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Single-cell transcriptomics and metabolomic analysis reveal adenosine-derived metabolites over-representation in pseudohypoxic neuroendocrine tumours
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-04 DOI: 10.1002/ctm2.70159
Yuval Kahan Yossef, Liav Sela Peremen, Alona Telerman, Gil Goldinger, Sergey Malitsky, Maxim Itkin, Reut Halperin, Naama Peshes Yaloz, Amit Tirosh
<p>Dear Editor,</p><p>Von Hippel−Lindau protein (pVHL) is a critical factor in the cellular oxygen sensing apparatus. pVHL-deficient tumours are characterized by a pseudohypoxic state and a consequent metabolic shift towards anaerobic metabolism. Based on unbiased metabolic analysis, supported by single-cell transcriptomics analysis, we report a potential tumorigenic role of adenosine in pVHL-deficient pancreatic neuroendocrine tumors (vPNET).</p><p>VHL disease, caused by germline DNA pathogenic variants (PVs) in the <i>VHL</i> gene,<span><sup>1</sup></span> is associated with predisposition for pancreatic neuroendocrine tumours (PNETs); hemangioblastoma(s) of the cerebellum, spine and retina; pheochromocytoma and paraganglioma, and renal cell carcinoma of clear-cell type.<span><sup>1</sup></span></p><p>The pVHL serves as the recognition unit of the ubiquitin system and identifies hypoxia-inducible factor 1α (HIF1α) to promote its degradation.<span><sup>2, 3</sup></span> pVHL-deficient states lead to HIF1α accumulation and pseudohypoxia,<span><sup>4, 5</sup></span> which promotes tumorigenesis and tumour progression and prompts a metabolic shift from oxidative pyruvate breakdown towards anaerobic glucose utilization.<span><sup>2, 6, 7</sup></span></p><p>Somatic <i>VHL</i> PVs are exceedingly rare in sporadic PNET (sPNET).<span><sup>8</sup></span> Hence, we hypothesized that <i>VHL</i> PV alone is insufficient for developing vPNET, and metabolic changes drive tumorigenesis. To elucidate this, we conducted tumour metabolomic profiling, single-cell transcriptomic studies and tissue immunohistochemical characterization of vPNET and sPNET (please see full methods in the Supplementary Material).</p><p>The current work initiated with an unbiased metabolomic analysis to investigate the metabolic environment in patient-derived tissue samples of vPNET and sPNET. Our analysis led to the putative identification of 217 polar metabolites (Supplementary Material) that demonstrated distinct metabolomic signatures and separation of vPNET versus sPNET (Figure 1A). To identify the metabolites that contributed most to the distinction between the groups, we performed a Variable Importance in Projection analysis, in which adenosine monophosphate (AMP) was identified as a dominant metabolite (Figure 1B). As shown in the volcano plot (Figure 1C) and heatmap (Figure 1D), vPNET had a higher representation of AMP as compared with sPNET.</p><p>Other metabolites that were significantly differentially represented between the groups were less likely to be related to PNET tumorigenesis based on the literature review. To independently validate the metabolomics analysis findings, we performed an unbiased snRNA seq analysis. Single-nucleus RNA sequencing was chosen, as it allows single-cell transcriptomic analysis of frozen samples.</p><p>In the snRNA sequencing analysis, 25 982 high-quality cells from two vPNET and five sPNET were identified and analysed. Using canonical correlat
{"title":"Single-cell transcriptomics and metabolomic analysis reveal adenosine-derived metabolites over-representation in pseudohypoxic neuroendocrine tumours","authors":"Yuval Kahan Yossef,&nbsp;Liav Sela Peremen,&nbsp;Alona Telerman,&nbsp;Gil Goldinger,&nbsp;Sergey Malitsky,&nbsp;Maxim Itkin,&nbsp;Reut Halperin,&nbsp;Naama Peshes Yaloz,&nbsp;Amit Tirosh","doi":"10.1002/ctm2.70159","DOIUrl":"https://doi.org/10.1002/ctm2.70159","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Von Hippel−Lindau protein (pVHL) is a critical factor in the cellular oxygen sensing apparatus. pVHL-deficient tumours are characterized by a pseudohypoxic state and a consequent metabolic shift towards anaerobic metabolism. Based on unbiased metabolic analysis, supported by single-cell transcriptomics analysis, we report a potential tumorigenic role of adenosine in pVHL-deficient pancreatic neuroendocrine tumors (vPNET).&lt;/p&gt;&lt;p&gt;VHL disease, caused by germline DNA pathogenic variants (PVs) in the &lt;i&gt;VHL&lt;/i&gt; gene,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; is associated with predisposition for pancreatic neuroendocrine tumours (PNETs); hemangioblastoma(s) of the cerebellum, spine and retina; pheochromocytoma and paraganglioma, and renal cell carcinoma of clear-cell type.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The pVHL serves as the recognition unit of the ubiquitin system and identifies hypoxia-inducible factor 1α (HIF1α) to promote its degradation.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; pVHL-deficient states lead to HIF1α accumulation and pseudohypoxia,&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; which promotes tumorigenesis and tumour progression and prompts a metabolic shift from oxidative pyruvate breakdown towards anaerobic glucose utilization.&lt;span&gt;&lt;sup&gt;2, 6, 7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Somatic &lt;i&gt;VHL&lt;/i&gt; PVs are exceedingly rare in sporadic PNET (sPNET).&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Hence, we hypothesized that &lt;i&gt;VHL&lt;/i&gt; PV alone is insufficient for developing vPNET, and metabolic changes drive tumorigenesis. To elucidate this, we conducted tumour metabolomic profiling, single-cell transcriptomic studies and tissue immunohistochemical characterization of vPNET and sPNET (please see full methods in the Supplementary Material).&lt;/p&gt;&lt;p&gt;The current work initiated with an unbiased metabolomic analysis to investigate the metabolic environment in patient-derived tissue samples of vPNET and sPNET. Our analysis led to the putative identification of 217 polar metabolites (Supplementary Material) that demonstrated distinct metabolomic signatures and separation of vPNET versus sPNET (Figure 1A). To identify the metabolites that contributed most to the distinction between the groups, we performed a Variable Importance in Projection analysis, in which adenosine monophosphate (AMP) was identified as a dominant metabolite (Figure 1B). As shown in the volcano plot (Figure 1C) and heatmap (Figure 1D), vPNET had a higher representation of AMP as compared with sPNET.&lt;/p&gt;&lt;p&gt;Other metabolites that were significantly differentially represented between the groups were less likely to be related to PNET tumorigenesis based on the literature review. To independently validate the metabolomics analysis findings, we performed an unbiased snRNA seq analysis. Single-nucleus RNA sequencing was chosen, as it allows single-cell transcriptomic analysis of frozen samples.&lt;/p&gt;&lt;p&gt;In the snRNA sequencing analysis, 25 982 high-quality cells from two vPNET and five sPNET were identified and analysed. Using canonical correlat","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70159","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multi-organ transcriptomic atlas reveals hallmarks of labour
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-04 DOI: 10.1002/ctm2.70208
Duan Ni, Ralph Nanan
<p>We present a multi-organ transcriptomic atlas of labour for unprecedented comprehensive profiling of both organ-specific and systemic signalling changes associated with labour across maternal and fetal compartments. Labour signifies the concluding phase of pregnancy. While pregnancy is known to induce pronounced maternal and fetal reprogramming,<span><sup>1</sup></span> specific alteration driven by labour remains elusive. In this context, previous studies have predominantly concentrated on individual organ systems,<span><sup>2</sup></span> limited to gene-level analyses for specific marker gene identification,<span><sup>3</sup></span> and more comprehensive overviews are lacking.</p><p>We surveyed Gene Expression Omnibus for all available transcriptomic datasets across both maternal and fetal compartments to collate a multi-organ transcriptomic atlas, cross-sectionally comparing labour versus non-labour (Supporting Information). The atlas contains 16 datasets, spanning six organ systems (maternal blood, subcutaneous fat, visceral fat, placenta, myometrium and cord blood mononuclear cells [CBMCs]), with 392 samples in total (Figure 1).