BACKGROUND:The purpose of this study was to investigate the effects of interleukin-1β (IL-1β) stimulation on the protection of macrophage-derived exosomes miR-146a (M-IL-exo-146a) on sepsis-induced myocardial injury (SMI) in vitro and in vivo . MATERIALS AND METHODS:Macrophage-derived exosomes (M-exo) and IL-1β-stimulated macrophage exosomes (M-IL-exo) were isolated from macrophages of sepsis with or without IL-1β. The expressions of miR-146a in M-exo and M-IL-exo were detected by fluorescence quantitative PCR. Related molecular biology technologies were used to evaluate the role and mechanism of M-exo-146a and M-IL-exo-146a on SMI and the enhancing effect of IL-1β. RESULTS:Compared with M-exo, the expression of miR-146a in M-IL-exo was significantly increased. M-IL-exo-146a significantly alleviated SMI by decreasing the level of serum myocardial enzymes, serum and myocardial oxidative stress and cytokines, and improved myocardial mitochondrial imbalance. The mechanism responsible for IL-1β enhancing the production of IL-M-exo miR-146a was via JNK-1/2 signal pathway. The mechanism responsible for M-exo-IL-miR-146a protecting SMI was related to miR-146a inhibiting inflammatory response and mitochondrial function via MAPK4/Drp-1 signal pathway. CONCLUSIONS:This study provides a new strategy for the treatment of SMI by delivering M-IL-exo.

Ischemic/hypoxic injury significantly damages vascular function, detrimentally impacting patient outcomes. Changes in mitochondrial structure and function are closely associated with ischemia/hypoxia-induced vascular dysfunction. The mechanism of this process remains elusive. Using rat models of ischemia and hypoxic vascular smooth muscle cells (VSMCs), we combined transmission electron microscopy, super-resolution microscopy, and metabolic analysis to analyze the structure and function change of mitochondrial cristae. Multi-omics approaches revealed arginase 1 (Arg1) upregulation in ischemic VSMCs, confirmed by in vivo and in vitro knockout models showing Arg1’s protective effects on mitochondrial cristae, mitochondrial and vascular function, and limited the release of mtDNA. Mechanistically, Arg1 interacting with Mic10 led to mitochondrial cristae remodeling, together with hypoxia-induced VDAC1 lactylation resulting in the opening of MPTP and release of mtDNA of VSMCs. The released mtDNA led to PANoptosis of VSMCs via activation of the cGAS-STING pathway. ChIP-qPCR results demonstrated that lactate-mediated Arg1 up-regulation was due to H3K18la upregulation. VSMCs targeted nano-material PLGA-PEI-siRNA@PM-α-SMA (NP-siArg1) significantly improved vascular dysfunction. This study uncovers a new mechanism of vascular dysfunction following ischemic/hypoxic injury: a damaging positive feedback loop mediated by lactate-regulated Arg1 expression between the nucleus and mitochondria, leading to mitochondria cristae disorder and mtDNA release, culminating in VSMCs PANoptosis. Targeting VSMCs Arg1 inhibition offers a potential therapeutic strategy to alleviate ischemia/hypoxia-induced vascular impairments.

Postoperative cognitive dysfunction (POCD) negatively impacts patients’ post-surgery recovery, and, in severe cases, raises the risk of mortality. Nonetheless, the underlying mechanism of POCD remains incompletely elucidated, and there is a notable dearth of effective treatment strategies. A randomized allocation was conducted among a total of 90 patients who underwent arthroplasty surgery, with 45 patients assigned to the dexmedetomidine group and 45 patients assigned to the control group. The Dexmedetomidine (DEX) group received an intravenous infusion of 1 µg/kg dexmedetomidine for 10 min, followed by a maintenance dose of 0.4 µg/kg/h for 30 min before surgery completion; the control (CON) group received 0.9

