Clinical and Translational Medicine最新文献

{"title":"Phosphoglycerate mutase 5 exacerbates alcoholic cardiomyopathy in male mice by inducing prohibitin-2 dephosphorylation and impairing mitochondrial quality control","authors":"Jun Tao,&nbsp;Junxiong Qiu,&nbsp;Junmeng Zheng,&nbsp;Ruibing Li,&nbsp;Xing Chang,&nbsp;Qingyong He","doi":"10.1002/ctm2.1806","DOIUrl":"10.1002/ctm2.1806","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The induction of mitochondrial quality control (MQC) mechanisms is essential for the re-establishment of mitochondrial homeostasis and cellular bioenergetics during periods of stress. Although MQC activation has cardioprotective effects in various cardiovascular diseases, its precise role and regulatory mechanisms in alcoholic cardiomyopathy (ACM) remain incompletely understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We explored whether two mitochondria-related proteins, phosphoglycerate mutase 5 (Pgam5) and prohibitin 2 (Phb2), influence MQC in male mice during ACM.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Myocardial Pgam5 expression was upregulated in a male mouse model of ACM. Notably, following ACM induction, heart dysfunction was markedly reversed in male cardiomyocyte-specific <i>Pgam5</i> knockout (<i>Pgam5^cKO</i>) mice. Meanwhile, in alcohol-treated male mouse-derived neonatal cardiomyocytes, <i>Pgam5</i> depletion preserved cell survival and restored mitochondrial dynamics, mitophagy, mitochondrial biogenesis and the mitochondrial unfolded protein response (mtUPR). We further found that in alcohol-treated cardiomyocyte, Pgam5 binds Phb2 and induces its dephosphorylation at Ser91. Alternative transduction of phospho-mimetic (Phb2^S91D) and phospho-defective (Phb2^S9A) Phb2 mutants attenuated and enhanced, respectively, alcohol-related mitochondrial dysfunction in cardiomyocytes. Moreover, transgenic male mice expressing <i>Phb2^S91D</i> were resistant to alcohol-induced heart dysfunction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We conclude that ACM-induced Pgam5 upregulation results in Pgam5-dependent Phb2^S91 dephosphorylation, leading to MQC destabilisation and mitochondrial dysfunction in heart. Therefore, modulating the Pgam5/Phb2 interaction could potentially offer a novel therapeutic strategy for ACM in male mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li><i>Pgam5</i> knockout attenuates alcohol-induced cardiac histopathology and heart dysfunction in male mice.</li>\u0000 \u0000 <li><i>Pgam5</i> KO reduces alcohol-induced myocardial inflammation, lipid peroxidation and metabolic dysfunction in male mice.</li>\u0000 \u0000 <li>Pgam5 depletion protects mitochondrial function in alcohol-ex","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1806","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981849","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":"HSP47 in human diseases: Navigating pathophysiology, diagnosis and therapy","authors":"Essak. S. Khan,&nbsp;Tobias Däinghaus","doi":"10.1002/ctm2.1755","DOIUrl":"10.1002/ctm2.1755","url":null,"abstract":"<p>Heat shock protein 47 (HSP47) is a chaperone protein responsible for regulating collagen maturation and transport, directly impacting collagen synthesis levels. Aberrant HSP47 expression or malfunction has been associated with collagen-related disorders, most notably fibrosis. Recent reports have uncovered new functions of HSP47 in various cellular processes. Hsp47 dysregulation in these alternative roles has been linked to various diseases, such as cancer, autoimmune and neurodegenerative disorders, thereby highlighting its potential as both a diagnostic biomarker and a therapeutic target. In this review, we discuss the pathophysiological roles of HSP47 in human diseases, its potential as a diagnostic tool, clinical screening techniques and its role as a target for therapeutic interventions.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1755","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970740","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 YTH domain-containing protein family: Emerging players in immunomodulation and tumour immunotherapy targets","authors":"Fenghe Li,&nbsp;Chong Zeng,&nbsp;Jie Liu,&nbsp;Lei Wang,&nbsp;Xiaorui Yuan,&nbsp;Li Yuan,&nbsp;Xiaomeng Xia,&nbsp;Wei Huang","doi":"10.1002/ctm2.1784","DOIUrl":"10.1002/ctm2.1784","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The modification of N6-methyladenosine (m6A) plays a pivotal role in tumor by altering both innate and adaptive immune systems through various pathways, including the regulation of messenger RNA. The YTH domain protein family, acting as “readers” of m6A modifications, affects RNA splicing, stability, and immunogenicity, thereby playing essential roles in immune regulation and antitumor immunity. Despite their significance, the impact of the YTH domain protein family on tumor initiation and progression, as well as their involvement in tumor immune regulation and therapy, remains underexplored and lacks comprehensive review.