|
1
|
Tan R, Yan Y, Yang H, Li Q, Guo H, Yang Z, Han X, Du Q. Clinical efficacy of ulinastatin in patients with pulmonary edema: A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 2025; 104:e41145. [PMID: 40184111 PMCID: PMC11709197 DOI: 10.1097/md.0000000000041145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 12/09/2024] [Accepted: 12/12/2024] [Indexed: 04/05/2025] Open
Abstract
OBJECTIVE To methodically assess the clinical impact of ulinastatin on patients suffering from pulmonary edema. METHODS PubMed, Web of Science, Cochrane Library, Embase, Chinese National Knowledge Infrastructure (CNKI), Wanfang data, Chinese Scientific Journal Database (VIP), and Chinese Biomedical Literature Database (CBM) databases were searched using such keywords as ulinastatin, pulmonary edema, and randomized controlled trial (RCT). The search time was from the establishment of the database to August 2023. Two researchers were responsible for literature screening and data collection respectively. After the risk of bias in the included studies was evaluated, meta-analysis was performed using statistical software RevMan 5.4 and GRADE profiler software was used to evaluate evidence quality. RESULTS Nine RCTs were included in the meta-analysis. Meta-analysis results showed that compared with conventional treatment group, the incidence of pulmonary edema of the patients in the ulinastatin group decreased, with odds ratios (OR) of 0.36 (95% CI: 0.20, 0.657), extravascular pulmonary water index (EVLWI) decreased, with mean difference (MD) of -0.75 (95% CI: -1.32, -0.17), ventilator use time decreased, with MD of -2.86 (95% CI: -0.26, 0.23), the intensive care unit (ICU) length of stay decreased, with MD of -1.56 (95% CI: -1.75, -1.38). The pulmonary vascular permeability index (PVPI) decreased in ulinastatin group, with MD of -0.10 (95% CI: -0.24, 0.03), but the difference was not statistically significant. CONCLUSION Compared with conventional treatment, ulinastatin may reduce the incidence of pulmonary edema, decrease EVLWI, ventilator use time and the ICU length of stay in patients with pulmonary edema, but it could not reduce PVPI.
Collapse
Affiliation(s)
- Ruimin Tan
- School of Clinical Medical, North China University of Science and Technology, Tangshan, Hebei, China
- Critical care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yating Yan
- School of Clinical Medical, North China University of Science and Technology, Tangshan, Hebei, China
- Critical care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Huihui Yang
- School of Clinical Medical, North China University of Science and Technology, Tangshan, Hebei, China
- Critical care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Qinghao Li
- Critical care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
- School of Graduate, Hebei Medical University, Shijiazhuang, Hebei, China
| | - He Guo
- Critical care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
- School of Graduate, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zinan Yang
- Critical care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
- School of Graduate, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xumin Han
- Critical care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
- School of Graduate, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Quansheng Du
- Critical care Department, Hebei General Hospital, Shijiazhuang, Hebei, China
| |
Collapse
|
|
2
|
Liu P, Wu Q, Li M. Efficacy of Ulinastatin in the Treatment of COVID-19: A Retrospective Study. Int J Gen Med 2024; 17:6421-6430. [PMID: 39735165 PMCID: PMC11681785 DOI: 10.2147/ijgm.s486434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 12/03/2024] [Indexed: 12/31/2024] Open
Abstract
Purpose This retrospective study aimed to evaluate the efficacy of ulinastatin in the treatment of COVID-19 patients compared to conventional therapy. Patients and Methods A total of 437 COVID-19 patients admitted to the Respiratory Oncology Department of our hospital between December 31, 2022, and July 8, 2023, were included in the study. Patients were classified into the observation group (n=62) receiving ulinastatin in addition to standard treatment and the control group (n=347) receiving standard treatment only. Clinical information, laboratory results, and treatment outcomes were collected and analyzed. Results The observation group showed an improvement in lymphocyte count compared to the control group. The clinical improvement rate in patients receiving ulinastatin for 7 days or longer was 92.1%, significantly higher than that of patients treated for less than 7 days (62.5%) and those receiving standard treatment (71.0%). No significant difference in total length of hospitalization was observed between the two groups, and no related adverse events occurred in either group. Conclusion Ulinastatin treatment improves lymphocyte counts in severe COVID-19 patients, and the clinical improvement rate is significantly higher with treatment duration of 7 days or longer. Larger-scale randomized controlled trials are warranted to further explore the role of ulinastatin in the management of COVID-19.