</p><p>Extensive analyses like gene set enrichment analysis (GSEA) were run, focusing on pathway-level changes during labour. For each organ system, we compared the results from different datasets and compiled the most consistent changes. In maternal blood, labour was linked to upregulation of allograft rejection, tumour necrosis factor (TNF)-NFκB-related, and Myc-related signalling (Figure 1). Myc signals were also enhanced in maternal adipose tissues in labour, accompanied by pronounced metabolic changes like enhanced glycolysis, oxidative phosphorylation (OXPHOS) and fatty acid metabolism (FAM) in both visceral and subcutaneous fat (Figure 1).</p><p>We next probed the organs directly implicated in labour like myometrium and placenta (Figure 1). Similar to adipose tissues, myometrium exhibited increased glycolysis and Myc signalling. TNF and interleukin (IL)-6 signalling were higher, possibly induced by mTORC1 activation. These were consistent across seven myometrial datasets.</p><p>Labor-associated immune activation was also found in the placenta, as TNF signalling was consistently higher (Figure 1), aligned with a previous report.<span><sup>2</sup></span> A published single-cell RNA-seq (scRNA-seq) dataset for placental tissues with/without labour was re-analyzed (Figure 1). As in the original study, eight different cell subsets were identified (endothelial cells, EC; decidual stromal cells, DSC; extravillous trophoblasts, EVT; smooth muscle cells, SMC; dendritic cells, DC; T cells, T; fibroblasts, FB; endometrial cells, EEC). EECs were excluded from downstream analysis due to low cellularity. GSEA found that all cell subsets upregulated the TNF signalling pathway in labour. They also generally displayed more active metabolic profiles, upregulating glycolysis, OXPHOS and FAM. An exception was EVTs, where the
{"title":"Multi-organ transcriptomic atlas reveals hallmarks of labour","authors":"Duan Ni,&nbsp;Ralph Nanan","doi":"10.1002/ctm2.70208","DOIUrl":"https://doi.org/10.1002/ctm2.70208","url":null,"abstract":"&lt;p&gt;We present a multi-organ transcriptomic atlas of labour for unprecedented comprehensive profiling of both organ-specific and systemic signalling changes associated with labour across maternal and fetal compartments. Labour signifies the concluding phase of pregnancy. While pregnancy is known to induce pronounced maternal and fetal reprogramming,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; specific alteration driven by labour remains elusive. In this context, previous studies have predominantly concentrated on individual organ systems,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; limited to gene-level analyses for specific marker gene identification,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; and more comprehensive overviews are lacking.&lt;/p&gt;&lt;p&gt;We surveyed Gene Expression Omnibus for all available transcriptomic datasets across both maternal and fetal compartments to collate a multi-organ transcriptomic atlas, cross-sectionally comparing labour versus non-labour (Supporting Information). The atlas contains 16 datasets, spanning six organ systems (maternal blood, subcutaneous fat, visceral fat, placenta, myometrium and cord blood mononuclear cells [CBMCs]), with 392 samples in total (Figure 1).&lt;/p&gt;&lt;p&gt;Extensive analyses like gene set enrichment analysis (GSEA) were run, focusing on pathway-level changes during labour. For each organ system, we compared the results from different datasets and compiled the most consistent changes. In maternal blood, labour was linked to upregulation of allograft rejection, tumour necrosis factor (TNF)-NFκB-related, and Myc-related signalling (Figure 1). Myc signals were also enhanced in maternal adipose tissues in labour, accompanied by pronounced metabolic changes like enhanced glycolysis, oxidative phosphorylation (OXPHOS) and fatty acid metabolism (FAM) in both visceral and subcutaneous fat (Figure 1).&lt;/p&gt;&lt;p&gt;We next probed the organs directly implicated in labour like myometrium and placenta (Figure 1). Similar to adipose tissues, myometrium exhibited increased glycolysis and Myc signalling. TNF and interleukin (IL)-6 signalling were higher, possibly induced by mTORC1 activation. These were consistent across seven myometrial datasets.&lt;/p&gt;&lt;p&gt;Labor-associated immune activation was also found in the placenta, as TNF signalling was consistently higher (Figure 1), aligned with a previous report.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; A published single-cell RNA-seq (scRNA-seq) dataset for placental tissues with/without labour was re-analyzed (Figure 1). As in the original study, eight different cell subsets were identified (endothelial cells, EC; decidual stromal cells, DSC; extravillous trophoblasts, EVT; smooth muscle cells, SMC; dendritic cells, DC; T cells, T; fibroblasts, FB; endometrial cells, EEC). EECs were excluded from downstream analysis due to low cellularity. GSEA found that all cell subsets upregulated the TNF signalling pathway in labour. They also generally displayed more active metabolic profiles, upregulating glycolysis, OXPHOS and FAM. An exception was EVTs, where the ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70208","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The utilisation of ctDNA approaches for residual disease detection during neoadjuvant and perioperative immunotherapy in oesophagogastric cancers
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-04 DOI: 10.1002/ctm2.70223
Ronan J. Kelly, Valsamo Anagnostou, Vincent K. Lam, Ali H. Zaidi
<p>The optimal management of operable oesophageal/GEJ (E/GEJ) cancer has been the subject of much debate with the traditional trimodality approach of chemoradiotherapy followed by surgery as established by the CROSS trial<span><sup>1</sup></span> in 2012 being challenged by the recently presented results of the ESOPEC trial<span><sup>2</sup></span> which demonstrated superiority of the perioperative fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) chemotherapy regimen. Unfortunately, ESOPEC a phase III German led study that enrolled patients between 2016 and 2020 did not compare FLOT to the other standard of care which is chemoradiation followed by adjuvant nivolumab. CheckMate 577 a phase III international adjuvant study<span><sup>3</sup></span> published in 2021 investigated the efficacy of the PD-1 inhibitor nivolumab as a systemic agent in an attempt to overcome the challenges posed by utilising radiation sensitising low-dose chemotherapy used in the CROSS regimen. CheckMate 577 demonstrated a doubling in median disease-free survival (mDFS) from 11.0 to 22.4 months (HR 0.69) with the use of adjuvant nivolumab in tumours that had failed to attain a pathological complete response (pCR) post trimodality therapy. mDFS was the primary endpoint of the study but interestingly the secondary endpoint of median distant metastasis-free survival was also increased from 17.6 to 28.3 months (HR 0.74), indicating a systemic effect for PD-1 inhibition above and beyond loco-regional benefits. As is the norm in large adjuvant studies, overall survival (OS) has not been reported as yet requiring a number of years to meet predefined events but challenges in interpretation will exist given the widespread use of immune checkpoint inhibitors (ICIs) in the metastatic setting.<span><sup>4</sup></span> The question therefore remains which is a better approach in operable E/GEJ cancers—perioperative FLOT or trimodality therapy followed by adjuvant nivolumab? In 2025, it may be the wrong question to ask whether chemotherapy or radiation is better, as the answer will vary depending on the biology of an individual's tumour. With the use of precision medicine, we would hope to be able to gain a more nuanced understanding and define an optimal way to select the most appropriate therapeutic options. This approach aims to ensure that patients achieve the best possible results while avoiding over- or under-treatment and undue toxicities.</p><p>The use of circulating tumour DNA (ctDNA) in detecting and tracking minimal residual disease (MRD) may improve upon the use of traditional ypTNM staging and pCR as surrogates for long-term survival.</p><p>In our study published in <i>Nature Medicine</i> in April 2024,<span><sup>5</sup></span> we sought to measure systemic tumour burden kinetics longitudinally using a tumour-agnostic, matched WBC DNA-informed deep sequencing approach coupled with a branched logic to assign variant cellular origin in the pre- and post-operative s
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引用次数: 0
Erratum for the “S100A7 as a potential diagnostic and prognostic biomarker of esophageal squamous cell carcinoma promotes M2 macrophage infiltration and angiogenesis” by Zhiliang Lu et al.
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-03 DOI: 10.1002/ctm2.70222

