This study sought to identify a single molecule capable of managing all three manifestations of metabolic syndrome–hyperglycaemia, dyslipidaemia and hypertension. Two Protein Data Bank (PDB) depositions were selected and used to establish the baseline affinity that any designed molecule in this study should ideally exceed in order to be considered for further optimisation. These were PDB depositions 3VN2 and 2P54 describing the bound co-ordinates of the Peroxisome Proliferator Activated Receptor (PPAR)γ partial agonist and Angiotensin II Receptor (Ang(II)R) blocker telmisartan and of the experimental PPARα fibrate agonist GW590735 bound to their respective cognate receptors. These small molecules were extracted from their cognate receptors, docked into their non-cognate counterparts, conformational analysis performed, and the optimal conformers were selected as template scaffolds in two parallel processes. The first was a fragment based de novo approach. Here, molecular moieties from the optimal telmisartan and GW590735 scaffolds modelled in their non-cognate targets and considered critical to binding were identified and modelled, in order to produce seed structures capable of sustaining molecular growth at user-directed sites designated as H.spc atoms subsequent to their being docked within the non-cognate Ligand Binding Pockets (LBPs). The second approach was a Virtual Screening (VS) exercise. Here, the optimal telmisartan and GW590735 conformers were submitted as query molecules to VS databases both individually and in the form of a consensus pharmacophore. This VS exercise identified structurally diverse molecules which were electronically and spatially similar to the queries and which were capable of modulating the target receptors. The molecular cohorts identified through both VS and the de novo approaches were filtered for Lipinski Rule compliance. The molecules that survived filtering were then re-docked into the non-cognate PPARα and/or γ_LBPs, conformational analysis re-performed and the affinity of the optimal conformer measured for its cognate receptor quantified. Comparison was made to the baseline and non-cognate receptor affinities previously established, and the molecules exhibiting dual affinities exceeding baseline values were selected for further optimisation. The use of the “tried and tested” Ang(II)R blocker and fibrate scaffolds as templates predisposes to the identification of novel structures devoid of unacceptable toxicity.
{"title":"Design of Novel Compounds with the Potential of Dual PPARγ/α Modulation for the Management of Metabolic Syndrome","authors":"C. Ellul, C. Shoemake","doi":"10.11131/2017/101311","DOIUrl":"https://doi.org/10.11131/2017/101311","url":null,"abstract":"This study sought to identify a single molecule capable of managing all three manifestations of metabolic syndrome–hyperglycaemia, dyslipidaemia and hypertension. Two Protein Data Bank (PDB) depositions were selected and used to establish the baseline affinity that any designed molecule in this study should ideally exceed in order to be considered for further optimisation. These were PDB depositions 3VN2 and 2P54 describing the bound co-ordinates of the Peroxisome Proliferator Activated Receptor (PPAR)γ partial agonist and Angiotensin II Receptor (Ang(II)R) blocker telmisartan and of the experimental PPARα fibrate agonist GW590735 bound to their respective cognate receptors. These small molecules were extracted from their cognate receptors, docked into their non-cognate counterparts, conformational analysis performed, and the optimal conformers were selected as template scaffolds in two parallel processes. The first was a fragment based de novo approach. Here, molecular moieties from the optimal telmisartan and GW590735 scaffolds modelled in their non-cognate targets and considered critical to binding were identified and modelled, in order to produce seed structures capable of sustaining molecular growth at user-directed sites designated as H.spc atoms subsequent to their being docked within the non-cognate Ligand Binding Pockets (LBPs). The second approach was a Virtual Screening (VS) exercise. Here, the optimal telmisartan and GW590735 conformers were submitted as query molecules to VS databases both individually and in the form of a consensus pharmacophore. This VS exercise identified structurally diverse molecules which were electronically and spatially similar to the queries and which were capable of modulating the target receptors. The molecular cohorts identified through both VS and the de novo approaches were filtered for Lipinski Rule compliance. The molecules that survived filtering were then re-docked into the non-cognate PPARα and/or γ_LBPs, conformational analysis re-performed and the affinity of the optimal conformer measured for its cognate receptor quantified. Comparison was made to the baseline and non-cognate receptor affinities previously established, and the molecules exhibiting dual affinities exceeding baseline values were selected for further optimisation. The use of the “tried and tested” Ang(II)R blocker and fibrate scaffolds as templates predisposes to the identification of novel structures devoid of unacceptable toxicity.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63479632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Systemic homeostasis in animals is maintained by a network of complex signalling pathways involving several kinds of endogenous molecules/metabolites. Over the years, the role of microbiota present in the digestive tract in animal physiology has been under focus and path-breaking findings have been reported. It seems that the gut microbiota has an influence in perhaps almost all the physiological functions, including the central nervous system in animals. The means by which the microbiota impinges control on the host system biology is manifold and complex. However, one of the mechanisms involve microbiota-derived metabolites that functions as ligands to modulate host tissue gene expression via the nuclear receptors (NRs), which is a novel way of exerting control over the host physiology. Few of the host NRs, such as the pregnane X receptor (PXR), farnesoid X receptor (FXR) and peroxisome-proliferator activated receptors (PPARs) gene transcriptional activities have been demonstrated to be modulated by the binding of microbial-secreted metabolites acting as ligands. Such interactions control vital functions in the host such as intestinal epithelial barrier protection, immune tolerance and anti-inflammatory responses. In this article, recent important findings in understanding gut microbiota-derived metabolites and select host NRs signalling will be briefly reviewed.
