SHOCK最新文献

{"title":"EUGENOL RESTRAINS ANGIOTENSIN II-INDUCED DEATH, INFLAMMATION AND FERROPTOSIS OF VASCULAR SMOOTH MUSCLE CELLS BY TARGETING STAT3/HMGB2 AXIS.","authors":"Birun Huang, Haiyan Chen, Xiulan Zhang","doi":"10.1097/SHK.0000000000002498","DOIUrl":"10.1097/SHK.0000000000002498","url":null,"abstract":"<p><strong>Abstract: </strong>Background: Eugenol has been found to inhibit a variety of disease processes, including abdominal aortic aneurysm (AAA) formation. However, the specific role and the underlying molecular mechanism of Eugenol in AAA progression need to be further revealed. Methods: Vascular smooth muscle cells (VSMCs) were pretreated with Eugenol, followed by treated with Angiotensin II (Ang-II). VSMCs were transfected with HMGB2 siRNA or overexpression vector and treated with Ang-II to confirm the effect of HMGB2 on AAA progression. Cell proliferation and death were determined using cell counting kit 8 assay, 5-ethynyl-2'-deoxyuridine assay, and flow cytometry. Inflammatory factors were examined by ELISA. Fe 2+ , glutathione, and malondialdehyde levels were tested to evaluate cell ferroptosis. The protein levels of ferroptosis-related markers, high mobility group box 2 (HMGB2), and STAT3 were measured using western blot. Human AAA tissues and normal abdominal aortic tissues were collected to detect HMGB2 mRNA expression by quantitative real-time PCR. The interaction between HMGB2 and STAT3 was confirmed by chromatin immunoprecipitation assay and dual-luciferase reporter assay. Results: Eugenol enhanced VSMCs proliferation, while restrained Ang-II-induced death, inflammation, and ferroptosis. HMGB2 was upregulated in AAA tissues and Ang-II-induced VSMCs, and Eugenol significantly decreased HMGB2 expression. HMGB2 knockdown reduced Ang-II-induced VSMCs death, inflammation, and ferroptosis, Besides, HMGB2 overexpression abolished the effect of Eugenol on Ang-II-induced VSMCs injury. Transcription factor STAT3 bound to HMGB2 promoter region to increase its expression. In addition, Eugenol decreased STAT3 expression to regulate HMGB2. Conclusion: Eugenol could slow down the development of AAA, which might be achieved by regulating STAT3/HMGB2 axis.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":"320-326"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142507120","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":"10.1097/SHK.0000000000002456","url":null,"abstract":"<p><strong>Abstract: </strong>Background: 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. Methods: 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 to measure mRNA expression, and western blotting assay or immunohistochemistry assay to analyze protein expression. Cell Counting Kit-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. Enzyme-linked immunosorbent assays were used to measure the levels of interleukin 1beta and tumor necrosis factor alpha. The levels of Fe 2+ and reactive oxygen species were determined using colorimetric and fluorometric assays, respectively. The glutathione 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 noncatalytic 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 . Results: 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. Conclusion: 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":"217-225"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","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}

{"title":"COMPREHENSIVE CHARACTERIZATION OF CYTOKINES IN PATIENTS UNDER EXTRACORPOREAL MEMBRANE OXYGENATION: EVIDENCE FROM INTEGRATED BULK AND SINGLE-CELL RNA SEQUENCING DATA USING MULTIPLE MACHINE LEARNING APPROACHES.","authors":"Zhen Chen, Jianhai Lu, Genglong Liu, Changzhi Liu, Shumin Wu, Lina Xian, Xingliang Zhou, Liuer Zuo, Yongpeng Su","doi":"10.1097/SHK.0000000000002425","DOIUrl":"10.1097/SHK.0000000000002425","url":null,"abstract":"<p><strong>Abstract: </strong>Background : Extracorporeal membrane oxygenation (ECMO) is an effective technique for providing short-term mechanical support to the heart, lungs, or both. During ECMO treatment, the inflammatory response, particularly involving cytokines, plays a crucial role in pathophysiology. However, the potential effects of cytokines on