Translational Research最新文献

{"title":"Spleen derived monocytes regulate pulmonary vascular permeability in Hepatopulmonary syndrome through the OSM-FGF/FGFR1 signaling","authors":"Liang Li,&nbsp;Jianzhong Li,&nbsp;Wendeng Li,&nbsp;Yuefeng Ma,&nbsp;Shaomin Li","doi":"10.1016/j.trsl.2024.05.010","DOIUrl":"10.1016/j.trsl.2024.05.010","url":null,"abstract":"<div><p>Hepatopulmonary syndrome (HPS) is a serious pulmonary complication in the advanced stage of liver disease. The occurrence of pulmonary edema in HPS patients is life-threatening. Increased pulmonary vascular permeability is an important mechanism leading to pulmonary edema, and endothelial glycocalyx (EG) is a barrier that maintains stable vascular permeability. However, in HPS, whether the pulmonary vascular EG changes and its regulatory mechanism are still unclear. Spleen derived monocytes are involved in the pathogenesis of HPS. However, whether they regulate the pulmonary vascular permeability in HPS patients or rats and what is the mechanism is still unclear. Healthy volunteers and HPS patients with splenectomy or not were enrolled in this study. We found that the respiration of HPS patients was significantly improved in response to splenectomy, while the EG degradation and pulmonary edema were aggravated. In addition, HPS patients expressed higher levels of oncostatin M (OSM) and fibroblast growth factor (FGF). Subsequently, the co-culture system of monocytes and human umbilical vein endothelial cells (HUVECs) was constructed. It was found that monocytes secreted OSM and activated the FGF/FGFR1 signaling pathway in HUVECs. Then, an HPS rat model was constructed by common bile duct ligation (CBDL) for in vivo verification. HPS rats were intravenously injected with OSM recombinant protein and/or TNF-α into the rats via tail vein 30 min before CBDL. The results showed that the respiration of HPS rats was improved after splenectomy, while the degradation of EG in pulmonary vessels and vascular permeability were increased, and pulmonary edema was aggravated. Moreover, the expression of OSM and FGF was upregulated in HPS rats, while both were downregulated after splenectomy. Intravenous injection of exogenous OSM eliminated the effect of splenectomy on FGF and improved EG degradation. It can be seen that during HPS, spleen-derived monocytes secrete OSM to promote pulmonary vascular EG remodeling by activating the FGF/FGFR1 pathway, thereby maintaining stable vascular permeability, and diminishing pulmonary edema. This study provides a promising therapeutic target for the treatment of HPS.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"271 ","pages":"Pages 93-104"},"PeriodicalIF":7.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141144498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ctDNA whole exome sequencing in pancreatic ductal adenocarcinoma unveils organ-dependent metastatic mechanisms and identifies actionable alterations in fast progressing patients","authors":"Marisol Huerta ,&nbsp;Jorge Martín-Arana ,&nbsp;Francisco Gimeno-Valiente ,&nbsp;Juan Antonio Carbonell-Asins ,&nbsp;Blanca García-Micó ,&nbsp;Belén Martínez-Castedo ,&nbsp;Fabián Robledo-Yagüe ,&nbsp;Daniel G. Camblor ,&nbsp;Tania Fleitas ,&nbsp;Miguel García Bartolomé ,&nbsp;Clara Alfaro-Cervelló ,&nbsp;Marina Garcés-Albir ,&nbsp;Dimitri Dorcaratto ,&nbsp;Elena Muñoz-Forner ,&nbsp;Víctor Seguí ,&nbsp;Isabel Mora-Oliver ,&nbsp;Valentina Gambardella ,&nbsp;Susana Roselló ,&nbsp;Luis Sabater ,&nbsp;Desamparados Roda ,&nbsp;Noelia Tarazona","doi":"10.1016/j.trsl.2024.05.003","DOIUrl":"10.1016/j.trsl.2024.05.003","url":null,"abstract":"<div><p>Understanding progression mechanisms and developing new targeted therapies is imperative in pancreatic ductal adenocarcinoma (PDAC). In this study, 80 metastatic PDAC patients were prospectively recruited and divided into discovery (n=37) and validation (n=43) cohorts. Tumor and plasma samples taken at diagnosis were pair analyzed using whole exome sequencing (WES) in patients belonging to the discovery cohort alone. The variant allele frequency (VAF) of KRAS mutations was measured by ddPCR in plasma at baseline and response assessment in all patients. Plasma WES identified at least one pathogenic variant across the cohort, uncovering oncogenic mechanisms, DNA repair, microsatellite instability, and alterations in the TGFb pathway. Interestingly, actionable mutations were mostly found in plasma rather than tissue. Patients with shorter survival showed enrichment in cellular organization regulatory pathways. Through WES we could identify a specific molecular profile of patients with liver metastasis, which exhibited exclusive mutations in genes related to the adaptive immune response pathway, highlighting the importance of the immune system in liver metastasis development. Moreover, KRAS mutations in plasma (both at diagnosis and persistent at follow-up) correlated with shorter progression free survival (PFS). Patients presenting a reduction of over 84.75 % in KRAS VAF at response assessment had similar PFS to KRAS-negative patients. Overall, plasma WES reveals molecular profiles indicative of rapid progression, potentially actionable targets, and associations between adaptive immune response pathway alterations and liver tropism.