{"title":"Gut Microbiota and Host Nuclear Receptors Signalling","authors":"H. Ranhotra","doi":"10.11131/2017/101316","DOIUrl":"https://doi.org/10.11131/2017/101316","url":null,"abstract":"Systemic homeostasis in animals is maintained by a network of complex signalling pathways involving several kinds of endogenous molecules/metabolites. Over the years, the role of microbiota present in the digestive tract in animal physiology has been under focus and path-breaking findings have been reported. It seems that the gut microbiota has an influence in perhaps almost all the physiological functions, including the central nervous system in animals. The means by which the microbiota impinges control on the host system biology is manifold and complex. However, one of the mechanisms involve microbiota-derived metabolites that functions as ligands to modulate host tissue gene expression via the nuclear receptors (NRs), which is a novel way of exerting control over the host physiology. Few of the host NRs, such as the pregnane X receptor (PXR), farnesoid X receptor (FXR) and peroxisome-proliferator activated receptors (PPARs) gene transcriptional activities have been demonstrated to be modulated by the binding of microbial-secreted metabolites acting as ligands. Such interactions control vital functions in the host such as intestinal epithelial barrier protection, immune tolerance and anti-inflammatory responses. In this article, recent important findings in understanding gut microbiota-derived metabolites and select host NRs signalling will be briefly reviewed.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45229950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Y. Lecarpentier, O. Schussler, V. Claes, Alexandre Vallée
Myofibroblasts are non-muscular contractile cells that occur physiologically in organs such as in stem villi of the human placenta during normal pregnancies. They have the ability to contract and relax in response to changes in the volume of the intervillous chamber. Myofibroblasts are also found in many pathological states, and are involved in wound healing and fibrosis processes in several organs such as liver, lung, kidney, and heart. During fibrosis, the contractile phenomenon is a relaxation-free mechanism, associated with the synthesis of collagen in the extracellular matrix (ECM), which leads to irreversible fibrosis, tissue retraction and finally apoptosis of the myofibroblasts. The molecular motor of myofibroblasts is the non-muscle myosin type II (NMII). Differentiation of fibroblasts into myofibroblast is largely regulated by the Transforming Growth Factor-β1 (TGF-β1). This system regulates the canonical WNT/β-catenin pathway in a positive manner and PPARγ in a negative manner. WNT/β-catenin promotes fibrosis while PPARγ prevents fibrosis. This review focuses on the contractile properties of myofibroblasts and on the TGF-β1 conductor which regulates the antagonism between PPARγ and the canonical WNT/β-catenin pathway.
