Biomolecules最新文献

{"title":"Molecular Profiling of Mouse Models of Loss or Gain of Function of the KCNT1 (Slack) Potassium Channel and Antisense Oligonucleotide Treatment.","authors":"Fangxu Sun, Huafeng Wang, Jing Wu, Imran H Quraishi, Yalan Zhang, Maysam Pedram, Benbo Gao, Elizabeth A Jonas, Viet Nguyen, Sijia Wu, Omar S Mabrouk, Paymaan Jafar-Nejad, Leonard K Kaczmarek","doi":"10.3390/biom14111397","DOIUrl":"10.3390/biom14111397","url":null,"abstract":"<p><p>The potassium sodium-activated channel subtype T member 1 (<i>KCNT1</i>) gene encodes the Slack channel K_Na1.1, which is expressed in neurons throughout the brain. Gain-of-function variants in <i>KCNT1</i> are associated with a spectrum of epilepsy syndromes, and mice carrying those variants exhibit a robust phenotype similar to that observed in patients. <i>Kcnt1</i> knockout (KO) mice, however, have a normal lifespan without any epileptic phenotype. To understand the molecular differences between these two models, we conducted a comprehensive proteomic analysis of the cerebral cortices of <i>Kcnt1</i> KO and <i>Kcnt1</i>^R455H/+ mice, an animal model bearing a cytoplasmic C-terminal mutation homologous to a human R474H variant that results in EIMFS. The greatest change observed in <i>Kcnt1</i> KO mice compared to the wild-type mice was the increased expression of multiple proteins of the inner mitochondrial membrane. Electron microscopy studies of cortical mitochondria from <i>Kcnt1</i> KO mice further confirmed a significant increase in the density of mitochondrial cristae compared to that in wild-type mice. <i>Kcnt1</i> reduction by a murine-specific <i>Kcnt1</i> antisense oligonucleotide (ASO) in <i>Kcnt1</i>^R455H/+ mice partially corrected the proteomic dysregulations in the disease model. The results support the hypothesis that ASO-mediated <i>KCNT1</i> reduction could be therapeutically useful in the treatment of <i>KCNT1</i> epilepsies.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resveratrol Inhibits Nucleosome Binding and Catalytic Activity of PARP1.","authors":"Darya O Koshkina, Natalya V Maluchenko, Anna N Korovina, Angelina A Lobanova, Alexey V Feofanov, Vasily M Studitsky","doi":"10.3390/biom14111398","DOIUrl":"10.3390/biom14111398","url":null,"abstract":"<p><p>The natural polyphenol resveratrol is a biologically active compound that interacts with DNA and affects the activity of some nuclear enzymes. Its effect on the interaction between nucleosomes and poly(ADP-ribose) polymerase-1 (PARP1) and on the catalytic activity of PARP1 was studied using Western blotting, spectrophotometry, electrophoretic mobility shift assay, and single particle Förster resonance energy transfer microscopy. Resveratrol inhibited PARP1 activity at micro- and sub-micromolar concentrations, but the inhibitory effect decreased at higher concentrations due to the aggregation of the polyphenol. The inhibition of PARP1 by resveratrol was accompanied by its binding to the enzyme catalytic center and a subsequent decrease in PARP1 affinity to nucleosomal DNA. Concurrent binding of talazoparib to the substrate binding pocket of PARP1, which occurs in the presence of resveratrol, restores the interaction of PARP1 with nucleosomes, suggesting that the binding sites of resveratrol and talazoparib overlap. The data suggest that resveratrol can be classified as a natural inhibitor of PARP1.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Affinity Fully Human Anti-EpCAM Antibody with Biased IL-2 Exhibits Potent Antitumor Activity.","authors":"Zhi Wang, Mingkai Wang, Quanxiao Li, Yanling Wu, Tianlei Ying","doi":"10.3390/biom14111399","DOIUrl":"10.3390/biom14111399","url":null,"abstract":"<p><p>Monoclonal antibodies (mAbs) are widely used in cancer therapy but often show limited efficacy for solid tumors. Enhancing anti-tumor activity by fusing cytokines to tumor-targeting mAbs, which specifically activate immune cells within the tumor microenvironment, represents a promising strategy. However, the optimal design and therapeutic efficacy of antibody-cytokine fusion formats remain unclear. The epithelial cell adhesion molecule (EpCAM), frequently overexpressed in a variety of carcinomas, serves as the target for immunotherapies. In this study, we identified a fully human mAb targeting EpCAM, designated as m801, from a previously constructed phage-displayed fully human antibody library. By fusing m801 with an IL-2 variant (IL-2v) in two configurations, m801.2 (2 anti-EpCAM Fab + 1 IL-2v) and m801.3 (1 anti-EpCAM Fab + 1 IL-2v), we identified m801.2 as the lead candidate due to its superior biophysical properties, including high thermal stability, homogeneity, and low aggregation. Furthermore, m801.2 showed strong binding affinity to EpCAM, with KD values of 0.6 nM, and an EpCAM-expressing tumor cell line, comparable to the original IgG m801. Additionally, m801.2 exhibited IL-2 receptor β subunit (IL-2Rβ)-biased binding activity, with a KD of 27.3 nM, resulting in superior effective T cell activation. In an SW480 xenograft mice model, m801.2 significantly inhibited tumor growth and demonstrated high tolerability. These findings suggest a valuable framework for the future design of immunocytokine therapies.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population-Level Cell Trajectory Inference Based on Gaussian Distributions.","authors":"Xiang Chen, Yibing Ma, Yongle Shi, Yuhan Fu, Mengdi Nan, Qing Ren, Jie Gao","doi":"10.3390/biom14111396","DOIUrl":"10.3390/biom14111396","url":null,"abstract":"<p><p>In the past decade, inferring developmental trajectories from single-cell data has become a significant challenge in bioinformatics. RNA velocity, with its incorporation of directional dynamics, has significantly advanced the study of single-cell trajectories. However, as single-cell RNA sequencing technology evolves, it generates complex, high-dimensional data with high noise levels. Existing trajectory inference methods, which overlook cell distribution characteristics, may perform inadequately under such conditions. To address this, we introduce CPvGTI, a Gaussian distribution-based trajectory inference method. CPvGTI utilizes a Gaussian mixture model, optimized by the Expectation-Maximization algorithm, to construct new cell populations in the original data space. By integrating RNA velocity, CPvGTI employs Gaussian Process Regression to analyze the differentiation trajectories of these cell populations. To evaluate the performance of CPvGTI, we assess CPvGTI's performance against several state-of-the-art methods using four structurally diverse simulated datasets and four real datasets. The simulation studies indicate that CPvGTI excels in pseudo-time prediction and structural reconstruction compared to existing methods. Furthermore, the discovery of new branch trajectories in human forebrain and mouse hematopoiesis datasets confirms CPvGTI's superior performance.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibroblast-Specific Protein-Protein Interactions for Myocardial Fibrosis from MetaCore Network.","authors":"Klaus M Frahm, Ekaterina Kotelnikova, Oksana Kunduzova, Dima L Shepelyansky","doi":"10.3390/biom14111395","DOIUrl":"10.3390/biom14111395","url":null,"abstract":"<p><p>Myocardial fibrosis is a major pathologic disorder associated with a multitude of cardiovascular diseases (CVD). The pathogenesis is complex and encompasses multiple molecular pathways. Integration of fibrosis-associated genes into the global MetaCore network of protein-protein interactions (PPI) offers opportunities to identify PPI with functional and therapeutic significance. Here, we report the generation of a fibrosis-focused PPI network and identification of fibroblast-specific arbitrators driving reparative and reactive myocardial fibrosis. In TGF-β-mediated fibroblast activation, developed network analysis predicts new regulatory mechanisms for fibrosis-associated genes. We introduce an efficient Erdös barrage approach to suppress activation of a number of fibrosis-associated nodes in order to reverse fibrotic cascades. In the network model each protein node is characterized by an Ising up or down spin corresponding to activated or repairing state acting on other nodes being initially in a neutral state. An asynchronous Monte Carlo process describes fibrosis progression determined by a dominant action of linked proteins. Our results suggest that the constructed Ising Network Fibrosis Interaction model offers network insights into fibrosis mechanisms and can complement future experimental efforts to counteract cardiac fibrosis.