Pub Date : 2024-09-03DOI: 10.3389/fmolb.2024.1451536
Sigrid Kirss, Anette Reinapu, Ekaterina Kabin, Julia Smirnova, Vello Tõugu, Peep Palumaa
Alzheimer’s disease (AD) is characterized by classic hallmarks such as amyloid plaques and neurofibrillary tangles, however, intensive research has broadened its scope to explore additional underlying mechanisms. Notably, disruptions in metal homeostasis, particularly involving copper, have gained significant attention. In AD pathology, an imbalance is evident: there is an excess of extracellular copper alongside a deficiency in intracellular copper in brain tissue. Our previous work demonstrated that α-lipoic acid (LA) can effectively shift copper from the extracellular space to the intracellular environment in a neuronal cell model. However, the precise mechanism of action and role of LA in copper metabolism remained elusive. In this study, we compared the cellular effects of LA with those of different synthetic copper-binding ligands: diethyldithiocarbamate (DETC), clioquinol (CQ), D-penicillamine (D-PA) and elesclomol (ES). Using differentiated SH-SY5Y cell culture as a neuronal model, we found that, unlike other synthetic compounds, natural ligand LA is not toxic in the presence of extracellular copper, even at high doses. LA gradually increased intracellular copper levels over 24 h. In contrast, DETC, CQ, and ES acted as fast copper ionophores, potentially explaining their higher toxicity compared to LA. D-PA did not facilitate copper uptake into cells. We demonstrated that a slow increase of LA inside the cells is enhanced in the presence of copper. Furthermore, the ability of LA to modulate the equilibrium of extra- and intracellular copper was evident when we added copper isotope 65Cu. The ratio of copper isotopes changed rapidly, reflecting the impact of LA on the equilibrium of copper distribution without affecting the copper transport network. Our results provide compelling evidence that α-lipoic acid holds promise as a non-toxic agent capable of normalizing copper metabolism in Alzheimer’s disease.
阿尔茨海默病（AD）以淀粉样蛋白斑块和神经纤维缠结等典型特征为特征，然而，深入的研究已经扩大了其范围，以探索更多的潜在机制。值得注意的是，金属平衡的破坏，尤其是涉及铜的破坏，已经引起了人们的极大关注。在注意力缺失症的病理中，失衡是显而易见的：在脑组织中，细胞外铜过量，而细胞内铜缺乏。我们之前的研究表明，在神经元细胞模型中，α-硫辛酸（LA）能有效地将铜从细胞外空间转移到细胞内环境。然而，LA在铜代谢过程中的确切作用机制和角色仍未确定。在这项研究中，我们比较了LA与不同合成铜结合配体（二乙基二硫代氨基甲酸乙酯（DETC）、氯喹诺尔（CQ）、D-青霉胺（D-PA）和伊利司莫（ES））的细胞效应。以分化的 SH-SY5Y 细胞培养作为神经元模型，我们发现，与其他合成化合物不同，天然配体 LA 在细胞外铜存在的情况下没有毒性，即使在高剂量下也是如此。相比之下，DETC、CQ 和 ES 是快速铜离子促进剂，这可能是它们的毒性高于 LA 的原因。D-PA 不能促进铜摄入细胞。我们证明，在铜存在的情况下，细胞内 LA 的缓慢增加会增强。此外，当我们加入铜同位素 65Cu 时，LA 调节细胞内外铜平衡的能力也显而易见。铜同位素的比例变化很快，这反映了LA在不影响铜运输网络的情况下对铜分布平衡的影响。我们的研究结果提供了令人信服的证据，表明α-硫辛酸有望成为一种无毒制剂，能够使阿尔茨海默氏症患者的铜代谢正常化。
{"title":"α-Lipoic acid: a potential regulator of copper metabolism in Alzheimer’s disease","authors":"Sigrid Kirss, Anette Reinapu, Ekaterina Kabin, Julia Smirnova, Vello Tõugu, Peep Palumaa","doi":"10.3389/fmolb.2024.1451536","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1451536","url":null,"abstract":"Alzheimer’s disease (AD) is characterized by classic hallmarks such as amyloid plaques and neurofibrillary tangles, however, intensive research has broadened its scope to explore additional underlying mechanisms. Notably, disruptions in metal homeostasis, particularly involving copper, have gained significant attention. In AD pathology, an imbalance is evident: there is an excess of extracellular copper alongside a deficiency in intracellular copper in brain tissue. Our previous work demonstrated that α-lipoic acid (LA) can effectively shift copper from the extracellular space to the intracellular environment in a neuronal cell model. However, the precise mechanism of action and role of LA in copper metabolism remained elusive. In this study, we compared the cellular effects of LA with those of different synthetic copper-binding ligands: diethyldithiocarbamate (DETC), clioquinol (CQ), D-penicillamine (D-PA) and elesclomol (ES). Using differentiated SH-SY5Y cell culture as a neuronal model, we found that, unlike other synthetic compounds, natural ligand LA is not toxic in the presence of extracellular copper, even at high doses. LA gradually increased intracellular copper levels over 24 h. In contrast, DETC, CQ, and ES acted as fast copper ionophores, potentially explaining their higher toxicity compared to LA. D-PA did not facilitate copper uptake into cells. We demonstrated that a slow increase of LA inside the cells is enhanced in the presence of copper. Furthermore, the ability of LA to modulate the equilibrium of extra- and intracellular copper was evident when we added copper isotope <jats:sup>65</jats:sup>Cu. The ratio of copper isotopes changed rapidly, reflecting the impact of LA on the equilibrium of copper distribution without affecting the copper transport network. Our results provide compelling evidence that α-lipoic acid holds promise as a non-toxic agent capable of normalizing copper metabolism in Alzheimer’s disease.