BackgroundMale urethral stricture disease (USD) is predominantly characterized by scar formation. There are few effective therapeutic drugs, and comprehensive molecular characterizations of USD formation remain undefined.MethodsThe proteomic profiling of twelve scar tissues and five matched normal adjacent tissues (NATs). Proteomic analysis methods were applied to explore the molecular characterizations of USD formation, including uncovering mechanistic pathways and providing novel biomarkers for scar formation.ResultsComparative proteomic analysis showed that the extracellular matrix (ECM) and complement cascade signaling were predominant in scar tissues. COL11A1 and CD248 significantly contributed to the accumulation of ECM components. Our study presented diverse molecular mechanisms of scar formation across different ages and suggested the potential effects of PXK in Age 1 (<45) patients. Furthermore, immune infiltration studies indicated the therapeutic potential of inhibiting the complement system (C4A, C4B) in Age 2 (≥45) patients, providing a potential clinical strategy for USD.ConclusionThis study illustrated the pathogenesis of USD formation and the diverse characteristics of USD patients with different ages, enhancing our understanding of the disease’s pathogenesis and providing a valuable resource for USD treatment.
{"title":"Comprehensive proteomic characterization of urethral stricture disease in the Chinese population","authors":"Jiangtao Gao, Hui Liu, Lingling Li, Chunmei Guo, Zhiyong Wang, Mengya Cheng, Subei Tan, Lu Chen, Jijing Shi, Hui Wu, Chao Feng, Guoying Yu, Chen Ding","doi":"10.3389/fmolb.2024.1401970","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1401970","url":null,"abstract":"BackgroundMale urethral stricture disease (USD) is predominantly characterized by scar formation. There are few effective therapeutic drugs, and comprehensive molecular characterizations of USD formation remain undefined.MethodsThe proteomic profiling of twelve scar tissues and five matched normal adjacent tissues (NATs). Proteomic analysis methods were applied to explore the molecular characterizations of USD formation, including uncovering mechanistic pathways and providing novel biomarkers for scar formation.ResultsComparative proteomic analysis showed that the extracellular matrix (ECM) and complement cascade signaling were predominant in scar tissues. COL11A1 and CD248 significantly contributed to the accumulation of ECM components. Our study presented diverse molecular mechanisms of scar formation across different ages and suggested the potential effects of PXK in Age 1 (&lt;45) patients. Furthermore, immune infiltration studies indicated the therapeutic potential of inhibiting the complement system (C4A, C4B) in Age 2 (≥45) patients, providing a potential clinical strategy for USD.ConclusionThis study illustrated the pathogenesis of USD formation and the diverse characteristics of USD patients with different ages, enhancing our understanding of the disease’s pathogenesis and providing a valuable resource for USD treatment.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774316","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 : 2024-07-26DOI: 10.3389/fmolb.2024.1423351
Minjae J. Kim, Mohamed M. Ibrahim, Monica M. Jablonski
Parasympathetic activation in the anterior eye segment regulates various physiological functions. This process, mediated by muscarinic acetylcholine receptors, also impacts intraocular pressure (IOP) through the trabecular meshwork. While FDA-approved M3 muscarinic receptor (M3R) agonists exist for IOP reduction, their systemic cholinergic adverse effects pose limitations in clinical use. Therefore, advancing our understanding of the cholinergic system in the anterior segment of the eye is crucial for developing additional IOP-reducing agents with improved safety profiles. Systems genetics analyses were utilized to explore correlations between IOP and the five major muscarinic receptor subtypes. Molecular docking and dynamics simulations were applied to human M3R homology model using a comprehensive set of human M3R ligands and 1,667 FDA-approved or investigational drugs. Lead compounds from the modeling studies were then tested for their IOP-lowering abilities in mice. Systems genetics analyses unveiled positive correlations in mRNA expressions among the five major muscarinic receptor subtypes, with a negative correlation observed only in M3R with IOP. Through modeling studies, rivastigmine and edrophonium emerged as the most optimally suited cholinergic drugs for reducing IOP via a potentially distinct mechanism from pilocarpine or physostigmine. Subsequent animal studies confirmed comparable IOP reductions among rivastigmine, edrophonium, and pilocarpine, with longer durations of action for rivastigmine and edrophonium. Mild cholinergic adverse effects were observed with pilocarpine and rivastigmine but absent with edrophonium. These findings advance ocular therapeutics, suggesting a more nuanced role of the parasympathetic system in the anterior eye segment for reducing IOP than previously thought.
