Clinical and Translational Medicine最新文献

{"title":"Angiotensin-converting enzyme 2 modulation of pyroptosis pathway in traumatic brain injury: A potential therapeutic target","authors":"Jinxiu Guo, Shiyuan Zhao, Xue Chu, Changshui Wang, Junjun Meng, Shanshan Wei, Jianhua Wang, Yujin Guo, Weihua Kong, Wenxue Sun, Tao Zhang, Ruili Dang, Mengqi Yang, Jing Chen, Pei Jiang","doi":"10.1002/ctm2.70167","DOIUrl":"10.1002/ctm2.70167","url":null,"abstract":"<p>Dear Editor,</p><p>Traumatic brain injury (TBI) is a significant public health concern, with its severity largely influenced by secondary molecular damage like oxidative stress, cell death and neuroinflammation. ACE2 mediates the enzymatic conversion of AngII to Ang-(1−7) and interacts with the G protein-coupled receptor MasR, resulting in antagonistic biological effects to those of AngII. Research has shown that the ACE2/Ang-(1–7)/MasR pathway mitigates neuroimmune overactivation, thereby decreasing neural damage and brain inflammation associated with cerebral haemorrhage and ischemia-reperfusion.<span><sup>1</sup></span> Understanding the regulation of ACE2 could provide novel insights into its neuroprotective mechanisms of ACE2 and offer fundamental knowledge regarding its underlying molecular signalling pathways. Following TBI, ACE2 levels in the injured cortical area significantly decreased (Figure 1A), reaching their lowest point 24 h post-injury (Figure S1A,D). The ACE2 protein was found in MAP2, IBA1 and GFAP-positive brain cells (Figure 1B,C), with co-expression analysis of ACE2 and IBA1 further supporting this conclusion (Figure 1H–J). Additionally, TBI disrupts the normal function of the renin-angiotensin system (Figure 1D–G). Behavioural experiments were verified to confirm the neuroprotective effect of ACE2 in vivo (Figure 1K). AVE0991, a synthetic Mas receptor agonist, replicates Angiotensin-(1−7) effects by activating MasR and providing anti-inflammatory, anti-oxidative and anti-apoptotic benefits. AVE0991 treatments significantly mitigated cognitive decline caused by TBI, demonstrated by decreased escape latency time and distance in the learning curve (Figure 1L–N). Additionally, AVE0991 improved motor coordination and balance in TBI mice, evidenced by shorter completion times in the horizontal ladder and balance beam tests and better scores (Figure 1O–R). CRISPR/Cas9 successfully constructed a mouse ACE2-knockout (KO) model (Figure S1B–F). ACE2-KO exacerbated behavioural impairment in mice following TBI (Figure S1H–N).</p><p>Pyroptosis, a recently identified form of inflammatory cell death, has been linked to various central nervous system disorders, including TBI.<span><sup>2, 3</sup></span> To investigate the impact of ACE2 depletion on TBI progression, transcriptome sequencing was performed, revealing 385 upregulated and 74 downregulated genes (Figure 2A). Enrichment analysis of these differentially expressed genes using Reactome highlighted the pyroptosis pathway (Figure 2B), with significant changes observed in pyroptosis-related factors such as Gsdmd, Casp1, Il18rap and illr2. The quantitative reverse transcriptase PCR (qRT-PCR) validation confirmed the upregulation of messenger ribonucleic acid levels for this pyroptosis (Figure S2C). Protein imprinting assessments revealed that ACE2 deletion exacerbated the activation of key pyroptosis factors GSDMD and CASP1 (Figure 2C–E), findings further supported by immunofluoresce","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906612","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":"Mesoscopic connectome enters the new age of single-neuron projectome","authors":"Ning Li, Hua He, Chun Xu","doi":"10.1002/ctm2.70155","DOIUrl":"10.1002/ctm2.70155","url":null,"abstract":"<p>The brain area hippocampus has come into the stage centre of neuroscience since the landmark study of Henry Molaison, who lost recent memories and the capability of forming new memories after the extirpation of his medial temporal lobe for epilepsy treatment.<span><sup>1</sup></span> Since then, a growing body of research has elucidated the hippocampal functions in learning and memory,<span><sup>1</sup></span> spatial cognition,<span><sup>2</sup></span> stress responses<span><sup>3</sup></span> and emotional behaviors.