炎细胞因子和氧化应激来减轻肝脏炎症，同时通过抑制RhoA/Rho激酶信号传导和转化生长因子-β (TGF-β)途径促进纤维化消退。然而，他汀类药物相关肌肉症状（SAMS）仍然是一个值得关注的问题，经常导致治疗不依从或停药。他汀类药物引起的肌病的分子机制包括甲羟戊酸途径的抑制、辅酶Q10的缺失、线粒体功能障碍和泛素-蛋白酶体系统的破坏。预防和管理SAMS的策略包括替代给药方案、他汀类药物转换以及使用辅酶Q10和维生素D补充等补充疗法。包括PCSK9抑制剂和营养药品在内的新方法也显示出减轻他汀类药物相关肌肉不良反应的希望。总之，他汀类药物为NAFLD治疗提供了一种很有前景的治疗途径，特别是对于心血管风险升高的患者。本文综述了他汀类药物在NAFLD中的治疗潜力、分子机制、他汀类药物诱导的肌病、肝外效应以及未来研究的预防策略。

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引用次数: 0

Hematological and biochemical responses to extreme hypoxia exposure after hypoxia preconditioning in Sprague–Dawley rats Sprague-Dawley大鼠缺氧预处理后对极度缺氧暴露的血液学和生化反应

Aspects of molecular medicine

Pub Date : 2025-05-15 DOI: 10.1016/j.amolm.2025.100088

Megha A. Nimje , Himadri Patir , Rajesh Kumar Tirpude , Prasanna K. Reddy , Bhuvnesh Kumar

Hypoxia preconditioning (HP) is postulated to induce adaptive changes in the body for endurance and hypoxic acclimatization. Its dosage (severity, intermittence, duration) determines its effectiveness. Male SD rats were subjected to HP by exposing them to intervals of hypoxia for different durations in a normobaric hypoxia chamber at 12 % FiO₂ for 4h consecutively for 1, 2, 3, 4 and 5 days. To assess the acclimating effect of HP, the animals were further subjected to severe hypoxic exposure to 8 % FiO₂ for 6h. Physiological variables (peripheral oxygen saturation-SpO₂, heart rate-HR, and respiratory rate-RR), protein expression parameters (HIF-1α, EPO, VEGF, and uNOS), biochemical metabolites and hematology and blood gas variables were studied during the course of the hypoxia preconditioning schedule. All the statistical comparisons were performed using one-way ANOVA following Tukey's correction. It was found Day 3-HP was associated with a greater SpO₂ level (p < 0.05) compared with those of other hypoxia preconditioned groups, the percentage of NRBC was lowest in day 3-HP. PCO₂ was lower during days 2, 3 and 4-HP. Circulatory metabolites (nitrate + nitrite-NO, L-arginine, citrulline, succinate, blood urea nitrogen, and L-lactate) changed significantly with different durations of hypoxia preconditioning. HIF-1α showed peak expression on HP-3 day, whereas EPO was highest during HP-2 day, and VEGF was significantly lower at p < 0.001 as compared to extreme hypoxia without HP. Reduced oxidative stress (ROS) and inflammation (histopathology) were observed during HP-3 day. Hypoxia preconditioning at 12 % FiO₂ for 3 days can be postulated to be a potent non-pharmacological modality for inducing physiological and molecular responses that can influence hypoxic acclimatization during exposure to extremely hypoxic conditions.