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142220185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
IntroductionDuring the last decade, there has been a significant rise in the use of therapeutic antibodies or passive immunotherapy for treating various conditions like inflammation and cancer. However, these proteins face challenges reaching the brain and often require specialized delivery methods such as single-domain antibodies (sdAbs). Traditional antibodies struggle to efficiently cross the blood-brain barrier (BBB), hindering their effectiveness. Receptor-mediated transcytosis (RMT) offers a promising pathway for transporting large molecules essential for brain function and treatment across the BBB.MethodsSdAbs and peptide ligands with an affinity for RMT receptors are commonly employed to enhance the transport of biotherapeutics compounds across the BBB. This research used a sdAbs phage-displayed library from 13 camelus dromedarius samples to identify sdABs that specifically bind to and are internalized by human BBB endothelial cells (ECs) through in vivo panning.Results and discussionOne sdAb, defined as FB24, was isolated, sequenced, translated into an open reading frame (ORF), and subjected to three-dimensional (3D) modeling. Molecular docking and molecular dynamics simulations were carried out by the HADDOCK web server and GROMACS, respectively, to evaluate the interaction between FB24 and EC receptors in silico. The docking results revealed that FB24 exhibited binding activity against potential EC receptors with −1.7 to −2.7 ranged z score and maintained a stable structure. The docked complex of FB24-RAGE (receptor for advanced glycation end products, also known as advanced glycation end product receptor [AGER]) showed 18 hydrogen bonds and 213 non-bonded contacts. It was chosen for further analysis by molecular dynamics simulations by GROMACS. This complex showed a stable condition, and its root mean square deviation (RMSD) was 0.218 nm. The results suggest that FB24 could serve as a suitable carrier vector for transporting therapeutic and diagnostic agents across the BBB to the brain through a non-invasive route.
{"title":"Molecular dynamics simulation of the brain-isolated single-domain antibody/nanobody from camels through in vivo phage display screening","authors":"Behnam Hasannejad-Asl, Hassan Hashemzadeh, Farkhondeh Pooresmaeil, Mehran Dabiri, Mohammad-Reza Pooresmaeil, Davoud Ahmadvand, Arshad Hosseini","doi":"10.3389/fmolb.2024.1414119","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1414119","url":null,"abstract":"IntroductionDuring the last decade, there has been a significant rise in the use of therapeutic antibodies or passive immunotherapy for treating various conditions like inflammation and cancer. However, these proteins face challenges reaching the brain and often require specialized delivery methods such as single-domain antibodies (sdAbs). Traditional antibodies struggle to efficiently cross the blood-brain barrier (BBB), hindering their effectiveness. Receptor-mediated transcytosis (RMT) offers a promising pathway for transporting large molecules essential for brain function and treatment across the BBB.MethodsSdAbs and peptide ligands with an affinity for RMT receptors are commonly employed to enhance the transport of biotherapeutics compounds across the BBB. This research used a sdAbs phage-displayed library from 13 <jats:italic>camelus dromedarius</jats:italic> samples to identify sdABs that specifically bind to and are internalized by human BBB endothelial cells (ECs) through <jats:italic>in vivo</jats:italic> panning.Results and discussionOne sdAb, defined as FB24, was