{"title":"The Myofibroblast: TGFβ-1, A Conductor which Plays a Key Role in Fibrosis by Regulating the Balance between PPARγ and the Canonical WNT Pathway","authors":"Y. Lecarpentier, O. Schussler, V. Claes, Alexandre Vallée","doi":"10.11131/2017/101299","DOIUrl":"https://doi.org/10.11131/2017/101299","url":null,"abstract":"Myofibroblasts are non-muscular contractile cells that occur physiologically in organs such as in stem villi of the human placenta during normal pregnancies. They have the ability to contract and relax in response to changes in the volume of the intervillous chamber. Myofibroblasts are also found in many pathological states, and are involved in wound healing and fibrosis processes in several organs such as liver, lung, kidney, and heart. During fibrosis, the contractile phenomenon is a relaxation-free mechanism, associated with the synthesis of collagen in the extracellular matrix (ECM), which leads to irreversible fibrosis, tissue retraction and finally apoptosis of the myofibroblasts. The molecular motor of myofibroblasts is the non-muscle myosin type II (NMII). Differentiation of fibroblasts into myofibroblast is largely regulated by the Transforming Growth Factor-β1 (TGF-β1). This system regulates the canonical WNT/β-catenin pathway in a positive manner and PPARγ in a negative manner. WNT/β-catenin promotes fibrosis while PPARγ prevents fibrosis. This review focuses on the contractile properties of myofibroblasts and on the TGF-β1 conductor which regulates the antagonism between PPARγ and the canonical WNT/β-catenin pathway.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49355833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Within the REACH Regulation (EC/1907/2006), the substitution principle for chemicals classified as Substances of Very High Concern (SVHC) for either human health or environmental risks has been implemented in order to support their replacement by suitable alternatives. Considering the thousands of chemicals to be tested within the frame of REACH, animal testing by internationally-accepted guidelines sounds unreasonable in terms of the required time, costs as well ethical issues. Hence, REACH recommended also the use of alternative methods to animal experimentation although no validated in silico or in vitro tools were available when regulation entried into force. To search for suitable alternatives to SVHC having an Endocrine Disruptor (ED)-like Mode-of-Action (MoA) by means of an integrated, tiered in silico-in vitro approach, the EU-granted project LIFE-EDESIA (contract no. LIFE12 ENV/IT/000633) is combining computational-based tools and cell-based bioassays, in order to develop a no-animal testing procedure to screen for chemicals having less or no toxicity in terms of endocrine disruption-like activities. A general view of the no-animal testing approach implementing REACH and the substitution principle will be given, emphasising ligand-nuclear receptor (NR) assessment by molecular docking (one of the LIFE-EDESIA in silico approaches) and the use of clinical biomarkers in in vitro toxicology to detect ED-like adverse effects in cell-based bioassays.
在REACH法规(EC/1907/2006)中，对被列为对人类健康或环境有风险的高度关注物质(SVHC)的化学品实施了替代原则，以支持用合适的替代品替代这些化学品。考虑到在REACH框架内需要测试的数千种化学品，从所需的时间、成本和伦理问题来看，按照国际公认的准则进行动物试验听起来不合理。因此，REACH还建议使用替代动物实验的方法，尽管在法规生效时没有经过验证的计算机或体外工具可用。为了寻找具有内分泌干扰物(ED)样作用模式(MoA)的SVHC的合适替代品，通过集成的、分层的硅体外方法，欧盟批准的LIFE-EDESIA项目(合同编号:LIFE12 (ENV/IT/000633)正在将基于计算的工具和基于细胞的生物测定相结合，以开发一种非动物试验程序，以筛选在内分泌干扰类活动方面毒性较小或没有毒性的化学品。本文将给出实施REACH和替代原则的非动物试验方法的总体观点，强调通过分子对接(LIFE-EDESIA in silico方法之一)评估配体-核受体(NR)，以及在体外毒理学中使用临床生物标志物来检测基于细胞的生物测定中的ed样不良反应。
{"title":"The Substitution Principle within the REACH Regulation: Nuclear Receptor-Bound Endocrine Disruptors","authors":"S. Lorenzetti, P. Cozzini","doi":"10.11131/2017/101205","DOIUrl":"https://doi.org/10.11131/2017/101205","url":null,"abstract":"Within the REACH Regulation (EC/1907/2006), the substitution principle for chemicals classified as Substances of Very High Concern (SVHC) for either human health or environmental risks has been implemented in order to support their replacement by suitable alternatives. Considering the thousands of chemicals to be tested within the frame of REACH, animal testing by internationally-accepted guidelines sounds unreasonable in terms of the required time, costs as well ethical issues. Hence, REACH recommended also the use of alternative methods to animal experimentation although no validated in silico or in vitro tools were available when regulation entried into force. \u0000To search for suitable alternatives to SVHC having an Endocrine Disruptor (ED)-like Mode-of-Action (MoA) by means of an integrated, tiered in silico-in vitro approach, the EU-granted project LIFE-EDESIA (contract no. LIFE12 ENV/IT/000633) is combining computational-based tools and cell-based bioassays, in order to develop a no-animal testing procedure to screen for chemicals having less or no toxicity in terms of endocrine disruption-like activities. \u0000A general view of the no-animal testing approach implementing REACH and the substitution principle will be given, emphasising ligand-nuclear receptor (NR) assessment by molecular docking (one of the LIFE-EDESIA in silico approaches) and the use of clinical biomarkers in in vitro toxicology to detect ED-like adverse effects in cell-based bioassays.