缺氧预处理（HP）被认为是诱导身体的适应性变化，以耐力和缺氧适应。它的剂量（严重程度、间歇性、持续时间）决定了它的有效性。将雄性SD大鼠置于12% FiO2的常压缺氧舱中，连续缺氧4小时，分别为1、2、3、4和5天。为了评估HP的适应效果，动物进一步接受8% FiO2的严重缺氧暴露6小时。研究缺氧预处理过程中的生理指标（外周氧饱和度- spo2、心率- hr、呼吸速率- rr）、蛋白表达参数（HIF-1α、EPO、VEGF、uNOS）、生化代谢物、血液学和血气指标。所有统计比较均采用Tukey校正后的单因素方差分析进行。发现第3天hp与较高的SpO2水平相关(p <；与其他低氧预处理组相比，NRBC百分比在第3-HP时最低。PCO2在第2、3和4 hp时较低。循环代谢物（硝酸盐+亚硝酸盐- no、l -精氨酸、瓜氨酸、琥珀酸盐、血尿素氮和l -乳酸）随缺氧预处理时间的不同而发生显著变化。HIF-1α在HP-3 d表达最高，EPO在HP-2 d表达最高，VEGF在HP-3 d表达显著降低；与无HP的极度缺氧相比为0.001。HP-3天观察到氧化应激（ROS）和炎症（组织病理学）的减少。在12% FiO2条件下缺氧预处理3天可以被认为是一种有效的非药物方式，可以诱导生理和分子反应，这些反应可以影响暴露于极缺氧条件下的缺氧适应。

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引用次数: 0

Comprehensive review on anti-obesity effects of plant-derived compounds: Evidence from 3T3-L1 adipocytes and high-fat diet models 植物源性化合物抗肥胖作用的综合综述：来自3T3-L1脂肪细胞和高脂饮食模型的证据

Aspects of molecular medicine

Pub Date : 2025-05-13 DOI: 10.1016/j.amolm.2025.100089

Sachin Gudasi, Mrityunjaya B. Patil

Obesity, a multifactorial chronic disease, poses a growing global health concern, contributing to increased incidences of type 2 diabetes, cardiovascular diseases, osteoarthritis, and several cancers. Despite various pharmacological attempts targeting lipid metabolism enzymes, the associated adverse effects have led to numerous drug withdrawals, underscoring the urgent need for safer and more effective therapeutic strategies. In this context, the present study explores the novel therapeutic potential of plant-derived bioactives, specifically formulated using gold nanoparticles (GNPs), for the management of obesity. We systematically investigated the modulation of critical adipogenic and lipogenic regulatory proteins—C/EBP-α, PPAR-α, perilipin-1, adiponectin, FABP4, FAS, and ACC in 3T3-L1 pre-adipocytes and high-fat diet-induced obese mice. Our findings demonstrate that GNP-encapsulated phytoconstituents significantly reduce intracellular lipid accumulation by activating AMPK, a key energy sensor that downregulates pro-adipogenic and lipogenic genes (PPAR-α, C/EBP-α, AP2, SREBP-1c, ACC1, FAS, and LPL), while concurrently upregulating lipolytic and thermogenic genes (HSL, PGC-1α, and SIRT1) and enhancing adiponectin expression. The novelty of this study lies in the synergistic application of nanotechnology and traditional plant-based therapeutics to target obesity at a molecular level, offering a dual advantage of enhanced bioavailability and targeted action. These outcomes provide compelling evidence for the use of functionalized nanoparticles as a next-generation anti-obesity strategy, with potential translational value for clinical application.

肥胖是一种多因素慢性疾病，引起了越来越多的全球健康关注，导致2型糖尿病、心血管疾病、骨关节炎和几种癌症的发病率增加。尽管各种针对脂质代谢酶的药理学尝试，相关的不良反应已导致许多药物停药，强调迫切需要更安全，更有效的治疗策略。在此背景下，本研究探索了植物源性生物活性物质的新型治疗潜力，特别是使用金纳米颗粒（GNPs）配制的植物源性生物活性物质，用于治疗肥胖。我们系统地研究了3T3-L1脂肪前细胞和高脂饮食诱导的肥胖小鼠中关键的脂肪生成和脂肪生成调节蛋白- c /EBP-α、PPAR-α、periilipin -1、脂联素、FABP4、FAS和ACC的调节。我们的研究结果表明，gnp包封的植物成分通过激活AMPK显著减少细胞内脂质积累，AMPK是一个关键的能量传感器，下调促脂肪和脂肪生成基因（PPAR-α、C/EBP-α、AP2、SREBP-1c、ACC1、FAS和LPL），同时上调脂肪分解和产热基因（HSL、PGC-1α和SIRT1），并增强脂联素的表达。这项研究的新颖之处在于纳米技术和传统植物疗法的协同应用，在分子水平上靶向肥胖，提供了增强生物利用度和靶向作用的双重优势。这些结果为功能化纳米颗粒作为下一代抗肥胖策略的使用提供了强有力的证据，具有潜在的临床应用转化价值。