patients receiving ECMO are not comprehensively understood. Methods : We acquired three ECMO support datasets, namely two bulk and one single-cell RNA sequencing (RNA-seq), from the Gene Expression Omnibus (GEO) combined with hospital cohorts to investigate the expression pattern and potential biological processes of cytokine-related genes (CRGs) in patients under ECMO. Subsequently, machine learning approaches, including support vector machine (SVM), random forest (RF), modified Lasso penalized regression, extreme gradient boosting (XGBoost), and artificial neural network (ANN), were applied to identify hub CRGs, thus developing a prediction model called CRG classifier. The predictive and prognostic performance of the model was comprehensively evaluated in GEO and hospital cohorts. Finally, we mechanistically analyzed the relationship between hub cytokines, immune cells, and pivotal molecular pathways. Results : Analyzing bulk and single-cell RNA-seq data revealed that most CRGs were significantly differentially expressed; the enrichment scores of cytokine and cytokine-cytokine receptor (CCR) interaction were significantly higher during ECMO. Based on multiple machine learning algorithms, nine key CRGs (CCL2, CCL4, IFNG, IL1R2, IL20RB, IL31RA, IL4, IL7, and IL7R) were used to develop the CRG classifier. The CRG classifier exhibited excellent prognostic values (AUC > 0.85), serving as an independent risk factor. It performed better in predicting mortality and yielded a larger net benefit than other clinical features in GEO and hospital cohorts. Additionally, IL1R2, CCL4, and IL7R were predominantly expressed in monocytes, NK cells, and T cells, respectively. Their expression was significantly positively correlated with the relative abundance of corresponding immune cells. Gene set variation analysis (GSVA) revealed that para-inflammation, complement and coagulation cascades, and IL6/JAK/STAT3 signaling were significantly enriched in the subgroup that died after receiving ECMO. Spearman correlation analyses and Mantel tests revealed that the expression of hub cytokines (IL1R2, CCL4, and IL7R) and pivotal molecular pathways scores (complement and coagulation cascades, IL6/JAK/STAT3 signaling, and para-inflammation) were closely related. Conclusion : A predictive model (CRG classifier) comprising nine CRGs based on multiple machine learning algorithms was constructed, potentially assisting clinicians in guiding individualized ECMO treatment. Additionally, elucidating the underlying mechanistic pathways of cytokines during ECMO will provide new insights into its treatment.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":"267-281"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11776881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TARGETING S100A9-TLR2 AXIS CONTROLS MACROPHAGE NLRP3 INFLAMMASOME ACTIVATION IN FATTY LIVER ISCHEMIA REPERFUSION INJURY.","authors":"Mingwei Sheng, Weihua Liu, Yingli Cao, Shixuan Wang, Yuanbang Lin, Wenli Yu","doi":"10.1097/SHK.0000000000002470","DOIUrl":"10.1097/SHK.0000000000002470","url":null,"abstract":"<p><strong>Abstract: </strong>Liver ischemia reperfusion (IR) injury significantly impacts clinical outcomes by increasing the risk of hepatic dysfunction after liver surgery. Fatty livers are more susceptible to IR stress. Recent studies have demonstrated that S100A9 plays a crucial role in both IR injury and the progression of liver steatosis. Nevertheless, the precise mechanisms underlying these effects remain unclear. In our study, transcriptome analysis of fatty livers subjected to IR insult in mice identified S100A9 as an important mediator. Employing loss-of-function approaches, we investigated the immune regulatory function of S100A9 and its downstream signaling in fatty liver IR injury. As expected, S100A9 emerged as one of the most significantly upregulated genes during the reperfusion stage in fatty livers. Genetic knockdown of S100A9 markedly ameliorated liver pathological damage, evidenced by reduced macrophage/neutrophil infiltration as well as the decreased expression of proinflammatory factors. Transcriptome/functional studies revealed that S100A9 triggered liver inflammatory response