<span><sup>4</sup></span> The core circuits within the hippocampal formation comprise a series of unidirectionally connected subregions including dentate gyrus (DG), <i>cornu ammonis</i> subfields (CA3 and CA1), and subicular complex.<span><sup>5, 6</sup></span> While this basic intrinsic circuity is maintained throughout from the septal (dorsal) to the temporal (ventral) axis in rodents (corresponding to the posterior-anterior axis in primates), the dorsal and ventral hippocampus (dHC and vHC) have distinct connectivity with cortical and subcortical areas and thereby exhibit disparate physiological functions.<span><sup>7-10</sup></span></p><p>In rodents, the dHC represents the “cold” hippocampus for spatial cognition and episodic memory, the vHC stands for the “hot” hippocampus for the emotion and stress responses.<span><sup>7</sup></span> The functional diversity of vHC is underscored by its axon projections to various downstream targets, as exemplified by the projection to the nucleus accumbens (NAc) for drug-induced place preference<span><sup>11</sup></span> and social memory,<span><sup>12</sup></span> the projection to the amygdala (Amy) for contextual fear conditioning,<span><sup>13</sup></span> the projection to lateral septum for feeding,<span><sup>14</sup></span> the projection to medial prefrontal cortex (mPFC) for anxiety,<span><sup>15</sup></span> social interaction<span><sup>16</sup></span> and spatial navigation,<span><sup>17</sup></span> and the projection to lateral hypothalamus for anxiety.<span><sup>18</sup></span> Thus, different subgroups of vHC neurons are defined by their axon projections to individual downstream targets (Figure 1A) and are hypothesized to underlie diverse functions closely related to these targets.<span><sup>19</sup></span> However, this view has been challenged by the fact that many vHC neurons sent co-projecting axons to multiple brain areas and engaged differently in behavioural functions. For instance, vHC neurons projecting to mPFC and Amy exhibited distinct functions in fear extinction compared to those projecting to either mPFC or Amy.<span><sup>20</sup></span> Ciocchi et al.<span><sup>15</sup></span> showed that vHC neurons projecting to mPFC and NAc were activated by goal-related behaviours, whereas vHC neurons that had triple projections to mPFC, NAc and Amy were activated by sharp wave/ripples. Furthermore, Chen et al.<span><sup>21</sup></span> reported that vHC neurons projectin","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11685600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906616","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":"Concurrent DNA hypomethylation and epigenomic reprogramming driven by androgen receptor binding in bladder cancer oncogenesis","authors":"Yu Xiao, Lingao Ju, Wan Jin, Hongwei Peng, Zongning Zhou, Mengxue Yu, Zilin Xu, Gang Wang, Kaiyu Qian, Yi Zhang, Xinghuan Wang","doi":"10.1002/ctm2.70153","DOIUrl":"10.1002/ctm2.70153","url":null,"abstract":"<p>The intratumor heterogeneity (ITH) of bladder cancer (BLCA) facilitates resistance to treatment and enables evasion of immune surveillance, directly impacting patient outcomes and clinical prognosis. Our group has newly developed a tool named EpiTrace, which enables tracking single-cell (sc) evolution via chromatin accessibility<span><sup>1</sup></span> and reveals the ITH of bladder cancer in all stages.<span><sup>2</sup></span> We also found that the TM4SF1-positive cancer subpopulation (TPCS) drives ITH diversification in BLCA via integrative single-cell atlas analysis.<span><sup>2</sup></span></p><p>Previous data suggest that Notch signalling might contribute to urothelium cell lineage specification.<span><sup>2</sup></span> Compared with that in normal urothelium cells and other cancer cells, the RNA expression of HES1 and HES4, effectors of Notch signalling, at the single-cell level is significantly lower in TPCS.