Collapse
Affiliation(s)
- Peng Liu
- School of Graduate, Tianjin Medical University, Tianjin, People’s Republic of China
- Department of Respiratory and Critical Care Medicine, Cangzhou Fifth Hospital (People’s Hospital of Qingxian), Cangzhou, People’s Republic of China
| | - Qi Wu
- Department of Respiratory Medicine, General Hospital of Tianjin Medical University, Tianjin, People’s Republic of China
| | - Mengjie Li
- Department of Respiratory and Critical Care Medicine, Cangzhou Fifth Hospital (People’s Hospital of Qingxian), Cangzhou, People’s Republic of China
| |
Collapse
|
|
3
|
He YR, Ding N, Han MC, He HY, Xuan LZ, Gu ZY, Zhong M, Ju MJ. Identification of common core genes and pathways in childhood sepsis and cancer by bioinformatics analysis. Discov Oncol 2024; 15:749. [PMID: 39636505 PMCID: PMC11621270 DOI: 10.1007/s12672-024-01651-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 11/28/2024] [Indexed: 12/07/2024] Open
Abstract
INTRODUCTION Sepsis and cancer are both leading causes of death worldwide, and they share several pathophysiological characteristics. Some studies have suggested a possible association between sepsis and cancer; however, few have investigated the core genes involved in both diseases. METHODS Core genes common to both sepsis and cancer were identified using pediatric sepsis datasets (GEO: GSE26378, GSE4607, GSE8121 and GSE13904) and cancer databases (TCGA: BRCA, COADREAD, ESCA, KIRC, LIHC, LUAD, STAD). Gene Ontology (GO) and Reactome enrichment analyses, along with a protein-protein interaction (PPI) network analysis, were performed. Pharmacophore screening was applied to predict the targets of oxymatrine and ulinastatin, and potential target genes shared by both cancer and sepsis were identified. Survival analysis was performed. The association between the target genes and tumor size and number of positive lymph nodes was investigated by Pearson correlation analysis. The association between the target genes and tumor stage was investigated by Fisher's exact test. Molecular docking analysis was performed to evaluate the affinity of the candidate drugs for their targets. RESULTS A total of 641 common genes were identified. GO enrichment analysis showed that common genes were enriched in neutrophil degranulation, inflammatory response and innate immune response. Reactome enrichment analysis showed that common genes were enriched in neutrophil degranulation, interleukin-4 and interleukin-13 signaling, transcriptional regulation of granulopoiesis and interleukin-10 signaling. The PPI network showed that the top 10 core genes were TLR4, IL1B, IL10, ITGAM, TLR2, PTPRC, CDK1, FOS, MMP9 and ITGB2. The survival analysis showed that the high expression of BCAT1, CSAD, G6PD, GM2A, MMP9, PYGL and TOP2A was associated with poorer prognosis in several cancers. Molecular docking showed that oxymatrine and ulinastatin can bind to protein targets with highly stable binding. CONCLUSIONS We identified genes with common effects on both childhood sepsis and cancer, which provides new insights into the association between sepsis and cancer. In addition, two drugs with potential clinical application value were identified. Further studies are required to validate the role of these common core genes in sepsis and cancer and to evaluate the potential utility of these drugs.