{"title":"Deepening insights into cholinergic agents for intraocular pressure reduction: systems genetics, molecular modeling, and in vivo perspectives","authors":"Minjae J. Kim, Mohamed M. Ibrahim, Monica M. Jablonski","doi":"10.3389/fmolb.2024.1423351","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1423351","url":null,"abstract":"Parasympathetic activation in the anterior eye segment regulates various physiological functions. This process, mediated by muscarinic acetylcholine receptors, also impacts intraocular pressure (IOP) through the trabecular meshwork. While FDA-approved M3 muscarinic receptor (M3R) agonists exist for IOP reduction, their systemic cholinergic adverse effects pose limitations in clinical use. Therefore, advancing our understanding of the cholinergic system in the anterior segment of the eye is crucial for developing additional IOP-reducing agents with improved safety profiles. Systems genetics analyses were utilized to explore correlations between IOP and the five major muscarinic receptor subtypes. Molecular docking and dynamics simulations were applied to human M3R homology model using a comprehensive set of human M3R ligands and 1,667 FDA-approved or investigational drugs. Lead compounds from the modeling studies were then tested for their IOP-lowering abilities in mice. Systems genetics analyses unveiled positive correlations in mRNA expressions among the five major muscarinic receptor subtypes, with a negative correlation observed only in M3R with IOP. Through modeling studies, rivastigmine and edrophonium emerged as the most optimally suited cholinergic drugs for reducing IOP via a potentially distinct mechanism from pilocarpine or physostigmine. Subsequent animal studies confirmed comparable IOP reductions among rivastigmine, edrophonium, and pilocarpine, with longer durations of action for rivastigmine and edrophonium. Mild cholinergic adverse effects were observed with pilocarpine and rivastigmine but absent with edrophonium. These findings advance ocular therapeutics, suggesting a more nuanced role of the parasympathetic system in the anterior eye segment for reducing IOP than previously thought.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774315","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}
Gliomas, the most prevalent and aggressive primary brain tumors, represent a diverse group of malignancies originating from glial cells. These tumors account for significant brain tumor-related morbidity and mortality, with higher incidence rates in North America and Europe compared to Asia and Africa. Genetic predispositions and environmental factors, particularly ionizing radiation, critically impact glioma risk. Epigenetics, particularly DNA methylation, plays a pivotal role in glioma research, with IDH-mutant gliomas showing aberrant methylation patterns contributing to tumorigenesis. Epigenetic clocks, biomarkers based on DNA methylation patterns predicting biological age, have revealed significant insights into aging and tumor development. Recent studies demonstrate accelerated epigenetic aging in gliomas, correlating with increased cancer risk and poorer outcomes. This review explores the mechanisms of epigenetic clocks, their biological significance, and their application in glioma research. Furthermore, the clinical implications of epigenetic clocks in diagnosing, prognosticating, and treating gliomas are discussed. The integration of epigenetic clock data into personalized medicine approaches holds promise for enhancing therapeutic strategies and patient outcomes in glioma treatment.