isolated, sequenced, translated into an open reading frame (ORF), and subjected to three-dimensional (3D) modeling. Molecular docking and molecular dynamics simulations were carried out by the HADDOCK web server and GROMACS, respectively, to evaluate the interaction between FB24 and EC receptors <jats:italic>in silico</jats:italic>. The docking results revealed that FB24 exhibited binding activity against potential EC receptors with −1.7 to −2.7 ranged z score and maintained a stable structure. The docked complex of FB24-RAGE (receptor for advanced glycation end products, also known as advanced glycation end product receptor [AGER]) showed 18 hydrogen bonds and 213 non-bonded contacts. It was chosen for further analysis by molecular dynamics simulations by GROMACS. This complex showed a stable condition, and its root mean square deviation (RMSD) was 0.218 nm. The results suggest that FB24 could serve as a suitable carrier vector for transporting therapeutic and diagnostic agents across the BBB to the brain through a non-invasive route.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142220223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BackgroundDeath Receptor 5 (DR5) is expressed on the surface of primary bone and soft tissue sarcoma cells, and its activation induces cell death primarily through apoptosis. The combination of DR5 agonists and commonly used chemotherapeutic agents, such as doxorubicin, can promote cell death. Currently, clinical trials are investigating the effectiveness of DR5 activation using new biological agents, such as bi-specific or tetravalent antibodies, in improving the survival of patients with relapsed or refractory cancers. Furthermore, investigations continue into the use of novel combination therapies to enhance DR5 response, for example, with inhibitor of apoptosis protein (IAP) antagonist agents [such as the second mitochondria-derived activator of caspase (SMAC) mimetics] and with immune checkpoint inhibitor anti-programmed death-ligand 1 (anti-PD-L1) or anti-programmed cell death-1 (anti-PD-1) antibodies. Other therapies include nanoparticle-mediated delivery of TRAIL plasmid DNA or TRAIL mRNA and stem cells as a vehicle for the targeted delivery of anti-cancer agents, such as TRAIL, to the tumor.Methodsscoping review of the literature from November 2017 to March 2024, utilizing PubMed and Google Scholar.ResultsNew agents under investigation include nanoTRAIL, anti-Kv10.1, multimeric IgM, and humanized tetravalent antibodies. Developments have been made to test novel agents, and imaging has been used to detect DR5 in preclinical models and patients. The models include 3D spheroids, genetically modified mouse models, a novel jaw osteosarcoma model, and patient-derived xenograft (PDX) animal models. There are currently two ongoing clinical trials focusing on the activation of DR5, namely, IGM-8444 and INBRX-109, which have progressed to phase 2. Further modifications of TRAIL delivery with fusion to single-chain variable fragments (scFv-TRAIL), directed against tumor-associated antigens (TAAs), and in the use of stem cells focus on targeted TRAIL delivery to cancer cells using bi-functional strategies.ConclusionIn vitro, in vivo, and clinical trials, as well as advances in imaging and theranostics, indicate that targeting DR5 remains a valid strategy in the treatment of some relapsed and refractory cancers.
{"title":"Targeting Death Receptor 5 (DR5) for imaging and treatment of primary bone and soft tissue tumors: an update of the literature","authors":"Zakareya Gamie, Anja Krippner-Heidenreich, Craig Gerrand, Kenneth Samora Rankin","doi":"10.3389/fmolb.2024.1384795","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1384795","url":null,"abstract":"BackgroundDeath Receptor 5 (DR5) is expressed on the surface of primary bone and soft tissue sarcoma cells, and its activation induces cell death primarily through apoptosis. The combination of DR5 agonists and commonly used chemotherapeutic agents, such as doxorubicin, can promote cell death. Currently, clinical trials are investigating the effectiveness of DR5 activation using new biological agents, such as bi-specific or tetravalent antibodies, in improving the survival of patients with relapsed or refractory cancers. Furthermore, investigations continue into the use of novel