Aspects of molecular medicine最新文献

Corrigendum to “In silico identification of potential inhibitors for the universal stress G4LZI3 protein from Schistosoma mansoni using molecular docking and molecular dynamics simulation analyses” [Aspects of Molecular Medicine 5 (2025) 100084] “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”[分子医学5(2025)100084]的更正

Aspects of molecular medicine

Pub Date : 2025-12-01 DOI: 10.1016/j.amolm.2025.100096

Lihle Mahamba, Mustafa Alhaji Isa, Abidemi Paul Kappo

引用次数: 0

De novo assembly of an admixed South African genome and its clinical application to genetic susceptibility to tuberculosis 混合南非基因组的重新组装及其对结核病遗传易感性的临床应用

Aspects of molecular medicine

Pub Date : 2025-11-05 DOI: 10.1016/j.amolm.2025.100098

Anel Sparks , Yolandi Swart , Craig J. Kinnear , Gian D. van der Spuy , Gerard Tromp , Brigitte Glanzmann , Marlo Möller

Despite ongoing efforts, the current human reference genome lacks diversity. Consequently, research using this resource might miss disease-causing variants in individuals whose ancestry does not correspond to that of the standard reference. Most individuals from South Africa are admixed to some extent, with ancestral contributions from several continental populations. This study set out to create a population-specific reference genome for admixed South Africans with the same coordinate system as the widely used GRCh38 reference. This approach was tested in diagnosing a South African individual with Mendelian susceptibility to mycobacterial disease (MSMD) using a novel approach that replaced portions of the reference genome with corresponding, but more variable portions of the population-specific sequences. We implemented the algorithm in a tool we named PopPatch. Short sequencing reads from two individuals were used for a rudimentary genome assembly which was then aligned to GRCh38p13. To test the algorithm and the generated reference genome, whole genome sequencing data from a TB-susceptible individual was aligned to SA_PopPatch and GRCh38, with variant call sets compared. The GRCh38p13 reference yielded no discoveries, while the SA_PopPatch reference identified a homozygous, non-synonymous single nucleotide variant in exon 20 of the JAK1 gene. This project introduces a novel method for creating population-specific reference genomes that align with the standard reference, ensuring congruency with databases based on the most widely used reference genome, GRCh38, while minimizing additional costs.

尽管不断努力，目前的人类参考基因组缺乏多样性。因此，使用这一资源的研究可能会遗漏那些血统与标准参考不相符的个体的致病变异。大多数来自南非的人在某种程度上是混血儿，祖先来自几个大陆种群。这项研究的目的是为南非混血人建立一个特定人群的参考基因组，与广泛使用的GRCh38参考基因组具有相同的坐标系。该方法在诊断一名南非分枝杆菌病孟德尔易感性个体（MSMD）时进行了测试，使用了一种新方法，该方法将参考基因组的部分替换为群体特异性序列的相应但更可变的部分。我们在一个名为PopPatch的工具中实现了这个算法。来自两个个体的短测序读数用于基本基因组组装，然后将其与GRCh38p13对齐。为了验证算法和生成的参考基因组，将一个结核病易感个体的全基因组测序数据与SA_PopPatch和GRCh38进行比对，并比较变异调用集。GRCh38p13参考文献没有发现，而SA_PopPatch参考文献在JAK1基因的外显子20上发现了一个纯合的非同义单核苷酸变异。该项目介绍了一种新的方法，用于创建与标准参考基因组一致的特定人群参考基因组，确保与基于最广泛使用的参考基因组GRCh38的数据库一致，同时最大限度地减少额外成本。

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引用次数: 0

A cautionary note on genomic complexity and bioinformatic analysis in cancer 癌症基因组复杂性和生物信息学分析的警示

Aspects of molecular medicine

Pub Date : 2025-11-04 DOI: 10.1016/j.amolm.2025.100097

Victoria A. Patten , Hocine Bendou , Denver T. Hendricks , Christopher G. Mathew , Wenlong Carl Chen , Joanna C. Fowler , Roshan K. Sood , Philip H. Jones , M. Iqbal Parker

