SHOCK最新文献

{"title":"SP1 MEDIATES OGD/R-INDUCED CARDIOMYOCYTE INJURY VIA ENHANCING THE TRANSCRIPTION OF USP46.","authors":"Xuming Ma, Luzhen Wang, Wanpeng Li, Yan Huang, Yan Zhu, Jing Li","doi":"10.1097/SHK.0000000000002401","DOIUrl":"10.1097/SHK.0000000000002401","url":null,"abstract":"<p><strong>Abstract: </strong>Background: One of the mechanisms responsible for the high mortality rate of acute myocardial infarction is myocardial ischemia-reperfusion injury (MI-RI). The present study focused on the role and regulatory mechanisms of specificity protein 1 (SP1) and ubiquitin-specific protease 46 (USP46) in oxygen-glucose deprivation/reperfusion (OGD/R)-induced cardiomyocyte injury. Methods: OGD/R was used to treat cardiomyocytes AC16 to mimic ischemia-reperfusion in vitro . Cell viability, proliferation, and apoptosis were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine, and flow cytometry assays. Enzyme-linked immunosorbent assays analyzed the concentrations of TNF-α and IL-1β. Several protein levels were analyzed by western blotting. The levels of iron (Fe 2+ ), reactive oxygen species, malondialdehyde, and the activities of superoxide dismutase were analyzed by commercial kits. Chromatin immunoprecipitation and dual-luciferase report assays assessed the relationship between USP46 and SP1. Results: USP46 and SP1 were upregulated in serum from MI patients and they had a positive correlation. OGD/R stimulation suppressed cardiomyocyte viability and proliferation, as well as induced cardiomyocyte inflammation, oxidative stress (OxS) injury, apoptosis, and ferroptosis, but these effects were impaired by USP46 or SP1 knockdown. SP1 could enhance the transcription of USP46, and USP46 overexpression reversed SP1 silencing-mediated effects on OGD/R-induced cardiomyocytes. SP1 mediated the AMPK signaling via USP46 . Conclusion: SP1 mediated OGD/R-induced cardiomyocyte inflammation, OxS injury, apoptosis, and ferroptosis by inactivating the AMPK signaling via enhancing the transcription of USP46.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":"327-335"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HETEROGENEOUS EXPANSION OF POLYMORPHONUCLEAR MYELOID-DERIVED SUPPRESSOR CELLS DISTINGUISHES HIGH-RISK SEPSIS IMMUNOPHENOTYPES IN UGANDA.","authors":"Matthew J Cummings, Vincent Guichard, Nicholas Owor, Thomas Ochar, Moses Kiwubeyi, Rittah Nankwanga, Richard Kibisi, Charles Kassaja, Jesse E Ross, Thomas S Postler, John Kayiwa, Steven J Reynolds, Martina Cathy Nakibuuka, Joweria Nakaseegu, Julius J Lutwama, W Ian Lipkin, Sankar Ghosh, Barnabas Bakamutumaho, Max R O'Donnell","doi":"10.1097/SHK.0000000000002403","DOIUrl":"10.1097/SHK.0000000000002403","url":null,"abstract":"<p><strong>Abstract: </strong>Background: Understanding of immune cell phenotypes associated with inflammatory and immunosuppressive host responses in sepsis is imprecise, particularly in low- and middle-income countries, where the global sepsis burden is concentrated. In these settings, elucidation of clinically relevant immunophenotypes is necessary to determine the relevance of emerging therapeutics and refine mechanistic investigations of sepsis immunopathology. Methods: In a prospective cohort of adults hospitalized with suspected sepsis in Uganda (N = 43; median age 46 years [IQR 36-59], 24 [55.8%] living with HIV, 16 [37.2%] deceased at 60 days), we combined high-dimensional flow cytometry with unsupervised machine learning and manual gating to define peripheral immunophenotypes associated with increased risk of 60-day mortality. Results: Patients who died showed heterogeneous expansion of polymorphonuclear myeloid-derived suppressor cells, with increased and decreased abundance of CD16 - PD-L1 dim and CD16 bright PD-L1 bright subsets, respectively, significantly associated with mortality. While differences between CD16 - PD-L1 dim cell abundance and mortality risk appeared consistent throughout the course of illness, those for the CD16 bright PD-L1 bright subset were more pronounced early after illness onset. Independent of HIV co-infection, depletion of CD4 + T cells, dendritic cells, and CD56 - CD16 bright NK cells were significantly associated with mortality risk, as was expansion of immature, CD56 + CD16 - CD11c + NK cells. Abundance of T cells expressing inhibitory checkpoint proteins (PD-1, CTLA-4, LAG-3) was similar between patients who died versus those who survived. Conclusions: This is the first study to define high-risk immunophenotypes among adults with sepsis in sub-Saharan Africa, an immunologically distinct region where biologically informed treatment strategies are needed. More broadly, our findings highlight the clinical importance and complexity of myeloid derived suppressor cell expansion during sepsis and support emerging data that suggest a host-protective role for PD-L1 myeloid checkpoints in acute critical illness.