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44168676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Steroid hormones regulate a wide range of processes in our body, and their effects are mediated by steroid receptors. In addition to their physiological role, these receptors mediate the effects of endocrine disrupting chemicals (EDCs) and are widely used targets for dugs involved in the treatment of numerous diseases, ranging from cancer to inflammatory disorders. Over the last fifteen years, the zebrafish has increasingly been used as an animal model in steroid receptor research. Orthologues of all human steroid receptor genes appear to be present in zebrafish. All zebrafish steroid receptors have been characterized in detail, and their expression patterns have been analyzed. Functional studies have been performed using morpholino knockdown of receptor expression and zebrafish lines carrying mutations in one of their steroid receptor genes. To investigate the activity of the receptors in vivo, specific zebrafish reporter lines have been developed, and transcriptomic studies have been carried out to identify biomarkers for steroid receptor action. In this review, an overview of research on steroid receptors in zebrafish is presented, and it is concluded that further exploitation of the possibilities of the zebrafish model system will contribute significantly to the advancement of steroid receptor research in the next decade.
{"title":"The First Fifteen Years of Steroid Receptor Research in Zebrafish; Characterization and Functional Analysis of the Receptors","authors":"M. Schaaf","doi":"10.11131/2017/101286","DOIUrl":"https://doi.org/10.11131/2017/101286","url":null,"abstract":"Steroid hormones regulate a wide range of processes in our body, and their \u0000 effects are mediated by steroid receptors. In addition to their physiological \u0000 role, these receptors mediate the effects of endocrine disrupting chemicals \u0000 (EDCs) and are widely used targets for dugs involved in the treatment of \u0000 numerous diseases, ranging from cancer to inflammatory disorders. Over the last \u0000 fifteen years, the zebrafish has increasingly been used as an animal model in \u0000 steroid receptor research. Orthologues of all human steroid receptor genes \u0000 appear to be present in zebrafish. All zebrafish steroid receptors have been \u0000 characterized in detail, and their expression patterns have been analyzed. \u0000 Functional studies have been performed using morpholino knockdown of receptor \u0000 expression and zebrafish lines carrying mutations in one of their steroid \u0000 receptor genes. To investigate the activity of the receptors in \u0000 vivo, specific zebrafish reporter lines have been developed, and \u0000 transcriptomic studies have been carried out to identify biomarkers for steroid \u0000 receptor action. In this review, an overview of research on steroid receptors in \u0000 zebrafish is presented, and it is concluded that further exploitation of the \u0000 possibilities of the zebrafish model system will contribute significantly to the \u0000 advancement of steroid receptor research in the next decade.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41696779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The lamprey Petromyzon marinus belongs to the agnathans, the oldest vertebrate lineage from which jawed vertebrates diverged about 500 million years ago. Therefore, it holds a key phylogenetic position to understand the evolution of vertebrates. As in jawed vertebrates, two thyroid hormone receptors have been described in lamprey. These receptors, referred to as TR1 and TR2, behave as genuine TRs but are considered as an independent duplications when compared to the orthologs characterized in jawed vertebrates, TRα and TRβ. Here, we show that the lamprey genome contains two additional TR sequences. Their assignment to bona fide thyroid hormone receptors is supported by sequence alignments and phylogenetic reconstructions. This led us to revisit the phylogeny of thyroid hormone receptors and to detect an acceleration of their evolutionary rates at the basis of vertebrates. Our analysis therefore suggests that major evolutionary shifts occurred at the receptor level just when the modern synthesis of thyroid hormone was established during early vertebrate evolution.