Aim: This study aimed to elucidate whether the application of the mitochondrial division inhibitor Mdivi-1 can protect organ function and prolong the treatment window for traumatic hemorrhagic shock. Methods: Before definitive hemostasis treatment, Mdivi-1 (0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg) was administered to uncontrolled hemorrhagic shock (UHS) model rats. Lactate Ringer's solution plus hydroxyethyl starch (130/0.4) was used as a control. The effects of Mdivi-1 on blood loss; fluid demand; survival time; vital organ function; myocardial mitochondrial structure; mitochondrial function of the heart, liver, kidney, and intestine; and oxidative stress at 1 h after hypotensive resuscitation (50-60 mm Hg) were investigated. In addition, we investigated the effect of varying doses of Mdivi-1 on the maintenance time of hypotensive resuscitation without definitive hemostasis and the beneficial effect of Mdivi-1 after prolonging the duration of hypotensive resuscitation to 2 h. Results: Compared to conventional resuscitative fluid, Mdivi-1 significantly reduced blood loss and fluid demand, improved important organ functions during hypotensive resuscitation, improved animal survival, and reduced the incidence of early death. Mdivi-1 significantly alleviated oxidative stress injury, reduced mitochondrial damage, and restored myocardial mitochondrial structure and mitochondrial function of the heart, liver, kidney, and intestine. In addition, Mdivi-1 increased the maintenance time of hypotensive resuscitation and improved rat survival after the duration of hypotensive resuscitation was prolonged to 2 h. Conclusion: Mdivi-1 significantly prolonged the treatment window for traumatic hemorrhagic shock to 2 h in UHS model rats. The underlying mechanism may be that Mdivi-1 inhibits excessive mitochondrial fission and oxidative stress and improves the structure and function of mitochondria.

Background:Hemorrhagic shock was a leading cause of death worldwide, with myocardial injury being a primary affected organ. As commonly used solutions in fluid resuscitation, acetated Ringer's (AR) and Lactate Ringer's solution (LR) were far from perfect for their adverse reactions such as lactic acidosis and electrolyte imbalances. In previous studies, TPP@PAMAM-MR (TPP-MR), a novel nanocrystal resuscitation fluid has been found to protect against myocardial injury in septic rats. However, its role in myocardial injury in rats with hemorrhagic shock and underlying mechanism is unclear. Methods:The hemorrhagic shock rats and hypoxia-treated cardiomyocytes (H9C2) were utilized to investigate the impact of TPP-MR on cardiac function, mitochondrial function, and lipid peroxidation. The expressions of ferritin-related proteins glutathione peroxidase 4 (GPX4), Acyl CoA Synthase Long Chain Family Member 4 (ACSL4), and Cyclooxygenase-2(COX2) were analyzed through Western blotting to explore the mechanism of TPP-MR on hemorrhagic myocardial injury. Results:TPP-MR, a novel nanocrystalline resuscitation fluid, was synthesized using TPP@PAMAM@MA as a substitute for L-malic acid. We found that TPP-MR resuscitation significantly reduced myocardial injury reflected by enhancing cardiac output, elevating mean arterial pressure (MAP), and improving perfusion. Moreover, TPP-MR substantially prolonged hemorrhagic shock rats' survival time and survival rate. Further investigations indicated that TPP-MR improved the mitochondrial function of myocardial cells, mitigated the production of oxidative stress agents (ROS) and increased the glutathione (GSH) content. Additionally, TPP-MR inhibited the expression of the ferroptosis-associated GPX4 protein, ACSL4 and COX2, thereby enhancing the antioxidant capacity. Conclusion:The results showed that TPP-MR had a protective effect on myocardial injury in rats with hemorrhagic shock, and its mechanism might be related to improving the mitochondrial function of myocardial cells and inhibiting the process of ferroptosis.

Myocardial ischemia-reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK-MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex-treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1) phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI.

BACKGROUND:The purpose of this study was to investigate the effects of cardiac homing peptide (CHP) engineered bone marrow mesenchymal stem cells (BMMSc) derived exosomes (B-exo) loaded miRNA-499a-5p on doxorubicin (DOX) induced cardiotoxicity.METHODS:miRNA chip analysis was used to analyze the differences between DOX induced H9c2 cells and control group. CHP engineering was performed on BMMSc derived exosomes to obtain C-B-exo. miRNA-499a-5p mimic was introduced into C-B-exo by electroporation technology to obtain C-B-exo-miRNA-499a-5p. DOX was used to establish a model of cardiotoxicity to evaluate the effects of C-B-exo- miRNA-499a-5p in vivo and in vitro . Western blot, immunohistochemistry, immunofluorescence, and other molecular biology methods were used to evaluate the role and mechanism of C-B-exo-miRNA-499a-5p on DOX induced cardiotoxicity.RESULTS:miRNA chip analysis revealed that miRNA-499a-5p was one of the most differentially expressed miRNAs and significantly decreased in DOX induced H9c2 cells as compared to the control group. Exo-and B-exo have a double-layer membrane structure in the shape of a saucer. After engineering the CHP of B-exo, the results showed that the delivery of miRNA-499a-5p significantly increased and significantly reached the target organ (heart). The experimental results showed that C-B-exo-miRNA-499a-5p significantly improved electrocardiogram, decreased myocardial enzyme, serum and cardiac cytokines, improved cardiac pathological changes, inhibited CD38/MAPK/NF-κB signal pathway.CONCLUSIONS:In this study, C-B-exo-miRNA-499a-5p significantly improved DOX-induced cardiotoxicity via CD38/MAPK/NF-κB signal pathway, providing a new idea and method for the treatment of DOX induced cardiotoxicity.

