Clinical and Translational Medicine最新文献

{"title":"Reduction of myeloid-derived suppressor cells in prostate cancer murine models and patients following white button mushroom treatment","authors":"Xiaoqiang Wang, Shoubao Ma, Przemyslaw Twardowski, Clayton Lau, Yin S. Chan, Kelly Wong, Sai Xiao, Jinhui Wang, Xiwei Wu, Paul Frankel, Timothy G. Wilson, Timothy W Synold, Cary Presant, Tanya Dorff, Jianhua Yu, David Sadava, Shiuan Chen","doi":"10.1002/ctm2.70048","DOIUrl":"10.1002/ctm2.70048","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>In a previously reported Phase I trial, we observed therapy-associated declines in circulating myeloid-derived suppressor cells (MDSCs) with the administration of white button mushroom (WBM) tablets in prostate cancer (PCa) patients. These observations led us to hypothesise that WBM could mitigate PCa progression by suppressing MDSCs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed bidirectional translational research to examine the immunomodulatory effects of WBM consumption in both syngeneic murine PCa models and patients with PCa participating in an ongoing randomised Phase II trial (NCT04519879).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In murine models, WBM treatment significantly suppressed tumour growth with a reduction in both the number and function of MDSCs, which in turn promoted antitumour immune responses mediated by T cells and natural killer (NK) cells. In patients, after consumption of WBM tablets for 3 months, we observed a decline in circulating polymorphonuclear MDSCs (PMN-MDSCs), along with an increase in cytotoxic CD8<sup>+</sup> T and NK cells. Furthermore, single immune cell profiling of peripheral blood from WBM-treated patients showed suppressed STAT3/IRF1 and TGFβ signalling in circulating PMN-MDSCs. Subclusters of PMN-MDSCs presented transcriptional profiles associated with responsiveness to fungi, neutrophil chemotaxis, leukocyte aggregation, and regulation of inflammatory response. Finally, in mouse models of PCa, we found that WBM consumption enhanced the anticancer activity of anti-PD-1 antibodies, indicating that WBM may be used as an adjuvant therapy with immune checkpoint inhibitors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results from PCa murine models and patients provide mechanistic insights into the immunomodulatory effects of WBM and provide a scientific foundation for WBM as a nutraceutical intervention to delay or prevent PCa progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>White button mushroom (WBM) treatment resulted in a reduction in pro-tumoural MDSCs, notably polymorphonuclear MDSCs (PMN-MDSCs), along with activation of anti-tumoural T and NK cells.</li>\u0000 \u0000 <li>Human single immune cell gene expression profiling shed light on the molecular alterations induced by WBM, specifically on PMN-MDSCs.</li>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399569","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}

{"title":"CRISPR-based approaches for studying inborn errors of immunity","authors":"Joey H. Li","doi":"10.1002/ctm2.70021","DOIUrl":"10.1002/ctm2.70021","url":null,"abstract":"<p>Inborn errors of immunity (IEI), formerly referred to as primary immunodeficiencies, affect millions of children worldwide.<span><sup>1</sup></span> Patients with IEI harbour germline mutations in genes responsible for immune system development or function, resulting in heightened susceptibility to infections as well as non-infectious sequelae such as increased incidence of malignancy or paradoxical autoimmunity.<span><sup>1</sup></span> While genetic testing is now a standard component of the workup for IEI, interpretation of results remains limited by our knowledge of causal pathogenic variants.<span><sup>2</sup></span> Currently, the primary method of identifying new variants associated with IEI depends on the clinical identification of a patient both bearing a novel mutation and presenting with severe or recurrent infections, pointing to a potential immune defect. While this approach has allowed us to greatly expand our identification of immunodeficient patients, the dependence on a chance encounter with a new patient represents a major barrier to identifying and providing prophylactic care for patients with unrecognized IEIs. Furthermore, this approach is limited to retrospectively identifying immunodeficient patients after they have already suffered from severe or recurrent infections. Therefore, a prospective laboratory-based screening method to identify putative IEI-associated genes followed by clinical validation of predicted pathogenic variants could improve our care for immunodeficient individuals.