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"271 ","pages":"Pages 105-115"},"PeriodicalIF":7.8,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S193152442400094X/pdfft?md5=02e166325d3766f9fb4febe438145c60&pid=1-s2.0-S193152442400094X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Advisory Board","authors":"","doi":"10.1016/S1931-5244(24)00099-9","DOIUrl":"https://doi.org/10.1016/S1931-5244(24)00099-9","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"269 ","pages":"Page ii"},"PeriodicalIF":7.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1931524424000999/pdfft?md5=48f260bb407e4d020be12bc4867001d1&pid=1-s2.0-S1931524424000999-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140902330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Information for Readers","authors":"","doi":"10.1016/S1931-5244(24)00101-4","DOIUrl":"https://doi.org/10.1016/S1931-5244(24)00101-4","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"269 ","pages":"Page IBC"},"PeriodicalIF":7.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140902132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Guidelines","authors":"","doi":"10.1016/S1931-5244(24)00100-2","DOIUrl":"https://doi.org/10.1016/S1931-5244(24)00100-2","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"269 ","pages":"Pages iii-iv"},"PeriodicalIF":7.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140902131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Counteracting TGM2 by a Fibroin peptide ameliorated Adriamycin-induced nephropathy via regulation of lipid metabolism through PANX1-PPAR α/PANK1 pathway","authors":"Shan-Shan Li,&nbsp;Qiao-Juan Liu,&nbsp;Jia-Xin Bao,&nbsp;Meng-ting Lu,&nbsp;Bing-Quan Deng,&nbsp;Wen-Wen Li,&nbsp;Chang-Chun Cao","doi":"10.1016/j.trsl.2024.05.006","DOIUrl":"10.1016/j.trsl.2024.05.006","url":null,"abstract":"<div><p>Peptide drug discovery for the treatment of chronic kidney disease (CKD) has attracted much attention in recent years due to the urge to find novel drugs and mechanisms to delay the progression of the disease. In this study, we identified a novel short peptide (named YR-7, primary sequence ‘YEVEDYR’) from the natural Fibroin protein, and demonstrated that it significantly alleviated pathological renal changes in ADR-induced nephropathy. PANX1 was identified as the most notably upregulated component by RNA-sequencing. Further analysis showed that YR-7 alleviated the accumulation of lipid droplets via regulation of the lipid metabolism-related proteins PPAR α and PANK1. Using chemical proteomics, fluorescence polarization, microscale thermophoresis, surface plasmon resonance, and molecular docking, YR-7 was proven to directly bind to β-barrel domains of TGM2 protein to inhibit lipid accumulation. TGM2 knockdown <em>in vivo</em> increased the protein levels of PPAR α and PANK1 while decreased the levels of fibrotic-related proteins to alleviate nephropathy. <em>In vitro</em>, overexpression TGM2 reversed the protective effects of YR-7. Co-immunoprecipitation indicated that TGM2 interacted with PANX1 to promote lipid deposition, and pharmacological inhibition or knockdown of PANX1 decreased the levels of PPAR α and PANK1 induced by ADR. Taken together, our findings revealed that TGM2-PANX1 interaction in promoting lipid deposition may be a new signaling in promoting ADR-induced nephropathy. And a novel natural peptide could ameliorate renal fibrosis through TGM2-PANX1-PPAR α/PANK1 pathway, which highlight the potential of it in the treatment of CKD.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"271 ","pages":"Pages 26-39"},"PeriodicalIF":7.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140909677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune cell distribution and DNA methylation signatures differ between tumor and stroma enriched compartment in pancreatic ductal adenocarcinoma","authors":"Erwin Tomasich ,&nbsp;Jakob Mühlbacher ,&nbsp;Katharina Wöran ,&nbsp;Teresa Hatziioannou ,&nbsp;Merima Herac ,&nbsp;Markus Kleinberger ,&nbsp;Julia Maria Berger ,&nbsp;Lea Katharina Dibon ,&nbsp;Luzia Berchtold ,&nbsp;Gerwin Heller ,&nbsp;Elisabeth Sophie Bergen ,&nbsp;Andrea Macher-Beer ,&nbsp;Gerald Prager ,&nbsp;Martin Schindl ,&nbsp;Matthias Preusser ,&nbsp;Anna Sophie Berghoff","doi":"10.1016/j.trsl.2024.05.005","DOIUrl":"10.1016/j.trsl.2024.05.005","url":null,"abstract":"<div><p>The presence of abundant tumor stroma is a prominent characteristic of pancreatic ductal adenocarcinomas (PDAC) that potentially influences disease progression and therapy response. This study aims to investigate immune cell infiltration and epigenetic profiles in tumor cell enriched (“Tumor”) and stroma cell enriched (“Stroma”) regions within human PDAC tissue