目的 基于网络药理学方法探讨地榆皂苷Ⅰ对脓毒症大鼠急性肺损伤的保护作用及机制,并通过实验进行验证.方法 使用网络药理学方法预测地榆皂苷Ⅰ治疗脓毒症急性肺损伤的潜在靶点.采用盲肠结扎穿孔术复制大鼠脓毒症模型进行实验验证.将192只SD大鼠按随机数字表法分为假手术组(Sham组)、脓毒症组(Sep组)、常规治疗组(CT组)和地榆皂苷Ⅰ治疗组(ZgⅠ组).Sham组、Sep组给予无菌生理盐水,CT组和ZgⅠ组大鼠给予相应剂量的林格氏液和地榆皂苷Ⅰ.观察各组大鼠动脉血气、血清炎症因子、肺湿/干质量比、肺组织病理变化、肺血管通透性、肺静脉紧密连接蛋白1(ZO-1)和血管内皮钙黏蛋白(VE-cadherin)蛋白表达、72 h存活情况.结果 网络药理学结果显示,地榆皂苷Ⅰ治疗脓毒症的潜在靶点有47个,基因本体功能富集分析和京都基因与基因组百科全书通路富集分析结果显示,其机制可能与活性氧族代谢正向调控(positive regulation of reactive oxygen species metabolic process)、损伤修复(would healing)、内皮细胞增殖调控(regulation to endothelial cell proliferation)、细胞激活(cell activation)、血管发生(blood vessel development)、氧化应激反应(response to oxidative stress)等生物学过程和细胞凋亡(apoptosis)、紧密连接(tight junction)、缺氧诱导因子1信号通路(HIF-1αsignaling pathway)等信号通路有关.实验验证结果显示,与Sham组比较,Sep组大鼠动脉氢离子浓度指数、动脉血氧分压水平显著降低(P<0.05),二氧化碳分压水平、血清肿瘤坏死因子α、白细胞介素6水平显著升高(P<0.05);肺湿/干质量比显著升高(P<0.05);肺静脉ZO-1、VE-cadherin蛋白表达水平显著降低(P<0.05);72 h存活率明显降低,存活时间显著缩短(P<0.05);肺组织病理观察结果显示,大鼠肺泡出现大范围破裂,肺泡壁增厚并伴有水肿,有明显炎性细胞浸润;肺血管通透性观察结果显示,大鼠肺表面颜色暗淡,有大量伊文思蓝渗出,左下肺呈明显深蓝色.与Sep组比较,CT组和ZgⅠ组以上指标水平大部分显著逆转(P<0.05),肺组织病理和肺血管通透性均明显改善,其中ZgⅠ组恢复程度大于CT组,接近Sham组结果.结论 地榆皂苷Ⅰ可显著减轻脓毒症大鼠炎症反应及急性肺损伤,其机制与血管功能和紧密连接信号通路有关.