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This review introduces the molecular characteristics of the YTH domain protein family and their physiological and pathological roles in biological behavior, emphasizing their mechanisms in regulating immune responses and antitumor immunity. Additionally, the review discusses the roles of the YTH domain protein family in immune-related diseases and tumor resistance, highlighting that abnormal expression or dysfunction of YTH proteins is closely linked to tumor resistance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>This review provides an in-depth understanding of the YTH domain protein family in immune regulation and antitumor immunity, suggesting new strategies and directions for immunotherapy of related diseases.</li>\u0000 \u0000 <li>These insights not only deepen our comprehension of m6A modifications and YTH protein functions but also pave the way for future research and clinical applications.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1784","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970741","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":"Oseltamivir (Tamiflu), a commonly prescribed antiviral drug, mitigates hearing loss in mice","authors":"Emma J. Sailor-Longsworth,&nbsp;Richard D. Lutze,&nbsp;Matthew A. Ingersoll,&nbsp;Regina G. Kelmann,&nbsp;Kristina Ly,&nbsp;Duane Currier,&nbsp;Taosheng Chen,&nbsp;Jian Zuo,&nbsp;Tal Teitz","doi":"10.1002/ctm2.1803","DOIUrl":"10.1002/ctm2.1803","url":null,"abstract":"<p>Dear Editor,</p><p>Hearing loss affects up to 10% of people worldwide and therapeutic interventions are desperately needed. Noise exposure and chemotherapy treatments are leading causes of this impairment, but currently there is only one FDA-approved drug for a subgroup of cisplatin-treated cancer patients.<span>^{1, 2}</span> Hearing loss can arise from damage to many different inner ear cell types with outer hair cell (OHC) and synaptic dysfunction as two of the most common aetiologies of hearing loss.<span>^2-4</span> Drug repurposing is a strategy for addressing unmet medical needs that can be quicker and more cost-effective than traditional drug development.<span>³</span> Here, we performed unbiased cell-based screens of 1300 FDA-approved drugs and tested our top candidate oseltamivir phosphate (brand name Tamiflu), a common influenza antiviral drug, in established cisplatin- and noise-induced hearing loss animal models. Our results support oseltamivir as a promising otoprotective therapeutic candidate for both cisplatin chemotherapy and traumatic noise exposure.</p><p>Oseltamivir phosphate and its active form, oseltamivir carboxylate, protect against cisplatin-induced hair cell loss in mouse cochlear explants without interfering with cisplatin's tumour killing efficacy in tumour cell lines. The prodrug, oseltamivir phosphate, tested at a dose of 3 µM, was a top hit in high-throughput screens reducing 95% of the caspase-3/7 cell death activity of cisplatin-treated cells.<span>^{3, 4}</span> In mouse P3 cochlear explants, the prodrug, oseltamivir phosphate, protected from cisplatin-induced OHC death with an EC₅₀ of 450 nM (Figure 1A,D), while the active antiviral drug, oseltamivir carboxylate (Figure 1B), had a similar EC₅₀ of 505 nM (Figure 1C,E). Importantly, oseltamivir cotreatment in three small cell lung carcinoma and three neuroblastoma cell lines did not interfere with cisplatin's ability to kill tumour cells (Figure 1F–K).