samples. By comparing those regions, we identified 25,410 differentially methylated positions (DMPs) distributed across 6,963 unique genes. Pathway enrichment analysis using the top 2,000 DMPs that were either hyper- or hypomethylated indicated that immune response pathways and the estrogen receptor pathway are epigenetically dysregulated in Tumor and Stroma regions, respectively. In terms of immune cell infiltration, we observed overall low levels of T cells in both regions. In Tumor regions however, occurrence of tumor-associated macrophages (TAMs) was higher than in Stroma regions (<em>p</em> = 0.02) concomitant with a dualistic distribution that stratifies PDAC patients into those with high and low TAM infiltration. By categorizing TAM levels into quartiles, our analysis revealed that PDAC patients with more than 1,515 TAMs per mm² exhibited significantly shorter overall survival (<em>p</em> = 0.036). Our data suggest that variations in inflammatory characteristics between the Tumor and Stroma defined compartments of PDAC may primarily stem from the presence of macrophages rather than lymphocytes. The abundance of TAMs within regions enriched with tumor cells correlates with patient survival, underscoring the potential significance of exploring therapeutic interventions targeting TAMs. Furthermore, directing attention towards the estrogen receptor pathway may represent a promising strategy to address the stroma cell component within the PDAC tumor microenvironment.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"271 ","pages":"Pages 40-51"},"PeriodicalIF":7.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1931524424001038/pdfft?md5=54cb0ec9997866301a308854efd67de6&pid=1-s2.0-S1931524424001038-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140909696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune checkpoint activity exacerbate renal interstitial fibrosis progression by enhancing PD-L1 expression in renal tubular epithelial cells","authors":"Yuting Zhang ,&nbsp;Xue Mi ,&nbsp;Yunchao Zhang ,&nbsp;Jipeng Li ,&nbsp;Yunlong Qin ,&nbsp;Peng He ,&nbsp;Ya Zhao ,&nbsp;Binxiao Su ,&nbsp;Lijie He","doi":"10.1016/j.trsl.2024.05.004","DOIUrl":"10.1016/j.trsl.2024.05.004","url":null,"abstract":"<div><p>Renal interstitial fibrosis (RIF) is often associated with inflammatory cell infiltration and no effective therapy. Programmed death cell-1 (PD-1) and its ligand PD-L1 were playing critical roles in T cell coinhibition and exhaustion, but the role in RIF is unclear. Here the data analyses of serum from 122 IgA nephrology (IgAN) patients showed that high level of soluble PD-1(sPD-1) was an independent risk factor for RIF and renal function progression. PD-L1 was also overexpressed in renal interstitial tissues from both IgAN patients with high level of sPD-1 and the unilateral ureteral obstruction (UUO) mouse. PD-L1 was significantly overexpressed in HK-2 cells with upregulated collagen and α-SMA when stimulated by inflammation or hypoxia in vitro. Additionally, matrix metalloproteinases (MMP-2) could increase the level of sPD-1 in culture supernatant when added in co-culture system of HK-2 and jurkat cells, which implied serum sPD-1 of IgAN might be cleaved by MMP-2 from T cells infiltrated into the tubulointerstitial inflammatory microenvironment. Crucially, injection of PD-L1 fusion protein, the blocker of sPD-1, could ameliorate kidney fibrosis in UUO mice by increasing T cell coinhibition and exhaustion, suggesting the therapeutic potential of PD-L1 fusion targeting for renal fibrosis. Take together, it reveals a novel causal role of sPD-1 in serum and PD-L1 of renal interstitial tissues in the development of renal fibrosis of IgAN, and targeting sPD-1 in serum by PD-L1 fusion protein is a potential therapeutic approach to prevent renal fibrosis of IgAN.</p></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"271 ","pages":"Pages 52-67"},"PeriodicalIF":7.8,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1931524424000951/pdfft?md5=3edab8408ba1a3f8c26668d2e4f47c24&pid=1-s2.0-S1931524424000951-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140900570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Information for Readers","authors":"","doi":"10.1016/S1931-5244(24)00088-4","DOIUrl":"https://doi.org/10.1016/S1931-5244(24)00088-4","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"268 ","pages":"Page IBC"},"PeriodicalIF":7.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140843694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Advisory Board","authors":"","doi":"10.1016/S1931-5244(24)00086-0","DOIUrl":"https://doi.org/10.1016/S1931-5244(24)00086-0","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"268 ","pages":"Page ii"},"PeriodicalIF":7.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1931524424000860/pdfft?md5=18e6601eac94f491e20cf5c80fa5239a&pid=1-s2.0-S1931524424000860-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140843692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}