胶质瘤是最常见和最具侵袭性的原发性脑肿瘤，是一组源自神经胶质细胞的多种恶性肿瘤。这些肿瘤导致了大量与脑肿瘤相关的发病率和死亡率，与亚洲和非洲相比，北美和欧洲的发病率更高。遗传易感性和环境因素，尤其是电离辐射，对胶质瘤的风险有着至关重要的影响。表观遗传学，尤其是 DNA 甲基化，在胶质瘤研究中起着举足轻重的作用，IDH 突变胶质瘤显示出异常的甲基化模式，导致肿瘤发生。表观遗传时钟是基于 DNA 甲基化模式预测生物年龄的生物标记，它揭示了衰老和肿瘤发生的重要规律。最近的研究表明，胶质瘤的表观遗传老化加速，与癌症风险增加和预后较差相关。本综述探讨了表观遗传时钟的机制、其生物学意义及其在胶质瘤研究中的应用。此外，还讨论了表观遗传时钟在胶质瘤诊断、预后和治疗中的临床意义。将表观遗传时钟数据整合到个性化医疗方法中，有望改善胶质瘤的治疗策略和患者预后。
{"title":"Epigenetic clocks and gliomas: unveiling the molecular interactions between aging and tumor development","authors":"Shiliang Chen, Yi Jiang, Cong Wang, Shiyuan Tong, Yibo He, Wenqiang Lu, Zhezhong Zhang","doi":"10.3389/fmolb.2024.1446428","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1446428","url":null,"abstract":"Gliomas, the most prevalent and aggressive primary brain tumors, represent a diverse group of malignancies originating from glial cells. These tumors account for significant brain tumor-related morbidity and mortality, with higher incidence rates in North America and Europe compared to Asia and Africa. Genetic predispositions and environmental factors, particularly ionizing radiation, critically impact glioma risk. Epigenetics, particularly DNA methylation, plays a pivotal role in glioma research, with IDH-mutant gliomas showing aberrant methylation patterns contributing to tumorigenesis. Epigenetic clocks, biomarkers based on DNA methylation patterns predicting biological age, have revealed significant insights into aging and tumor development. Recent studies demonstrate accelerated epigenetic aging in gliomas, correlating with increased cancer risk and poorer outcomes. This review explores the mechanisms of epigenetic clocks, their biological significance, and their application in glioma research. Furthermore, the clinical implications of epigenetic clocks in diagnosing, prognosticating, and treating gliomas are discussed. The integration of epigenetic clock data into personalized medicine approaches holds promise for enhancing therapeutic strategies and patient outcomes in glioma treatment.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774314","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 : 2024-07-26DOI: 10.3389/fmolb.2024.1455817
Jana Schepers, Timo Löser, Christian Behl
Aggregation of alpha-Synuclein (αSyn) has been connected to several neurodegenerative diseases, such as Parkinson’s disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), that are collected under the umbrella term synucleinopathies. The membrane binding abilities of αSyn to negatively charged phospholipids have been well described and are connected to putative physiological functions of αSyn. Consequently, αSyn-related neurodegeneration has been increasingly connected to changes in lipid metabolism and membrane lipid composition. Indeed, αSyn aggregation has been shown to be triggered by the presence of membranes in vitro, and some genetic risk factors for PD and DLB are associated with genes coding for proteins directly involved in lipid metabolism. At the same time, αSyn aggregation itself can cause alterations of cellular lipid composition and brain samples of patients also show altered lipid compositions. Thus, it is likely that there is a reciprocal influence between cellular lipid composition and αSyn aggregation, which can be further affected by environmental or genetic factors and ageing. Little is known about lipid changes during physiological ageing and regional differences of the lipid composition of the aged brain. In this review, we aim to summarise our current understanding of lipid changes in connection to αSyn and discuss open questions that need to be answered to further our knowledge of αSyn related neurodegeneration.
{"title":"Frontiers | Lipids and α-Synuclein: adding further variables to the equation","authors":"Jana Schepers, Timo Löser, Christian Behl","doi":"10.3389/fmolb.2024.1455817","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1455817","url":null,"abstract":"Aggregation of alpha-Synuclein (αSyn) has been connected to several neurodegenerative diseases, such as Parkinson’s disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), that are collected under the umbrella term synucleinopathies. The membrane binding abilities of αSyn to negatively charged phospholipids have been well described and are connected to putative physiological functions of αSyn. Consequently, αSyn-related neurodegeneration has been increasingly connected to changes in lipid metabolism and membrane lipid composition. Indeed, αSyn aggregation has been shown to be triggered by the presence of membranes in vitro, and some genetic risk factors for PD and DLB are associated with genes coding for proteins directly involved in lipid metabolism. At the same time, αSyn aggregation itself can cause alterations of cellular lipid composition and brain samples of patients also show altered lipid compositions. Thus, it is likely that there is a reciprocal influence between cellular lipid composition and αSyn aggregation, which can be further affected by environmental or genetic factors and ageing. Little is known about lipid changes during physiological ageing and regional differences of the lipid composition of the aged brain. In this review, we aim to summarise our current understanding of lipid changes in connection to αSyn and discuss open questions that need to be answered to further our knowledge of αSyn related neurodegeneration.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141937845","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 : 2024-07-25DOI: 10.3389/fmolb.2024.1452184
Lorena Pochini
Polyamines interact with different molecular targets to regulate a vast range of cellular processes. A network of enzymes and transport systems is crucial for the maintenance of polyamine homeostasis. Indeed, polyamines after synthesis must be distributed to the various tissues and some intracellular organelles. Differently from the well characterized enzymes devoted to polyamine synthesis, the transport systems are not unequivocally identified or characterized. Besides some ATPases which have been identified as polyamine transporters, much less is known about solute carriers (SLC) involved in the transport of these compounds. Only two SLCs have been unequivocally identified as polyamine transporters: SLC18B1 (VPAT) and SLC22A4 (OCTN1). Transport studies have been performed with cells transfected with the cDNAs encoding the two and other SLCs or, in the case of OCTN1, also by in vitro assay using proteoliposomes harboring the recombinant human protein. According to the role proposed for OCTN1, polyamines have been associated with prolonged and quality of life. This review provides an update on the most recent findings concerning the polyamine transporters or the prediction of the putative ones.