</p><p>To test a laboratory-based approach to prospectively identify and validate new IEI-associated gene variants, we focused on human natural killer (NK) cells and performed functional knockout screening of developmentally expressed transcription factors using CRISPR.<span><sup>3</sup></span> NK cells play a critical role during the early defense against viral infection via direct cytotoxicity against infected cells as well as the production of inflammatory mediators like interferon (IFN)-γ. This is highlighted by the increased and often fatal susceptibility to viral infection displayed by NK cell-deficient individuals.<span><sup>4</sup></span> However, the transcriptional regulators of human NK cell function that could lead to primary NK cell immunodeficiency when mutated remain poorly understood. We applied a CRISPR-Cas9 ribonucleoprotein (cRNP) electroporation protocol previously optimized by our group for primary immune cells to directly examine the role of 31 distinct transcription factors in mature primary human peripheral blood mononuclear cell (PBMC)-derived NK cells and identified a single gene, <i>MEF2C</i>, required for all tested effector functions.<span><sup>3, 5</sup></span> <i>MEF2C</i> knockout resulted in defective NK cell proliferation, cytotoxicity against tumor cells, degranulation, and production of inflammatory cytokines. We validated these findings by studying a small clinical cohort of two pediatric patients beari","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380156","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}

{"title":"Prediction of COVID-19 severity using machine learning","authors":"Kanita Karaduzovic-Hadziabdic, Muhamed Adilovic, Lu Zhang, Andrew I Lumley, Pranay Shah, Muhammad Shoaib, Venkata Satagopam, Prashant Kumar Srivastava, Costanza Emanueli, Simona Greco, Alisia Madè, Teresa Padro, Pedro Domingo, Mitja Lustrek, Markus Scholz, Maciej Rosolowski, Marko Jordan, Bettina Benczik, Bence Ágg, Péter Ferdinandy, Andrew H Baker, Guy Fagherazzi, Markus Ollert, Joanna Michel, Gabriel Sanchez, Hüseyin Firat, Timo Brandenburger, Fabio Martelli, Lina Badimon, Yvan Devaux, COVIRNA consortium (www.covirna.eu)","doi":"10.1002/ctm2.70042","DOIUrl":"10.1002/ctm2.70042","url":null,"abstract":"<p>Dear Editor,</p><p>Prediction of COVID-19 severity is a critical task in the decision-making process during the initial stages of the disease, enabling personalised surveillance and care of COVID-19 patients. To develop a machine learning (ML) model for the prediction of COVID-19 severity, a consortium of 15 institutions from 12 European countries analysed expression data of 2906 blood long noncoding RNAs (lncRNAs) and clinical data collected from four independent cohorts, totalling 564 patients with COVID-19. This predictive model based on age and five lncRNAs predicted disease severity with an area under the receiver operating characteristic curve (AUC) of .875 [.868–.881] and an accuracy of .783 [.775–.791].</p><p>The sudden onset of the COVID-19 pandemic caught the world unprepared, leading to more than 774 million confirmed cases and over 7 million reported deaths worldwide (over a period from January 2020 to March 2024), according to the World Health Organization (WHO).<span><sup>1</sup></span> Other than having an impact on the respiratory system, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can also infect nonpulmonary cells such as cardiac and brain cells leading to cardiovascular or neurological symptoms.<span><sup>2</sup></span> With the recent advances in high throughput sequencing, a large number of RNA signatures have emerged as promising biomarkers involved in the progression of various diseases, including cardiovascular diseases.<span><sup>3</sup></span> As a response to the COVID-19 pandemic, partners of the EU-CardioRNA COST Action network<span><sup>4-6</sup></span> joined forces in the H2020-funded COVIRNA project to develop an RNA-based diagnostic test using artificial intelligence (AI) that can help predict clinical outcomes after COVID-19.