</p><p>Oseltamivir protects mice from cisplatin ototoxicity after a single, high dose of cisplatin and in a clinically relevant, multicycle cisplatin protocol. Adult FVB/NJ mice were treated orally with 50 mg/kg oseltamivir phosphate, 45 min before one dose of 30 mg/kg cisplatin (Figure 2A). We measured auditory brainstem response (ABR) as a test of hearing function. ABR measures nerve electrical activities from the cochleae to the brain. The ABR threshold is the lowest decibel sound pressure level (dB SPL) an animal can hear at. Mice cotreated with oseltamivir and cisplatin had 15 dB lower ABR threshold shifts at the 32 kHz region and displayed reduction in OHC death at the middle and basal cochlear regions compared to cisplatin-treated mice (Figure 2B–E). Utilising a clinically relevant multicycle cisplatin mouse model that mimics cisplatin treatment in humans (Figure 2F),<span>^4-6</span> mice were treated orally with 50, 10 or 2 mg/kg oseltam","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1803","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916221","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":"Potential pharmaceuticals targeting neuroimmune interactions in treating acute lung injury","authors":"Di Wu,&nbsp;Ximing Liao,&nbsp;Jing Gao,&nbsp;Yixuan Gao,&nbsp;Qiang Li,&nbsp;Wei Gao","doi":"10.1002/ctm2.1808","DOIUrl":"10.1002/ctm2.1808","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and main body</h3>\u0000 \u0000 <p>Although interactions between the nervous and immune systems have been recognized decades ago, it has become increasingly appreciated that neuroimmune crosstalk is among the driving factors of multiple pulmonary inflammatory diseases including acute lung injury (ALI). Here, we review the current understanding of nerve innervations towards the lung and summarize how the neural regulation of immunity and inflammation participates in the onset and progression of several lung diseases, especially ALI. We then present advancements in the development of potential drugs for ALI targeting neuroimmune interactions, including cholinergic anti-inflammatory pathway, sympathetic-immune pathway, purinergic signalling, neuropeptides and renin-angiotensin system at different stages from preclinical investigation to clinical trials, including the traditional Chinese medicine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This review highlights the importance of considering the therapeutic strategy of inflammatory diseases within a conceptual framework that integrates classical inflammatory cascade and neuroimmune circuits, so as to deepen the understanding of immune modulation and develop more sophisticated approaches to treat lung diseases represented by ALI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>The lungs present abundant nerve innervations.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Neuroimmune interactions exert a modulatory effect in the onset and progression of lung inflammatory diseases, especially acute lung injury.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>The advancements of potential drugs for ALI targeting neuroimmune crosstalk at different stages from preclinical investigation to clinical trials are elaborated.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Point out the direction for the development of neuroimmune pharmacology in the future.</p>\u0000 </li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1808","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916222","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":"Whole genome doubling in adenomyosis","authors":"Xiaopei Chao,&nbsp;Xiaojing Chen,&nbsp;Haiqi Su,&nbsp;Xiao Shang,&nbsp;Huanwen Wu,&nbsp;Yan You,&nbsp;Siqi Wang,&nbsp;Hui Li,&nbsp;Zhenzhen Li,&nbsp;Lan Zhu,&nbsp;Jiayan Wu,&nbsp;Jinghe Lang,&nbsp;Lei Li","doi":"10.1002/ctm2.1809","DOIUrl":"10.1002/ctm2.1809","url":null,"abstract":"<p>Whole genome doubling (WGD) was found to be associated with an early onset of the disease and a higher response rate to endocrine therapy among adenomyosis (AM) patients. The clinical manifestation could not be explained by commonly found driver genes in AM and endometriosis (EM).</p><p>AM is one of the most common benign gynecologic diseases. The prevalence of AM has been estimated to range from 5% to 70%,<span>^1-3</span> with the highest incidence observed in women in their 40s.<span>^{4, 5}</span> Despite various conservative treatment regimens for preserving fertility in women with AM.<span>^{6, 7}</span> Currently there are no reliable strategies for predicting its occurrence and exacerbation. WGD events are defined if the ploidy of the major allele exceeds 1.5 on at least 50% of at least 11 autosomes.<span>⁸</span> While WGD events have been extensively explored in tumorigenesis, metastasis, treatment, and prognosis of solid tumours, little is known about WGD in the context of AM. Thus, the aims of this study are to analyze the genomic and transcriptomic characteristics of eutopic and ectopic endometrium harvested from patients with AM and EM.