Collapse
Affiliation(s)
- Yi-Ran He
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Ni Ding
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Ming-Chen Han
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Hong-Yu He
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Li-Zhen Xuan
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Zhun-Yong Gu
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Ming Zhong
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Min-Jie Ju
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.
| |
Collapse
|
|
4
|
Wei X, Long M, Fan Z, Hou Y, Yang L, Du Y. Ulinastatin attenuates renal fibrosis by regulating AMPK/HIF-1α signaling pathway-mediated glycolysis. Sci Rep 2024; 14:28032. [PMID: 39543285 PMCID: PMC11564816 DOI: 10.1038/s41598-024-78092-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 10/28/2024] [Indexed: 11/17/2024] Open
Abstract
Renal fibrosis is a common outcome of chronic kidney diseases and glycolysis drives the development of renal fibrosis in damaged kidneys. Ulinastatin (UTI) is a broad-spectrum protease inhibitor with anti-inflammatory and antioxidant properties with anti-fibrosis effects. In this study, we aimed to verify whether UTI could exert anti-renal fibrosis effects by inhibiting glycolysis and explored the potential mechanisms. Renal fibrosis was induced in mice via unilateral ureteral obstruction (UUO). Transforming growth factor-β1 stimulates human kidney proximal tubular epithelial cells to undergo fibrotic changes. Histopathological staining was used to observe the pathological changes in the kidneys. The levels of fibrosis biomarkers, glycolytic enzymes, and key signaling molecules were determined using gene and protein assays. Cellular energy metabolism was measured using Seahorse XF24 analyzer. Modulated the activity of adenylate-activated protein kinase (AMPK) and hypoxia-inducible factor-1α (HIF-1α) to confirm that AMPK can regulate HIF-1α-mediated glycolysis. Furthermore, UTI and AMPK knockdown were combined to verify whether UTI could attenuate glycolysis via the AMPK pathway. UTI pretreatment improved UUO-induced renal injury and fibrosis. The expression of fibrosis biomarkers and glycolytic enzymes was reduced by UTI at both mRNA and protein levels. UTI treatment decreased the rate of glycolysis and the production of glycolytic intermediates in fibrotic cells and tissues. Furthermore, AMPK can regulate HIF-1α-mediated glycolysis in renal tubular epithelial cells. Finally, the attenuation of glycolysis by UTI was related to AMPK/HIF-1α pathway, and this effect was inhibited by knockdown AMPK. UTI can effectively alleviate renal fibrosis, which may be partly attributed to the reduction of glycolysis by regulating AMPK/HIF-1α pathway.
Collapse
Affiliation(s)
- Xuejiao Wei
- Department of Nephrology, The First Hospital of Jilin University, No.1 Xinmin Street, Chaoyang District, Changchun, Jilin, China
| | - Mengtuan Long
- Department of Nephrology, The First Hospital of Jilin University, No.1 Xinmin Street, Chaoyang District, Changchun, Jilin, China
| | - Zhongyu Fan
- Department of Nephrology, The First Hospital of Jilin University, No.1 Xinmin Street, Chaoyang District, Changchun, Jilin, China
| | - Yue Hou
- Department of Nephrology, The First Hospital of Jilin University, No.1 Xinmin Street, Chaoyang District, Changchun, Jilin, China
| | - Liming Yang
- Department of Nephrology, The First Hospital of Jilin University, No.1 Xinmin Street, Chaoyang District, Changchun, Jilin, China
| | - Yujun Du
- Department of Nephrology, The First Hospital of Jilin University, No.1 Xinmin Street, Chaoyang District, Changchun, Jilin, China.
| |
Collapse
|
|
5
|
Xu D, Shan Y, Liu Q, Liang P, Hao X, Zhang J, Yu Z, Li W, Gao F, Tao X, Gu Q, Ma Y, Chen W. Effectiveness of ulinastatin in critical care patients in real world: a retrospective multi-center study. Expert Rev Clin Pharmacol 2024:1-8. [PMID: 39351759 DOI: 10.1080/17512433.2024.2402433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 09/05/2024] [Indexed: 10/04/2024]
Abstract
OBJECTIVES Ulinastatin has been applied in various diseases associated with inflammation, but its effectiveness lacks real-world evidence. We aimed to evaluate the effectiveness of ulinastatin based on a real-world database in the intensive care unit (ICU) patients. METHODS This was a retrospective cohort study. ICU patient data from multi-centers in China were collected. Propensity score matching (PSM) was applied. The effectiveness of ulinastatin was evaluated by mortality, length of stay in the ICU and mechanical ventilation duration. Kaplan-Meier method was used to estimate the hazard ratio and plot the survival curve. RESULTS A total of 2036 patients were analyzed after PSM. Mortality was significantly lower in the ulinastatin group than in the non-ulinastatin group (hazard ratio for death: 0.77; 95% confidence interval: 0.62-0.96; p = 0.018). Ulinastatin significantly reduced mortality at 28 days (10.0% vs. 13.6%), 60 days (13.9% vs. 18.2%) and 90 days (14.7% vs. 18.5%), length of stay in the ICU (median 8.0 d vs. 13.0 d), and mechanical ventilation duration (median 24.0 h vs. 25.0 h; p < 0.05). CONCLUSIONS Ulinastatin was beneficial for patients in the ICU, mainly by reducing mortality, length of ICU stay, and mechanical ventilation duration. This study provides evidence of the clinical effectiveness of ulinastatin.