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引用次数: 0

In-silico identification of phytochemicals as potential therapeutic agents to inhibit the HMG-CoA reductase activity using computational approach 利用计算机方法在计算机上鉴定植物化学物质作为抑制HMG-CoA还原酶活性的潜在治疗剂

Aspects of molecular medicine

Pub Date : 2025-05-09 DOI: 10.1016/j.amolm.2025.100086

Sheetal Dagar , Anil Panwar , Dushyant Gahalyan , Neeru Redhu , Mukesh Kumar , Sunil Kumar , Varruchi Sharma , Heera Ram , Ravikant Verma , Anil Sharma

Phytochemicals, have long been studied for various severe metabolic illnesses and degenerative diseases like heart disease and cancer because of their significant therapeutic effects. In animal cells, cholesterol serves a critical role being a component of cell membranes and essential for the normal functioning of precursor cells to some steroid hormones. Three-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) is converted into mevalonate by the HMG-CoA Reductase (HMGCR) enzyme to produce cholesterol. However, when cholesterol levels are high, it may result in atherosclerosis. Statins, also known as synthetic drugs which decrease cholesterol, are therefore designed to work by targeting this enzyme. For patients with dyslipidemia, the side effects of excessive statin therapy have proven alarming hence using natural plant-based inhibitors is a promising alternative. Computational approach helps to identified many drugs that can target HMG-CO A Reductase. In this study, using in-silico molecular docking via auto-dock, 20 medicinal plants with 120 phytochemicals, reported as having antihyperlipidemic activity through deep literature study, were screened as HMG-CoA reductase enzyme inhibitors. The virtual molecular docking results reveals that five bioactive compounds; Sominone, Guggulsterone, Phytosterol, Withanolide A and Basilol, had higher binding affinities towards the HMG-CO A Reductase having binding energies of −9.33, −8.99, −8.87, −8.58, and −8.48 kcal/mol, respectively. ADMET properties of selected compounds were analysed using swiss adme tool. Results showed that out of five compounds three follow Lipinski rule of five, having ADMET properties. The HMG-CoA reductase-ligand complex's stability was validated by RMSD, RMSF, Rg, H-bond results and principal component analysis. The resulting trajectories of converged period of MD were further exploited in MM-P/G/BSA calculations to derive accurate estimates of binding free energies. This leads one to the conclusion that five phytochemicals, Sominone, Guggulsterone, Phytosterol, Withanolide A and Basilol can serve as potential inhibitors in regulating HMGCR's function may assist the development of effective anti-hyperlipedemic drugs.

植物化学物质长期以来一直被研究用于各种严重的代谢性疾病和退行性疾病，如心脏病和癌症，因为它们具有显著的治疗作用。在动物细胞中，胆固醇作为细胞膜的组成部分起着至关重要的作用，对某些类固醇激素的前体细胞的正常功能至关重要。3-羟基-3-甲基戊二酰辅酶A （HMG-CoA）通过HMG-CoA还原酶（HMGCR）转化为甲羟戊酸盐产生胆固醇。然而，当胆固醇水平过高时，可能会导致动脉粥样硬化。他汀类药物，也被称为降低胆固醇的合成药物，因此被设计成针对这种酶起作用。对于患有血脂异常的患者，过量他汀类药物治疗的副作用已被证明是令人担忧的，因此使用天然植物抑制剂是一个很有前途的选择。计算方法有助于确定许多靶向HMG-CO A还原酶的药物。本研究采用自动对接的硅基分子对接技术，通过深入的文献研究，筛选出20种药用植物中含有120种植物化学物质的HMG-CoA还原酶抑制剂。虚拟分子对接结果显示5种生物活性化合物；对HMG-CO - A还原酶的结合能分别为- 9.33、- 8.99、- 8.87、- 8.58和- 8.48 kcal/mol，其中皂苷酮、古古酮、植物甾醇、威纳醇A和巴西罗酮具有较高的结合亲和力。用瑞士adme工具分析了所选化合物的ADMET性质。结果表明，五种化合物中有三种符合Lipinski法则，具有ADMET性质。通过RMSD、RMSF、Rg、氢键结果和主成分分析验证了HMG-CoA还原酶-配体复合物的稳定性。在MM-P/G/BSA计算中进一步利用所得的MD收敛周期轨迹，得到了结合自由能的精确估计。因此，Sominone、Guggulsterone、Phytosterol、Withanolide A和Basilol这5种植物化学物质可能是调控HMGCR功能的潜在抑制剂，有助于开发有效的抗高脂血症药物。