Variant calling in complex genomic regions remains a critical challenge in cancer genomics, yet systematic evaluations of false positive rates in such regions are rarely reported. This investigative study examined somatic mutations in esophageal squamous cell carcinoma (ESCC) using Whole Genome Sequencing (WGS) data, that identified a high frequency of putative mutations in MUC3A, a gene with an inherently complex sequence architecture. Quantitative laboratory validation attempts failed to confirm any of these computationally predicted mutations, prompting systematic re-analysis. By assessing multiple variant calling algorithms and implementing a Panel of Normals (PON) filtering strategy, we demonstrate that standard bioinformatics pipelines generated extensive false positive calls in MUC3A, with false positive rates approaching 100 % for this gene. While previous studies have acknowledged limitations in variant calling for repetitive or homologous regions, our work provides evidence of complete analytical failure in the MUC3A gene, and establishes a reproducible framework for identifying such artefacts. These findings address a critical research gap by quantifying the magnitude of false discovery in complex genomic contexts and demonstrating that multi-tool consensus approaches combined with PON filtering are insufficient without accompanied experimental validation. We recommend mandatory quantitative confirmation for variants identified in sequence-complex genes and advocate for transparent reporting of validation rates in cancer genomic studies to prevent propagation of spurious findings in literature. This paper provides a cautionary warning to future research to take into consideration the limitations of alignment and variant calling tools and to employ a combination of tools to obtain robust and reliable results.

复杂基因组区域的变异召唤仍然是癌症基因组学的一个关键挑战，然而对这些区域的假阳性率的系统评估很少有报道。本研究利用全基因组测序（WGS）数据检测了食管鳞状细胞癌（ESCC）的体细胞突变，发现MUC3A基因的假定突变频率很高，MUC3A基因具有固有的复杂序列结构。定量实验室验证尝试未能证实任何这些计算预测的突变，促使系统的重新分析。通过评估多种变体调用算法并实施正常面板（PON）过滤策略，我们证明了标准生物信息学管道在MUC3A中产生了广泛的假阳性调用，该基因的假阳性率接近100%。虽然以前的研究已经承认了重复或同源区域的变异召唤的局限性，但我们的工作提供了MUC3A基因完全分析失败的证据，并建立了一个可重复的框架来识别此类伪影。这些发现通过量化复杂基因组背景下错误发现的程度，解决了一个关键的研究空白，并表明如果没有伴随的实验验证，多工具共识方法结合PON过滤是不够的。我们建议对序列复杂基因中发现的变异进行强制性定量确认，并主张在癌症基因组研究中透明地报告验证率，以防止文献中虚假发现的传播。本文为今后的研究提供了一个警示性的警告，即考虑到校准和变体调用工具的局限性，并使用工具的组合来获得稳健和可靠的结果。

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引用次数: 0

Antioxidant, anti-inflammatory and cytotoxicity properties of medicinal plants used for producing herbal products against hepatic diseases in Ghana 加纳用于生产治疗肝病的草药产品的药用植物的抗氧化、抗炎和细胞毒性

Aspects of molecular medicine

Pub Date : 2025-07-11 DOI: 10.1016/j.amolm.2025.100093

Dongsogo Julius , Larbie Christopher , Appiah-Oppong Regina , Emekpe Benjamin , Daniel Ataanya Abera , Yusif Mubarik , Iddrisu Abdul-Mumeen

Medicinal plants have become the option for management of liver diseases because of their availability, cost effectiveness and lesser side effects compared to pharmaceutical drugs. Various parts of plants including roots, leaves, stem, bark and seed have been reportedly used to treat liver diseases including jaundice, hepatitis, hepatosteatosis, hepatocellular carcinoma, hepatobillary disorders and hepatocellular carcinoma. Phytochemicals exhibit anti-oxidant and anti-inflammatory properties due to the presence of acidic polyhydroxyl groups in the phenols. These hydroxyl groups quench free radicals from oxygen, nitrogen and sulphur reactive species thereby inhibiting oxidative stress, inflammation and fibrogenic processes. The objective of the study was to determine the antioxidant, anti-inflammatory and cytotoxicity properties of medicinal plants for the purpose of selecting more efficacious raw materials for herbal products. Ethanolic and methanolic extracts of 13 medicinal plants were test for level of total phenols, flavonoids, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) reducing potential, ferric reducing (FRAP), total antioxidant binding capacity (ABTS), red cell antihemolysis assay and 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) cytotoxicity. Except for DPPH scavenging activity, there was significance of difference between the methanolic and ethanolic extracts, total phenols (p = 0.03), flavonoids (p = 0.024), FRAP (p = 0.02), ABTS (p = 0.00) and red cell hemolysis (p = 0.010). There was correlation between phytochemicals, phenols and flavonoids and antioxidant markers, DPPH, FRAP, ABTS and red cell hemolysis (p < 0.05). Syzygium aromaticum, Curcuma longa, Taraxacum officinalis and Moringa oleifera exhibited the highest inhibitory anti-inflammatory and antioxidant properties. The study indicates that, phytochemical, antioxidant and inflammatory properties varied with the kind of plant, concentration of extract, extractant and polyphenol content. These properties should be evaluated in selecting materials for drug formulation.