</p><p>This study included a total of 79 AM patients, 22 EM patients and 20 controls (Tables S1–S3). Fresh samples of endometrium, AM lesions, and EM lesions were obtained using aseptic procedures. Paired peripheral blood samples were collected preoperatively within one day before surgery and anaesthesia. Tissue samples were sent for whole exome sequencing (WES) analysis, RNA-sequencing, and pathological evaluation to ensure accurate histological diagnosis. The analysis of allele-specific DNA copy number was used to determine the WGD status. B-allele frequency values (BAF) and log <i>R</i> values were calculated based on read coverage and GC content in the same region of different specimen types. Ploidy levels were interpreted from BAF and log <i>R</i> values using the ASCAT software.<span>⁹</span> WGD was detected in 33 samples from 29 patients (Figure 1A,B). The median ploidy was 3.9 (range: 3.3–4.6) in WGD samples, compared to 2.0 (range: 1.9–2.4) in non-WGD samples (Wilcoxon rank sum test, <i>p </i>&lt; 2.2e-16, Figure 1C, Table S4). Ploidy levels for each autosome were determined based on the criteria of major allele ploidy being greater than 1.5 on at least 50% of at least 11 autosomes<span>⁸</span> (Figure 1D). WGD samples showed a significantly higher proportion of the genome subject to loss of heterozygosity (LOH) compared to non-WGD samples (<i>p </i>= 1.5e-06, Figure 1E), as well as a significantly lower proportion of the genome subject to haploid LOH in WGD samples (<i>p </i>= 6.8e-08, Figure 1E). However, within the specific histological types, the distribution of LOH varied without consistent differences (Figure S1).</p><p>The distribution of WGD events in AM patients, EM patients, and controls was similar (<i>p </i>= .781, Fi","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1809","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916223","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":"Macrophage OTUD1-CARD9 axis drives isoproterenol-induced inflammatory heart remodelling","authors":"Jinfu Qian,&nbsp;Qinyan Wang,&nbsp;Jiachen Xu,&nbsp;Shiqi Liang,&nbsp;Qingsong Zheng,&nbsp;Xiaocheng Guo,&nbsp;Wu Luo,&nbsp;Weijian Huang,&nbsp;Xiaohong Long,&nbsp;Julian Min,&nbsp;Yi Wang,&nbsp;Gaojun Wu,&nbsp;Guang Liang","doi":"10.1002/ctm2.1790","DOIUrl":"10.1002/ctm2.1790","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chronic inflammation contributes to the progression of isoproterenol (ISO)-induced heart failure (HF). Caspase-associated recruitment domain (CARD) families are crucial proteins for initiation of inflammation in innate immunity. Nonetheless, the relevance of CARDs in ISO-driven cardiac remodelling is little explored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study utilized Card9^−/− mice and reconstituted C57BL/6 mice with either Card9^−/− or Otud1^−/− marrow-derived cells. Mechanistic studies were conducted in primary macrophages, cardiomyocytes, fibroblasts and HEK-293T cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Here, we demonstrated that CARD9 was substantially upregulated in murine hearts infused with ISO. Either whole-body CARD9 knockout or myeloid-specific CARD9 deletion inhibited ISO-driven murine cardiac inflammation, remodelling and dysfunction. CARD9 deficiency in macrophages prevented ISO-induced inflammation and alleviated remodelling changes in cardiomyocytes and fibroblasts. Mechanistically, we found that ISO enhances the activity of CARD9 by upregulating ovarian tumour deubiquitinase 1 (OTUD1) in macrophages. We further demonstrated that OTUD1 directly binds to the CARD9 and then removes the K33-linked ubiquitin from CARD9 to promote the assembly of the CARD9-BCL10-MALT1 (CBM) complex, without affecting CARD9 stability. The ISO-activated CBM complex results in NF-κB activation and macrophage-based inflammatory gene overproduction, which then enhances cardiomyocyte hypertrophy and fibroblast fibrosis, respectively. Myeloid-specific OTUD1 deletion also attenuated ISO-induced murine cardiac inflammation and remodelling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These results suggested that the OTUD1-CARD9 axis is a new pro-inflammatory signal in ISO-challenged macrophages and targeting this axis has a protective effect against ISO-induced HF.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Macrophage CARD9 was elevated in heart tissues of mice under chronic ISO administration.</li>\u0000 \u0000 <li>Either whole-body CARD9 knockout or myeloid-specific CARD9 deficiency protected mice from ISO-induced inflammatory heart remodeling.