<span><sup>2</sup></span> As ASCL1/2 expression is difficult to assess via single-cell RNA sequencing because of the low expression abundance resulting from the repression of the Notch signal, we used single-cell assay for transposase-accessible chromatin (scATAC) data to infer their transcriptional activity. Compared with those in other cells, scATAC-inferred HES1 and HES4 expression levels were decreased in TPCS. In contrast, ASCL1 and ASCL2 transcription factors (TFs) activities are increased in TPCS without apparent transcriptional upregulation (Figure 1A), suggesting derepression of ASCL1/2 from HES1/4. In accordance with the results of the cell-cell signalling analysis and coregulated transcription network activity, SMAD4 transcription activity was increased, whereas its RNA level did not change (Figure 1A). A change in transcription factor activity was also noted for other TFs, including FOXA1 (Figure 1A and Figures S1 and S2).</p><p>Elucidating the underlying molecular mechanisms for HES1 and HES4 repression requires the interrogation of the epigenetic information of both TPCS-like and less malignant cancer cells. FOXA1 is known to be a master pioneering factor that is differentially expressed in muscle-invasive bladder cancer (MIBC) downstream of BMP signalling and determines tumour phenotype.<span><sup>3</sup></span> In prostate cancer, androgen receptor (AR) directly interacts with FOXA1, driving cancer growth and survival.<span><sup>4</sup></span> BLCA incidence is 3–4 times higher in males<span><sup>5, 6</sup></span>; however, when diagnosed with BLCA, women tend to present with more advanced disease stages compared to men, resulting in poorer treatment outcomes and higher mortality rates.<span><sup>7, 8</sup></span> Emerging research suggests that AR may facilitate the occurrence, progression, and recurrence of BLCA, potentially leading to the observed sex disparities.<span><sup>9</sup></span> Therefore, we investigated how FOXA1 and AR binding epigenetically reprograms enhancers in BLCA epigenetically reprograms e","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11681005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892444","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":"Revealing the heterogeneity of treatment resistance in less-defined subtype diffuse large B cell lymphoma patients by integrating programmed cell death patterns and liquid biopsy","authors":"Wei Hua,&nbsp;Jie Liu,&nbsp;Yue Li,&nbsp;Hua Yin,&nbsp;Hao-Rui Shen,&nbsp;Jia-Zhu Wu,&nbsp;Yi-Lin Kong,&nbsp;Bi-Hui Pan,&nbsp;Jun-Heng Liang,&nbsp;Li Wang,&nbsp;Jian-Yong Li,&nbsp;Rui Gao,&nbsp;Jin-Hua Liang,&nbsp;Wei Xu","doi":"10.1002/ctm2.70150","DOIUrl":"10.1002/ctm2.70150","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Precision medicine in less-defined subtype diffuse large B-cell lymphoma (DLBCL) remains a challenge due to the heterogeneous nature of the disease. Programmed cell death (PCD) pathways are crucial in the advancement of lymphoma and serve as significant prognostic markers for individuals afflicted with lymphoid cancers. To identify robust prognostic biomarkers that can guide personalized management for less-defined subtype DLBCL patients, we integrated multi-omics data derived from 339 standard R-CHOP-treated patients diagnosed with less-defined subtype DLBCL from three independent cohorts. By employing various machine learning algorithms, we pinpointed eight pivotal genes linked to PCD, specifically FLT3, SORL1, CD8A, BCL2L1, COL13A1, MPG, DYRK2 and CAMK2B. Following this, we established a Programmed Cell Death Index (PCDI) utilizing the aforementioned genes and amalgamated it with pertinent clinical characteristics to formulate a predictive nomogram model for prognosis. We observed a significant correlation between the PCDI, pre-treatment circulating tumour DNA (ctDNA) burden, minimal residual disease (MRD) status and immune features. Furthermore, our research indicated that patients with elevated PCDI scores could potentially show resistance to conventional chemotherapy treatments, yet they might derive an advantage from alternative inhibitors targeting specific signalling pathways. Conclusively, leveraging these results, we have created an online analytical tool (https://xulymphoma.shinyapps.io/PCDI_pred/) designed for the prognostic prediction of patients with less-defined subtype DLBCL. This tool facilitates the forecasting of outcomes for these patients, enhancing the precision of their clinical management.