Background:Intestinal barrier dysfunction is an important complication of sepsis, while the treatment is limited. Recently, parthenolide (PTL) has attracted much attention as a strategy of sepsis, but whether nano parthenolide (Nano PTL) is therapeutic in sepsis-induced intestinal barrier dysfunction is obscured.Methods:In this study, cecal ligation and puncture (CLP)-induced sepsis rats and lipopolysaccharide (LPS)-stimulated intestinal epithelial cells (IECs) were used to investigate the effect of PTL on intestinal barrier dysfunction. Meanwhile, we synthesized Nano PTL and compared the protective effect of Nano PTL with ordinary PTL on intestinal barrier function in septic rats and IECs. Network pharmacology and serotonin 2A (5-HTR2A) inhibitor were used to explore the mechanism of PTL on the intestinal barrier function of sepsis.Results:The encapsulation rate of Nano PTL was 95±1.5%, the drug loading rate was 11±0.5%, and the average uptake rate of intestinal epithelial cells was 94%. Ordinary PTL and Nano PTL improved the survival rate and survival time of septic rats, reduced the mean arterial pressure and the serum level of inflammatory cytokines, and protected the liver and kidney functions in vivo, and increased the value of transmembrane resistance (TEER) reduced the reactive oxygen species (ROS) and apoptosis in IECs in vitro through 5-HTR2A. Nano PTL had better effect than ordinary PTL.Conclusion:Ordinary PTL and Nano PTL can protect the intestinal barrier function of septic rats by inhibiting apoptosis and ROS through up-regulating 5-HTR2A, Nano PTL is better than ordinary PTL.

Sepsis-induced myocardial dysfunction (SIMD) is a prevalent and severe form of organ dysfunction with elusive underlying mechanisms and limited treatment options.In this study, the cecal ligation and puncture and lipopolysaccharide (LPS) were used to reproduce sepsis model in vitro and vivo.The level of voltage-dependent anion channel 2 (VDAC2) malonylation and myocardial malonyl-CoA were detected by mass spectrometry and LC-MS-based metabolomics.Role of VDAC2 malonylation on cardiomyocytes ferroptosis and treatment effect of mitochondrial targeting nano material TPP-AAV were observed.The results showed that VDAC2 lysine malonylation was significantly elevated after sepsis.In addition, the regulation of VDAC2 lysine 46 (K46) malonylation by K46E and K46Q mutation affected mitochondrial-related ferroptosis and myocardial injury.The molecular dynamic simulation and circular dichroism further demonstrated that VDAC2 malonylation altered the N-terminus structure of the VDAC2 channel, causing mitochondrial dysfunction, increasing mitochondrial ROS levels, and leading to ferroptosis.Malonyl-CoA was identified as the primary inducer of VDAC2 malonylation.Furthermore, the inhibition of malonyl-CoA using ND-630 or ACC2 knock-down significantly reduced the malonylation of VDAC2, decreased the occurrence of ferroptosis in cardiomyocytes, and alleviated SIMD.The study also found that the inhibition of VDAC2 malonylation by synthesizing mitochondria targeting nano material TPP-AAV could further alleviate ferroptosis and myocardial dysfunction following sepsis.In summary, our findings indicated that VDAC2 malonylation plays a crucial role in SIMD and that targeting VDAC2 malonylation could be a potential treatment strategy for SIMD.

BackgroundTo identify differentially expressed lipid metabolism-related genes (DE-LMRGs) responsible for immune dysfunction in sepsis. MethodsThe lipid metabolism-related hub genes were screened using machine learning algorithms, and the immune cell infiltration of these hub genes were assessed by CIBERSORT and Single-sample GSEA. Next, the immune function of these hub genes at the single-cell level were validated by comparing multiregional immune landscapes between septic patients (SP) and healthy control (HC). Then, the support vector machine-recursive feature elimination (SVM-RFE) algorithm was conducted to compare the significantly altered metabolites critical to hub genes between SP and HC. Furthermore, the role of the key hub gene was verified in sepsis rats and LPS-induced cardiomyocytes, respectively. ResultsA total of 508 DE-LMRGs were identified between SP and HC, and 5 hub genes relevant to lipid metabolism (MAPK14, EPHX2, BMX, FCER1A, and PAFAH2) were screened. Then, we found an immunosuppressive microenvironment in sepsis. The role of hub genes in immune cells was further confirmed by the single-cell RNA landscape. Moreover, significantly altered metabolites were mainly enriched in lipid metabolism-related signaling pathways and were associated with MAPK14. Finally, inhibiting MAPK14 decreased the levels of inflammatory cytokines and improved the survival and myocardial injury of sepsis. ConclusionThe lipid metabolism-related hub genes may have great potential in prognosis prediction and precise treatment for sepsis patients.