{"title":"Involvement of mammalian SoLute Carriers (SLC) in the traffic of polyamines","authors":"Lorena Pochini","doi":"10.3389/fmolb.2024.1452184","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1452184","url":null,"abstract":"Polyamines interact with different molecular targets to regulate a vast range of cellular processes. A network of enzymes and transport systems is crucial for the maintenance of polyamine homeostasis. Indeed, polyamines after synthesis must be distributed to the various tissues and some intracellular organelles. Differently from the well characterized enzymes devoted to polyamine synthesis, the transport systems are not unequivocally identified or characterized. Besides some ATPases which have been identified as polyamine transporters, much less is known about solute carriers (SLC) involved in the transport of these compounds. Only two SLCs have been unequivocally identified as polyamine transporters: SLC18B1 (VPAT) and SLC22A4 (OCTN1). Transport studies have been performed with cells transfected with the cDNAs encoding the two and other SLCs or, in the case of OCTN1, also by <jats:italic>in vitro</jats:italic> assay using proteoliposomes harboring the recombinant human protein. According to the role proposed for OCTN1, polyamines have been associated with prolonged and quality of life. This review provides an update on the most recent findings concerning the polyamine transporters or the prediction of the putative ones.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774318","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}
To investigate the genetic diversity of Triplophysa tenuis in the Shule River Basin of Gansu province, three populations were sequenced via RAD-seq technology. Twenty-nine microsatellite (SSR) markers with polymorphisms were finally screened to access the genetic diversity among the populations, of which 15 had high polymorphisms. The quantity of the alleles detected in the three populations of T. tenuis varied from 2 to 24. The locus with the most alleles was SSRC1, which had 24 alleles. Among the 29 SSRs, the range of effective allele number, observed heterozygosity, expected heterozygosity, and polymorphic information content were 1.246–16.615, 0.222–1, 0.198–0.940, and 0.178–0.937, respectively. Most of the identified loci were in the Hardy–Weinberg equilibrium. Analysis of the population structure revealed that the Yumen and Changma populations shared the same origin, while the Qiaowan population was different from them. The developed SSR markers discovered in this study will contribute to the conservation research on T. tenuis and the conservation of the fishery resources of the Shule River, providing scientific guidance for the development and utilization of T. tenuis resources and environmental protection.
为研究甘肃省疏勒河流域三疣梭子蟹（Triplophysa tenuis）的遗传多样性，利用RAD-seq技术对三个种群进行了测序。最终筛选出29个具有多态性的微卫星（SSR）标记，其中15个标记具有较高的多态性。在 T. tenuis 的三个种群中检测到的等位基因数量从 2 个到 24 个不等。等位基因最多的位点是 SSRC1，有 24 个等位基因。在 29 个 SSR 中，有效等位基因数、观察杂合度、预期杂合度和多态信息含量的范围分别为 1.246-16.615、0.222-1、0.198-0.940 和 0.178-0.937。大部分已确定的位点处于哈代-温伯格平衡状态。种群结构分析表明，玉门种群与长马种群同源，而桥湾种群与之不同。本研究发现的SSR标记将有助于天牛的保护研究和疏勒河渔业资源的保护，为天牛资源的开发利用和环境保护提供科学指导。
{"title":"Analysis of genetic diversity among three Triplophysa tenuis populations by RAD-seq","authors":"Wenqiong Wu, Junqiang Qiu, Yue Lin, Xike Li, Wenjuan Li, Yuanliang Duan, Yuanshuai Fu","doi":"10.3389/fmolb.2024.1373754","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1373754","url":null,"abstract":"To investigate the genetic diversity of <jats:italic>Triplophysa tenuis</jats:italic> in the Shule River Basin of Gansu province, three populations were sequenced via RAD-seq technology. Twenty-nine microsatellite (SSR) markers with polymorphisms were finally screened to access the genetic diversity among the populations, of which 15 had high polymorphisms. The quantity of the alleles detected in the three populations of <jats:italic>T. tenuis</jats:italic> varied from 2 to 24. The locus with the most alleles was SSRC1, which had 24 alleles. Among the 29 SSRs, the range of effective allele number, observed heterozygosity, expected heterozygosity, and polymorphic