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引用次数: 0

In silico identification of potential inhibitors for the universal stress G4LZI3 protein from Schistosoma mansoni using molecular docking and molecular dynamics simulation analyses 基于分子对接和分子动力学模拟分析的曼氏血吸虫通用胁迫G4LZI3蛋白潜在抑制剂的计算机鉴定

Aspects of molecular medicine

Pub Date : 2025-04-29 DOI: 10.1016/j.amolm.2025.100084

Lihle Mahamba, Mustafa Alhaji Isa, Abidemi Paul Kappo

Human schistosomiasis is a debilitating, neglected tropical disease affecting millions worldwide. Control efforts primarily rely on health education, improved sanitation, snail host management, and mass drug administration with Praziquantel (PZQ). PZQ has some limitations, such as its lower effectiveness against immature parasites and the potential for developing resistance. This requires the urgent need for new treatment approaches. The universal stress protein G4LZI3 helps the Schistosoma mansoni parasite survive when it is under stress from its host. Because of this, it emerges as a promising target for developing new drugs. Despite its biological relevance, G4LZI3 has not been previously investigated as a druggable target, highlighting a significant research gap in schistosomiasis drug discovery. To find potential inhibitors of G4LZI3, we conducted a virtual screening using the RASPD⁺ tool, which led us to select 7889 ligands from the CoCoNut database. These ligands were filtered based on physicochemical properties (Lipinski's Rule of Five, Veber's Rule, Egan's Filter, and the Ghose filter), pharmacokinetics, and Pan-Assay Interference Structures (PAINS) criteria, followed by molecular docking. Fifteen compounds demonstrated strong binding affinities, with binding energies ranging from −10.6 to −8.50 kcal/mol, exceeding that of PZQ (−8.4 kcal/mol). From these, six compounds were selected for further analysis, including molecular dynamics (MD) simulation, solvent-accessible surface area (SASA), and molecular mechanics generalized Born surface area (MM-GBSA) calculations. MD simulation of 200 ns revealed that CNP0475438, CNP0415153, and CNP0353858 achieved significant stability and favourable interactions with G4LZI3. These findings show these compounds as promising candidates for S. mansoni inhibition, pending experimental validation. The results identify novel scaffolds with vigorous predicted activity and provide a rational starting point for experimental optimization and development of new antiparasitic therapies that address praziquantel resistance and efficacy limitations in endemic regions.

人类血吸虫病是一种使人衰弱、被忽视的热带疾病，影响全世界数百万人。控制工作主要依靠健康教育、改善卫生条件、蜗牛寄主管理和吡喹酮（PZQ）的大规模用药。PZQ具有一定的局限性，如对未成熟寄生虫的有效性较低，并且可能产生耐药性。这就迫切需要新的治疗方法。通用应激蛋白G4LZI3帮助曼氏血吸虫在宿主的应激下存活。正因为如此，它成为开发新药的一个有希望的目标。尽管具有生物学意义，但G4LZI3此前尚未作为可药物靶点进行研究，这凸显了血吸虫病药物发现的重大研究空白。为了寻找G4LZI3的潜在抑制剂，我们使用RASPD+工具进行了虚拟筛选，这使我们从CoCoNut数据库中选择了7889个配体。这些配体根据理化性质（Lipinski’s Rule of Five, Veber’s Rule, Egan’s Filter和Ghose Filter）、药代动力学和泛分析干扰结构（Pan-Assay Interference Structures， PAINS）标准进行筛选，然后进行分子对接。15个化合物表现出较强的结合亲和力，结合能在−10.6 ~−8.50 kcal/mol之间，超过PZQ的- 8.4 kcal/mol。从中选择6个化合物进行进一步分析，包括分子动力学（MD）模拟、溶剂可及表面积（SASA）和分子力学广义Born表面积（MM-GBSA）计算。200 ns的MD模拟表明，CNP0475438、CNP0415153和CNP0353858与G4LZI3具有显著的稳定性和良好的相互作用。这些发现表明，这些化合物是有希望的候选曼氏梭菌抑制，有待实验验证。结果确定了具有高预测活性的新型支架，并为实验优化和开发新的抗寄生虫疗法提供了合理的起点，以解决吡喹酮在流行地区的耐药性和疗效限制。