{"title":"New Insights into Vertebrate Thyroid Hormone Receptor Evolution","authors":"G. Holzer, V. Laudet","doi":"10.11131/2017/101287","DOIUrl":"https://doi.org/10.11131/2017/101287","url":null,"abstract":"The lamprey Petromyzon marinus belongs to the agnathans, the oldest vertebrate lineage from which jawed vertebrates diverged about 500 million years ago. Therefore, it holds a key phylogenetic position to understand the evolution of vertebrates. As in jawed vertebrates, two thyroid hormone receptors have been described in lamprey. These receptors, referred to as TR1 and TR2, behave as genuine TRs but are considered as an independent duplications when compared to the orthologs characterized in jawed vertebrates, TRα and TRβ. Here, we show that the lamprey genome contains two additional TR sequences. Their assignment to bona fide thyroid hormone receptors is supported by sequence alignments and phylogenetic reconstructions. This led us to revisit the phylogeny of thyroid hormone receptors and to detect an acceleration of their evolutionary rates at the basis of vertebrates. Our analysis therefore suggests that major evolutionary shifts occurred at the receptor level just when the modern synthesis of thyroid hormone was established during early vertebrate evolution.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47672077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In silico techniques are an emerging field in Food Science. In silicomeans done using computer, also defined as dry experiments while traditional lab experiments are commonly defined as wet experiments. These techniques come from Medicinal Chemistry and Computational Chemistry where they have been known for many decades. Common applications of informatics techniques in Food Science are traditionally statistics and QSAR (Quantitative Structure Activity Relationship) approaches. However, massive screening of databases of chemicals, docking and scoring of most promising chemicals into known receptors are not common applications in food science, i.e. food safety, food security, food toxicology, predictive toxicology, etc. One of the most important questions we would like to answer is: could we merge in silico and in vitro tests for a better food safety? Because we live in a world of chemicals where more than 110 million chemical compounds are known to exist to date (source: CAS, Chemical abstract Service), we are exposed to many of these chemicals during our lifetime. Unfortunately, it is not realistic to think we can check the safety of such huge number of compounds. If indeed it is true that humans produce about 500∼1000 chemicals every year, we have to be conscious about the potential of some of them to negatively affect our metabolic and physiological pathways, and about the possibility to encounter potential disruptors in our daily life. Unfortunately, this huge number of chemicals is too big to be investigated by means of standard experimental approaches, as in vitro and in vivo test, in particular if we consider the number of possible associated metabolites. Computational methods could represent a valuable alternative to dramatically reduce the number of potential disruptors to be experimentally tested. Nuclear Receptors represent an important class of potential targets for medicinal chemistry and food safety; thus, computational techniques, widely applied in medicinal chemistry field, can represent valuable tools also in food science. Food additives, food contact materials, mycotoxins, plasticizers and their metabolites can interact with this class of receptors acting as endocrine disruptors. In silicomethods can predict these potential interactions between a ligand (food additive, mycotoxins, food contact material, etc.) and a receptor of known 3D structure, representing a unique way to test the effect of a huge amount of chemicals without in vitro tests. In vitro tests must be applied only for molecules predicted as good possible interactors. It should be stated, however, that in silico interaction prediction is not an absolute certainty of the real activation of the receptor made by the ligand, where binding of a ligand within a cavity of a receptor is not always synonymous with a receptor activation, it is necessary to understand the whole complex biochemical pathway.
{"title":"Nuclear Receptors: From Drugs to Food, and from In Silico to In Vitro","authors":"P. Cozzini, F. Spyrakis","doi":"10.11131/2017/101319","DOIUrl":"https://doi.org/10.11131/2017/101319","url":null,"abstract":"In silico techniques are an emerging field in Food Science. In silicomeans done using computer, also defined as dry experiments while traditional lab experiments are commonly defined as wet experiments. These techniques come from Medicinal Chemistry and Computational Chemistry where they have been known for many decades. Common applications of informatics techniques in Food Science are traditionally statistics and QSAR (Quantitative Structure Activity Relationship) approaches. However, massive screening of databases of chemicals, docking and scoring of most promising chemicals into known receptors are not common applications in food science, i.e. food safety, food security, food toxicology, predictive toxicology, etc. One of the most important questions we would like to answer is: could we merge in silico and in vitro tests for a better food safety? Because we live in a world of chemicals where more than 110 million chemical compounds are known to exist to date (source: CAS, Chemical abstract Service), we are exposed to many of these chemicals during our lifetime. Unfortunately, it is not realistic to think we can check the safety of such huge number of compounds. If indeed it is true that humans produce about 500∼1000 chemicals