combination therapies to enhance DR5 response, for example, with inhibitor of apoptosis protein (IAP) antagonist agents [such as the second mitochondria-derived activator of caspase (SMAC) mimetics] and with immune checkpoint inhibitor anti-programmed death-ligand 1 (anti-PD-L1) or anti-programmed cell death-1 (anti-PD-1) antibodies. Other therapies include nanoparticle-mediated delivery of TRAIL plasmid DNA or TRAIL mRNA and stem cells as a vehicle for the targeted delivery of anti-cancer agents, such as TRAIL, to the tumor.Methodsscoping review of the literature from November 2017 to March 2024, utilizing PubMed and Google Scholar.ResultsNew agents under investigation include nanoTRAIL, anti-Kv10.1, multimeric IgM, and humanized tetravalent antibodies. Developments have been made to test novel agents, and imaging has been used to detect DR5 in preclinical models and patients. The models include 3D spheroids, genetically modified mouse models, a novel jaw osteosarcoma model, and patient-derived xenograft (PDX) animal models. There are currently two ongoing clinical trials focusing on the activation of DR5, namely, IGM-8444 and INBRX-109, which have progressed to phase 2. Further modifications of TRAIL delivery with fusion to single-chain variable fragments (scFv-TRAIL), directed against tumor-associated antigens (TAAs), and in the use of stem cells focus on targeted TRAIL delivery to cancer cells using bi-functional strategies.Conclusion<jats:italic>In vitro</jats:italic>, <jats:italic>in vivo</jats:italic>, and clinical trials, as well as advances in imaging and theranostics, indicate that targeting DR5 remains a valid strategy in the treatment of some relapsed and refractory cancers.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142220191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BackgroundThe progression of chronic hepatitis B (CHB) to liver fibrosis and even cirrhosis is often unknown to patients, but noninvasive markers capable of effectively identifying advanced liver fibrosis remains absent.ObjectiveBased on the results of liver biopsy, we aimed to construct a new nomogram to validate the stage of liver fibrosis in CHB patients by the basic information of CHB patients and routine laboratory tests.MethodsPatients with CHB diagnosed for the first time in the First Affiliated Hospital of Anhui Medical University from 2010 to 2018 were selected, and their basic information, laboratory tests and liver biopsy information were collected. Eventually, 974 patients were enrolled in the study, while all patients were randomized into a training cohort (n = 732) and an internal validation cohort (n = 242) according to a 3:1 ratio. In the training cohort, least absolute shrinkage and selection operator (Lasso) regression were used for predictor variable screening, and binary logistic regression analysis was used to build the diagnostic model, which was ultimately presented as a nomogram. The predictive accuracy of the nomograms was analyzed by running operating characteristic curve (ROC) to calculate area under curve (AUC), and the calibration was evaluated. Decision curve analysis (DCA) was used to determine patient benefit. In addition, we validated the built models with internal as well as external cohort (n = 771), respectively.ResultsUltimately, the training cohort, the internal validation cohort, and the external validation cohort contained sample sizes of 188, 53, and 149, respectively, for advanced liver fibrosis. Gender, albumin (Alb), globulin (Glb), platelets (PLT), alkaline phosphatase (AKP), glutamyl transpeptidase (GGT), and prothrombin time (PT) were screened as independent predictors. Compared with the aminotransferase-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4), and King’s score, the model in the training cohort (AUC = 0.834, 95% CI 0.800–0.868, p < 0.05) and internal validation cohort (AUC = 0.804, 95% CI 0.742–0.866, p < 0.05) showed the best discrimination and the best predictive performance. In addition, DCA showed that the clinical benefit of the nomogram was superior to the APRI, FIB-4 and King’s scores in all cohorts.ConclusionThis study constructed a validated nomogram model with predictors screened from clinical variables which could be easily used for the diagnosis of advanced liver fibrosis in CHB patients.