information content were 1.246–16.615, 0.222–1, 0.198–0.940, and 0.178–0.937, respectively. Most of the identified loci were in the Hardy–Weinberg equilibrium. Analysis of the population structure revealed that the Yumen and Changma populations shared the same origin, while the Qiaowan population was different from them. The developed SSR markers discovered in this study will contribute to the conservation research on <jats:italic>T. tenuis</jats:italic> and the conservation of the fishery resources of the Shule River, providing scientific guidance for the development and utilization of <jats:italic>T. tenuis</jats:italic> resources and environmental protection.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774317","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 : 2024-07-25DOI: 10.3389/fmolb.2024.1421597
Xing Su, Li-Yan Han, Jing Wang, Ying Zhang, Peng-Yu Luo, Shuai Gao, Yu-Chen Fan, Jing-Wei Wang, Kai Wang
BackgroundHepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) is a syn-drome with a high short-term mortality rate, and its prognosis is critical in clinical management. This study aimed to investigate the clinical significance of glutathione peroxidase 4 (GPX4) in the occurrence and development of HBV-ACLF and its prognostic value for 90-day mortality.MethodsThe expression levels of GPX4, oxidative stress-related molecules and inflammatory cytokines in serum or peripheral blood mononuclear cells (PBMCs) of 289 participants were determined by RT-qPCR or ELISA, and the methylation level of GPX4 promoter in PBMCs was determined by MethyLight.ResultsThe expression levels of GPX4 in the PBMCs and serum of HBV-ACLF patients were lower than those in non-HBV-associated acute-on-chronic liver failure (non-HBV ACLF) patients, patients with chronic hepatitis B (CHB) and healthy control (HC) individuals, while the methylation level of the GPX4 promoter was greater. In HBV-ACLF patients, the methylation level of the GPX4 promoter is correlated with oxidative stress, inflammation-related molecules, and some clinicopathological indicators. The methylation level of the GPX4 promoter was identified as an independent risk factor for 90-day mortality in HBV-ACLF patients and yielded a larger area under the receiver operating characteristic curve (AUROC) than the model for end-stage liver disease (MELD) score in predicting 90-day mortality.ConclusionThe GPX4 promoter methylation level has promising potential as a predictor of 90-day mortality in patients with HBV-ACLF.
{"title":"Hypermethylation of the glutathione peroxidase 4 promoter predicts poor prognosis in patients with hepatitis B virus-associated acute-on-chronic liver failure","authors":"Xing Su, Li-Yan Han, Jing Wang, Ying Zhang, Peng-Yu Luo, Shuai Gao, Yu-Chen Fan, Jing-Wei Wang, Kai Wang","doi":"10.3389/fmolb.2024.1421597","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1421597","url":null,"abstract":"BackgroundHepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) is a syn-drome with a high short-term mortality rate, and its prognosis is critical in clinical management. This study aimed to investigate the clinical significance of glutathione peroxidase 4 (GPX4) in the occurrence and development of HBV-ACLF and its prognostic value for 90-day mortality.MethodsThe expression levels of GPX4, oxidative stress-related molecules and inflammatory cytokines in serum or peripheral blood mononuclear cells (PBMCs) of 289 participants were determined by RT-qPCR or ELISA, and the methylation level of GPX4 promoter in PBMCs was determined by MethyLight.ResultsThe expression levels of GPX4 in the PBMCs and serum of HBV-ACLF patients were lower than those in non-HBV-associated acute-on-chronic liver failure (non-HBV ACLF) patients, patients with chronic hepatitis B (CHB) and healthy control (HC) individuals, while the methylation level of the <jats:italic>GPX4</jats:italic> promoter was greater. In HBV-ACLF patients, the methylation level of the <jats:italic>GPX4</jats:italic> promoter is correlated with oxidative stress, inflammation-related molecules, and some clinicopathological indicators. The methylation level of the <jats:italic>GPX4</jats:italic> promoter was identified as an independent risk factor for 90-day mortality in HBV-ACLF patients and yielded a larger area under the receiver operating characteristic curve (AUROC) than the model for end-stage liver disease (MELD) score in predicting 90-day mortality.ConclusionThe GPX4 promoter methylation level has promising potential as a predictor of 90-day mortality in patients with HBV-ACLF.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774323","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 : 2024-07-24DOI: 10.3389/fmolb.2024.1429180