Lu Z, Zheng S, Liu C, et al. S100A7 as a potential diagnostic andprognostic biomarker of esophageal squamous cellcarcinoma promotes M2 macrophage infiltrationand angiogenesis. Clin Transl Med. 2021;11:e459. doi: 10.1002/ctm2.459

The reason for the correction:

We proofread the entire article and found that the Western Blot band of the p65 protein in the S100A7 siRNA silencing group in Figure 3H on page 6 accidentally used the same band as the p65 protein in the S100A7 siRNA silencing group in Figure 3G during the editing process.

The western Blot band of p65 protein in the S100A7 siRNA silencing group in Figure 3H that needs errata is marked with a red block below.

{"title":"Erratum for the “S100A7 as a potential diagnostic and prognostic biomarker of esophageal squamous cell carcinoma promotes M2 macrophage infiltration and angiogenesis” by Zhiliang Lu et al.","authors":"","doi":"10.1002/ctm2.70222","DOIUrl":"https://doi.org/10.1002/ctm2.70222","url":null,"abstract":"<p>Lu Z, Zheng S, Liu C, et al. S100A7 as a potential diagnostic andprognostic biomarker of esophageal squamous cellcarcinoma promotes M2 macrophage infiltrationand angiogenesis. <i>Clin Transl Med</i>. 2021;11:e459. doi: 10.1002/ctm2.459</p><p>The reason for the correction:</p><p>We proofread the entire article and found that the Western Blot band of the p65 protein in the S100A7 siRNA silencing group in Figure 3H on page 6 accidentally used the same band as the p65 protein in the S100A7 siRNA silencing group in Figure 3G during the editing process.</p><p>The western Blot band of p65 protein in the S100A7 siRNA silencing group in Figure 3H that needs errata is marked with a red block below.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70222","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Artificial metabzyme-driven metabolic reprogramming and precision oncology
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-30 DOI: 10.1002/ctm2.70215
Xi Hu, Daishun Ling
<p>Abnormal metabolism is a biological hallmark of cancer and represents critical targets for therapeutic intervention, as it unveils potential vulnerabilities for treatment.<span><sup>1</sup></span> To sustain continuous proliferation and metastasis, tumour cells undergo several metabolic adaptations to cope with the nutrient-deficient microenvironment. Recent advancements have demonstrated the successful translation of identified metabolic dysregulations in cancer cells into FDA-approved metabolic inhibitors. Currently, several metabolic regulators are being developed or are undergoing clinical trials for the treatment of various cancers, such as nucleotide synthesis inhibitors (e.g. aminopterin, methotrexate and pemetrexed), indoleamine 2,3-dioxygenase 1 inhibitors (e.g. linrodostat and KHK2455), isocitrate dehydrogenases inhibitors (e.g. ivosidenib and enasidenib), glutaminase inhibitors (e.g. telaglenastat and telaglenastat), lactate efflux inhibitors (e.g. AZD3965), tyrosine mimetics (e.g. racemetyrosine), and so on.<span><sup>2, 3</sup></span> However, despite significant advancements in the development of drugs targeting cancer genomic alterations and the tumour microenvironment, the progress in targeting cancer metabolism—particularly non-nucleotide metabolism—remains in its nascent stages. A major challenge in targeting cancer metabolism for therapy lies in achieving effective antitumour effects while minimizing toxicity to normal cells, as many metabolic pathways essential for tumour cell survival are also shared by normal cells, resulting in a narrow therapeutic window and potential for significant toxicity.<span><sup>4</sup></span></p><p>Xanthine oxidoreductase (XOR), a key enzyme in purine catabolism containing redox-active molybdenum (Mo) and iron (Fe) centres, catalyses the oxidation of hypoxanthine to xanthine and xanthine to uric acid (UA).<span><sup>5</sup></span> Its expression and activity are significantly reduced in tumour tissues from liver, breast, gastrointestinal, colorectal, ovarian and non-small cell lung cancers, with low XOR levels strongly associated with poor prognosis and recurrence.<span><sup>6, 7</sup></span> Moreover, the documented immunosuppressive properties of certain xanthine derivatives<span><sup>8</sup></span> and the notable role of UA in enhancing anti-tumour immunity<span><sup>9</sup></span> underscore the pivotal relevance of XOR in cancer research, suggesting its potential as both a therapeutic target and a mediator of immune responses. Leveraging this insight, we engineered FeMoO<sub>4</sub> nanocatalysts, an artificial metabzyme graced with Fe<sup>2+</sup> and tetrahedral Mo<sup>4+</sup> active centres, to seamlessly simulate XOR's catalytic essence.<span><sup>10</sup></span> Upon entering tumour cells with low XOR levels and elevated xanthine substrates, the FeMoO<sub>4</sub> metabzyme efficiently catalyses the conversion of xanthine into excess UA. Interestingly, UA metabolite, in turn, trigger
{"title":"Artificial metabzyme-driven metabolic reprogramming and precision oncology","authors":"Xi Hu,&nbsp;Daishun Ling","doi":"10.1002/ctm2.70215","DOIUrl":"10.1002/ctm2.70215","url":null,"abstract":"&lt;p&gt;Abnormal metabolism is a biological hallmark of cancer and represents critical targets for therapeutic intervention, as it unveils potential vulnerabilities for treatment.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; To sustain continuous proliferation and metastasis, tumour cells undergo several metabolic adaptations to cope with the nutrient-deficient microenvironment. Recent advancements have demonstrated the successful translation of identified metabolic dysregulations in cancer cells into FDA-approved metabolic inhibitors. Currently, several metabolic regulators are being developed or are undergoing clinical trials for the treatment of various cancers, such as nucleotide synthesis inhibitors (e.g. aminopterin, methotrexate and pemetrexed), indoleamine 2,3-dioxygenase 1 inhibitors (e.g. linrodostat and KHK2455), isocitrate dehydrogenases inhibitors (e.g. ivosidenib and enasidenib), glutaminase inhibitors (e.g. telaglenastat and telaglenastat), lactate efflux inhibitors (e.g. AZD3965), tyrosine mimetics (e.g. racemetyrosine), and so on.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; However, despite significant advancements in the development of drugs targeting cancer genomic alterations and the tumour microenvironment, the progress in targeting cancer metabolism—particularly non-nucleotide metabolism—remains in its nascent stages. A major challenge in targeting cancer metabolism for therapy lies in achieving effective antitumour effects while minimizing toxicity to normal cells, as many metabolic pathways essential for tumour cell survival are also shared by normal cells, resulting in a narrow therapeutic window and potential for significant toxicity.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Xanthine oxidoreductase (XOR), a key enzyme in purine catabolism containing redox-active molybdenum (Mo) and iron (Fe) centres, catalyses the oxidation of hypoxanthine to xanthine and xanthine to uric acid (UA).&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Its expression and activity are significantly reduced in tumour tissues from liver, breast, gastrointestinal, colorectal, ovarian and non-small cell lung cancers, with low XOR levels strongly associated with poor prognosis and recurrence.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; Moreover, the documented immunosuppressive properties of certain xanthine derivatives&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; and the notable role of UA in enhancing anti-tumour immunity&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; underscore the pivotal relevance of XOR in cancer research, suggesting its potential as both a therapeutic target and a mediator of immune responses. Leveraging this insight, we engineered FeMoO&lt;sub&gt;4&lt;/sub&gt; nanocatalysts, an artificial metabzyme graced with Fe&lt;sup&gt;2+&lt;/sup&gt; and tetrahedral Mo&lt;sup&gt;4+&lt;/sup&gt; active centres, to seamlessly simulate XOR's catalytic essence.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; Upon entering tumour cells with low XOR levels and elevated xanthine substrates, the FeMoO&lt;sub&gt;4&lt;/sub&gt; metabzyme efficiently catalyses the conversion of xanthine into excess UA. Interestingly, UA metabolite, in turn, trigger","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Histone methyltransferase KMT2A promotes pulmonary fibrogenesis via targeting pro-fibrotic factor PU.1 in fibroblasts
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-30 DOI: 10.1002/ctm2.70217
Wenting Lyu, Hui Wang, Tong Ji, Ling Liu, Haoran Chen, Li Fan, Guanning Zhong, Naihui Wan, Suwan Chen, Jingyu Chen, Hourong Cai, Hongyang Xu, Dongjin Wang, Jinghong Dai