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引用次数: 0

Identification and exploration of novel FGFR-1 inhibitors in the Lotus database for Cholangiocarcinoma (CCA) treatment Lotus数据库中用于胆管癌（CCA）治疗的新型FGFR-1抑制剂的鉴定和探索

Aspects of molecular medicine

Pub Date : 2025-04-26 DOI: 10.1016/j.amolm.2025.100085

Samuel Aduramurewa Osunnaya , Wilberforce K. Ndarawit , Ifeoluwa Aderibigbe , Ibilola A. Omolopo , Precious O. Aribisala , Ayodele Oluwasegun Elekan , Adeola Sakirat Adeyemo , Sheriffdeen Abiola Amoo , Olatunde Simbiat Olamiposi , Njogu M. Kimani , Taiwo Hamidat Olaide , Adedoyin John-Joy Owolade , Damilola Samuel Bodun

Cholangiocarcinoma (CCA) is a rare but aggressive cancer affecting the bile duct, with limited treatment options and a poor prognosis. This study employed a machine learning algorithm and molecular docking using Maestro to screen 215,925 compounds from the Lotus database, aiming to identify potential fibroblast growth factor receptor-1 (FGFR1) inhibitors as therapeutic agents. Five promising compounds were identified, with binding energies ranging from −10.018 to −8.439 kcal/mol, all outperforming the standard drug Dovitinib (−8.419 kcal/mol). Molecular mechanics calculations and MM/GBSA analysis confirmed the structural stability and favorable binding energies of the protein-ligand complexes. Additionally, 100-ns molecular dynamic simulations demonstrated that the top three compounds remained stable within FGFR1's active site, supported by root mean square deviation, root mean square fluctuation, and hydrogen bond interactions. Overall, these five compounds show promise as potential therapeutic agents for CCA and warrant further investigation for drug development.

胆管癌（CCA）是一种罕见但侵袭性的影响胆管的癌症，治疗选择有限且预后差。本研究采用机器学习算法和Maestro分子对接从Lotus数据库中筛选215,925种化合物，旨在确定潜在的成纤维细胞生长因子受体-1 （FGFR1）抑制剂作为治疗剂。5个化合物的结合能范围为−10.018 ~−8.439 kcal/mol，均优于标准药物Dovitinib（−8.419 kcal/mol）。分子力学计算和MM/GBSA分析证实了蛋白质-配体复合物的结构稳定性和良好的结合能。此外，100-ns分子动力学模拟表明，前三种化合物在FGFR1活性位点内保持稳定，这是由均方根偏差、均方根波动和氢键相互作用支持的。综上所述，这五种化合物有望成为CCA的潜在治疗药物，值得进一步的药物开发研究。

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引用次数: 0

Hepatoprotective potential of vanillic acid against isoniazid-rifampicin-induced liver toxicity 香草酸对异烟肼-利福平所致肝毒性的保护作用

Aspects of molecular medicine

Pub Date : 2025-04-25 DOI: 10.1016/j.amolm.2025.100087

Mohd Islam Ansari, Nazneen Dubey, Aditya Ganeshpurkar

Liver toxicity induced by antitubercular drugs, such as isoniazid and rifampicin, poses a significant clinical challenge due to oxidative stress and hepatocellular damage. This study evaluated the hepatoprotective potential of vanillic acid in mitigating drug-induced liver injury in rats. Hepatotoxicity was induced by administering isoniazid and rifampicin, followed by treatment with vanillic acid at two different doses (50 mg/kg and 100 mg/kg). Silymarin, a well-known hepatoprotective agent, was used as a reference standard. Biochemical markers, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), superoxide dismutase (SOD), catalase, and bilirubin, were assessed to evaluate liver function and oxidative stress.