Moumita Dutta, Priyamvada Acharya
Viruses have been responsible for many epidemics and pandemics that have impacted human life globally. The COVID-19 pandemic highlighted both our vulnerability to viral outbreaks, as well as the mobilization of the scientific community to come together to combat the unprecedented threat to humanity. Cryo-electron microscopy (cryo-EM) played a central role in our understanding of SARS-CoV-2 during the pandemic and continues to inform about this evolving pathogen. Cryo-EM with its two popular imaging modalities, single particle analysis (SPA) and cryo-electron tomography (cryo-ET), has contributed immensely to understanding the structure of viruses and interactions that define their life cycles and pathogenicity. Here, we review how cryo-EM has informed our understanding of three distinct viruses, of which two - HIV-1 and SARS-CoV-2 infect humans, and the third, bacteriophages, infect bacteria. For HIV-1 and SARS-CoV-2 our focus is on the surface glycoproteins that are responsible for mediating host receptor binding, and host and cell membrane fusion, while for bacteriophages, we review their structure, capsid maturation, attachment to the bacterial cell surface and infection initiation mechanism.
{"title":"Cryo-electron microscopy in the study of virus entry and infection","authors":"Moumita Dutta, Priyamvada Acharya","doi":"10.3389/fmolb.2024.1429180","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1429180","url":null,"abstract":"Viruses have been responsible for many epidemics and pandemics that have impacted human life globally. The COVID-19 pandemic highlighted both our vulnerability to viral outbreaks, as well as the mobilization of the scientific community to come together to combat the unprecedented threat to humanity. Cryo-electron microscopy (cryo-EM) played a central role in our understanding of SARS-CoV-2 during the pandemic and continues to inform about this evolving pathogen. Cryo-EM with its two popular imaging modalities, single particle analysis (SPA) and cryo-electron tomography (cryo-ET), has contributed immensely to understanding the structure of viruses and interactions that define their life cycles and pathogenicity. Here, we review how cryo-EM has informed our understanding of three distinct viruses, of which two - HIV-1 and SARS-CoV-2 infect humans, and the third, bacteriophages, infect bacteria. For HIV-1 and SARS-CoV-2 our focus is on the surface glycoproteins that are responsible for mediating host receptor binding, and host and cell membrane fusion, while for bacteriophages, we review their structure, capsid maturation, attachment to the bacterial cell surface and infection initiation mechanism.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774320","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}
Actin remodeling proteins are important in immune diseases and regulate cell cytoskeletal responses. These responses play a pivotal role in maintaining the delicate balance of biological events, protecting against acute or chronic inflammation in a range of diseases. Cofilin (CFL) and actin depolymerization factor (ADF) are potent actin-binding proteins that cut and depolymerize actin filaments to generate actin cytoskeleton dynamics. Although the molecular mechanism by which actin induces actin cytoskeletal reconstitution has been studied for decades, the regulation of actin in the inflammatory process has only recently become apparent. In this paper, the functions of the actin cytoskeleton and ADF/cofilin superfamily members are briefly introduced, and then focus on the role of CFL1 in inflammatory response.