背景慢性乙型肝炎（CHB）进展为肝纤维化甚至肝硬化的过程往往不为患者所知，但能够有效识别晚期肝纤维化的无创标志物仍然缺乏。目的基于肝活检结果，我们旨在通过CHB患者的基本信息和常规实验室检查构建一个新的提名图，以验证CHB患者肝纤维化的阶段。方法选取2010年至2018年在安徽医科大学第一附属医院首次确诊的CHB患者，收集其基本信息、实验室检查和肝活检信息。最终，974名患者被纳入研究，所有患者按照3:1的比例随机分为训练队列（n = 732）和内部验证队列（n = 242）。在训练队列中，使用最小绝对收缩和选择算子（Lasso）回归进行预测变量筛选，并使用二元逻辑回归分析建立诊断模型，最终以提名图的形式呈现。通过运行特征曲线（ROC）计算曲线下面积（AUC）来分析提名图的预测准确性，并对校准进行评估。决策曲线分析（DCA）用于确定患者的获益情况。此外，我们还分别用内部和外部队列（n = 771）验证了建立的模型。结果最终，训练队列、内部验证队列和外部验证队列中的晚期肝纤维化样本量分别为 188、53 和 149。性别、白蛋白（Alb）、球蛋白（Glb）、血小板（PLT）、碱性磷酸酶（AKP）、谷氨酰转肽酶（GGT）和凝血酶原时间（PT）被筛选为独立的预测因素。与转氨酶与血小板比值指数（APRI）、纤维化-4指数（FIB-4）和King评分相比，训练队列（AUC = 0.834，95% CI 0.800-0.868，p <0.05）和内部验证队列（AUC = 0.804，95% CI 0.742-0.866，p <0.05）中的模型显示出最好的区分度和最佳的预测性能。此外，DCA显示，在所有队列中，提名图的临床效益均优于APRI、FIB-4和King's评分。
{"title":"Development and validation of a nomogram for predicting advanced liver fibrosis in patients with chronic hepatitis B","authors":"Kexing Han, Jianfeng Wang, Xizhen Song, Luyang Kang, Junjie Lin, Qinggang Hu, Weijie Sun, Yufeng Gao","doi":"10.3389/fmolb.2024.1452841","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1452841","url":null,"abstract":"BackgroundThe progression of chronic hepatitis B (CHB) to liver fibrosis and even cirrhosis is often unknown to patients, but noninvasive markers capable of effectively identifying advanced liver fibrosis remains absent.ObjectiveBased on the results of liver biopsy, we aimed to construct a new nomogram to validate the stage of liver fibrosis in CHB patients by the basic information of CHB patients and routine laboratory tests.MethodsPatients with CHB diagnosed for the first time in the First Affiliated Hospital of Anhui Medical University from 2010 to 2018 were selected, and their basic information, laboratory tests and liver biopsy information were collected. Eventually, 974 patients were enrolled in the study, while all patients were randomized into a training cohort (n = 732) and an internal validation cohort (n = 242) according to a 3:1 ratio. In the training cohort, least absolute shrinkage and selection operator (Lasso) regression were used for predictor variable screening, and binary logistic regression analysis was used to build the diagnostic model, which was ultimately presented as a nomogram. The predictive accuracy of the nomograms was analyzed by running operating characteristic curve (ROC) to calculate area under curve (AUC), and the calibration was evaluated. Decision curve analysis (DCA) was used to determine patient benefit. In addition, we validated the built models with internal as well as external cohort (n = 771), respectively.ResultsUltimately, the training cohort, the internal validation cohort, and the external validation cohort contained sample sizes of 188, 53, and 149, respectively, for advanced liver fibrosis. Gender, albumin (Alb), globulin (Glb), platelets (PLT), alkaline phosphatase (AKP), glutamyl transpeptidase (GGT), and prothrombin time (PT) were screened as independent predictors. Compared with the aminotransferase-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4), and King’s score, the model in the training cohort (AUC = 0.834, 95% CI 0.800–0.868, <jats:italic>p</jats:italic> &lt; 0.05) and internal validation cohort (AUC = 0.804, 95% CI 0.742–0.866, <jats:italic>p</jats:italic> &lt; 0.05) showed the best discrimination and the best predictive performance. In addition, DCA showed that the clinical benefit of the nomogram was superior to the APRI, FIB-4 and King’s scores in all cohorts.ConclusionThis study constructed a validated nomogram model with predictors screened from clinical variables which could be easily used for the diagnosis of advanced liver fibrosis in CHB patients.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142220190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Borderline ovarian tumors (BOTs), which are a special type of epithelial tumor of the ovary, lie between benign and malignant tumors and have low malignant potential. Due to the fact that the early symptoms of these tumors are relatively subtle, they are not easy to diagnose clinically. This study explores advancements in clinical detection methods and provides a comprehensive overview of molecules such as cell migration factors, cell transcription factors, cell damage repair factors, cell cycle regulators, and tumor suppressor genes that are related to the development of BOTs and their related mechanisms in recent years, thus aiming to provide more sensitive, specific, and efficient differential diagnosis and treatment plans for patients to improve their prognosis and survival outcomes.