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Developing the Programmed Cell Death Index (PCDI) utilizing multiple machine learning algorithms for patients with less-defined subtype diffuse large B-cell lymphoma.</li>\u0000 \u0000 <li>The difference in clinical characteristics, circulating tumour DNA burden and immune profiling between patients with distinct PCDI groups.</li>\u0000 \u0000 <li>A potentially effective regimen was speculated for patients with high PCDI scores who tend to exhibit worse progression-free survival.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11680560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892458","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":"Erratum for the research article “The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super-enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis-generating study” by Huang et al","authors":"Lei Huang,&nbsp;Hui Yang,&nbsp;Kaidi Chen,&nbsp;Jing Yuan,&nbsp;Jie Li,&nbsp;Guanghai Dai,&nbsp;Mancang Gu,&nbsp;Yan Shi","doi":"10.1002/ctm2.70158","DOIUrl":"10.1002/ctm2.70158","url":null,"abstract":"<p>Some inadvertent mistake in our paper entitled “The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super-enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis-generating study” ^[<span>¹</span>^] and published in <i>Clinical and translational medicine</i> came to our attention recently:</p><p>(1) There was an unintentional mistake in the placement and assembly of representative individual bioluminescence images in the original Figure 2A, which does not impact the statistical analysis, the described findings, or the conclusions. We would like to correct the representative individual bioluminescence image in the red block of the original Figure 2A as (Figure 1):</p><p>(2) There was an unintentional mistake in loading control band placement in Western blot, which does not influence the described findings or the conclusions. We would like to correct the loading control GAPDH in the red block of the original Figure 1I as (Figure 2).</p><p>And correct the loading control GAPDH in the red block of the original Figure 5C and E as (Figure 3):</p><p>The corrections do not have any impact on the described findings, the conclusions, or any other part of the manuscript. We sincerely apologize for any inconvenience caused.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11680547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892451","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":"Deficiency of ATF3 facilitates both angiotensin II-induced and spontaneously formed aortic aneurysm and dissection development by activating cGAS–STING pathway","authors":"Yifan Du,&nbsp;Poyi Hu,&nbsp;Xiangchao Ding,&nbsp;Dashuai Wang,&nbsp;Jingjing Luo,&nbsp;Sheng Le,&nbsp;Lingyun Ren,&nbsp;Manhua Chen,&nbsp;Ping Ye,&nbsp;Jiahong Xia","doi":"10.1002/ctm2.70147","DOIUrl":"10.1002/ctm2.70147","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;Sporadic aortic aneurysm and dissection (AAD) is a critical condition characterised by the progressive loss of vascular smooth muscle cells (VSMCs) and the breakdown of the extracellular matrix. However, the molecular mechanisms responsible for the phenotypic switch and loss of VSMCs in AAD are not fully understood.&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 this study, we employed a discovery-driven, unbiased approach. This approach encourages us to explore the unknown functions of activating transcription factor 3 (ATF3) rather than merely confirming existing hypotheses, while no assumptions were made about ATF3 prior to the experiments. We ensured the unbiased nature of our assessment by conducting morphological evaluations with two independent observers in a blinded manner. We identified elevated expression of ATF3 in both human sporadic AAD tissues and mouse AAD models. VSMC-specific ATF3 conditional knockout (Atf3 cKO) mice showed notable enlargement, dissection and rupture in both thoracic and abdominal aortic regions after exposure to Ang II. Interestingly, older Atf3 cKO mice exhibited spontaneous aortic dissections and senescence of the aortic wall. Mechanistically, ATF3 deficiency led to the degradation of P21 through ubiquitination. Impaired DNA repair in VSMCs resulted in micronuclei formation in the cytoplasm, activating the  cyclicGMP-AMP synthase- stimulator of interferon genes (cGAS–STING) pathway and inducing VSMC phenotypic switching and apoptosis. Finally, both pharmacological complementation of P21 function and knockdown of STING expression alleviated ATF3 deficiency-induced AAD.