Background Sepsis is a life-threatening disease with a poor prognosis, and metabolic disorders play a crucial role in its development. This study aims to identify key metabolites that may be associated with the accurate diagnosis and prognosis of sepsis. Methods Septic patients and healthy individuals were enrolled to investigate metabolic changes using non-targeted liquid chromatography-high-resolution mass spectrometry metabolomics. Machine learning algorithms were subsequently employed to identify key differentially expressed metabolites (DEMs). Prognostic-related DEMs were then identified using univariate and multivariate Cox regression analyses. The septic rat model was established to verify the effect of phenylalanine metabolism-related gene MAOA on survival and mean arterial pressure after sepsis. Results A total of 532 DEMs were identified between healthy control and septic patients using metabolomics. The main pathways affected by these DEMs were amino acid biosynthesis, phenylalanine metabolism, tyrosine metabolism, glycine, serine and threonine metabolism, and arginine and proline metabolism. To identify sepsis diagnosis-related biomarkers, support vector machine (SVM) and random forest (RF) algorithms were employed, leading to the identification of four biomarkers. Additionally, analysis of transcriptome data from sepsis patients in the GEO database revealed a significant up-regulation of the phenylalanine metabolism-related gene MAOA in sepsis. Further investigation showed that inhibition of MAOA using the inhibitor RS-8359 reduced phenylalanine levels and improved mean arterial pressure and survival rate in septic rats. Finally, using univariate and multivariate cox regression analysis, six DEMs were identified as prognostic markers for sepsis. Conclusions This study employed metabolomics and machine learning algorithms to identify differential metabolites that are associated with the diagnosis and prognosis of sepsis patients. Unraveling the relationship between metabolic characteristics and sepsis provides new insights into the underlying biological mechanisms, which could potentially assist in the diagnosis and treatment of sepsis. Trial registration This human study was approved by the Ethics Committee of the Research Institute of Surgery (2021–179) and was registered by the Chinese Clinical Trial Registry (Date: 09/12/2021, ChiCTR2200055772).

Background: The precise diagnostic and prognostic biological markers were needed in immunotherapy for sepsis. Considering the role of necroptosis and immune cell infiltration in sepsis, differentially expressed necroptosis-related genes (DE-NRGs) were identified, and the relationship between DE-NRGs and the immune microenvironment in sepsis was analyzed.Methods: Machine learning algorithms were applied for screening hub genes related to necroptosis in the training cohort. CIBERSORT algorithms were employed for immune infiltration landscape analysis. Then, the diagnostic value of these hub genes was verified by the receiver operating characteristic (ROC) curve and nomogram. In addition, consensus clustering was applied to divide the septic patients into different subgroups, and quantitative real-time PCR was used to detect the mRNA levels of the hub genes between septic patients (SP) (n = 30) and healthy controls (HC) (n = 15). Finally, a multivariate prediction model based on heart rate, temperature, white blood count and 4 hub genes was established.Results: A total of 47 DE-NRGs were identified between SP and HC and 4 hub genes (BACH2, GATA3, LEF1, and BCL2) relevant to necroptosis were screened out via multiple machine learning algorithms. The high diagnostic value of these hub genes was validated by the ROC curve and Nomogram model. Besides, the immune scores, correlation analysis and immune cell infiltrations suggested an immunosuppressive microenvironment in sepsis. Septic patients were divided into 2 clusters based on the expressions of hub genes using consensus clustering, and the immune microenvironment landscapes and immune function between the 2 clusters were significantly different. The mRNA levels of the 4 hub genes significantly decreased in SP as compared with HC. The area under the curve (AUC) was better in the multivariate prediction model than in other indicators.Conclusion: This study indicated that these necroptosis hub genes might have great potential in prognosis prediction and personalized immunotherapy for sepsis.

Sepsis is a heterogeneous disease state triggered by an uncontrolled inflammatory host response with high mortality and morbidity in severely ill patients. Unfortunately, the treatment effectiveness varies among sepsis patients and the underlying mechanisms have yet to be elucidated. The present aim is to explore featured metabolism-related genes that may become the biomarkers in patients with sepsis. In this study, differentially expressed genes (DEGs) between sepsis and non-sepsis in whole blood samples were identified using two previously published datasets (GSE95233 and GSE54514). A total of 66 common DEGs were determined, namely, 52 upregulated and 14 downregulated DEGs. The Gene Set Enrichment Analysis (GSEA) results indicated that these DEGs participated in several metabolic processes including carbohydrate derivative, lipid, organic acid synthesis oxidation reduction, and small-molecule biosynthesis in patients with sepsis. Subsequently, a total of 8 hub genes were screened in the module with the highest score from the Cytoscape plugin cytoHubba. Further study showed that these hub DEGs may be robust markers for sepsis with high area under receiver operating characteristic curve (AUROC). The diagnostic values of these hub genes were further validated in myocardial tissues of septic rats and normal controls by untargeted metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS). Immune cell infiltration analysis revealed that different infiltration patterns were mainly characterized by B cells, T cells, NK cells, monocytes, macrophages, dendritics, eosinophils, and neutrophils between sepsis patients and normal controls. This study indicates that metabolic hub genes may be hopeful biomarkers for prognosis prediction and precise treatment in sepsis patients.