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":"336-343"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141627545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RETRACTION SHOCK PAPER.","authors":"","doi":"10.1097/SHK.0000000000002407","DOIUrl":"10.1097/SHK.0000000000002407","url":null,"abstract":"","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":"62 3","pages":"457"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142111605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MECHANISM OF MICRORNA-218-5P IN MITOCHONDRIAL BIOGENESIS OF SEPSIS-INDUCED ACUTE KIDNEY INJURY BY THE REGULATION OF PGC-1Α.","authors":"Jing Kuang, Jun Fang, Shuli Hu, Xiuhong Yang, Xuepeng Fan","doi":"10.1097/SHK.0000000000002410","DOIUrl":"10.1097/SHK.0000000000002410","url":null,"abstract":"<p><strong>Abstract: </strong>Background: Sepsis-induced acute kidney injury (SI-AKI) is a kind of kidney dysfunction, which brings a lot of suffering. This study aimed to figure out the role of the miR-218-5p/PGC-1α axis in SI-AKI. Methods: AKI mouse model was established through cecal ligation and puncture. PGC-1α expression was activated using an activator ZLN005 before the serum and tissue samples were collected. Next, pathological structure and apoptosis of kidney tissues were observed. Levels of blood urea nitrogen, serum creatinine, and indicators of inflammation and oxidative stress were assessed. Moreover, reactive oxygen species and mitochondrial membrane potential levels, adenosine 5'-triphosphate content, and mitochondrial ultrastructure of kidney tissues were observed. HK2 cells were treated by lipopolysaccharide (LPS) to mimic sepsis in vitro , followed by evaluation of cell survival and apoptosis, inflammation, and oxidative stress. Subsequently, the binding relation between PGC-1α and miR-218-5p was predicted and validated. Then expression of PGC-1α and miR-218-5p was detected. PGC-1α and miR-218-5p expression were intervened to detect their influences in mitochondrial biogenesis. At last, miR-218-5p was overexpressed in ZLN005 (PGC-1α activating agent) pretreated SI-AKI mice to validate the mechanism. Results: PGC-1α is poorly expressed in SI-AKI, but overexpression of PGC-1α using ZLN005 alleviated SI-AKI injury and promoted mitochondrial biogenesis in AKI mice, and relieved LPS-induced cell injury. PGC-1α is a target of miR-218-5p. Downregulation of miR-218-5p expression in HK2 cells attenuated mitochondrial biogenesis disorder. Inhibition of PGC-1α annulled the role of miR-218-5p silencing in cells. In vivo , miR-218-5p overexpression partly reversed the protective role of ZLN005 in SI-AKI mice. Conclusion: miR-218-5p targeted PGC-1α to disrupt mitochondrial biogenesis, thereby exacerbating SI-AKI.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":"426-436"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141420672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanical left ventricular unloading in cardiogenic shock treated with venoarterial extracorporeal membrane oxygenation: a systematic review and meta-analysis.","authors":"Yuki Kotani, Taihei Yamamoto, Takatoshi Koroki, Takahiko Yaguchi, Yuta Nakamura, Mayuko Tonai, Toshiyuki Karumai, Pasquale Nardelli, Giovanni Landoni, Yoshiro Hayashi","doi":"10.1097/SHK.0000000000002463","DOIUrl":"https://doi.org/10.1097/SHK.0000000000002463","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate if mechanical left ventricular unloading could reduce mortality in patients with cardiogenic shock undergoing venoarterial extracorporeal membrane oxygenation (VA-ECMO).</p><p><strong>Methods: </strong>We searched MEDLINE, Embase, and the Cochrane Library for randomized controlled trials and propensity score-matched studies published until December 20, 2023. The primary outcome was mortality at the longest follow-up. We used a Mantel-Haenszel random effects meta-analysis and reported the pooled results with a risk ratio (RR) and 95% confidence interval (CI). The review protocol was registered on PROSPERO International prospective register of systematic review (CRD42024498665).