</li>\u0000 \u0000 <li>ISO promoted the assembly of CBM complex and then activated ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11310286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906063","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":"Metastasis-enhancing protein KITENIN confers temozolomide resistance on glioblastoma with unmethylated MGMT via upregulation of cancer stem cell makers","authors":"Eun-Jung Ahn,&nbsp;Yeong Jin Kim,&nbsp;Md Rashedunnabi Akanda,&nbsp;Se-Jeong Oh,&nbsp;Tae-Young Jung,&nbsp;Shin Jung,&nbsp;Jae-Hyuk Lee,&nbsp;Sung Sun Kim,&nbsp;Yong Yeon Jeong,&nbsp;Hyung-Ho Ha,&nbsp;Hoon Hyun,&nbsp;Hangun Kim,&nbsp;Joon Haeng Rhee,&nbsp;Kyung Keun Kim,&nbsp;Kyung-Hwa Lee,&nbsp;Kyung-Sub Moon","doi":"10.1002/ctm2.1804","DOIUrl":"10.1002/ctm2.1804","url":null,"abstract":"<p>Dear Editor,</p><p>Temozolomide (TMZ) is a key chemotherapeutic agent for glioblastoma (GBM), but resistance to TMZ and genetic heterogeneity pose significant challenges. Particularly, unmethylated MGMT promoter (<i>un</i>methyl-MGMT) status has been identified as a poor prognostic indicator for the survival of GBM patients.<span>¹</span> While MGMT promoter methylation status has been traditionally linked to TMZ resistance, recent research points to additional factors. Cancer stem cells (CSCs) may contribute to chemo-/radio resistance in GBM by enhancing DNA response mechanisms.<span>²</span> Among CSC markers, aldehyde dehydrogenase 1A1 (ALDH1A1) and CD44 are associated with oncogenic capacity, stemness preservation and therapeutic resistance.<span>^{3, 4}</span> KAI1 COOH-terminal interacting tetraspanin (KITENIN), a glycoprotein implicated in tumour progression and metastasis across various cancers,<span>⁵</span> has been linked to GBM progression, through epithelial–mesenchymal transition (EMT) and CSC factors.<span>⁶</span> Current study proposes that KITENIN promotes TMZ resistance by inducing CSC markers CD44 and ALDH1A1 in GBM with <i>un</i>methyl-MGMT.</p><p>To investigate the connection between KITENIN and CSC markers in GBM, we analysed human GBM samples and KITENIN-modulated GBM cells. Immunohistochemistry (IHC) analysis of human GBM samples revealed a significant correlation between high KITENIN expression and increased CSC marker expression (Figure 1A). This observation was corroborated by Western blot analysis, which demonstrated co-directional expression of ALDH1A1 and KITENIN (Figure S1A). Further investigation using stable KITENIN-modulated GBM cells showed that KITENIN knockdown in U251 cells led to downregulation of ALDH1A1, CD44 and CD133, while KITENIN overexpression in GL261 cells resulted in their upregulation (Figure 1B). To validate these results, we examined primary GBM cells with varying KITENIN expression levels (Figure 1C,D). Cells with high KITENIN expression (GBM no. 8) exhibited upregulation of both CSC and EMT markers compared to those with low KITENIN expression (GBM no. 6; Figure 1E). This observation was further substantiated through double immunofluorescence staining of GBM paraffin sections (Figure 1F). KITENIN-<i>si</i> treatment significantly reduced the expression of CSC (Figure 1G) and EMT (Figure S1B) markers in primary GBM cells (no. 8) and stable KITENIN-overexpressed GL261 cells, reinforcing the link between KITENIN and these markers.</p><p>To further explore this connection, we employed the lichen substrate usnic acid (UA), a known KITENIN inhibitor.<span>⁷</span> UA treatment resulted in significant reduction of KITENIN, ALDH1A1 and CD44 expression (Figure 1H), accompanied by decreased sphere-/colony-forming abilities (Figure 1I,J). Moreover, UA inhibited invasion and migration through reducing EMT factors, even at low doses (Figure","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11310266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906064","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":"Single-cell sequencing combined with spatial transcriptomics reveals that the IRF7 gene in M1 macrophages inhibits the occurrence of pancreatic cancer by regulating lipid metabolism-related mechanisms","authors":"Ting Zhan,&nbsp;Yanli Zou,&nbsp;Zheng Han,&nbsp;XiaoRong Tian,&nbsp;Mengge Chen,&nbsp;Jiaxi Liu,&nbsp;Xiulin Yang,&nbsp;Qingxi Zhu,&nbsp;Meng Liu,&nbsp;Wei Chen,&nbsp;Mingtao Chen,&nbsp;Xiaodong Huang,&nbsp;Jie Tan,&nbsp;Weijie Liu,&nbsp;Xia Tian","doi":"10.1002/ctm2.1799","DOIUrl":"10.1002/ctm2.1799","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The main focus of this study is to explore the molecular mechanism of IRF7 regulation on RPS18 transcription in M1-type macrophages in pancreatic adenocarcinoma (PAAD) tissue, as well as the transfer of RPS18 by IRF7 via exosomes to PAAD cells and the regulation of