via regulating toll-like receptor 2 (TLR2)/activating transcription factor 4 (ATF4) signaling. Additionally, TLR2 expression was notably increased in macrophages from ischemic fatty livers. In vitro , recombinant S100A9-stimulated macrophages exhibited the elevated production of proinflammatory factors and TLR2/ATF4 pathway activation. Intriguingly, S100A9 facilitated ATF4 nuclear translocation and enhanced NEK7/NLRP3 inflammasome activation in macrophages. In conclusion, our study identified S100A9 as a key regulator responsible for macrophage NLRP3 inflammasome activation and subsequent inflammatory injury in fatty liver IR process. Targeting TLR2/ATF4 signaling may offer a novel therapeutic strategy for mitigating S100A9-mediated liver injury.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":"292-298"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11776876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142507128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ROLE OF CASPASE-1/CASPASE-11-HMGB1-RAGE/TLR4 SIGNALING IN THE EXACERBATION OF EXTRAPULMONARY SEPSIS-INDUCED LUNG INJURY BY MECHANICAL VENTILATION.","authors":"Xibing Ding, Shuqing Jin, Weitian Tian, Yizhe Zhang, Li Xu, Tong Zhang, Zhixia Chen, Fangfang Niu, Quan Li","doi":"10.1097/SHK.0000000000002471","DOIUrl":"10.1097/SHK.0000000000002471","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Abstract: &lt;/strong&gt;Background: Mechanical ventilation (MV) is a clinically important measure for respiratory support in critically ill patients. Although moderate tidal volume MV does not cause lung injury, it can further exacerbate lung injury in a pathological state such as sepsis. This pathological process is known as the \"two-hit\" theory, whereby an initial lung injury (e.g., infection, trauma, or sepsis) triggers an inflammatory response that activates immune cells, presenting the lung tissue in a fragile state and rendering it more susceptible to subsequent injury. The second hit occurs when MV is applied to lung tissue in a fragile state, and it is noteworthy that this MV is harmless to healthy lung tissue, further aggravating preexisting lung injury through unknown mechanisms. This interaction between initial injury and subsequent MV develops a malignant cycle significantly exacerbating lung injury and severely hampering patient prognosis. The two-hit theory is critical to understanding the complicated mechanisms of ventilator-associated lung injury and facilitates the subsequent development of targeted therapeutic strategies. Methods and Results: The cecum ligation and perforation mice model was used to mimic clinical sepsis patients. After 12 h, the mice were mechanically ventilated for 2 to 6 h. MV by itself did not lead to HMGB1 release, but significantly strengthened HMGB1 in plasma and cytoplasm of lung tissue in septic mice. Plasma and lung tissue activation of cytokines and chemokines, mitogen-activated protein kinase signaling pathway, neutrophil recruitment, and acute lung injury were progressively decreased in LysM HMGB1 -/- (Hmgb1 deletion in myeloid cells) and iHMGB1 -/- mice (inducible HMGB1 -/- mouse strain where the Hmgb1 gene was globally deleted after tamoxifen treatment). Compared with C57BL/6 mice, although EC-HMGB1 -/- (Hmgb1 deletion in endothelial cells) mice did not have lower levels of inflammation, neutrophil recruitment and lung injury were reduced. Compared with LysM HMGB1 -/- mice, EC-HMGB1 -/- mice had higher levels of inflammation but significantly lower neutrophil recruitment and lung injury. Overall, iHMGB1 -/- mice had the lowest levels of all the above indicators. The level of inflammation, neutrophil recruitment, and the degree of lung injury were decreased in RAGE -/- mice, and even the above indices were further decreased in TLR4/RAGE -/- mice. Levels of inflammation and neutrophil recruitment were decreased in caspase-11 -/- and caspase-1/11 -/- mice, but there was no statistical difference between these two gene knockout mice. Conclusions: These data show for the first time that the caspase-1/caspase-11-HMGB1-TLR4/RAGE signaling pathway plays a key role in mice model of sepsis-induced lung injury exacerbated by MV. Different