</p><p><strong>Results: </strong>We identified two randomized controlled trials and eleven propensity score-matched studies, totaling 9858 patients. Mechanical left ventricular unloading was significantly associated with reduced mortality at the longest follow-up (RR, 0.89; 95% CI, 0.84-0.94; P = 0.0001; moderate certainty of evidence), which was confirmed in studies using intraaortic ballon pump (IABP). Benefits of mechanical unloading were also observed in terms of successful VA-ECMO weaning (RR, 1.15; 95% CI, 1.02-1.29; P = 0.02; low certainty of evidence) and favorable neurological outcome (two studies; RR, 2.45; 95% CI, 1.62-3.69; P < 0.0001; low certainty of evidence), although we observed an increased incidence of major bleeding (RR, 1.27; 95% CI, 1.02-1.59; P = 0.03; low certainty of evidence) and hemolysis (RR, 1.49; 95% CI, 1.10-2.02; P = 0.01; moderate certainty of evidence).</p><p><strong>Conclusions: </strong>Among adult patients with cardiogenic shock treated with VA-ECMO, mechanical left ventricular unloading was associated with reduced mortality, which was confirmed in studies using IABP as an unloading device.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma Proteome, Metabolome Mendelian Randomization Identifies Sepsis Therapeutic Targets.","authors":"Ruiming Deng, Guiming Huang, Juan Zhou, Kai Zeng","doi":"10.1097/SHK.0000000000002465","DOIUrl":"https://doi.org/10.1097/SHK.0000000000002465","url":null,"abstract":"<p><strong>Background: </strong>The interrelation between the plasma proteome and plasma metabolome with sepsis presents a multifaceted dynamic that necessitates further research to elucidate the underlying causal mechanisms.</p><p><strong>Methods: </strong>Our investigation used public genome-wide association study (GWAS) data to explore the relationships among the plasma proteome, metabolome, and sepsis, considering different sepsis subgroup. Initially, two-sample MR established causal connections between the plasma proteome and metabolome with sepsis. Subsequently, multivariate and iterative MR analyses were performed to understand the complex interactions in plasma during sepsis. The validity of these findings was supported by thorough sensitivity analyses.</p><p><strong>Result: </strong>The study identified 25 plasma proteins that enhance risk and 34 that act as protective agents in sepsis. Post p-value adjustment (0.05/1306), ICAM5 emerged with a positive correlation to sepsis susceptibility (p-value = 2.14E-05, OR = 1.10, 95% CI = 1.05-1.15), with this significance preserved across three sepsis subgroup examined. Additionally, 29 plasma metabolites were recognized as risk factors, and 15 as protective factors for sepsis outcomes. Following p-value adjustment (0.05/997), elevated levels of 1,2,3-benzenetriol sulfate (2) was significantly associated with increased sepsis risk (p-value = 3.37E-05, OR = 1.18, 95% CI = 1.09-1.28). Further scrutiny revealed that this plasma metabolite notably augments the abundance of ICAM5 protein (p-value = 3.52E-04, OR = 1.11, 95% CI = 1.04-1.17), devoid of any detected heterogeneity, pleiotropy, or reverse causality. Mediated MR revealed ICAM5 mediated 11.9% of 1,2,3-benzenetriol sulfate (2)'s total effect on sepsis progression.</p><p><strong>Conclusion: </strong>This study details the causal link between the plasma proteome and metabolome with sepsis, highlighting the roles of ICAM5 and 1,2,3-benzenetriol sulfate (2) in sepsis progression, both independently and through crosstalk.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RELATIONSHIP BETWEEN TRPM4 RS8104571 GENOTYPE, CIRCULATING TRPM4 AND SUR1, AND CLINICAL OUTCOME FOLLOWING TRAUMATIC BRAIN INJURY.","authors":"Joseph D Krocker, Madeline E Cotton, Janet R Ashley, Jacob B Schriner, Baron K Osborn, Yao-Wei Willa Wang, Charles S Cox, Charles E Wade","doi":"10.1097/SHK.0000000000002468","DOIUrl":"10.1097/SHK.0000000000002468","url":null,"abstract":"<p><strong>Abstract: </strong>The variant single nucleotide polymorphism rs8104571 has been associated with poor outcomes following traumatic brain injury (TBI) and is most prevalent in those of African ancestry. This single nucleotide polymorphism (SNP) resides within a gene coding for the TRPM4 protein, which complexes with SUR1 protein to create a transmembrane ion channel and is believed to contribute to cellular swelling and cell death in neurological tissue. Our study evaluates the relationship between circulating TRPM4 and SUR1, rs8104571 genotype, and clinical outcome in TBI patients. Trauma patients