Background

Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease driven by both environmental and genetic factors. Epigenetics refers to changes in gene expression or cellular phenotype that do not involve alterations to DNA sequence. KMT2A is a member of the SET family which catalyses H3K4 methylation.

Results

Through microarray and single-cell sequencing data, we discovered KMT2A-positive fibroblasts were increased in IPF lung tissues. KMT2A level was increased in IPF and bleomycin-induced pulmonary fibrosis mice lung tissues collected in our centre. Mice with AAV6-induced KMT2A knockdown in fibroblast showed attenuated pulmonary fibrosis after bleomycin treatment. Bioinformation also revealed that transcription factor PU.1 was a target of KMT2A. We demonstrated that PU.1 levels were increased in IPF tissues, bleomycin-induced mice lung tissues and primary fibrotic fibroblasts. KMT2A knockdown decreases PU.1 expression in vitro while KMT2A overexpression induces PU.1 activation. PU.1 fibroblast-specific knockout mice showed attenuated lung fibrosis induced by bleomycin. Furthermore, we demonstrated KMT2A up-regulated PU.1 in fibroblasts by catalysing H3K4me3 at the promoter of the PU.1 gene. The KMT2A transcription complex inhibitor mm102 treatment attenuated bleomycin-induced pulmonary fibrosis.

Conclusion

The current study indicated that histone modification participates in the pathogenesis of IPF and KMT2A may have the potential to be a therapeutic target of IPF treatment.