Results revealed significant elevation in AST, ALT, ALP, and bilirubin levels and a reduction in antioxidant enzymes (SOD and catalase) in the isoniazid and rifampicin-treated group, indicating severe liver damage. Co-administration of vanillic acid significantly reduced these elevated markers and restored antioxidant enzyme levels in a dose-dependent manner. The higher dose of vanillic acid (100 mg/kg) exhibited a more pronounced hepatoprotective effect, comparable to silymarin. These findings suggest that vanillic acid exerts its protective effects by enhancing antioxidant defense, reducing oxidative stress, and preserving liver cell integrity.

This study highlights the therapeutic potential of vanillic acid in preventing drug-induced liver toxicity and underscores its role as a promising candidate for hepatoprotection during antitubercular therapy. Further investigation into its molecular mechanisms and clinical applicability is warranted.

由于氧化应激和肝细胞损伤，异烟肼和利福平等抗结核药物引起的肝毒性是一个重大的临床挑战。本研究评价了香草酸对大鼠药物性肝损伤的保护作用。先给药异烟肼和利福平，然后用两种不同剂量的香草酸（50 mg/kg和100 mg/kg）诱导肝毒性。以水飞蓟素为标准品，水飞蓟素是一种著名的保肝剂。生化指标包括天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、碱性磷酸酶（ALP）、超氧化物歧化酶（SOD）、过氧化氢酶和胆红素，评估肝功能和氧化应激。结果显示异烟肼和利福平治疗组AST、ALT、ALP和胆红素水平显著升高，抗氧化酶（SOD和过氧化氢酶）降低，提示肝损伤严重。共同施用香草酸可显著降低这些升高的标记物，并以剂量依赖的方式恢复抗氧化酶水平。较高剂量的香草酸（100 mg/kg）表现出更明显的肝保护作用，与水飞蓟素相当。这些发现表明，香草酸通过增强抗氧化防御、减少氧化应激和保持肝细胞完整性发挥其保护作用。本研究强调了香草酸在预防药物性肝毒性方面的治疗潜力，并强调了其在抗结核治疗中作为肝保护的有希望的候选药物的作用。其分子机制和临床应用有待进一步研究。

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引用次数: 0

Understanding the interplay of malarial pathogenesis, host immune response and oxidative stress: Implications for disease progression and therapeutic strategies 了解疟疾发病机制、宿主免疫反应和氧化应激的相互作用：对疾病进展和治疗策略的影响

Aspects of molecular medicine

Pub Date : 2025-04-12 DOI: 10.1016/j.amolm.2025.100082

Muzi Nicolas Buthelezi , Kgaugelo Josephine Masia , Priscilla Masamba , Mthokozisi Blessing Cedric Simelane , Abidemi Paul Kappo

Despite sustained efforts, malaria elimination in developing countries, particularly in Africa, remains a to be a public burden due to the evolution and emergence of resistance to most of the currently available antimalarials and insecticides. Over time, it has been argued that a thorough understanding of the parasite's biology and pathogenesis is important because it arises from a dynamic interplay between the host and the parasite. The lifecycle of the malarial parasite is complex, involving distinct developmental stages that each express specific antigens, which in turn trigger the immune system to either protect or promote pathophysiology. Malaria pathogenesis is thus a complex interplay of Plasmodum-induced red blood cell alterations and microvascular irregularities that lead to clinical symptoms and disease severity. Immune activation during malarial infection triggers a robust production of reactive oxygen and nitrogen species (ROS/RNS), contributing to oxidative stress, a characteristic seen during malarial infection and believed to exacerbate malarial pathophysiology. Therefore, this manuscript will examine the cellular mechanism underlying malarial pathophysiology, zoom in on oxidative stress, how it is linked to malarial severity and pathophysiology, and how it could be targeted to ameliorate ROS-mediated associated complications in malaria.