&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;Our study indicates that ATF3 is essential for genomic DNA stability in VSMCs through the P21–cGAS–STING pathway, suggesting that enhancing ATF3 expression in VSMCs could help prevent sporadic AAD.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;ATF3 deficiency led to degradation of P21 through ubiquitination, which abolished the G1 phase arrest.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;VSMCs had no time window to repair the damaged DNA, leading to generation of micronuclei in cytoplasm.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;Cytoplasmic micronuclei facilitating the activation of cGAS–STING pathway, thus induci","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11680558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892447","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":"The antiarthritic effect of CBR-470-1 in hypoxic environment is to increase the level of NOD-like receptor family pyrin domain containing 3 ubiquitination by decreasing phosphoglycerate kinase 1 activity","authors":"Ao Duan,&nbsp;Zemeng Ma,&nbsp;Xiaolong Shao,&nbsp;Zhencheng Xiong,&nbsp;Chaoyi Zhang,&nbsp;Wenzheng Liu,&nbsp;Guanglin Wang,&nbsp;Shouye Hu,&nbsp;Wei Lin","doi":"10.1002/ctm2.70118","DOIUrl":"10.1002/ctm2.70118","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;Hypoxia can affect the occurrence and development of inflammation in humans, but its effects on the disease progression of osteoarthritis (OA) remain unclear. Synovial macrophages play an essential role in the progression of arthritis. Specifically, the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) in macrophages induces the secretion of a series of inflammatory factors, accelerating the progression of OA.&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;The effects of CBR-470-1 were assessed in a mouse model of OA induced by destabilization of the medial meniscus (DMM) by micro-computed tomography imaging, Safranin-O and Fast Green staining, immunofluorescence staining and enzyme-linked immunosorbent assay. Western Blot analysis was used to explore the underlying mechanism of these experimental results. Additionally, a co-culture system of THP-1 and chondrocytes was established to investigate the impact of CBR-470-1 on chondrocyte proliferation, apoptosis, migration and the regulation of chondrocyte-related proteins within the system.&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;In hypoxic conditions, CBR-470-1 significantly inhibited the progression of OA in the DMM-induced OA mouse model, but that effect disappeared in the DMM-induced OA phosphoglycerate kinase 1 (PGK1)&lt;sup&gt;fl/fl&lt;/sup&gt;Lyz2-Cre mouse model. Not only that, CBR-470-1 can also improve the proliferation and migration of chondrocytes, reduce the apoptosis rate of chondrocytes, and regulate the expression of chondrocyte-related proteins in the co-culture system of THP-1 and chondrocytes.&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 conducted a series of in vitro and in vivo experiments, revealing that hypoxia plays a pro-inflammatory role by increasing PGK1 activity and reducing the binding of the deubiquitinating enzyme ubiquitin-specific peptidase 14 to NLRP3, thereby reducing the ubiquitination level of NLRP3. CBR-470-1, a specific inhibitor of PGK1, can reduce PGK1 activity to reverse the role of hypoxia in the progression of OA. These findings lay a foundation for the development of OA treatment in a hypoxic environment.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Hypoxia plays a pro-inflammatory role by increasing PGK1 activity and thereby decreasing the ubiquitination level of NLRP3.