with moderate to severe TBI were included in this retrospective study. rs8104571 genotyping and admission plasma TRPM4 and SUR1 quantification was performed with real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Adequate plasma for TRPM4 and SUR1 ELISA quantification was available for 289 patients, 54 of whom were African American (AA). Plasma TRPM4 concentration was increased in those with a variant rs8104571 allele compared to wild type when controlling for demographics and injury characteristics in the overall cohort (P = 0.04) and within the AA subgroup (P = 0.01). There was no significant association between plasma TRPM4 or SUR1 and clinical outcome (each P > 0.05). Plasma TRPM4 abundance increased with acute kidney injury severity (P = 0.02). The association between increased plasma TRPM4 and variant rs810457 supports an underlying mechanism involving increased neuroinflammation with a subsequent increase in the leakage of TRPM4 from the central nervous system into circulation. Alternative sources of plasma TRPM4 including the kidney cannot be excluded and may play a significant role in the pathophysiology of trauma as well.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NINJ1: A Novel Sepsis Severity and Mortality Biomarker.","authors":"Yongbin Wu, Tao Li, Sichuang Tan, Ruoyu Song, Kaiyuan Song, Jiankang Zhou, Xianzhong Xiao, Kangkai Wang, Huali Zhang, Sipin Tan","doi":"10.1097/SHK.0000000000002460","DOIUrl":"https://doi.org/10.1097/SHK.0000000000002460","url":null,"abstract":"<p><strong>Background: </strong>Multiple cell death modalities are implicated in sepsis pathobiology. However, the clinical relevance of NINJ1, a key mediator of plasma membrane rupture during lytic cell death, in sepsis progression and outcomes has remained poorly explored.</p><p><strong>Methods: </strong>Circulating NINJ1 levels were measured in 116 septic ICU patients, 16 non-septic ICU controls, and 16 healthy controls. Comparative analysis of serum NINJ1 across these groups was performed. Correlations between NINJ1 and clinical disease severity scores (SOFA, APACHE II) as well as laboratory parameters were examined in the sepsis cohort. Furthermore, we assessed the prognostic performance of NINJ1 for predicting 28-day mortality in septic patients using receiver operating characteristic (ROC) analyses.</p><p><strong>Results: </strong>Circulating NINJ1 levels were elevated in septic patients and positively correlated with sepsis severity scores. NINJ1 also showed positive correlations with liver injury markers (AST/ALT) and coagulation parameters (D-dimer, APTT, PT, TT) in sepsis. Further analysis using the ISTH overt DIC scoring system revealed an association between NINJ1 and sepsis-induced coagulopathy.ROC analysis demonstrated NINJ1 outperformed traditional inflammatory biomarkers PCT and CRP in predicting 28-day sepsis mortality, although its prognostic accuracy was lower than SOFA and APACHE II scores. Combining NINJ1 with SOFA improved mortality prediction from an AUC of 0.6843 to 0.773.</p><p><strong>Conclusions: </strong>Circulating NINJ1 serves as a novel sepsis biomarker indicative of disease severity, coagulopathy and mortality risk, and its integration with SOFA and APACHE II scores substantially enhances prognostic risk stratification. These findings highlight the prospective clinical utility of NINJ1 for sepsis prognostication and monitoring, warranting further validation studies to facilitate implementation.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP31 promotes the inflammatory response of human lung organoids to lipopolysaccharide treatment.","authors":"Wenbiao Xiao, Bingwen Lin, Ying Wang, Peng Huang, Jiandong Lin, Xiongjian Xiao","doi":"10.1097/SHK.0000000000002464","DOIUrl":"https://doi.org/10.1097/SHK.0000000000002464","url":null,"abstract":"<p><strong>Background: </strong>Acute lung injury (ALI) is a severe condition characterized by a high mortality rate, driven by an uncontrolled inflammatory response. Emerging evidence has underscored the crucial role of the ubiquitin system in ALI. However, due to their vast number, the specific functions of individual ubiquitination regulators remain unclear.