药用植物已成为肝病治疗的选择，因为它们的可获得性、成本效益和与药物相比副作用较小。据报道，植物的不同部分，包括根、叶、茎、皮和种子，已被用于治疗肝脏疾病，包括黄疸、肝炎、肝骨赘病、肝细胞癌、肝胆管疾病和肝细胞癌。由于酚类中存在酸性多羟基，植物化学物质具有抗氧化和抗炎特性。这些羟基可以淬灭氧、氮和硫活性物质中的自由基，从而抑制氧化应激、炎症和纤维化过程。本研究的目的是确定药用植物的抗氧化、抗炎和细胞毒性，以便选择更有效的草药产品原料。测定13种药用植物乙醇和甲醇提取物的总酚、总黄酮、2,2 -二苯基-1-吡啶肼（DPPH）还原电位、铁还原电位（FRAP）、总抗氧化结合能力（ABTS）、红细胞抗溶血试验和3-(4,5 -二甲基噻唑-2)- 2,5 -二苯基溴化四唑（MTT）细胞毒性。除DPPH清除活性外，甲醇和乙醇提取物、总酚（p = 0.03）、总黄酮（p = 0.024）、FRAP （p = 0.02）、ABTS （p = 0.00）和红细胞溶血（p = 0.010）均有显著性差异。植物化学物质、酚类和类黄酮与抗氧化标志物、DPPH、FRAP、ABTS和红细胞溶血存在相关性(p <；0.05)。香薷、姜黄、蒲公英和辣木的抗炎和抗氧化活性最强。研究表明，植物化学、抗氧化和抗炎性能随植物种类、提取物浓度、萃取剂浓度和多酚含量的不同而不同。在选择药物配方材料时应评估这些特性。

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引用次数: 0

Neurological mechanism of the dietary supplementations of lycopene on chemotherapy-induced cognitive dysfunction/chemobrain and hippocampal toxicity in the rat model 膳食补充番茄红素对大鼠化疗诱导的认知功能障碍/化学脑和海马毒性的神经机制

Aspects of molecular medicine

Pub Date : 2025-07-10 DOI: 10.1016/j.amolm.2025.100094

Sunday Aderemi Adelakun , Jacob Adewale Siyanbade , Akwu Bala Peter , Mistura Abisola Salami , Bisade Esther Adeyeluwa , Opeyemi Zainab Kaka

Background

Chemo-brain signifies the memory and cognitive challenges cancer patients encounter during and after chemotherapy. Lycopene (LP) is a naturally occurring carotenoid with potent anti-reactive oxygen species (ROS) characteristics. This study investigates the effect of Lycopene on Chemotherapy-induced cognitive dysfunction and hippocampal toxicity in rat models.

Method

Thirty Adult male Sprague-Dawley rats were divided into five groups of five (n = 6) rats each. Group A control received normal saline. Group B received a single dose of 10 mg/kg bwt cisplatin (CP, i.p.) on the first day. Group C received 100 mg/kg bwt of Lycopene (LP) (i.p) once daily. Group D received a single dose of 10 mg/kg CP (i.p.) on the first day, followed by 100 mg/kg bwt of LP (i.p) once daily. Group E was treated with 100 mg/kg bwt of LP (i.p) once daily, followed by a single dose of 10 mg/kg bwt CP (i.p.) on the last day. The experiment lasted for 28 days. Hippocampus histology, oxidative stress, neuro-inflammation, apoptotic markers, brain acetylcholinesterase (AChE) activity, and levels of dopamine (DA), gamma-aminobutyric acid GABA, and serotonin 5-HT were investigated.

Results

Lycopene attenuation of malondialdehyde and nitric oxide levels with elevated glutathione levels and intensified superoxide dismutase and catalase activities. Lycopene decreased the levels of inflammatory and apoptotic markers. In addition, LP reduced AChE activity, and elevated glial fibrillary acidic proteins increased neurotransmitter and brain-derived neurotrophic factors.

Conclusion

Lycopene protected chemobrain rats, decreasing inflammation and apoptosis, increasing antioxidant enzyme activities, and attenuating lipid peroxidation.

化疗脑（chemo -brain）是指癌症患者在化疗期间和化疗后遇到的记忆和认知挑战。番茄红素（LP）是一种天然存在的类胡萝卜素，具有有效的抗活性氧（ROS）特性。本研究探讨番茄红素对大鼠化疗诱导的认知功能障碍和海马毒性的影响。方法30只成年雄性Sprague-Dawley大鼠随机分为5组，每组5只（n = 6）。A组对照组给予生理盐水。B组患者第1天给予顺铂单剂量10 mg/kg bwt （CP, ig）。C组给予番茄红素（LP）（i.p） 100 mg/kg bwt，每日1次。D组在第一天给予单剂量10 mg/kg CP (i.p)，随后给予100 mg/kg bwt LP (i.p)，每日1次。E组每日给予100 mg/kg bwt LP (i.p) 1次，最后1天给予10 mg/kg bwt CP （i.p）单剂量。试验期28 d。观察海马组织、氧化应激、神经炎症、凋亡标志物、脑乙酰胆碱酯酶（AChE）活性、多巴胺（DA）、γ -氨基丁酸GABA、血清素5-HT水平。结果番茄红素抑制丙二醛和一氧化氮水平，使谷胱甘肽水平升高，超氧化物歧化酶和过氧化氢酶活性增强。番茄红素降低炎症和凋亡标志物的水平。此外，LP降低了AChE活性，升高的胶质纤维酸性蛋白增加了神经递质和脑源性神经营养因子。结论番茄红素对化学脑大鼠具有保护作用，可减少炎症和细胞凋亡，提高抗氧化酶活性，减轻脂质过氧化。