{"title":"Advances in understanding the molecular mechanisms of borderline ovarian tumors","authors":"Shiying Chen, Li Huang, Meili Liang, Yajing Xie, Zhimei Zhou, Yumin Ke, Zhuna Wu","doi":"10.3389/fmolb.2024.1429852","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1429852","url":null,"abstract":"Borderline ovarian tumors (BOTs), which are a special type of epithelial tumor of the ovary, lie between benign and malignant tumors and have low malignant potential. Due to the fact that the early symptoms of these tumors are relatively subtle, they are not easy to diagnose clinically. This study explores advancements in clinical detection methods and provides a comprehensive overview of molecules such as cell migration factors, cell transcription factors, cell damage repair factors, cell cycle regulators, and tumor suppressor genes that are related to the development of BOTs and their related mechanisms in recent years, thus aiming to provide more sensitive, specific, and efficient differential diagnosis and treatment plans for patients to improve their prognosis and survival outcomes.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142220218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.3389/fmolb.2024.1440276
Christian Müller, Leticia Oliveira-Ferrer, Volkmar Müller, Barbara Schmalfeldt, Sabine Windhorst
IntroductionActin-binding proteins (ABPs) are essential for the regulation of morphological plasticity required for tumor cells to metastasize. The aim of this study was to perform an unbiased bioinformatic approach to identify the key ABPs significantly associated with the metastatic potential of breast cancer cells.MethodsMicroarray data from 181 primary breast cancer samples from our hospital were used, and all genes belonging to the Gene Ontology term actin cytoskeleton organization were obtained from QuickGO. Association with metastasis-free survival probability was tested using Cox proportional hazards regression, and pairwise co-expression was tested by Pearson correlations. Differential expression between different subgroups was analyzed using Wilcoxon tests for dichotomous traits and Kruskal–Wallis tests for categorical traits. Validation was performed using four publicly available breast cancer datasets.ResultsARHGAP25 was significantly associated with a low metastatic potential, and CFL1, TMSB15A, and ACTL8 were significantly associated with a high metastatic potential. A significantly higher expression of CFL1, TMSB15A, and ACTL8 mRNA was found in the more aggressive Her2-positive and triple-negative subtypes as well as in ER-negative samples. Also, these genes were co-expressed in the same tumors. However, only mRNA levels of CFL1 were increased in pN1 compared to pN0 patients. External validation revealed that CFL1 and TMSB15A had significant associations with consistent hazard ratios in two breast cancer cohorts, and among these, CFL1 exhibited the highest hazard ratios.ConclusionCFL1 showed the strongest correlation with the metastatic potential of breast tumors. Thus, targeted inhibition of CFL1 might be a promising approach to treat malignant breast cancer cells.
{"title":"Transcriptome-based identification of key actin-binding proteins associated with high metastatic potential in breast cancer","authors":"Christian Müller, Leticia Oliveira-Ferrer, Volkmar Müller, Barbara Schmalfeldt, Sabine Windhorst","doi":"10.3389/fmolb.2024.1440276","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1440276","url":null,"abstract":"IntroductionActin-binding proteins (ABPs) are essential for the regulation of morphological plasticity required for tumor cells to metastasize. The aim of this study was to perform an unbiased bioinformatic approach to identify the key ABPs significantly associated with the metastatic potential of breast cancer cells.MethodsMicroarray data from 181 primary breast cancer samples from our hospital were used, and all genes belonging to the Gene Ontology term actin cytoskeleton organization were obtained from QuickGO. Association with metastasis-free survival probability was tested using Cox proportional hazards regression, and pairwise co-expression was tested by Pearson correlations. Differential expression between different subgroups was analyzed using Wilcoxon tests for dichotomous traits and Kruskal–Wallis tests for categorical traits. Validation was performed using four publicly available breast cancer datasets.Results<jats:italic>ARHGAP25</jats:italic> was significantly associated with a low metastatic potential, and <jats:italic>CFL1</jats:italic>, <jats:italic>TMSB15A</jats:italic>, and <jats:italic>ACTL8</jats:italic> were significantly associated with a high metastatic potential. A significantly higher expression of <jats:italic>CFL1</jats:italic>, <jats:italic>TMSB15A,</jats:italic> and <jats:italic>ACTL8</jats:italic> mRNA was found in the more aggressive Her2-positive and triple-negative subtypes as well as in ER-negative samples. Also, these genes were co-expressed in the same tumors. However, only mRNA levels of <jats:italic>CFL1</jats:italic> were increased in pN1 compared to pN0 patients. External validation revealed that <jats:italic>CFL1</jats:italic> and <jats:italic>TMSB15A</jats:italic> had significant associations with consistent hazard ratios in two breast cancer cohorts, and among these, <jats:italic>CFL1</jats:italic> exhibited the highest hazard ratios.Conclusion<jats:italic>CFL1</jats:italic> showed the strongest correlation with the metastatic potential of breast tumors. Thus, targeted inhibition of <jats:italic>CFL1</jats:italic> might be a promising approach to treat malignant breast cancer cells.