Key points

  • KMT2A plays a role in pulmonary fibrogenesis.
  • KMT2A regulates PU.1 transcription in fibroblasts through H3K4me3 at promoter.
  • KMT2A inhibitor attenuates pulmonary fibrosis in mice.
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引用次数: 0
Oestrogen suppresses the adipogenesis of fibro/adipogenic progenitors through reactivating the METTL3–ESR1-mediated loop in post-menopausal females
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-28 DOI: 10.1002/ctm2.70206
Hao Zhou, Shujing Feng, Jinkui Cai, Xiexiang Shao, Siyuan Zhu, Han Zhou, Yongmin Cao, Ru Wang, Xingzuan Lin, Jianhua Wang
<div> <section> <h3> Background</h3> <p>Post-menopausal women experience more severe muscular fatty infiltration, though the mechanisms remain unclear. The decline in estrogen levels is considered as a critical physiological alteration during post-menopause. Fibro/adipogenic progenitors (FAPs) are identified as major contributors to muscular fatty infiltration. This study aimed to investigate the detailed mechanism underlying the excessive muscular fatty infiltration in postmenopausal females.</p> </section> <section> <h3> Methods</h3> <p>Supraspinatus muscle samples were collected from female patients with or without menopause, and from mice with or without ovariectomy (OVX), to evaluate muscular fatty infiltration and isolated FAPs. The expressions of (estrogen receptor 1) ESR1, methyltransferase-like 3 (METTL3), and adipogenesis ability in FAPs from post-menopausal women and OVX mice were investigated. RNA sequencing (RNA-Seq) was performed to explore the gene expression profiles and potential mechanisms in FAPs from Pdgfrα-CreERT2; Esr1 knockout (Esr1 KO) mice and Esr1 flox/flox (Esr1 f/f) mice. The interplay of the METTL3-ESR1 mediated loop and its role in regulating adipogenesis in FAPs were investigated using dual luciferase reporter assays, chromatin immunoprecipitation (ChIP), and protein and RNA stability assays. The effects of estrogen supplementation on muscular fatty infiltration and locomotor function in OVX mice were evaluated by immunofluorescent staining and functional analysis.</p> </section> <section> <h3> Results</h3> <p>Decreased expression of ESR1/METTL3 and increased adipogenesis ability in FAPs was found in post-menopausal female. METTL3-mediated m6A methylation promoted ESR1 mRNA stability at the post-transcriptional level in FAPs. METTL3-mediated m6A modification promoted ESR1 expression by stabilizing ESR1 mRNA, while ESR1 acted as a transcription factor that enhanced METTL3 transcription in turn. ESR1 also suppressed the transcription of the adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARγ), thereby inhibiting adipogenesis in FAPs. Reactivation of the METTL3-ESR1 mediated loop by estrogen alleviated excessive adipogenesis in FAPs from post-menopausal women, and it also reduced muscular fatty infiltration, and improved locomotor function in OVX mice.</p> </section> <section> <h3> Conclusion</h3> <p>Excessive muscular fatty infiltration in post-menopausal women arose from the disruption of the METTL3-ESR1 mediated loop of FAPs due to estrogen deficiency. Reactivation of the METTL3-ESR
{"title":"Oestrogen suppresses the adipogenesis of fibro/adipogenic progenitors through reactivating the METTL3–ESR1-mediated loop in post-menopausal females","authors":"Hao Zhou,&nbsp;Shujing Feng,&nbsp;Jinkui Cai,&nbsp;Xiexiang Shao,&nbsp;Siyuan Zhu,&nbsp;Han Zhou,&nbsp;Yongmin Cao,&nbsp;Ru Wang,&nbsp;Xingzuan Lin,&nbsp;Jianhua Wang","doi":"10.1002/ctm2.70206","DOIUrl":"10.1002/ctm2.70206","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Post-menopausal women experience more severe muscular fatty infiltration, though the mechanisms remain unclear. The decline in estrogen levels is considered as a critical physiological alteration during post-menopause. Fibro/adipogenic progenitors (FAPs) are identified as major contributors to muscular fatty infiltration. This study aimed to investigate the detailed mechanism underlying the excessive muscular fatty infiltration in postmenopausal females.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Supraspinatus muscle samples were collected from female patients with or without menopause, and from mice with or without ovariectomy (OVX), to evaluate muscular fatty infiltration and isolated FAPs. The expressions of (estrogen receptor 1) ESR1, methyltransferase-like 3 (METTL3), and adipogenesis ability in FAPs from post-menopausal women and OVX mice were investigated. RNA sequencing (RNA-Seq) was performed to explore the gene expression profiles and potential mechanisms in FAPs from Pdgfrα-CreERT2; Esr1 knockout (Esr1 KO) mice and Esr1 flox/flox (Esr1 f/f) mice. The interplay of the METTL3-ESR1 mediated loop and its role in regulating adipogenesis in FAPs were investigated using dual luciferase reporter assays, chromatin immunoprecipitation (ChIP), and protein and RNA stability assays. The effects of estrogen supplementation on muscular fatty infiltration and locomotor function in OVX mice were evaluated by immunofluorescent staining and functional analysis.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Decreased expression of ESR1/METTL3 and increased adipogenesis ability in FAPs was found in post-menopausal female. METTL3-mediated m6A methylation promoted ESR1 mRNA stability at the post-transcriptional level in FAPs. METTL3-mediated m6A modification promoted ESR1 expression by stabilizing ESR1 mRNA, while ESR1 acted as a transcription factor that enhanced METTL3 transcription in turn. ESR1 also suppressed the transcription of the adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARγ), thereby inhibiting adipogenesis in FAPs. Reactivation of the METTL3-ESR1 mediated loop by estrogen alleviated excessive adipogenesis in FAPs from post-menopausal women, and it also reduced muscular fatty infiltration, and improved locomotor function in OVX mice.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Excessive muscular fatty infiltration in post-menopausal women arose from the disruption of the METTL3-ESR1 mediated loop of FAPs due to estrogen deficiency. Reactivation of the METTL3-ESR","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11774659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Proteomic profiling of the serum of patients with COVID-19 reveals key factors in the path to clinical improvement
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-27 DOI: 10.1002/ctm2.70201
Hye Seong, Chae-Hyeon Lee, Seo-Gyu Park, Kyoung-Min Choi, Su-Min Lee, Jisoo Han, Ha-Song Bae, Su-Bhin Han, Sung-Jin Kim, Eunjung Kim, Jae-Young Kim, Joon Young Song