&lt;/li&gt;\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11680553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892465","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":"ZSH-2208: A novel retinoid with potent anti-tumour effects on ESCC stem cells via RARγ–TNFAIP3 axis","authors":"Ruoxue Chen,&nbsp;Xuan Huang,&nbsp;Jiayun Hou,&nbsp;Junjie Ni,&nbsp;Wenrui Zhao,&nbsp;Quanlin Li,&nbsp;Heng Jiao,&nbsp;Xin Cao","doi":"10.1002/ctm2.70148","DOIUrl":"10.1002/ctm2.70148","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Backgroud</h3>\u0000 \u0000 <p>Oesophageal cancer ranks among the most prevalent malignant tumours globally, primarily consisting of oesophageal squamous cell carcinoma (ESCC). Cancer stem cells (CSCs) accelerate the progression ESCC via their strong self-renewal and tumourigenic capabilities, presenting significant clinical challenges due to increased risks of recurrence and drug resistance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Our previous study has reported WYC-209, which is capable of inducing apoptosis of CSCs in melanoma and hepatoma, but is ineffective against ESCC. Additionally, clinical studies in ESCC still lack drug candidates that effectively target CSCs. Therefore, our team developed a series of novel retinoids that target retinoic acid receptors (RARs), with enhanced potency, broader efficacy and minimised toxic side effects against CSCs. Following iterative optimisation and pharmacological validation, ZSH-2208 was identified as the most promising candidate for effectively targeting ESCC tumour-repopulating cells (TRCs). Mechanistic exploration revealed that ZSH-2208 inhibits the growth of ESCC-TRCs through modulation of the RARγ–TNFAIP3 axis. The clinical significance of the key molecule TNFAIP3 in ESCC has also been demonstrated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This study introduces ZSH-2208, a novel retinoid specifically targeting ESCC-TRCs, which holds significant potential for clinical application in ESCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>The ESCC-TRCs replicates the characteristics of ESCC stem cells, which are inhibited by ZSH-2208.</p>\u0000 </li>\u0000 \u0000 <li>In vivo and in vitro experiments demonstrated that ZSH-2208, a novel RA analogue, effectively inhibits the growth of ESCC-TRCs through the RARγ–TNFAIP3 axis.</li>\u0000 \u0000 <li>\u0000 <p>Low levels of TNFIP3 protein may be associated with improved survival probability in ESCC patients.</p>\u0000 </li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892497","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":"Identification of metabolic dysregulation and biomarkers for clear cell renal cell carcinoma","authors":"Bin Zheng,&nbsp;Kan Liu,&nbsp;Qing Ouyang,&nbsp;Ji Feng,&nbsp;Shouqing Cao,&nbsp;Li Wang,&nbsp;Tongyu Jia,&nbsp;ShengPan Wu,&nbsp;Xin Ma,&nbsp;Xu Zhang,&nbsp;Xiubin Li","doi":"10.1002/ctm2.70142","DOIUrl":"10.1002/ctm2.70142","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Clear cell renal cell carcinoma (ccRCC) is the most common RCC histology and a metabolic disease characterized by reprogramming of energetic metabolism, enabling cancer cells to proliferate rapidly and survive.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Understanding these metabolic changes may provide opportunities for discovering biomarkers, improving tumour detection and developing new therapeutic strategies.&lt;/p&gt;&lt;p&gt;This study aimed to identify and validate metabolites as biomarkers to improve clinical diagnosis, facilitate risk stratification and predict prognosis in ccRCC. We used targeted metabolomics to screen for metabolic biomarkers and compared the differential metabolites between our data and other six published studies&lt;span&gt;&lt;sup&gt;2-6&lt;/sup&gt;&lt;/span&gt; (Table S1). Detailed information on metabolite measurement and methods is provided in the Supporting Information.&lt;/p&gt;&lt;p&gt;In our cohort, 90 tissues (30 from early patients, 30 from advanced patients and 30 from normal tissues) were collected from 60 ccRCC patients (Table S2). Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) analyses revealed a clear separation between the two groups (Figure S1A,B). The trend of quality control samples and permutated R2, and Q2 values indicated good analytical reproducibility and low risk of overfitting (Figure S1D,E). The differential analysis demonstrated that 163 metabolites (67 metabolites up-regulated and 96 metabolites down-regulated) from 23 distinct classes were significantly altered in tumour tissues (Figure 1A–F and Table S3). Then, we divided patients into early and advanced cohorts to perform differential analyses. The PCA and PLS-DA analyses showed distinct differences (Figure S1B,C). 