every year, we have to be conscious about the potential of some of them to negatively affect our metabolic and physiological pathways, and about the possibility to encounter potential disruptors in our daily life. Unfortunately, this huge number of chemicals is too big to be investigated by means of standard experimental approaches, as in vitro and in vivo test, in particular if we consider the number of possible associated metabolites. Computational methods could represent a valuable alternative to dramatically reduce the number of potential disruptors to be experimentally tested. Nuclear Receptors represent an important class of potential targets for medicinal chemistry and food safety; thus, computational techniques, widely applied in medicinal chemistry field, can represent valuable tools also in food science. Food additives, food contact materials, mycotoxins, plasticizers and their metabolites can interact with this class of receptors acting as endocrine disruptors. In silicomethods can predict these potential interactions between a ligand (food additive, mycotoxins, food contact material, etc.) and a receptor of known 3D structure, representing a unique way to test the effect of a huge amount of chemicals without in vitro tests. In vitro tests must be applied only for molecules predicted as good possible interactors. It should be stated, however, that in silico interaction prediction is not an absolute certainty of the real activation of the receptor made by the ligand, where binding of a ligand within a cavity of a receptor is not always synonymous with a receptor activation, it is necessary to understand the whole complex biochemical pathway.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44433338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A long neglected hepatic manifestation of the metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) arise as serious health burden with alarming global prevalence. The disease complex is currently attracting considerable interest of drug discovery and many experimental approaches are studied in all stages of clinical development. Peroxisome proliferator-activated receptors (PPARs) have a successful history as pharmaceutical targets in the treatment of several aspects of the metabolic syndrome and, therefore, a putative therapeutic value of PPAR modulators in NAFLD/NASH is obvious. However, so far only the PPARα/δ agonist elafibranor has revealed clear efficacy and reached an advanced stage of development while the far more established PPAR subtypes PPARα and PPARγ have disappointed. Still, clinical trial design and population might have obscured beneficial activities and, in addition, synergistic multi-target approaches as well as selective PPAR modulators could generate safer approaches with higher therapeutic efficacy.
{"title":"Therapeutic Potential of Peroxisome Proliferator-Activated Receptor Modulation in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis","authors":"L. Gellrich, D. Merk","doi":"10.11131/2017/101310","DOIUrl":"https://doi.org/10.11131/2017/101310","url":null,"abstract":"A long neglected hepatic manifestation of the metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) arise as serious health burden with alarming global prevalence. The disease complex is currently attracting considerable interest of drug discovery and many experimental approaches are studied in all stages of clinical development. Peroxisome proliferator-activated receptors (PPARs) have a successful history as pharmaceutical targets in the treatment of several aspects of the metabolic syndrome and, therefore, a putative therapeutic value of PPAR modulators in NAFLD/NASH is obvious. However, so far only the PPARα/δ agonist elafibranor has revealed clear efficacy and reached an advanced stage of development while the far more established PPAR subtypes PPARα and PPARγ have disappointed. Still, clinical trial design and population might have obscured beneficial activities and, in addition, synergistic multi-target approaches as well as selective PPAR modulators could generate safer approaches with higher therapeutic efficacy.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45951748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shimpi Bedi, Heather A Hostetler, Stanley Dean Rider
Liver X receptor alpha (LXRα) is crucial for the maintenance of lipid and cholesterol homeostasis. Ligand binding and dimerization with retinoid X receptor (RXR) or peroxisome proliferator-activated receptor (PPAR) is required for forming active DNA binding complexes leading to gene regulation. Structure based prediction and solvent accessibility of LXRα LBD shows that residues H383, E387, H390, L414, and R415 which are located in helices 9 and 10 may be critical for mediating protein-protein interactions. In this study, LXRα interface residues were individually mutated to determine their effects on ligand binding, protein-protein association, subcellular localization, and transactivation activity. LXRα L414R and R415A lacked binding to T-0901317, but retained binding to 25-Hydroxycholesterol. In vitro assay and a cell based assay demonstrated that LXRα L414R was specifically impaired for interactions with RXRα but not PPARα suggesting that charge reversal at the interface provides selectivity to LXRα dimerization. Furthermore, binding of LXRα L414R or R415A with PPARα exhibited minimal conformational changes in the dimer secondary structure. Interestingly, all LXRα mutants exhibited lower levels of ligand dependent luciferase activity driven by the SREBP-1c or ApoA1 promoter. Taken together, our data demonstrates that intact hydrophobic interactions and salt bridges at the interface mediate efficient ligand-dependent transactivation activities.