<p>Dear Editor,</p><p>This study uncovers new molecular insights into the coronavirus disease (COVID-19) remission process and identifies potential predictive markers through proteomic profiling of patient serum, potentially guiding clinical decision making.</p><p>COVID-19 caused by the SARS-CoV-2 virus has triggered a global health crisis. Many proteomic studies using patient sera have been conducted to understand the host's response to this disease and identify potential therapeutic target.<span><sup>1-4</sup></span> However, the precise mechanisms underlying the diverse clinical presentations of patients with SARS-CoV-2 infection remain unclear. Additionally, only a few studies have investigated the molecular factors or biomarkers that may influence clinical improvement of patients who have already exhibited severe symptoms. In this study, proteomic analysis of serum samples from a unique patient cohort, including individuals whose COVID-19 symptoms worsened and those who improved from moderate or severe conditions, identified 14 differentially expressed proteins (DEPs). Pathway and network analysis of these proteins revealed potential biological processes central to COVID-19 remission, particularly complement regulation. Remarkably, elevated levels of complement C2 in the patient serum could be an early marker for detecting clinical deterioration in patients with COVID-19.</p><p>The study design, patient clinical data, and the proteomics analysis, including statistical and bioinformatics analysis, are detailed in the Supporting Information (Section 1). Briefly, proteomic analyses were conducted using sera collected from a cohort of 20 patients with COVID-19 and five healthy individuals as controls. Patients with COVID-19 were categorised into different prognostic groups based on the National Institute of Allergy and Infectious Disease Ordinal Scale score (Table S1): those who improved from mild COVID-19 (G1), individuals with deteriorating COVID-19 symptoms (G2), individuals who improved from moderate to mild COVID-19 (G3), and those who improved from severe to mild COVID-19 (G4). Table S2 presents the baseline characteristics of patients with COVID-19 and healthy controls, and Table S3 presents a comparison of the laboratory test results across the subject groups. After depleting high-abundance proteins using High-Select HSA/Immunoglobulin Depletion Resin (Thermo Scientific), sera from patients were processed for proteomic analysis via in-gel trypsin digestion and liquid chromatography‒mass spectrometry/mass spectrometry (LC‒MS/MS). The study design is illustrated in Figure 1. Using this proteomics approach, a total of 181 proteins were identified and quantified (Figure S1 and Dataset S1). Protein intensities were normalised,<span><sup>5</sup></span> and DEPs (fold-change > 2, <i>p</i> < .05) were identified using MaxQuant software and statistical tools. Pathway enrichment and interaction networks of DEPs were analysed using STRING dat
{"title":"Proteomic profiling of the serum of patients with COVID-19 reveals key factors in the path to clinical improvement","authors":"Hye Seong,&nbsp;Chae-Hyeon Lee,&nbsp;Seo-Gyu Park,&nbsp;Kyoung-Min Choi,&nbsp;Su-Min Lee,&nbsp;Jisoo Han,&nbsp;Ha-Song Bae,&nbsp;Su-Bhin Han,&nbsp;Sung-Jin Kim,&nbsp;Eunjung Kim,&nbsp;Jae-Young Kim,&nbsp;Joon Young Song","doi":"10.1002/ctm2.70201","DOIUrl":"10.1002/ctm2.70201","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;This study uncovers new molecular insights into the coronavirus disease (COVID-19) remission process and identifies potential predictive markers through proteomic profiling of patient serum, potentially guiding clinical decision making.&lt;/p&gt;&lt;p&gt;COVID-19 caused by the SARS-CoV-2 virus has triggered a global health crisis. Many proteomic studies using patient sera have been conducted to understand the host's response to this disease and identify potential therapeutic target.&lt;span&gt;&lt;sup&gt;1-4&lt;/sup&gt;&lt;/span&gt; However, the precise mechanisms underlying the diverse clinical presentations of patients with SARS-CoV-2 infection remain unclear. Additionally, only a few studies have investigated the molecular factors or biomarkers that may influence clinical improvement of patients who have already exhibited severe symptoms. In this study, proteomic analysis of serum samples from a unique patient cohort, including individuals whose COVID-19 symptoms worsened and those who improved from moderate or severe conditions, identified 14 differentially expressed proteins (DEPs). Pathway and network analysis of these proteins revealed potential biological processes central to COVID-19 remission, particularly complement regulation. Remarkably, elevated levels of complement C2 in the patient serum could be an early marker for detecting clinical deterioration in patients with COVID-19.&lt;/p&gt;&lt;p&gt;The study design, patient clinical data, and the proteomics analysis, including statistical and bioinformatics analysis, are detailed in the Supporting Information (Section 1). Briefly, proteomic analyses were conducted using sera collected from a cohort of 20 patients with COVID-19 and five healthy individuals as controls. Patients with COVID-19 were categorised into different prognostic groups based on the National Institute of Allergy and Infectious Disease Ordinal Scale score (Table S1): those who improved from mild COVID-19 (G1), individuals with deteriorating COVID-19 symptoms (G2), individuals who improved from moderate to mild COVID-19 (G3), and those who improved from severe to mild COVID-19 (G4). Table S2 presents the baseline characteristics of patients with COVID-19 and healthy controls, and Table S3 presents a comparison of the laboratory test results across the subject groups. After depleting high-abundance proteins using High-Select HSA/Immunoglobulin Depletion Resin (Thermo Scientific), sera from patients were processed for proteomic analysis via in-gel trypsin digestion and liquid chromatography‒mass spectrometry/mass spectrometry (LC‒MS/MS). The study design is illustrated in Figure 1. Using this proteomics approach, a total of 181 proteins were identified and quantified (Figure S1 and Dataset S1). Protein intensities were normalised,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; and DEPs (fold-change &gt; 2, &lt;i&gt;p&lt;/i&gt; &lt; .05) were identified using MaxQuant software and statistical tools. Pathway enrichment and interaction networks of DEPs were analysed using STRING dat","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Neutrophil extracellular traps promote growth of lung adenocarcinoma by mediating the stability of m6A-mediated SLC2A3 mRNA-induced ferroptosis resistance and CD8(+) T cell inhibition
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-26 DOI: 10.1002/ctm2.70192
Li Xu, Yi Kong, Kang Li, Jia Li, Fang Xu, Yan Xu, Shuzhi Liang, Bolin Chen