79 metabolites were significantly different between early tumour and paired normal tissues (39 metabolites up-regulated and 40 metabolites down-regulated) (Figure 1G and Table S3), and 64 metabolites significantly distinguished advanced tumour from paired normal tissues (25 metabolites up-regulated and 39 metabolites down-regulated) (Figure 1H and Table S3). The pathway enrichment analysis of differential metabolites revealed eight intersected KEGG pathways. Two metabolic processes were substantially enriched in the early-stage cohort, while three processes were enriched in the advanced-stage cohort (Figure 1I,J and Table S4).&lt;/p&gt;&lt;p&gt;To understand the differences in metabolites between early and advanced stages, we used the unsupervised clustering analysis. Among early patients, two early clusters (A and B) were identified, and patients in early cluster A had the worst prognosis. Similarly, in the advanced cohort, we identified three advanced clusters (A, B and C) and found that patients in the advanced cluster B had the worst prognosis and patients in the advanced cluster C had a better prognosis (Figure 2A–D and Figure S1F–L). Then, we found elevated tryptophan and creatine in early-cluster B. Similarly, in advanced-cluster","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 12","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892442","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":"Intestinal oxygen utilisation and cellular adaptation during intestinal ischaemia–reperfusion injury","authors":"Paraschos Archontakis-Barakakis,&nbsp;Theodoros Mavridis,&nbsp;David-Dimitris Chlorogiannis,&nbsp;Georgios Barakakis,&nbsp;Eleni Laou,&nbsp;Daniel I. Sessler,&nbsp;George Gkiokas,&nbsp;Athanasios Chalkias","doi":"10.1002/ctm2.70136","DOIUrl":"10.1002/ctm2.70136","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The gastrointestinal tract can be deranged by ailments including sepsis, trauma and haemorrhage. Ischaemic injury provokes a common constellation of microscopic and macroscopic changes that, together with the paradoxical exacerbation of cellular dysfunction and death following restoration of blood flow, are collectively known as ischaemia–reperfusion injury (IRI). Although much of the gastrointestinal tract is normally hypoxemic, intestinal IRI results when there is inadequate oxygen availability due to poor supply (pathological hypoxia) or abnormal tissue oxygen use and metabolism (dysoxia). Intestinal oxygen uptake usually remains constant over a wide range of blood flows and pressures, with cellular function being substantively compromised when ischaemia leads to a &gt;50% decline in intestinal oxygen consumption. Restoration of perfusion and oxygenation provokes additional injury, resulting in mucosal damage and disruption of intestinal barrier function. The primary cellular mechanism for sensing hypoxia and for activating a cascade of cellular responses to mitigate the injury is a family of heterodimer proteins called hypoxia-inducible factors (HIFs). The HIF system is connected to numerous biochemical and immunologic pathways induced by IRI and the concentration of those proteins increases during hypoxia and dysoxia. Activation of the HIF system leads to augmented transcription of specific genes in various types of affected cells, but may also augment apoptotic and inflammatory processes, thus aggravating gut injury.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>During intestinal ischaemia, mitochondrial oxygen uptake is reduced when cellular oxygen partial pressure decreases to below the threshold required to maintain normal oxidative metabolism.</li>\u0000 \u0000 <li>Upon reperfusion, intestinal hypoxia may persist because microcirculatory flow remains impaired and/or because available oxygen is consumed by enzymes, intestinal cells and neutrophils.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892454","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}