</p><p><strong>Materials and methods: </strong>In this study, we established human lung organoids (HLOs) derived from human embryonic stem cells and subjected them to lipopolysaccharide (LPS) treatment to induce an inflammatory response, mimicking ALI. Subsequently, we detected the expression of inflammatory cytokines, including tumour necrosis factor alpha (TNF-α), interleukin 6, interleukin 18 (IL-18), and interleukin-1β (IL-1β), by qPCR experiments. We also detected changes in the mRNA expression of several USPs before and after HLOs treatment and thus screened for USPs that had significant changes in HLOs after LPS stimulation. After screening for USP, we silenced the USP in HLOs and then subjected them to LPS treatment, and TNF-α, IL-6, IL-18, and IL-1β expressions were detected using qPCR assays. Meanwhile, Western blot was used to detect changes in NOD-, LRR- and pyrin domain-containing 3 (NLRP3) and apoptosis-associated Speck-like protein containing a CARD (ASC) protein level in HLOs.</p><p><strong>Results: </strong>Through screening the expression of 40 ubiquitin-specific proteases (USPs), which are responsible for removing ubiquitination, we identified several USPs that exhibited differential expression in LPS-treated HLOs compared to untreated HLOs. Notably, USP31 emerged as the most significantly upregulated USP, and the knockdown of USP31 markedly attenuated the inflammatory response of HLOs to LPS treatment.</p><p><strong>Conclusions: </strong>USP31 may play a facilitating role in the inflammatory response during ALI.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL14/IGF2BP2-mediated m6A modification of STEAP1 aggravates acute lung injury induced by sepsis.","authors":"Junhua Lai, Shaochi Yu, Xia Li, Qiuxing Wei, Jian Qin","doi":"10.1097/SHK.0000000000002456","DOIUrl":"https://doi.org/10.1097/SHK.0000000000002456","url":null,"abstract":"<p><strong>Background: </strong>Acute lung injury (ALI) is a severe complication of sepsis, characterized by inflammation, edema, and injury to alveolar cells, leading to high mortality rates. Septic ALI is a complex disease involving multiple factors and signaling pathways. STEAP family member 1 (STEAP1) has been reported to be upregulated in a sepsis-induced ALI model. However, the role of STEAP1 in the regulation of septic ALI is not yet fully understood.</p><p><strong>Methods: </strong>The study stimulated human pulmonary microvascular endothelial cells (HPMECs) using lipopolysaccharides (LPS) to establish an in vitro ALI model. The study used quantitative real-time polymerase chain reaction (qRT-PCR) to measure mRNA expression, and western blotting assay or immunohistochemistry (IHC) assay to analyze protein expression. Cell counting kit-8 (CCK-8) assay was performed to assess cell viability. Flow cytometry was conducted to analyze cell apoptosis. Tube formation assay was used to analyze the tube formation rate of human umbilical vein endothelial cells (HUVECs). Enzyme-linked immunosorbent assays (ELISAs) were used to measure the levels of interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). The levels of Fe2+ and reactive oxygen species (ROS) were determined using colorimetric and fluorometric assays, respectively. The glutathione (GSH) level was also determined using a colorimetric assay. m6A RNA immunoprecipitation assay, dual-luciferase reporter assay, and RNA immunoprecipitation assay were performed to identify the association of STEAP1 with methyltransferase 14, N6-adenosine-methyltransferase non-catalytic subunit (METTL14) and insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2). The transcript half-life of STEAP1 was analyzed by actinomycin D assay. Finally, a rat model of polymicrobial sepsis was established to analyze the effects of STEAP1 knockdown on lung injury in vivo.</p><p><strong>Results: </strong>We found that the mRNA expression levels of STEAP1 and METTL14 were upregulated in the blood of ALI patients induced by sepsis compared to healthy volunteers. LPS treatment increased the protein levels of STEAP1 and METTL14 in HPMECs. STEAP1 depletion attenuated LPS-induced promoting effects on HPMECs' apoptosis, inflammatory response, and ferroptosis, as well as LPS-induced inhibitory effect on tube formation. We also found that METTL14 and IGF2BP2 stabilized STEAP1 mRNA expression through the m6A methylation modification process. Moreover, METTL14 silencing attenuated LPS-induced effects by decreasing STEAP1 expression in HPMECs, and STEAP1 silencing ameliorated cecal ligation and puncture-induced lung injury of mice.</p><p><strong>Conclusion: </strong>METTL14/IGF2BP2-mediated m6A modification of STEAP1 aggravated ALI induced by sepsis. These findings suggest potential therapeutic targets for the treatment of this disease.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}