species of HMGB1 knockout mice have different lung-protective mechanisms in the two-hit model, and location is the key to function. Specifically, LysM HMGB1 -/- mice ","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":"299-311"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126600","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":"FLUID OVERLOAD MODIFIES HEMODYNAMIC IMPACT OF CONTINUOUS RENAL REPLACEMENT THERAPY: EVIDENCE OF A COVERT CARDIORENAL SYNDROME?","authors":"Sameer Thadani, Anna Lang, Christin Silos, Jack Price, Ben Gelbart, Katri Typpo, Christopher Horvat, Dana Y Fuhrman, Tara Neumayr, Ayse Akcan Arikan","doi":"10.1097/SHK.0000000000002483","DOIUrl":"10.1097/SHK.0000000000002483","url":null,"abstract":"<p><strong>Abstract: </strong>Background: Fluid overload (FO) in critically ill children correlates with higher morbidity and mortality rates. Continuous renal replacement therapy (CRRT) is commonly employed to manage FO. In adults, both FO and CRRT adversely affect myocardial function. It remains unclear if children experience similar cardiovascular effects. Methods: Observational single-center study on children (<18 years) receiving CRRT at Texas Children's Hospital from 11/2019 to 3/2021. Excluded were those with end-stage renal disease, pacemakers, extracorporeal membrane oxygenation, ventricular assist devices, apheresis, or without an arterial line. Electrocardiometry (ICON Osypka Medical GmbH, Berlin, Germany) which is noninvasive and utilizes bioimpedance, was applied to obtain hemodynamic data over the first 48 h of CRRT. Our aim was to identify how FO >15% affects hemodynamics in children receiving CRRT. Results: Seventeen children, median age 43 months (interquartile range [IQR] 12-124), were included. The median FO at CRRT initiation was 14.4% (2.4%-25.6%), with 9 (53%) patients having FO >15%. Differences were noted in systemic vascular resistance index (1,277 [IQR 1088-1,666] vs. 1,030 [IQR 868-1,181] dynes/s/cm 5 /m 2 , P < 0.01), and cardiac index (3.90 [IQR 3.23-4.75] vs. 5.68 [IQR 4.65-6.32] L/min/m 2 , P < 0.01), with no differences in heart rate or mean arterial pressure between children with and without FO. Conclusion: FO affects the hemodynamic profile of children on CRRT, with those having FO >15% showing higher systemic vascular resistance index and lower cardiac index, despite heart rate and mean arterial pressure remaining unchanged. Our study illustrates the feasibility and utility of electrocardiometry in these patients, suggesting future research employ this technology to further explore the hemodynamic effects of dialysis in children.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":"233-239"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142507121","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":"Endothelial-specific knockout of the scramblase TMEM16F impairs in vivo clot formation.","authors":"Grace Bonson, Aaron R Lambert, Adrian M Sackheim, Abigail Howard, Sophia H Piffard, Carlos Lescieur-Garcia, Jade Cleary, Luisa Rubinelli, Annarita DiLorenzo, Devdoot Majumdar, Grant Hennig, Mark T Nelson, Kalev Freeman","doi":"10.1097/SHK.0000000000002553","DOIUrl":"https://doi.org/10.1097/SHK.0000000000002553","url":null,"abstract":"<p><strong>Objective: </strong>Loss of function of the phospholipid scramblase (PLS) TMEM16F results in Scott Syndrome, a hereditary bleeding disorder generally attributed to intrinsic platelet dysfunction. The role of TMEM16F in endothelial cells, however, is not well understood. We sought to test the hypothesis that endothelial TMEM16F contributes to hemostasis by measuring bleeding time and venous clotting in endothelial-specific knockout (ECKO) mice.