ILF3 expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>By utilising single-cell RNA sequencing (scRNA-seq) data and spatial transcriptomics (ST) data from the Gene Expression Omnibus database, we identified distinct cell types with significant expression differences in PAAD tissue. Among these cell types, we identified those closely associated with lipid metabolism. The differentially expressed genes within these cell types were analysed, and target genes relevant to prognosis were identified. Flow cytometry was employed to assess the expression levels of target genes in M1 and M2 macrophages. Cell lines with target gene knockout were constructed using CRISPR/Cas9 editing technology, and cell lines with target gene knockdown and overexpression were established using lentiviral vectors. Additionally, a co-culture model of exosomes derived from M1 macrophages with PAAD cells was developed. The impact of M1 macrophage-derived exosomes on the lipid metabolism of PAAD cells in the model was evaluated through metabolomics analysis. The effects of M1 macrophage-derived exosomes on the viability, proliferation, division, migration and apoptosis of PAAD cells were assessed using MTT assay, flow cytometry, EdU assay, wound healing assay, Transwell assay and TUNEL staining. Furthermore, a mouse PAAD orthotopic implantation model was established, and bioluminescence imaging was utilised to assess the influence of M1 macrophage-derived exosomes on the intratumoural formation capacity of PAAD cells, as well as measuring tumour weight and volume. The expression of proliferation-associated proteins in tumour tissues was examined using immunohistochemistry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Through combined analysis of scRNA-seq and ST technologies, we discovered a close association between M1 macrophages in PAAD samples and lipid metabolism signals, as well as a negative correlation between M1 macrophages and cancer cells. The construction of a prognostic risk score model identified RPS18 and IRF7 as two prognostically relevant genes in M1 macrophages, exhibiting negative and positive correlations, respectively. Mechanistically, it was found that IRF7 in M1 macrophages can inhibit the transcription of RPS18, reducing the transfer of RPS18 to PAAD cells via exosomes, consequently affecting the expression of ILF3 in PAAD cells. IRF7/RPS18 in M1 macropha","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11310283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906065","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 article “Cullin-associated and neddylation-dissociated 1 regulate reprogramming of lipid metabolism through SKP1-Cullin-1-F-boxFBXO11 -mediated heterogeneous nuclear ribonucleoprotein A2/B1 ubiquitination and promote hepatocellular carcinoma” by Zhang H et al.","authors":"","doi":"10.1002/ctm2.1805","DOIUrl":"10.1002/ctm2.1805","url":null,"abstract":"<p>The authors acknowledge an error in the presentation of Oil Red staining images of liver cancer tissue in the AAV-shCAND1 group within the mouse primary liver cancer model in Figure. 8I. Figure 8I mistakenly displayed images from the AAV-shCAND1 group of the PDX model, rather than the intended primary liver cancer model.</p><p><b>Original Version</b>:</p><p><b>Description</b>:</p><p>To test the strategy, we also used a myr-AKT/NRASV12-induced mouse liver cancer model, which had abnormal lipid metabolism. The mice injected with AAV-shCAND1 had decreased tumor sizes and reduced lipid accumulation compared to the control mice. Intratumoral injection of AAV-shCAND1 decreased CAND1, hnRNPA2B1, FASN, ACC1, ACLY, and lipid accumulation (Figure 8I).</p><p><b>Picture of the original version</b> Figure 8 <b>with red block</b>:</p><p>We replaced the image of oil red staining of mouse liver in the AAV-shCAND1 group in Figure 8I with a new image.</p><p>We sincerely apologize for this oversight. The corrected Figure 8, presented below, now accurately depicts the Oil Red staining results from the primary liver cancer model.</p><p><b>Corrected picture</b>: Figure 8</p><p>In addition, the description of Figure 8 in the results section of the original version does not need to be changed.</p><p>The authors apologize for these errors and for any inconvenience caused and appreciate your understanding and support. The corrections have no impact on the experimental outcome or conclusions</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11306278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901104","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}