BACKGROUND:Myocardial dysfunction played a vital role in organ damage after sepsis. Fluid resuscitation was the essential treatment in which Lactate Ringer's solution (LR) was commonly used. Since LR easily led to hyperlactatemia, its resuscitation effect was limited. Malate Ringer's solution (MR) was a new resuscitation crystal liquid. Whether MR had a protective effect on myocardial injury in sepsis and the relevant mechanism need to be studied. METHODS:The cecal ligation and puncture (CLP) inducing septic model and lipopolysaccharide (LPS) stimulating cardiomyocytes were used, and the cardiac function, the morphology and function of mitochondria were observed. The protective mechanism of MR on myocardial injury was explored by proteomics. Then the effects of TPP@PAMAM-MR, which consisted of the mitochondria- targeting polymer embodied malic acid, was further observed. RESULTS:Compared with LR, MR resuscitation significantly prolonged survival time, improved the cardiac function, alleviated the damages of liver, kidney and lung following sepsis in rats. The proteomics of myocardial tissue showed that differently expressed proteins between MR and LR infusion involved oxidative phosphorylation, apoptosis. Further study found that MR decreased ROS, improved the mitochondrial morphology and function, and ultimately enhanced mitochondrial respiration and promoted ATP production. Moreover, MR infusion decreased the expression of apoptosis-related proteins and increased the expression of anti-apoptotic proteins. TPP@PAMAM@MA was a polymer formed by wrapping L-malic acid with poly amido amine (PAMAM) modified triphenylphosphine material. TPP@PAMAM-MR (TPP-MR), which was synthesized by replacing the L-malic acid of MR with TPP@PAMAM@MA, was more efficient in targeting myocardial mitochondria and was superior to MR in protecting the sepsis-inducing myocardial injury. CONCLUSION:MR was suitable for protecting myocardial injury after sepsis. The mechanism was related to MR improving the function and morphology of cardiomyocyte mitochondria and inhibiting cardiomyocyte apoptosis. The protective effect of TPP-MR was superior to MR.

Chronic obstructive pulmonary disease (COPD) is a group of lung diseases characterized by limited airflow. COPD has many complications. COPD complicated with intestinal injury is one of the main complications. The aim of the present study was to reveal the material basis of COPD complicated with intestinal injury. 221 COPD patients were enrolled in this study. The metabolites in serum of COPD patients and healthy people were analyzed by ultra-high performance liquid chromatography (UPLC) and quadrupole time-of-flight mass spectrometry (TOF-MS). The role and mechanisms of the metabolic biomarkers from lung to intestine were investigated with xanthine oxidase (XO), heat shock protein 70 (HSP70) knockout mice, intestinal flora analysis and an isotopic tracking method. Hypoxanthine (Hyp) was identified one of the most significant changed metabolites in serum of COPD patients, it could shuttle from the lungs to intestine to mediate the intestine injury. Silence of or knocking out XO and HSP70 aggravated colon tissue injury of COPD. 15N13C labeled Hyp injected via trachea was detected in colon tissue. The possible mechanism of Hyp-mediated intestinal tissue injury was through HSP70/Nrf-2 signaling pathway. Hyp was an important biomarker of COPD patients, which can mediate the intestinal tissue injury. The mechanism was related to intestinal flora and HSP70/Nrf-2 signaling pathway. This finding provided a theoretical and experimental basis for COPD complicated with intestinal injury.Trial Registration Details: Clinical Trials: www.chictr.org.cn: chiCTR170019814Funding Information: This research was supported by National Natural Science Foundation of China (81400800).Declaration of Interests: The authors declare no conflict of interest.Ethics Approval Statement: WT mice (ICR, 6 weeks, 16-18g), xanthine oxidase (XO) KO mice (ICR, XO-/- , 6 weeks, 16-18g) and HSP70 (ICR, HSP70-/-, 6 weeks, 16-18g) were obtained from the Cyagen Biosciences Inc. and the ICR mice (8 weeks, 18-20 g) were obtained from Army Medical Center, Army Medical University, and the Affiliated Nanjing Hospital of Nanjing University of Chinese Medicine. All animal operations were approved by the Research Council and Animal Care and Use Committee of Animal Center of Army Medical Center, Army Medical University, and the Affiliated Nanjing Hospital of Nanjing University of Chinese Medicine. All patient experiments were performed under the guidance of the Helsinki Declaration and approved by the Research Council of Affiliated Nanjing Hospital of Nanjing University of Chinese Medicine (KY2017019).