尽管作出了持续努力，发展中国家，特别是非洲的疟疾消除工作仍然是一项公共负担，因为对大多数现有抗疟药和杀虫剂产生了抗药性。随着时间的推移，人们一直认为彻底了解寄生虫的生物学和发病机制是重要的，因为它源于宿主和寄生虫之间的动态相互作用。疟原虫的生命周期很复杂，涉及不同的发育阶段，每个阶段都表达特定的抗原，进而触发免疫系统保护或促进病理生理。因此，疟疾发病机制是疟原虫引起的红细胞改变和微血管不规则的复杂相互作用，从而导致临床症状和疾病严重程度。疟疾感染期间的免疫激活触发活性氧和活性氮（ROS/RNS）的大量产生，导致氧化应激，这是疟疾感染期间的一种特征，据信会加剧疟疾的病理生理。因此，本文将研究疟疾病理生理的细胞机制，聚焦氧化应激，它如何与疟疾严重程度和病理生理相关联，以及它如何能够靶向改善ros介导的疟疾相关并发症。

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引用次数: 0

Diagnostic potential of monocyte subsets, TNF-α, and IL-6 in pediatric celiac disease: A case-control study 单核细胞亚群、TNF-α和IL-6在小儿乳糜泻中的诊断潜力：一项病例对照研究

Aspects of molecular medicine

Pub Date : 2025-04-10 DOI: 10.1016/j.amolm.2025.100083

Naglaa Makram Farag , Noura Elbakry , Mahmoud Mousa , Mohamed S. Hemeda , Zamzam Hassan Mohamed

Celiac disease (CD) is a chronic autoimmune disorder of the small intestine, which is triggered by dietary gluten, especially in individuals with a genetic instinct. Monocytes play an important role in modifying intestinal immunity and inflammation, yet the importance of their subgroups in CD is not clear.

Methods

The case-control study was held at the Pediatric Outpatient Clinic of Minia University Hospital, including 57 CD patients and 29 age- and sex-matched healthy controls. Clinical examination, laboratory check, and history were demonstrated for all participants. The serum levels of the IL-6 and TNF-α cytokines were measured using ELISA, and most analysis was done using flow cytometry. The variable with significant differences was further evaluated for its clinical ability.

Results

Monocytes are more prevalent in CD patients than in controls. In the case group, the average level of monocyte CD14+/CD16+ and CD14–/CD16+ was much higher than in the control group of CD patients (P-value <0.001). Additionally, CD patients who tested positive for antibodies had much higher levels of certain monocyte types compared to those who tested negative (p-values of 0.003, 0.011, and 0.001, respectively). Cytokines were not balanced, as levels of TNF-α and IL-6 were much higher in CD patients than in the control group. There was a significant positive relationship (p-value <0.001) between different types of monocytes and the amounts of autoantibodies, TNF-α, and IL-6.

Conclusion

TNF-α, IL-6, and certain types of monocytes could be useful indicators for diagnosing CD, as we found important differences between the groups we studied.

乳糜泻（CD）是一种慢性小肠自身免疫性疾病，由饮食中的麸质诱发，尤其是在具有遗传本能的个体中。该病例对照研究在米尼亚大学医院儿科门诊进行，包括 57 名 CD 患者和 29 名年龄和性别匹配的健康对照者。所有参与者均接受了临床检查、实验室检查和病史询问。血清中的 IL-6 和 TNF-α 细胞因子水平采用 ELISA 法进行测量，大部分分析采用流式细胞术进行。结果CD患者的单核细胞多于对照组。在病例组中，单核细胞 CD14+/CD16+ 和 CD14-/CD16+ 的平均水平远远高于 CD 患者对照组（P 值为 0.001）。此外，抗体检测呈阳性的 CD 患者与抗体检测呈阴性的患者相比，某些类型的单核细胞水平要高得多（P 值分别为 0.003、0.011 和 0.001）。细胞因子并不平衡，CD 患者的 TNF-α 和 IL-6 水平远高于对照组。不同类型的单核细胞与自身抗体、TNF-α 和 IL-6 的数量之间存在明显的正相关关系（p 值为 0.001）。

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引用次数: 0