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142220217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.3389/fmolb.2024.1331369
Ahmed Majeed Al-Shammari, Marwa Ibrahim Salman
IntroductionNewcastle disease virus (NDV) AMHA1 is capable of killing cancer cells by direct replication or induction of apoptosis alongside other pathways. In this study, we report the potent antimetastatic and anticancer activities of NDV AMHA1 in a 3D spheroid model of breast cancer metastasis.Methodswe used two breast cancer cell lines AMJ13 and MCF7 in our metastasis model system.ResultsFirst, we showed that NDV AMHA1 can infect and kill breast cancer cells in proliferating adherent cells and tumor spheroids using different virus doses and studying virus replication kinetics. We showed that NDV can infect and spread within the spheroids that represent metastasis before and after reattachment. Furthermore, we evaluated the ability of NDV to induce apoptosis in cancer spheroids and by virus tracking showed that NDV infection is essential for the elimination of these metastasis spheroids.DiscussionThe mechanism by which NDV induces cell killing in the metastasis model is the induction of caspase-3 and P21 and inhibition of Ki67 in cancer cells, but not in normal cells. In conclusion, these results indicate that NDV AMHA1 has the ability to kill breast cancer metastases in suspension or attached, and this is a novel finding of NDV AMHA1 being a possibly efficient therapy against human metastatic breast cancer.
{"title":"Antimetastatic and antitumor activities of oncolytic NDV AMHA1 in a 3D culture model of breast cancer","authors":"Ahmed Majeed Al-Shammari, Marwa Ibrahim Salman","doi":"10.3389/fmolb.2024.1331369","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1331369","url":null,"abstract":"IntroductionNewcastle disease virus (NDV) AMHA1 is capable of killing cancer cells by direct replication or induction of apoptosis alongside other pathways. In this study, we report the potent antimetastatic and anticancer activities of NDV AMHA1 in a 3D spheroid model of breast cancer metastasis.Methodswe used two breast cancer cell lines AMJ13 and MCF7 in our metastasis model system.ResultsFirst, we showed that NDV AMHA1 can infect and kill breast cancer cells in proliferating adherent cells and tumor spheroids using different virus doses and studying virus replication kinetics. We showed that NDV can infect and spread within the spheroids that represent metastasis before and after reattachment. Furthermore, we evaluated the ability of NDV to induce apoptosis in cancer spheroids and by virus tracking showed that NDV infection is essential for the elimination of these metastasis spheroids.DiscussionThe mechanism by which NDV induces cell killing in the metastasis model is the induction of caspase-3 and P21 and inhibition of Ki67 in cancer cells, but not in normal cells. In conclusion, these results indicate that NDV AMHA1 has the ability to kill breast cancer metastases in suspension or attached, and this is a novel finding of NDV AMHA1 being a possibly efficient therapy against human metastatic breast cancer.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142220219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.3389/fmolb.2024.1446822
Robert Moulder, Santosh D. Bhosale, Keijo Viiri, Riitta Lahesmaa
IntroductionOrganoid models enable three-dimensional representation of cellular systems, providing flexible and accessible research tools, and can highlight key biomolecules. Such models of the intestinal epithelium can provide significant knowledge for the study of celiac disease and provide an additional context for the nature of markers observed from patient biopsy data.MethodsUsing LC–MS/MS, the proteomes of the crypt and enterocyte-like states of a mouse mini-gut organoid model were measured. The data were further compared with published biopsy data by comparing the changes induced by gluten challenge after a gluten-free diet.Results and discussionThese analyses identified 4,850 protein groups and revealed how 400 putative biomarkers of dietary challenge were differentially expressed in the organoid model. In addition to the extensive changes within the differentiated cells, the data reiterated the disruption of the crypt–villus axis after gluten challenge. The mass spectrometry data are available via ProteomeXchange with the identifier PXD025690.