{"title":"The role of actin cytoskeleton CFL1 and ADF/cofilin superfamily in inflammatory response","authors":"Jianxiao Xing, Ying Wang, Aihong Peng, Junqin Li, Xuping Niu, Kaiming Zhang","doi":"10.3389/fmolb.2024.1408287","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1408287","url":null,"abstract":"Actin remodeling proteins are important in immune diseases and regulate cell cytoskeletal responses. These responses play a pivotal role in maintaining the delicate balance of biological events, protecting against acute or chronic inflammation in a range of diseases. Cofilin (CFL) and actin depolymerization factor (ADF) are potent actin-binding proteins that cut and depolymerize actin filaments to generate actin cytoskeleton dynamics. Although the molecular mechanism by which actin induces actin cytoskeletal reconstitution has been studied for decades, the regulation of actin in the inflammatory process has only recently become apparent. In this paper, the functions of the actin cytoskeleton and ADF/cofilin superfamily members are briefly introduced, and then focus on the role of CFL1 in inflammatory response.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774324","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 : 2024-07-24DOI: 10.3389/fmolb.2024.1390257
Tian-Qi Li, Yan Liu, Chong Feng, Jin Bai, Zi-Rou Wang, Xiang-Yu Zhang, Xin-Xing Wang
To alleviate bone loss, most current drugs target osteoclasts. Saikosaponin A (Ssa), a triterpene saponin derived from Bupleurum falcatum (also known as Radix bupleuri), has immunoregulatory, neuromodulatory, antiviral, anticancer, anti-convulsant, anti-inflammatory, and anti-proliferative effects. Recently, modulation of bone homeostasis was shown to involve ferroptosis. Herein, we aimed to determine Ssa’s inhibitory effects on osteoclastogenesis and differentiation, whether ferroptosis is involved, and the underlying mechanisms. Tartrate‐resistant acid phosphatase (TRAP) staining, F‐actin staining, and pit formation assays were conducted to confirm Ssa-mediated inhibition of RANKL-induced osteoclastogenesis in vitro. Ssa could promote osteoclast ferroptosis and increase mitochondrial damage by promoting lipid peroxidation, as measured by iron quantification, FerroOrange staining, Dichloro-dihydro-fluorescein diacetate, MitoSOX, malondialdehyde, glutathione, and boron-dipyrromethene 581/591 C11 assays. Pathway analysis showed that Ssa can promote osteoclasts ferroptosis by inhibiting the Nrf2/SCL7A11/GPX4 axis. Notably, we found that the ferroptosis inhibitor ferrostatin-1 and the Nrf2 activator tert-Butylhydroquinone reversed the inhibitory effects of Ssa on RANKL-induced osteoclastogenesis. In vivo, micro-computed tomography, hematoxylin and eosin staining, TRAP staining, enzyme-linked immunosorbent assays, and immunofluorescence confirmed that in rats with periodontitis induced by lipopolysaccharide, treatment with Ssa reduced alveolar bone resorption dose-dependently. The results suggested Ssa as a promising drug to treat osteolytic diseases.
{"title":"Saikosaponin A attenuates osteoclastogenesis and bone loss by inducing ferroptosis","authors":"Tian-Qi Li, Yan Liu, Chong Feng, Jin Bai, Zi-Rou Wang, Xiang-Yu Zhang, Xin-Xing Wang","doi":"10.3389/fmolb.2024.1390257","DOIUrl":"https://doi.org/10.3389/fmolb.2024.1390257","url":null,"abstract":"To alleviate bone loss, most current drugs target osteoclasts. Saikosaponin A (Ssa), a triterpene saponin derived from <jats:italic>Bupleurum falcatum</jats:italic> (also known as Radix bupleuri), has immunoregulatory, neuromodulatory, antiviral, anticancer, anti-convulsant, anti-inflammatory, and anti-proliferative effects. Recently, modulation of bone homeostasis was shown to involve ferroptosis. Herein, we aimed to determine Ssa’s inhibitory effects on osteoclastogenesis and differentiation, whether ferroptosis is involved, and the underlying mechanisms. Tartrate‐resistant acid phosphatase (TRAP) staining, F‐actin staining, and pit formation assays were conducted to confirm Ssa-mediated inhibition of RANKL-induced osteoclastogenesis <jats:italic>in vitro</jats:italic>. Ssa could promote osteoclast ferroptosis and increase mitochondrial damage by promoting lipid peroxidation, as measured by iron quantification, FerroOrange staining, Dichloro-dihydro-fluorescein diacetate, MitoSOX, malondialdehyde, glutathione, and boron-dipyrromethene 581/591 C11 assays. Pathway analysis showed that Ssa can promote osteoclasts ferroptosis by inhibiting the Nrf2/SCL7A11/GPX4 axis. Notably, we found that the ferroptosis inhibitor ferrostatin-1 and the Nrf2 activator tert-Butylhydroquinone reversed the inhibitory effects of Ssa on RANKL-induced osteoclastogenesis. <jats:italic>In vivo</jats:italic>, micro-computed tomography, hematoxylin and eosin staining, TRAP staining, enzyme-linked immunosorbent assays, and immunofluorescence confirmed that in rats with periodontitis induced by lipopolysaccharide, treatment with Ssa reduced alveolar bone resorption dose-dependently. The results suggested Ssa as a promising drug to treat osteolytic diseases.","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774321","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}
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