<span><sup>7</sup></span> We chose to implement a targeted sequencing approach using the FIMICS panel of 2906 cardiac-enriched or heart failure-associated lncRNAs previously characterised by our consortium.<span><sup>8</sup></span> In the present study, we aimed to apply the FIMICS panel to identify lncRNAs that will predict disease severity of COVID-19 patients. We used an approach based on ML to conduct the predictive analysis, as ML algorithms are suitably capable of analysing the complex relationships between biomedical data.<span><sup>9</sup></span></p><p>The overall workflow of the study is illustrated in Figure 1A. Briefly, four European cohorts were included in the study consisting of a total of 564 patients with COVID-19: the PrediCOVID cohort from Luxembourg (<i>n</i> = 162; recruitment period May 2020 to present), the COVID19_OMICS-COVIRNA cohort from Italy (<i>n</i> = 100; recruitment period March 2020 to January 2021), the TOCOVID cohort from Spain (<i>n</i> = 233; recruitment period April 2020 to June 2021), and the MiRCOVID cohort from Germany (<i>n</i> = 69; recruitment period April 2020 to November 2021). Patient characteristics are presented in Table 1. ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380158","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}

{"title":"Harnessing apoptotic cells to enhance efficiency of macrophage-based cell therapy","authors":"Imke Liebold, Lidia Bosurgi","doi":"10.1002/ctm2.70008","DOIUrl":"10.1002/ctm2.70008","url":null,"abstract":"<p>Phagocytosis of apoptotic cells by macrophages, also known as efferocytosis, is a core function of macrophages in every tissue of our body. Here the prompt elimination of dying cells ensures the reestablishment of homeostasis in physiological and pathological conditions.</p><p>By leading to the accumulation of apoptotic cells, impaired efferocytosis is indeed a key contributor to many diseases, from autoimmune conditions such as systemic lupus erythematosus to cancer. Restoring phagocytosis by inhibiting “do-not-eat me” signals or by blocking the programmed cell death protein 1-programmed death-ligand 1 (PD1-PD-L1) axis, increases macrophage phagocytosis of tumour cells, thereby enhancing survival in mouse models of cancer in a macrophage-dependent manner.<span><sup>1, 2</sup></span></p><p>Besides its involvement in the direct clean-up of dying cells, efferocytosis also directly shapes the function of phagocytic macrophages. This complicates our understanding of the impact of the efferocytic process on the damaged environment.</p><p>It is long-established that the engulfment of apoptotic cells by macrophages leads to the induction of molecules with immunosuppressive functions, such as interleukin (IL)-10, transforming growth factor beta 1, prostaglandins and platelet-activating factors while reducing the secretion of proinflammatory cytokines such as tumour necrosis factor-alpha, IL-1β and IL-8.<span><sup>3, 4</sup></span> Thus, in certain disease settings, efficient efferocytosis is required to prevent chronic inflammation. In line with this, during a helminth infection, the uptake of dying cells promotes macrophage acquisition of a tissue remodelling profile and the associated parasite clearance.<span><sup>5</sup></span> Additionally, metabolites released by apoptotic cells, such as spermidine and adenosine, contribute to fostering anti-inflammatory properties in the engulfing macrophages.<span><sup>6</sup></span></p><p>Consistent with these findings, apoptotic cells and their subsequent clearance by efferocytic macrophages have uncovered numerous potential therapeutic opportunities while also bringing to light several challenges.</p><p>The beneficial consequences of administering apoptotic cells have been reported in clinical practice. Infusion of apoptotic cells as a result of extracorporeal photopheresis, a procedure that induces cell death in peripheral blood mononuclear cells by ultraviolet light exposure, has been effectively used in patients with hematologic malignancies who undergo hematopoietic cell transplantation. This helps to prevent- acute graft-versus-host disease. Based on various promising data on pre-clinical models,<span><sup>7</sup></span> the induction of apoptosis in peripheral blood leukocytes and their consequent infusion is also planned to be tested in patients with rheumatoid arthritis (NCT02903212). Despite being used in clinical settings, the mechanism by which apoptotic cell transfer prevents pathological inflamm","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380157","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}