</p><p><strong>Materials and methods: </strong>We initially evaluated the extent to which TMEM16F contributes to endothelial calcium events produced by trauma factors in vitro, using a pharmacological approach. Cultured endothelial cells were exposed to histones in the presence or absence of the PLS inhibitor, niclosamide, for live-cell calcium imaging and flow cytometry with annexin V staining. We then applied a genetic approach to specifically ablate TMEM16F in vascular endothelial cells in vivo using a murine tamoxifen-inducible cre-lox system under control of a Cdh5 promoter. Hemostasis was evaluated by measuring tail bleeding time after a distal 5 mm tail resection. Venous thrombus formation was evaluated by creating a surgical stenosis of the inferior vena cava (IVC) and harvesting the resultant clot 24 hours post-procedure for measurement. Blood samples were obtained via IVC cannulation to assay plasma-based coagulation. Mesenteric arteries were isolated and cannulated for assessment of endothelial-dependent vasodilation by pressure myography.</p><p><strong>Results: </strong>Pretreatment with the PLS inhibitor niclosamide prevented pathological calcium signals and mitigated PS translocation in cultured endothelial cells exposed to extracellular histones. TMEM16F ECKO mice exhibited prolonged bleeding compared to controls (time, 205.6 +/- 234.5 vs. 38.1 +/- 29.11 sec; p < 0.05). The ECKO mice also generated significantly smaller IVC thrombi (length, 0.9 +/- 1.4 vs. 4.7 +/- 3.3 mm; p < 0.05). TMEM16F ablation did not impact prothrombin time or endothelial-dependent vasodilatory function.</p><p><strong>Conclusions: </strong>Endothelial TMEM16F function is essential for normal hemostasis. ECKO of TMEM16F is sufficient to produce a coagulopathic phenotype, as shown by the prolonged bleeding time after tail transection and decreased thrombus generation in response to IVC stenosis. Because endothelial calcium events are pathologically amplified in response to trauma factors, these results suggest that TMEM16F may play a role in trauma-induced coagulopathy.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143060630","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":"MicroRNA-146b targets HIF-1α AND attenuates cardiomyocyte apoptosis and fibrosis in doxorubicin-induced heart failure.","authors":"Min Wang, Rui Lu, Liang Peng, Ling-Ling Xu, Shang-Fei He, Tao Guo, Ming-Jun Lu, Yi Luo, Tong-Tao Cui","doi":"10.1097/SHK.0000000000002546","DOIUrl":"https://doi.org/10.1097/SHK.0000000000002546","url":null,"abstract":"<p><strong>Abstract: </strong>The global prevalence of heart failure is still growing, which imposes a heavy economic burden. The role of microRNA-146b (miR-146b) in HF remain largely unknown. This study aims to explore the role and mechanism of miR-146b in HF. Method: We applied Reverse transcription-polymerase chain reaction (RT-PCR) to search for differential microRNAs between myocardial tissues of heart failure patients and controls. We also used RT-PCR to detect the miR-146b expression in primary neonatal mouse cardiomyocytes (NMCMs) and mice models of doxorubicin induced HF. In vivo experiments, echocardiography was performed at baseline and weeks 6. After that we harvested mice' heart and evaluated the cardiomyocyte with hematoxylin and eosin (HE), Masson trichrome staining and TUNEL staining. Through bioinformatics analysis, we found HIF-1α might be the target gene of miR-146b which validated by luciferase reporter gene assay. Subsequently, mRNA and protein expression levels of HIF-1α were detected by overexpression or inhibition of miR-146b in primary NMCMs. Results: We found that miR-146b expression was decreased in myocardial tissues of HF patients compared with controls (p < 0.01). MiR-146b levels were notably down regulated in HF models. MiR-146b knockout mice showed a more pronounced decrease in cardiac function and more severe myocardial fibrosis and apoptosis than wild type. Meanwhile, over expression or repression of miR-146b in primary neonatal mouse cardiomyocytes could inhibit or upregulate HIF-1α mRNA and protein expression. Conclusion: Our study shows that miR-146b may be a protective factor for cardiomyocytes by modulating HIF-1α.