To investigate the potential mechanisms underlying neutrophil extracellular traps (NETs) confer ferroptosis resistance and CD8(+) T cell inhibition in lung adenocarcinoma (LUAD). By the intravenous injection of LLC cells into the tail vein, a LUAD mouse model was created. Phorbol-12-myristate-13-acetate (PMA) stimulated neutrophils to facilitate NETs formation and combined with NETs inhibitor DNase I to explore NETs mechanism on LLC cell proliferation, migration, ferroptosis resistance, and CD8(+) T cell activity. CitH3, myeloperoxidase (MPO), cell-free DNA, and MPO-DNA levels in LUAD were increased, indicating an increase in NETs formation in LUAD. PMA promoted NETs formation in tumours of mice, increased the number of CD3(+)CD4(+) T cells, decreased perforin, granzyme A, granzyme B, IFNγ, and TNF-α levels, and promoted LUAD growth and the number of lung tumour nodules, indicating that PMA promoted NETs formation, reduced the activity of CD8(+)T cells, and promoted LUAD growth. DNase I partially reversed the effects of PMA. NETs promoted LLC cell proliferation and migration, while DNase I reversed NETs effects. Erastin inhibited LLC cell proliferation and migration and promoted ferroptosis. NETs partially reversed Erastin effects. Further results showed that NETs promoted LLC cell proliferation and migration and inhibited ferroptosis by promoting YTHDF2-mediated SLC2A3 mRNA degradation. Sh-YTHDF2 partially reversed the effect of NETs on LLC cells, whereas si-SLC2A3 partially reversed sh-YTHDF2 effects on LLC cells. In addition, NETs inhibited LLC cell ferroptosis by inhibiting CD8(+) T cell activity. Sh-YTHDF2 and DNase I inhibited NETs formation in tumours, increased the activity of CD8(+) T cells and inhibited LUAD growth. Our results suggested that NETs promoted the growth of LUAD through inhibiting ferroptosis and CD8(+) T cell activity by promoting YTHDF2-mediated SLC2A3 mRNA degradation.