{"title":"N6-methyladenosine-mediated upregulation of LNCAROD confers radioresistance in esophageal squamous cell carcinoma through stabilizing PARP1","authors":"Xiaobo Shi,&nbsp;Xiaozhi Zhang,&nbsp;Xinran Huang,&nbsp;Ruijuan Zhang,&nbsp;Shupei Pan,&nbsp;Shan Huang,&nbsp;Yuchen Wang,&nbsp;Yue Ke,&nbsp;Wei Guo,&nbsp;Xiaoxiao Liu,&nbsp;Yu Hao,&nbsp;You Li,&nbsp;Xu Zhao,&nbsp;Yuchen Sun,&nbsp;Jing Li,&nbsp;Hongbing Ma,&nbsp;Xixi Zhao","doi":"10.1002/ctm2.70039","DOIUrl":"10.1002/ctm2.70039","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Radiotherapy is a primary therapeutic modality for esophageal squamous cell carcinoma (ESCC), but its effectiveness is still restricted due to the resistance of cancer cells to radiation. Long non-coding RNAs (lncRNAs) and N⁶-methyladenosine (m6A) have been shown to play significant roles in tumour radioresistance. However, the precise manifestation and role of m6A-modified lncRNAs in ESCC radioresistance remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Bioinformatics analysis was conducted to identify m6A-modified lncRNAs implicated in the radioresistance of ESCC. A series of functional experiments were performed to investigate the function of LNCAROD in ESCC. Methylated RNA immunoprecipitation, chromatin isolation by RNA purification-mass spectrometry, RNA immunoprecipitation, and co-immunoprecipitation experiments were performed to explore the mechanism of m6A-mediated upregulation of LNCAROD expression and the downstream mechanism enhancing the radioresistance of ESCC. The efficacy of LNCAROD in vivo was assessed using murine xenograft models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Herein, we identified LNCAROD as a novel METTL3-mediated lncRNA that enhanced radioresistance in ESCC cells and was post-transcriptionally stabilised by YTHDC1. Moreover, we confirmed that LNCAROD prevented ubiquitin-proteasome degradation of PARP1 protein by facilitating PARP1-NPM1 interaction, thereby contributing to homologous recombination-mediated DNA double-strand breaks repair and enhancing the radiation resistance of ESCC cells. Silencing LNCAROD in a nude mouse model of ESCC in vivo resulted in slower tumour growth and increased radiosensitivity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings enhance the understanding of m6A-modified lncRNA-driven machinery in ESCC radioresistance and underscore the significance of LNCAROD in this context, thereby contributing to the development of a potential therapeutic target for ESCC patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375221","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}

{"title":"Discovery of a selective cytochrome P450 4A inhibitor for the treatment of metabolic dysfunction-associated fatty liver disease","authors":"Minji Lee,&nbsp;Myung Jin Son,&nbsp;Sin-Hyoung Hong,&nbsp;Jae-Sung Ryu,&nbsp;Ji-Hyeon Min,&nbsp;Dong-Eon Lee,&nbsp;Ji Hoon Lee,&nbsp;Nam Doo Kim,&nbsp;Shi-Young Park,&nbsp;Darong Kim,&nbsp;Jeongmin Joo,&nbsp;Jisung Kwak,&nbsp;Kook Hwan Kim,&nbsp;Yong-Ho Lee,&nbsp;Byeong-Rak Keum,&nbsp;Hyun Seok Song,&nbsp;Youngae Jung,&nbsp;Koon Soon Kim,&nbsp;Gun-Hwa Kim","doi":"10.1002/ctm2.1816","DOIUrl":"10.1002/ctm2.1816","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Metabolic dysfunction-associated fatty liver disease (MAFLD), a revised definition of nonalcoholic fatty liver disease (NAFLD), comprises patients with hepatic steatosis who fulfil the criteria of overweight/obesity, type II diabetes mellitus (T2DM), or more than two metabolic abnormalities,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; providing a valuable tool for identifying patients with fatty liver at higher risk of disease progression.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; MAFLD is a complex disease in which various pathogenic factors contribute to its progression, including fat accumulation, lipotoxicity, oxidative stress, and endoplasmic reticulum (ER) stress. The heterogeneous risk profile of MAFLD presents challenges for effective treatment. Within the mammalian liver, cytochrome P450 4A (CYP4A) functions as a fatty acid hydroxylase, actively participating in oxidative metabolism and catalyzing the breakdown of lipid peroxides, consequently generating reactive oxygen species (ROS). Previous research has demonstrated that targeting CYP4A shows potential in exploring the pathophysiology of liver diseases, including MAFLD and diabetes.