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143060633","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":"Informing ICU Digital Twins: Dynamic Assessment of Cardiorespiratory Failure Trajectories in Patients with Sepsis.","authors":"Grace Yao Hou, Amos Lal, Phillip J Schulte, Yue Dong, Oguz Kilickaya, Ognjen Gajic, Xiang Zhong","doi":"10.1097/SHK.0000000000002536","DOIUrl":"https://doi.org/10.1097/SHK.0000000000002536","url":null,"abstract":"<p><strong>Abstract: </strong>Understanding clinical trajectories of sepsis patients is crucial for prognostication, resource planning, and to inform digital twin models of critical illness. This study aims to identify common clinical trajectories based on dynamic assessment of cardiorespiratory support using a validated electronic health record data that covers retrospective cohort of 19,177 patients with sepsis admitted to ICUs of Mayo Clinic Hospitals over eight-year period. Patient trajectories were modeled from ICU admission up to 14 days using an unsupervised machine learning two-stage clustering method based on cardiorespiratory support in ICU and hospital discharge status. Of 19,177 patients, 42% were female with a median age of 65 (IQR, 55-76) years, APACHE III score of 70 (IQR, 56-87), hospital length of stay (LOS) of 7 (IQR, 4-12) days, and ICU LOS of 2 (IQR, 1-4) days. Four distinct trajectories were identified: fast recovery (27% with a mortality rate of 3.5% and median hospital LOS of 3 (IQR, 2-15) days), slow recovery (62% with a mortality rate of 3.6% and hospital LOS of 8 (IQR, 6-13) days), fast decline (4% with a mortality rate of 99.7% and hospital LOS of 1 (IQR, 0-1) day), and delayed decline (7% with a mortality rate of 97.9% and hospital LOS of 5 (IQR, 3-8) days). Distinct trajectories remained robust and were distinguished by Charlston comorbidity index, Apache III scores, day 1 and day 3 SOFA (p < 0.001 ANOVA). These findings provide a foundation for developing prediction models and digital twin decision support tools, improving both shared decision-making and resource planning.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029344","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":"Dysregulated Clot Mechanics and Kinetics Impacted by Injury Severity, Predict Mortality After Trauma.","authors":"Andrew R Gosselin, Christopher G Bargoud, Abhishek Sawalkar, Shane Mathew, Ashley Toussaint, Matthew Greenen, Susette M Coyle, Marie Macor, Anandi Krishnan, Julie Goswami, Joseph S Hanna, Valerie Tutwiler","doi":"10.1097/SHK.0000000000002544","DOIUrl":"https://doi.org/10.1097/SHK.0000000000002544","url":null,"abstract":"<p><strong>Abstract: </strong>Introduction: Coagulopathy following traumatic injury impairs stable blood clot formation and exacerbates mortality from hemorrhage. Understanding how these alterations impact blood clot stability is critical to improving resuscitation. Furthermore, the incorporation of machine learning algorithms to assess clinical markers, coagulation assays and biochemical assays allows us to define the contributions of these factors to mortality. In this study, we aimed to quantify changes in clot formation and mechanics after traumatic injury and their correlation to mortality.Materials and Methods: Plasma was isolated from injured patients upon arrival to the emergency department prior to blood product administration, or procedural intervention. Coagulation kinetics and mechanics of healthy donors and patient plasma were compared with rheological, turbidity and thrombin generation assays. ELISA's were performed to determine tissue plasminogen activator (tPA) and D-dimer concentration. Recursive elimination with random forest models were used to assess the predictive strength of clinical and laboratory factors.Results: Sixty-three patients were included in the study. Median injury severity score (ISS) was 17, median age was 38 years, and mortality was 30%. Trauma patients exhibited reduced clot stiffness, increased fibrinolysis, and reduced thrombin generation compared to healthy donors. Deceased patients exhibited the greatest deviation from healthy levels. Fibrinogen, clot stiffness, D-dimer and tPA all demonstrated significant correlation to ISS. Machine-learning algorithms identified the importance of coagulation kinetics and clot structure on patient outcomes.Conclusions: Rheological markers of coagulopathy and biochemical factors are associated with injury severity and are highly predictive of mortality after trauma, providing evidence for integrated predictive models and therapeutic strategies.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029340","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}