目的:研究中性粒细胞胞外捕获物(NET)赋予肺腺癌(LUAD)抗铁蛋白沉积和CD8(+)T细胞抑制作用的潜在机制。通过向尾静脉注射LLC细胞,建立了LUAD小鼠模型。光稳定剂-12-肉豆蔻酸-13-醋酸酯(PMA)刺激中性粒细胞以促进NETs的形成,并结合NETs抑制剂DNase I来探讨NETs对LLC细胞增殖、迁移、抗铁锈色素沉着和CD8(+)T细胞活性的影响机制。LUAD中CitH3、髓过氧化物酶(MPO)、细胞游离DNA和MPO-DNA水平升高,表明LUAD中NETs形成增加。PMA 促进了小鼠肿瘤中 NETs 的形成,增加了 CD3(+)CD4(+) T 细胞的数量,降低了穿孔素、颗粒酶 A、颗粒酶 B、IFNγ 和 TNF-α 的水平,促进了 LUAD 的生长和肺肿瘤结节的数量,表明 PMA 促进了 NETs 的形成,降低了 CD8(+)T 细胞的活性,促进了 LUAD 的生长。DNase I能部分逆转PMA的影响。NETs促进了LLC细胞的增殖和迁移,而DNase I则逆转了NETs的作用。Erastin抑制LLC细胞的增殖和迁移,并促进铁突变。NETs 可部分逆转 Erastin 的作用。进一步的结果显示,NETs通过促进YTHDF2介导的SLC2A3 mRNA降解,促进了LLC细胞的增殖和迁移,抑制了铁凋亡。Sh-YTHDF2部分逆转了NETs对LLC细胞的影响,而si-SLC2A3部分逆转了sh-YTHDF2对LLC细胞的影响。此外,NETs还通过抑制CD8(+)T细胞的活性来抑制LLC细胞的铁突变。Sh-YTHDF2和DNase I抑制了肿瘤中NETs的形成,提高了CD8(+)T细胞的活性,抑制了LUAD的生长。我们的研究结果表明,NETs通过抑制铁突变和CD8(+)T细胞活性,促进YTHDF2介导的SLC2A3 mRNA降解,从而促进LUAD的生长。
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引用次数: 0
Engineering the future of medicine: Natural products, synthetic biology and artificial intelligence for next-generation therapeutics
IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-24 DOI: 10.1002/ctm2.70146
Emre F. Bülbül, Helge B. Bode, Steven Schmitt, Kenan A. J. Bozhüyük

The eXchange Unit between Thiolation domains approach and artificial intelligence (AI)-driven tools like Synthetic Intelligence are transforming nonribosomal peptide synthetase and polyketide synthase engineering, enabling the creation of novel bioactive compounds that address critical challenges like antibiotic resistance and cancer. These innovations expand chemical space and optimize biosynthetic pathways, offering precise and scalable therapeutic solutions. Collaboration across synthetic biology, AI, and clinical research is essential to translating these breakthroughs into next-generation treatments and revolutionizing drug discovery and patient care.

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引用次数: 0
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Clinical and Translational Medicine
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