&lt;span&gt;&lt;sup&gt;3-5&lt;/sup&gt;&lt;/span&gt; Taking these findings together, we suggest that CYP4A holds significant promise for the treatment of MAFLD, and the discovery of a CYP4A inhibitor may serve as a potent drug candidate.&lt;/p&gt;&lt;p&gt;We identified CYP4A inhibitors through in silico analysis. Among several hit compounds, C418 significantly reduced CYP4A enzyme activity. Subsequently, we synthesized derivatives, namely C4181 (C1) and C4182 (C2) (Figure 1A). Both C1 and C2 exhibited substantial reduction at a dose of 5 µM (Figures S1A and S2A), demonstrating potent inhibition with IC&lt;sub&gt;50&lt;/sub&gt; (Figure 1B). Importantly, neither compound exhibited cytotoxic effects (Figure S1B,C) and demonstrated drug-like properties in various assays, including CYP inhibition, metabolic stability, plasma stability, and permeability (Tables S1 and S2).&lt;/p&gt;&lt;p&gt;We investigated the effects of novel CYP4A inhibitors using HepG2 cells exposed to lipid overload or induced ER stress. C1 and C2 increased glucose uptake (Figures S1D and S2B) and significantly mitigated lipid accumulation and ROS generation (Figures S1E,F and S2C,D). Furthermore, they restored the expression of proteins implicated in gluconeogenesis, lipogenesis, and ER stress (Figures S1G-K and S2E), indicating the effectiveness of CYP4A inhibitors in in vitro models. Additionally, we determine the effect of C1 and C2 in various in vivo models, encompassing diet-induced T2DM, &lt;i&gt;db/db&lt;/i&gt; mice, and metabolic dysfunction-associated steatohepatitis (MASH). In the diet-induced T2DM model, we determined the optimal concentration of C1 and C2 (Figure S3) and observed a significant reduction in body mass without affecting food intake (Figure 1C,D). Glucose tolerance and insulin tolerance testing (ITT) exhibited significant improvements (Figure 1E), and serum glucose and insulin concentrations were abrog","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375220","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}

{"title":"Gut microbiota of miR-30a-5p-deleted mice aggravate high-fat diet-induced hepatic steatosis by regulating arachidonic acid metabolic pathway","authors":"Ruiying Wang,&nbsp;Xiaocheng Zhang,&nbsp;Yutian Wang,&nbsp;Yijun Lin,&nbsp;Yuling Zhou,&nbsp;Yan Wang,&nbsp;Gang Li","doi":"10.1002/ctm2.70035","DOIUrl":"10.1002/ctm2.70035","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;Patients with non-alcoholic fatty liver disease (NAFLD) often exhibit hepatic steatosis and dyslipidemia. Studies have shown that intestinal microorganisms are closely related to the occurrence of NAFLD and atherosclerosis. Our previous study has underscored the protective role of microRNA-30a-5p (miR-30a-5p) against atherosclerosis.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods and Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In the present study, we aimed to elucidate the effect and underlying mechanism of the intestinal microorganisms of miR-30a-5p knockout (KO) mice on NAFLD. Our findings demonstrated that KO exacerbated high-fat diet (HFD)-induced hepatic steatosis and disrupted liver function, as evidenced by elevated levels of total cholesterol, low-density lipoprotein, alanine aminotransferase, aspartate transaminase, and total bile acids in serum. Fecal microbiota from HFD-fed KO mice induced hepatic steatosis, dyslipidemia, and higher levels of enzymes indicative of liver damage in wild-type mice. Remarkably, KO mice significantly intensified the above effects. 16s rDNA sequencing and metabolomics of the intestinal microbiota in the HFD-treated KO and WT mice showed that the loss of miR-30a-5p resulted in intestinal microbiota imbalance and was highly related to the arachidonic acid metabolic pathway. Targeted metabolomic in the liver tissues unveiled upregulation of COX-related (PGF2a, 8-iso-PGF2a and PGF2) and LOX-related (LTB4, LTD4, 12S-HETE and 15S-HETE) factors in HFD-treated KO mice. Immunohistochemistry and transcriptional analyses showed that miR-30a-5p affected arachidonic acid metabolism through the LOX/COX pathways. Besides, COX/LOX pathways and hepatic steatosis were reversed after reintroducing miR-30a-5p in HFD-treated KO mice.