{"title":"Comparative proteomics analysis of the mouse mini-gut organoid: insights into markers of gluten challenge from celiac disease intestinal biopsies","authors":"Robert Moulder, Santosh D. Bhosale, Keijo Viiri, Riitta Lahesmaa","doi":"10.3389/fmolb.2024.1446822","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1446822","url":null,"abstract":"IntroductionOrganoid models enable three-dimensional representation of cellular systems, providing flexible and accessible research tools, and can highlight key biomolecules. Such models of the intestinal epithelium can provide significant knowledge for the study of celiac disease and provide an additional context for the nature of markers observed from patient biopsy data.MethodsUsing LC–MS/MS, the proteomes of the crypt and enterocyte-like states of a mouse mini-gut organoid model were measured. The data were further compared with published biopsy data by comparing the changes induced by gluten challenge after a gluten-free diet.Results and discussionThese analyses identified 4,850 protein groups and revealed how 400 putative biomarkers of dietary challenge were differentially expressed in the organoid model. In addition to the extensive changes within the differentiated cells, the data reiterated the disruption of the crypt–villus axis after gluten challenge. The mass spectrometry data are available via ProteomeXchange with the identifier PXD025690.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142220070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.3389/fmolb.2024.1426575
Wuhui Zhu, Huan Li, Ming Zhang, Bing Ji, Zongtao Liu
BackgroundStudies on the relationships between diseases of the urinary system and human plasma proteomes have identified several potential biomarkers. However, none of these studies have elucidated the causal relationships between plasma proteins and urolithiasis.ObjectiveThe objective of the study was to investigate the potential risks of plasma metabolites in urolithiasis using a two-sample Mendelian randomization (MR) study.MethodsA total of 1,400 metabolites were identified in the most comprehensive genome-wide association study (GWAS) of plasma metabolomics in a European population to date, and single-nucleotide polymorphisms (SNPs) were used as the instrumental variables for the plasma metabolites. The European GWAS data for urinary calculi included 482,123 case samples and 6,223 control samples (ebi-a-GCST90018935). The associations between the plasma metabolites and risk of urolithiasis were evaluated by inverse variance weighting (IVW) and supplemented by sensitivity analyses of the MR-Egger and MR-PRESSO tests.ResultsFor the first time, we found a causal relationship between two plasma metabolites (p < 1.03 × 10−4) and urolithiasis (p < 0.05). The chemical 4-hydroxychlorothalonil, which is an intermediate product of the pesticide hydroxychlorothalonil, could promote urolithiasis (odds ratio (OR) = 1.12) as a risk factor. Moreover, 1-stearoyl-2-arachidonoyl-GPC, which is an important component of phospholipid metabolism in the human body, can inhibit urolithiasis (OR = 0.94).ConclusionsOur results suggest that blood metabolites can be used as blood markers and drug targets in the prevention, diagnosis, and treatment of urolithiasis; furthermore, our results can provide a basis for policy makers to formulate prevention and treatment policies for urolithiasis.
{"title":"Plasma metabolites as potential markers and targets to prevent and treat urolithiasis: a Mendelian randomization study","authors":"Wuhui Zhu, Huan Li, Ming Zhang, Bing Ji, Zongtao Liu","doi":"10.3389/fmolb.2024.1426575","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1426575","url":null,"abstract":"BackgroundStudies on the relationships between diseases of the urinary system and human plasma proteomes have identified several potential biomarkers. However, none of these studies have elucidated the causal relationships between plasma proteins and urolithiasis.ObjectiveThe objective of the study was to investigate the potential risks of plasma metabolites in urolithiasis using a two-sample Mendelian randomization (MR) study.MethodsA total of 1,400 metabolites were identified in the most comprehensive genome-wide association study (GWAS) of plasma metabolomics in a European population to date, and single-nucleotide polymorphisms (SNPs) were used as the instrumental variables for the plasma metabolites. The European GWAS data for urinary calculi included 482,123 case samples and 6,223 control samples (ebi-a-GCST90018935). The associations between the plasma metabolites and risk of urolithiasis were evaluated by inverse variance weighting (IVW) and supplemented by sensitivity analyses of the MR-Egger and MR-PRESSO tests.ResultsFor the first time, we found a causal relationship between two plasma metabolites (<jats:italic>p</jats:italic> &lt; 1.03 × 10<jats:sup>−4</jats:sup>) and urolithiasis (<jats:italic>p</jats:italic> &lt; 0.05). The chemical 4-hydroxychlorothalonil, which is an intermediate product of the pesticide hydroxychlorothalonil, could promote urolithiasis (odds ratio (OR) = 1.12) as a risk factor. Moreover, 1-stearoyl-2-arachidonoyl-GPC, which is an important component of phospholipid metabolism in the human body, can inhibit urolithiasis (OR = 0.94).ConclusionsOur results suggest that blood metabolites can be used as blood markers and drug targets in the prevention, diagnosis, and treatment of urolithiasis; furthermore, our results can provide a basis for policy makers to formulate prevention and treatment policies for urolithiasis.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142220222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：