Adrenodoxin (Adx) as an important factor in oxidative stress system, Adx is involved in the regulation of mitochondrial homeostasis. However, its specific mechanism is not clear. The purpose of this paper was to investigate the effect of Adx on mitochondria in sepsis pneumonia (SP) and at the same time, the intervention effect of graphitized-forsythoside A (Gra-FA) was evaluated.Sepsis mouse model and A549 cell model were established by lipopolysaccharide (LPS). Cytokines and Related oxidative stress indicators in serum and lung of mice and supernatant of A549 cells were detected by enzyme-linked immunosorbent assay (ELISA). Hematoxylin- eosin (HE) staining was used to observe the pathological changes in lung of LPS mice. Western blot, immunohistochemistry and immunofluorescence were used to detect the expression of Adx and NLRP3 inflammasome in lung of septic mice and A549 cells. Mitochondrial function (mitochondrial respiration) test was used to evaluate the effect of Adx on pulmonary mitochondrial function in sepsis. Molecular docking and molecular dynamics evaluation of the interaction of FA and Adx and the interaction of Adx and NLRP3, severally. Adx knockout mice, Adx silenced A549 cells were used to verify the mechanism of Gra-FA on SP.The results shown that Adx was increased in sepsis as compared with WT group. It was also found that the increase of Adx was accompanied by the activation of NLRP3 inflammasome. Adx caused mitochondrial dysfunctions in lung tissue of septic mice by activating NLRP3 inflammasome. Knockout of Adx or silenced of Adx markedly decreased NLRP3 inflammasome led to improve mitochondrial dysfunctions in lung tissue of sepsis. At the same time, the results showed that Gra-FA significantly reduced NLRP3 by inhibiting Adx, and then improved the mitochondrial function. Molecular docking shown that FA has good interaction with Adx. In addition, molecular dynamics results showed that Adx has good affinity and regulation for NLRP3.Adx could disrupt the mitochondrial function of sepsis lung tissue by activating NLRP3. The deletion of Adx could significantly improve the mitochondrial function. At the same time, Gra-FA could improve the concentration of pneumonia by inhibiting NLRP3 activation by Adx.Funding: None to declare. Conflict of Interest: None to declare. Ethical Approval: All animals’ operations were approved by the Research Council and Animal Care and Use Committee of Animal Center of Army Medical Center, Army Medical University and the Affiliated Nanjing Hospital of Nanjing University of Chinese Medicine.

Objective To investigate the protective effects of parthenolide (PTL) on intestinal barrier function in septic rats. Methods The septic model of rats was established by cecal ligation and puncture (CLP), and SD rats (200±20 g, male/female) were randomly divided into 6 groups: normal control (NC) group, sepsis (Sep) group, conventional treatment (LR) group (lactated Ringer's solution resuscitation+dopamine+cefuroxime sodium), and parthenolide (PTL) groups (1, 5 and 10 mg/kg parthenolide respectively on the basis of LR group). The changes of arterial blood pressure, survival rate and survival time of rats in each group were observed, and the optimal concentration of parthenolide in the treatment was determined. Moreover, the effects of parthenolide (at the optimal concentration) on the intestinal permeability, intestinal pathology, inflammatory cytokine levels, as well as liver and kidney functions in septic rats were further investigated. Results As compared with the NC group, the survival rate and survival time of septic rats were significantly decreased, so was the mean arterial pressure (MAP), while the levels of blood inflammatory cytokines were increased, and the liver and kidney functions were damaged. Conventional treatment improved the survival rate and survival time of septic rats to a certain extent, reduced the levels of inflammation cytokines and alleviated the liver and kidney damages. When compared with the LR group, the survival rates of 1, 5, and 10 mg/kg PTL groups were increased by 6.3%, 43.8%, and 18.8%, respectively, and the MAP in the PTL groups was elevated by 1.4%, 12.8%, and 7.1%, respectively, with those of 5 mg/kg PTL more significant. Further research found that PTL remarkably ameliorated the intestinal barrier function in septic rats, shown as a 55.1% reduction in the content of intestinal Evans blue (EB), a 69.5% decline in blood D-lactic acid concentration as compared with the LR group (P < 0.05), along with an improvement in intestinal epithelial structure, and a decrease in epithelial cell necrosis. In addition, PTL reduced the inflammatory cytokine levels greatly and improved the liver and kidney functions in septic rats. Conclusion PTL shows obvious protective effects on the intestinal barrier function of septic rats, and its mechanism may be related to the inhibition of septic inflammatory response.