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Route to Measure Exact Parameters of Bio-Nanostructures Self-Assembly.","authors":"Mikhail Kryuchkov, Jana Valnohova, Vladimir L Katanaev","doi":"10.3390/biom14111388","DOIUrl":"10.3390/biom14111388","url":null,"abstract":"<p><p>Artificial bio-nanocoatings, primarily composed of proteins, offer a broad range of applications across various fields thanks to their unique properties. Proteins, as major components of these structures, enable a high degree of customization, such as mutations, conjugation with other molecules or nanoparticles, or the inclusion of an enzymatic activity. Their ability to self-assembly simplifies the production of bio-nanocoatings, making this process efficient and environment-friendly. Despite these advantages, a comprehensive understanding of the underlying self-assembly mechanism is lacking, and the reaction rates governing this process have not been characterized. In this article, we introduce a novel method to determine the key parameters describing the self-assembly mechanism of bio-nanostructures. For the first time, this approach enables an accurate calculation of the autocatalytic and self-inhibitory parameters controlling the process. Through mathematical modeling, our method enhances the understanding of how the protein-based nanocoatings form and opens new avenues for their application in nanotechnology and synthetic biology. Improved control over the self-assembly processes may enable the development of nanomaterials optimized for specific functions, such as drug delivery, biosensing, and bioactive surface fabrication.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Wolfram Syndrome 1: The <i>WFS1</i> Gene's Role in Alzheimer's Disease and Sleep Disorders.","authors":"Valerio Caruso, Luciana Rigoli","doi":"10.3390/biom14111389","DOIUrl":"10.3390/biom14111389","url":null,"abstract":"<p><p>The <i>WFS1</i> gene was first identified in Wolfram Syndrome 1 (WS1), a rare autosomal recessive genetic disorder characterized by severe and progressive neurodegenerative changes. <i>WFS1</i>'s role in various cellular mechanisms, particularly in calcium homeostasis and the modulation of endoplasmic reticulum (ER) stress, suggests its potential involvement in the pathogenesis of Alzheimer's disease (AD) and sleep disorders. Because it is involved in maintaining ER balance, calcium signaling, and stress responses, <i>WFS1</i> plays a multifaceted role in neuronal health. Numerous studies have shown that the absence or improper expression of <i>WFS1</i> disrupts these cellular processes, leading to neurodegeneration and making neurons more vulnerable. In AD, <i>WFS1</i> dysfunction is thought to contribute to the accumulation of amyloid-β (Aβ) plaques and tau tangles, thereby accelerating disease progression. Additionally, <i>WFS1</i> plays an essential role in sleep regulation by influencing neuronal excitability and neurotransmitter release, which may explain the sleep disturbances frequently observed in neurodegenerative diseases. Due to its involvement in the pathological mechanisms of AD and sleep disorders, <i>WFS1</i> is regarded as a potential early diagnostic marker for these diseases. Further research is required to fully elucidate <i>WFS1</i>'s role in the cellular pathway, perhaps facilitating the development of new therapeutic strategies for Alzheimer's disease and sleep disorders.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"\"A Friend Among Strangers\" or the Ambiguous Roles of Runx2.","authors":"Kseniia Azarkina, Ekaterina Gromova, Anna Malashicheva","doi":"10.3390/biom14111392","DOIUrl":"10.3390/biom14111392","url":null,"abstract":"<p><p>The transcription factor Runx2 plays a crucial role in regulating osteogenic differentiation and skeletal development. This factor not only controls the expression of genes involved in bone formation, but also interacts with signaling pathways such as the Notch pathway, which are essential for body development. However, studies have produced conflicting results regarding the relationship between Runx2 and the Notch pathway. Some studies suggest a synergistic interaction between these molecules, while others suggest an inhibitory one, for example, the interplay between Notch signaling, Runx2, and vitamin D3 in osteogenic differentiation and bone remodeling. The findings suggest a complex relationship between Notch signaling and osteogenic differentiation, with ongoing research needed to clarify the mechanisms involved and resolve existing contradictions regarding role of Notch in this process. Additionally, there is increasing evidence of contradictory roles for Runx2 in various tissues and organs, both under normal conditions and in pathological states. This diversity of roles makes Runx2 a potential therapeutic target, offering new directions for research. In this review, we have discussed the mechanisms of osteogenic differentiation and the important role of Runx2 in this process. We have also examined its relationship with different signaling pathways. However, there are still many uncertainties and inconsistencies in our current understanding of these interactions. Additionally, given that Runx2 is also involved in numerous other events in various tissues, we have tried to comprehensively examine its functions outside the skeletal system.