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study reveals the pivotal mechanism by which miR-30a-5p and intestinal microbes regulate hepatic steatosis and abnormal lipid metabolism, offering promising avenues for NAFLD and atherosclerosis therapeutics.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;MiR-30a-5p deletion aggravated hepatic steatosis and lipid disorder induced by an HFD in mice. Gut microbiota participated in the regulation of hepatic steatosis in the context of miR-30a-5p. Gut microbiota metabolism-related arachidonic acid metabolic pathway contributed to miR-30a-5p-regulated hepatic steatosis and lipid disorder. Reintroducing miR-30a-5p reversed hepatic steatosis and arachidonic acid metabolism disorder caused by HFD and miR-30a-5p deletion.&lt;/p&gt;\u0000 &lt;/section","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364600","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}

{"title":"Structural inequality and temporal brain dynamics across diverse samples","authors":"Sandra Baez,&nbsp;Hernan Hernandez,&nbsp;Sebastian Moguilner,&nbsp;Jhosmary Cuadros,&nbsp;Hernando Santamaria-Garcia,&nbsp;Vicente Medel,&nbsp;Joaquín Migeot,&nbsp;Josephine Cruzat,&nbsp;Pedro A. Valdes-Sosa,&nbsp;Francisco Lopera,&nbsp;Alfredis González-Hernández,&nbsp;Jasmin Bonilla-Santos,&nbsp;Rodrigo A. Gonzalez-Montealegre,&nbsp;Tuba Aktürk,&nbsp;Agustina Legaz,&nbsp;Florencia Altschuler,&nbsp;Sol Fittipaldi,&nbsp;Görsev G. Yener,&nbsp;Javier Escudero,&nbsp;Claudio Babiloni,&nbsp;Susanna Lopez,&nbsp;Robert Whelan,&nbsp;Alberto A Fernández Lucas,&nbsp;David Huepe,&nbsp;Marcio Soto-Añari,&nbsp;Carlos Coronel-Oliveros,&nbsp;Eduar Herrera,&nbsp;Daniel Abasolo,&nbsp;Ruaridh A. Clark,&nbsp;Bahar Güntekin,&nbsp;Claudia Duran-Aniotz,&nbsp;Mario A. Parra,&nbsp;Brian Lawlor,&nbsp;Enzo Tagliazucchi,&nbsp;Pavel Prado,&nbsp;Agustin Ibanez","doi":"10.1002/ctm2.70032","DOIUrl":"10.1002/ctm2.70032","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Structural income inequality – the uneven income distribution across regions or countries – could affect brain structure and function, beyond individual differences. However, the impact of structural income inequality on the brain dynamics and the roles of demographics and cognition in these associations remains unexplored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we assessed the impact of structural income inequality, as measured by the Gini coefficient on multiple EEG metrics, while considering the subject-level effects of demographic (age, sex, education) and cognitive factors. Resting-state EEG signals were collected from a diverse sample (countries = 10; healthy individuals = 1394 from Argentina, Brazil, Colombia, Chile, Cuba, Greece, Ireland, Italy, Turkey and United Kingdom). Complexity (fractal dimension, permutation entropy, Wiener entropy, spectral structure variability), power spectral and aperiodic components (1/<i>f</i> slope, knee, offset), as well as graph-theoretic measures were analysed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Findings</h3>\u0000 \u0000 <p>Despite variability in samples, data collection methods, and EEG acquisition parameters, structural inequality systematically predicted electrophysiological brain dynamics, proving to be a more crucial determinant of brain dynamics than individual-level factors. Complexity and aperiodic activity metrics captured better the effects of structural inequality on brain function. Following inequality, age and cognition emerged as the most influential predictors. The overall results provided convergent multimodal metrics of biologic embedding of structural income inequality characterised by less complex signals, increased random asynchronous neural activity, and reduced alpha and beta power, particularly over temporoposterior regions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings might challenge conventional neuroscience approaches that tend to overemphasise the influence of individual-level factors, while neglecting structural factors. Results pave the way for neuroscience-informed public policies aimed at tackling structural inequalities in diverse populations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364602","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}