{"title":"MUTATIONS IN LIVER X RECEPTOR ALPHA THAT IMPAIR DIMERIZATION AND LIGAND DEPENDENT TRANSACTIVATION.","authors":"Shimpi Bedi, Heather A Hostetler, Stanley Dean Rider","doi":"10.11131/2017/101302","DOIUrl":"10.11131/2017/101302","url":null,"abstract":"<p><p>Liver X receptor alpha (LXRα) is crucial for the maintenance of lipid and cholesterol homeostasis. Ligand binding and dimerization with retinoid X receptor (RXR) or peroxisome proliferator-activated receptor (PPAR) is required for forming active DNA binding complexes leading to gene regulation. Structure based prediction and solvent accessibility of LXRα LBD shows that residues H383, E387, H390, L414, and R415 which are located in helices 9 and 10 may be critical for mediating protein-protein interactions. In this study, LXRα interface residues were individually mutated to determine their effects on ligand binding, protein-protein association, subcellular localization, and transactivation activity. LXRα L414R and R415A lacked binding to T-0901317, but retained binding to 25-Hydroxycholesterol. <i>In vitro</i> assay and a cell based assay demonstrated that LXRα L414R was specifically impaired for interactions with RXRα but not PPARα suggesting that charge reversal at the interface provides selectivity to LXRα dimerization. Furthermore, binding of LXRα L414R or R415A with PPARα exhibited minimal conformational changes in the dimer secondary structure. Interestingly, all LXRα mutants exhibited lower levels of ligand dependent luciferase activity driven by the SREBP-1c or ApoA1 promoter. Taken together, our data demonstrates that intact hydrophobic interactions and salt bridges at the interface mediate efficient ligand-dependent transactivation activities.</p>","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630223/pdf/nihms906808.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35426512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-01-01Epub Date: 2017-10-20DOI: 10.11131/2017/101308
Lai Peng, Stephanie C Piekos, Grace L Guo, Xiao-Bo Zhong
The liver is a vital organ with critical functions in metabolism of various biologically useful materials, synthesis of several vital proteins, detoxification of toxic substances, and immune defense. Most liver functions are not mature at birth and many changes happen during postnatal liver development, which lead to differential vulnerabilities of the liver at different developmental stages. However, the details of what changes occur in liver after birth, at what developmental stages they occur, and molecular mechanisms in the regulation of the developmental process are not clearly known. The nuclear receptor Farnesoid X receptor (FXR) is an important transcriptional regulator in liver. Here, we used RNA-Sequencing to analyze the transcriptome of mouse liver from perinatal to adult ages in both C57BL/6 and Fxr-/- mice. We have defined a clear timeline of functional transition from prenatal through neonatal and adolescent to adult in C57BL/6 mice. Without FXR, activation of neonatal-specific pathways was prolonged and maturation of multiple metabolic pathways was delayed. The loss of FXR also led to increased expression of 27 other transcription regulators. Our data support a conclusion that developmental transcriptome revealed significant functional transition during postnatal liver development and FXR plays an important role in control of postnatal liver maturation.
{"title":"Role of Farnesoid X Receptor in the Determination of Liver Transcriptome during Postnatal Maturation in Mice.","authors":"Lai Peng, Stephanie C Piekos, Grace L Guo, Xiao-Bo Zhong","doi":"10.11131/2017/101308","DOIUrl":"10.11131/2017/101308","url":null,"abstract":"<p><p>The liver is a vital organ with critical functions in metabolism of various biologically useful materials, synthesis of several vital proteins, detoxification of toxic substances, and immune defense. Most liver functions are not mature at birth and many changes happen during postnatal liver development, which lead to differential vulnerabilities of the liver at different developmental stages. However, the details of what changes occur in liver after birth, at what developmental stages they occur, and molecular mechanisms in the regulation of the developmental process are not clearly known. The nuclear receptor Farnesoid X receptor (FXR) is an important transcriptional regulator in liver. Here, we used RNA-Sequencing to analyze the transcriptome of mouse liver from perinatal to adult ages in both C57BL/6 and <i>Fxr</i><sup>-/-</sup> mice. We have defined a clear timeline of functional transition from prenatal through neonatal and adolescent to adult in C57BL/6 mice. Without FXR, activation of neonatal-specific pathways was prolonged and maturation of multiple metabolic pathways was delayed. The loss of FXR also led to increased expression of 27 other transcription regulators. Our data support a conclusion that developmental transcriptome revealed significant functional transition during postnatal liver development and FXR plays an important role in control of postnatal liver maturation.</p>","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36126694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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