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Integrin Blockade on Experimental Spondyloarthritis.","authors":"Enoch Yau, Melissa Lim, Zoya Qaiyum, Shaghayegh Foroozan Boroojeni, Michael Tang, Addison Pacheco, Fataneh Tavasolian, Robert D Inman","doi":"10.3390/biom14111386","DOIUrl":"10.3390/biom14111386","url":null,"abstract":"<p><p>Spondyloarthritis (SpA) describes a group of diseases characterized by chronic inflammation in the spine and peripheral joints. While pathogenesis is still unclear, proinflammatory gut-derived immune cells have been identified in the joints of SpA patients. We previously identified an enriched population of integrin-expressing cells in the joints of SpA patients. Entry of gut-derived cells into joints may be mediated by these integrins. In the current study, we used the SKG murine model of SpA to study the impact of integrin blockade. Mice were injected with antibodies against the integrin α4β7 or the β7 monomer twice a week. Treatment with antibodies against α4β7 reduced disease severity in curdlan-injected SKG mice, with disease scores being comparable between treatment initiation times. Targeting the β7 monomer led to reduced arthritis severity compared to targeting the α4β7 dimer. Treatment with antibodies against α4β7 or β7 decreased expression of these integrins in CD4+ T cells, with the frequency of αE+β7+ T cells in the spleen and lymph nodes correlating with disease severity. In summary, we showed that integrin blockade showed potential for ameliorating disease in a murine model of SpA, lending support for further studies testing integrin blockade in SpA.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell RNA-Seq Analysis Links DNMT3B and PFKFB4 Transcriptional Profiles with Metastatic Traits in Hepatoblastoma.","authors":"Christophe Desterke, Raquel Francés, Claudia Monge, Agnès Marchio, Pascal Pineau, Jorge Mata-Garrido","doi":"10.3390/biom14111394","DOIUrl":"10.3390/biom14111394","url":null,"abstract":"<p><p>Hepatoblastoma is the most common primary liver cancer in children. Poor outcomes are primarily associated with patients who have distant metastases. Using the Mammalian Metabolic Enzyme Database, we investigated the overexpression of metabolic enzymes in hepatoblastoma tumors compared to noncancerous liver tissue in the GSE131329 transcriptome dataset. For the overexpressed enzymes, we applied ElasticNet machine learning to assess their predictive value for metastasis. A metabolic expression score was then computed from the significant enzymes and integrated into a clinical-biological logistic regression model. Forty-one overexpressed enzymes distinguished hepatoblastoma tumors from noncancerous liver tissues. Eighteen of these enzymes predicted metastasis status with an AUC of 0.90, demonstrating 85.7% sensitivity and 92.3% specificity. ElasticNet machine learning identified <i>DNMT3B</i> and <i>PFKFB4</i> as key predictors of metastasis. Univariate analyses confirmed the significance of these enzymes, with respective <i>p</i>-values of 0.0058 and 0.0091. A metabolic score based on <i>DNMT3B</i> and <i>PFKFB4</i> expression discriminated metastasis status and high-risk CHIC scores (<i>p</i>-value = 0.005). The metabolic score was more sensitive than the C1/C2 classifier in predicting metastasis (accuracy: 0.72 vs. 0.55). In a regression model integrating the metabolic score with epidemiological parameters (gender, age at diagnosis, histological type, and clinical PRETEXT stage), the metabolic score was confirmed as an independent adverse predictor of metastasis (<i>p</i>-value = 0.003, odds ratio: 2.12). This study identified the dual overexpression of <i>PFKFB4</i> and <i>DNMT3B</i> in hepatoblastoma patients at risk of metastasis (high-risk CHIC classification). The combined tumor expression of <i>DNMT3B</i> and <i>PFKFB4</i> was used to compute a metabolic score, which was validated as an independent predictor of metastatic status in hepatoblastoma.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11591731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}