{"title":"Deubiquitination of RIPK2 by OTUB2 augments NOD2 signalling and protective effects in intestinal inflammation","authors":"Xue Du,&nbsp;Jun Xu,&nbsp;Fuqi Mei,&nbsp;Jiangyun Shen,&nbsp;Bincheng Zhou,&nbsp;Zhenhu Zhu,&nbsp;Zhongding Li,&nbsp;Xian Su,&nbsp;Jianmin Li,&nbsp;Dirk Schlüter,&nbsp;Jing Ruan,&nbsp;Xu Wang","doi":"10.1002/ctm2.70038","DOIUrl":"10.1002/ctm2.70038","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, but the molecular mechanisms underlying IBD are incompletely understood. In this study, we explored the role and regulating mechanism of otubain 2 (OTUB2), a deubiquitinating enzyme, in IBD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To study the function of OTUB2 in IBD, we generated <i>Otub2</i>^–/– mice and treated them with dextran sulfate sodium (DSS) to induce experimental colitis. Bone marrow transplantation was performed to identify the cell populations that were affected by OTUB2 in colitis. The molecular mechanism of OTUB2 in signal transduction was studied by various biochemical methods.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>OTUB2 was highly expressed in colon-infiltrating macrophages in both humans with IBD and mice with DSS-induced experimental colitis. Colitis was significantly aggravated in <i>Otub2</i>^–/– mice and bone marrow chimeric mice receiving <i>Otub2</i>^–/– bone marrow. OTUB2-deficiency impaired the production of cytokines and chemokines in macrophages in response to the NOD2 agonist muramyl dipeptide (MDP). Upon MDP stimulation, OTUB2 promoted NOD2 signaling by stabilizing RIPK2. Mechanistically, OTUB2 inhibited the proteasomal degradation of RIPK2 by removing K48-linked polyubiquitination on RIPK2, which was mediated by the active C51 residue in OTUB2. In mice, OTUB2 ablation abolished the protective effects of MDP administration in colitis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study identified OTUB2 as a novel regulator of intestinal inflammation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364599","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}

{"title":"O-GlcNAcylation promotes malignancy and cisplatin resistance of lung cancer by stabilising NRF2","authors":"Yihan Zhang,&nbsp;Changning Sun,&nbsp;Leina Ma,&nbsp;Guokai Xiao,&nbsp;Yuchao Gu,&nbsp;Wengong Yu","doi":"10.1002/ctm2.70037","DOIUrl":"10.1002/ctm2.70037","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The transcription factor NRF2 plays a significant role in regulating genes that protect cells from oxidative damage. O-GlcNAc modification, a type of posttranslational modification, is crucial for cellular response to stress. Although the involvement of both NRF2 and O-GlcNAc in maintaining cellular redox balance and promoting cancer malignancy has been demonstrated, the potential mechanisms remain elusive.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The immunoblotting, luciferase reporter, ROS assay, co-immunoprecipitation, and immunofluorescence was used to detect the effects of global cellular O-GlcNAcylation on NRF2. Mass spectrometry was utilised to map the O-GlcNAcylation sites on NRF2, which was validated by site-specific mutagenesis and O-GlcNAc enzymatic labelling. Human lung cancer samples were employed to verify the association between O-GlcNAc and NRF2. Subsequently, the impact of NRF2 O-GlcNAcylation in lung cancer malignancy and cisplatin resistance were evaluated in vitro and in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>NRF2 is O-GlcNAcylated at Ser103 residue, which hinders its binding to KEAP1 and thus enhances its stability, nuclear localisation, and transcription activity. Oxidative stress and cisplatin can elevate the phosphorylation of OGT at Thr444 through the activation of AMPK kinase, leading to enhanced binding of OGT to NRF2 and subsequent elevation of NRF2 O-GlcNAcylation. Both in cellular and xenograft mouse models, O-GlcNAcylation of NRF2 at Ser103 promotes the malignancy of lung cancer. In human lung cancer tissue samples, there was a significant increase in global O-GlcNAcylation, and elevated levels of NRF2 and its O-GlcNAcylation compared to paired adjacent normal tissues. Chemotherapy promotes NRF2 O-GlcNAcylation, which in turn decreases cellular ROS levels and drives lung cancer cell survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings indicate that OGT O-GlcNAcylates NRF2 at Ser103, and this modification plays a role in cellular antioxidant, lung cancer malignancy, and cisplatin resistance.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364601","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}