Objective To investigate the protective effects of sterofundin on myocardial injury in septic rats. Methods A total of 280 SPF SD rats (half male and female, 12~14 weeks old, 200~220 g) were randomly divided into 4 groups: sham operation (Sham) group, sepsis (Sep) group, conventional treatment (Ct) group (with Ringer's lactate solution+dopamine+cefuroxime sodium), and malate ringer's solution (Mr) group (with sterofundin+dopamine+cefuroxime sodium). The rat model of sepsis was inflicted by cecal ligation and puncture (CLP). Subsequently, the effects of sterofundin treatment on the myocardial injury, cardiac output (CO), oxygen supply and consumption, liver and kidney perfusion, liver and kidney functions, survival time and survival rate of septic rats were observed. Results The cardiac output (CO), cardiac index (CI) and stroke index (SI) were significantly decreased in the Sep group, while the injuries were improved to some extent in the Ct group (P < 0.05). As compared with the Sep group, the improvement was more obvious in the Mr group, with CO, CI and SI values increased by 48.9%, 52.9% and 21.7% respectively, and the values were also greatly higher than those in the Ct group (P < 0.05). The mean arterial blood pressure was remarkably declined to about 70 mmHg in the Sep group, slightly improved to around 90 mmHg in the Ct group, and notably elevated in the Mr group by 43.2% when compared with the Sep group (P < 0.05). In addition, the liver and kidney functions were significantly ameliorated in the Mr group, along with decreased troponin T and lactate dehydrogenase, enhanced oxygen supply and consumption, alleviated myocardial interstitial edema and less myocardial fiber breakage, which greatly improved the survival rate of animals (P < 0.05). Conclusion Sterofundin obviously improves the heart function and thus plays a protective role in organ functions in septic rats.

INTRODUCTION:Vascular leakage plays a vital role in sepsis-induced multi-organ dysfunction. Currently, no specific measures are available for vascular leakage. Ferroptosis, as a recently recognized form of cell death, plays a crucial role in cell dysfunction. It is still unknown whether ferroptosis participates in the occurrence of organ dysfunction following sepsis. Our previous study showed that dexmedetomidine (Dex) could alleviate sepsis-induced organ dysfunction. However, whether the mechanism is related to ferroptosis is not clear.METHODS:The publicly available datasets of septic patients were reanalyzed, and septic models in vivo and vitro by cecal ligation and puncture and lipopolysaccharide-stimulated vascular endothelial cells (VECs) were applied. The occurrence of ferroptosis in septic patients and rats was observed, and the protective effects of Dex on ferroptosis, and related mechanisms on regulating metabolic reprogramming and mitochondrial fission were further studied.RESULTS:The transcriptomics data of patients from the GEO database showed that ferroptosis was closely related to sepsis. Sepsis induced significant ferroptosis in VECs by metabolomics analysis. The level of lipid peroxidation was increased in VECs, and the mitochondrial cristae was decreased after sepsis. Metabolomics analysis showed that Dex activated the pentose phosphate pathway and increased glutathione in VECs via up-regulation of G6PD expression. Dex could antagonize sepsis-induced the decrease in the level of Nrf2. The Nrf2 inhibitor reversed the protective effect of Dex on ferroptosis. Further study showed that Dex significantly alleviated sepsis-induced mitochondrial over-division, improved mitochondrial function, and decreased ROS, further inhibiting the ferroptosis of VECs. Dex alleviated the permeability of vessels by reducing ferroptosis and enhanced the intercellular junction of VECs.CONCLUSION:Dex protects vascular leakage following sepsis by inhibiting ferroptosis. The mechanism is mainly related to metabolic reprogramming via Nrf2 up-regulation and inhibition of mitochondrial fission.