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引用次数: 0

In silico identification of potential HDAC3 inhibitors through machine learning, molecular docking, and molecular dynamics simulations for drug repurposing 通过机器学习、分子对接和药物再利用的分子动力学模拟，在计算机上识别潜在的HDAC3抑制剂

Aspects of molecular medicine

Pub Date : 2025-06-18 DOI: 10.1016/j.amolm.2025.100092

Damilare P. Dosunmu , Rachael Oluwakamiye Abolade , Mujeebat Bashiru , Adedoyin John-Joy Owolade , Muyiwa Kolawole Samuel , Ebunoluwa Omorilewa Boluwatife , Ayomadewa Mercy Olatunya , Precious O. Aribisala , Samuel Aduramurewa Osunnaya , Micheal Abimbola Oladosu , Ebenezer Ayomide Oni , Damilola Samuel Bodun

Background

Histone Deacetylase 3 (HDAC3) is an epigenetic enzyme that controls cell cycle progression, apoptosis, and gene expression. Overexpression of HDAC3 has been shown to be a potential contributing factor to the development and spread of breast cancer, and it has recently been identified as a promising target in breast cancer. As a result, repurposing currently approved drugs as novel HDAC3 inhibitors may reduce the labor-intensive and time-consuming process of developing new molecules.

Materials and methods

We sourced 4288 compounds from the ZINC15-approved drugs. We then employed both virtual and structure-based screening to identify and repurpose current drugs as selective inhibitors against the HDAC3 target protein. MD simulation was performed to assess the dynamic behavior and stability of the top ligand complexes for 100 ns.

Results

This computational screening obtained the top five compounds with docking scores of

-

10.96,

-

10.32,

-

9.83,

-

9.83, and

-

8.81 kcal/mol, respectively, in comparison with the reference ligand, BG45 (−4.18 kcal/mol), suggesting they may be more potent HDAC3 inhibitors. The MD simulation study of the top hit ligand-protein complex (HDAC3-ZINC000095618609 complex) revealed stable conformational changes. The results of pharmacokinetic and drug-likeness properties of the top-performing compounds reveal their potential to be considered viable HDAC3 inhibitors.

Conclusion

This study highlights the potential of drug repurposing as a cost-effective and faster approach to cancer treatment. here we have identified drugs have the potential to be repurposed as HDAC3 inhibitors; however, additional in vitro and in vivo studies are needed to confirm their efficacy.

组蛋白去乙酰化酶3 （HDAC3）是一种表观遗传酶，控制细胞周期进程、细胞凋亡和基因表达。HDAC3的过表达已被证明是乳腺癌发展和扩散的潜在促进因素，最近已被确定为乳腺癌的一个有希望的靶点。因此，重新利用目前批准的药物作为新的HDAC3抑制剂可能会减少开发新分子的劳动密集型和耗时的过程。材料和方法我们从zinc15批准的药物中获得了4288个化合物。然后，我们采用虚拟筛选和基于结构的筛选来鉴定和重新利用现有药物作为针对HDAC3靶蛋白的选择性抑制剂。在100 ns的时间内，通过MD模拟评价了顶配体配合物的动力学行为和稳定性。结果与参考配体BG45 （- 4.18 kcal/mol）相比，计算筛选得到的前5个化合物的对接分数分别为- 10.96、- 10.32、- 9.83、- 9.83和- 8.81 kcal/mol，表明它们可能是更有效的HDAC3抑制剂。顶部命中配体-蛋白复合物（HDAC3-ZINC000095618609复合物）的MD模拟研究显示其构象发生了稳定的变化。表现最好的化合物的药代动力学和药物相似特性的结果显示它们被认为是可行的HDAC3抑制剂的潜力。结论：本研究强调了药物再利用作为一种成本效益高、速度快的癌症治疗方法的潜力。在这里，我们已经确定了药物有可能被重新用作HDAC3抑制剂；然而，需要进一步的体外和体内研究来证实其有效性。

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引用次数: 0

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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