Collapse
Affiliation(s)
- Deduo Xu
- Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Yi Shan
- Department of Emergency and Critical Care Medicine, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Qinghua Liu
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Pei Liang
- Department of Pharmacy, Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xin Hao
- Dalian Medicinovo Technology Co. Ltd, Beijing, China
| | - Jinyuan Zhang
- Beijing Medicinovo Technology Co. Ltd, Beijing, China
| | - Ze Yu
- Beijing Medicinovo Technology Co. Ltd, Beijing, China
| | - Wenfang Li
- Department of Emergency and Critical Care Medicine, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Fei Gao
- Beijing Medicinovo Technology Co. Ltd, Beijing, China
| | - Xia Tao
- Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Qin Gu
- Department of Critical Care Medicine, Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yabin Ma
- Department of Pharmacy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wansheng Chen
- Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai, China
- The SATCM Key Laboratory for New Resources & Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| |
Collapse
|
|
6
|
Lin PH, Xu Y, Bali SK, Kim J, Gimeno A, Roberts ET, James D, Almeida NMS, Loganathan N, Fan F, Wilson AK, Jonathan Amster I, Moremen KW, Liu J, Jiménez-Barbero J, Huang X. Solid-Phase-Supported Chemoenzymatic Synthesis and Analysis of Chondroitin Sulfate Proteoglycan Glycopeptides. Angew Chem Int Ed Engl 2024; 63:e202405671. [PMID: 38781001 PMCID: PMC11772155 DOI: 10.1002/anie.202405671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 05/22/2024] [Accepted: 05/23/2024] [Indexed: 05/25/2024]
Abstract
Proteoglycans (PGs), consisting of glycosaminoglycans (GAGs) linked with the core protein through a tetrasaccharide linkage region, play roles in many important biological events. The chemical synthesis of PG glycopeptides is extremely challenging. In this work, the enzymes required for synthesis of chondroitin sulfate (CS) PG (CSPG) have been expressed and the suitable sequence of enzymatic reactions has been established. To expedite CSPG synthesis, the peptide acceptor was immobilized on solid phase and the glycan units were directly installed enzymatically onto the peptide. Subsequent enzymatic chain elongation and sulfation led to the successful synthesis of CSPG glycopeptides. The CS dodecasaccharide glycopeptide was the longest homogeneous CS glycopeptide synthesized to date. The enzymatic synthesis was much more efficient than the chemical synthesis of the corresponding CS glycopeptides, which could reduce the total number of synthetic steps by 80 %. The structures of the CS glycopeptides were confirmed by mass spectrometry analysis and NMR studies. In addition, the interactions between the CS glycopeptides and cathepsin G were studied. The sulfation of glycan chain was found to be important for binding with cathepsin G. This efficient chemoenzymatic strategy opens new avenues to investigate the structures and functions of PGs.
Collapse
Affiliation(s)
- Po-Han Lin
- Department of Chemistry, Michigan State University, East Lansing, Michigan, 48824, United States
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan, 48824, United States
| | - Yongmei Xu
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, 27599, United States
| | - Semiha Kevser Bali
- Department of Chemistry, Michigan State University, East Lansing, Michigan, 48824, United States
| | - Jandi Kim
- Department of Chemistry, University of Georgia, Athens, GA 30602, United States
| | - Ana Gimeno
- Chemical Glycobiology Lab, Center for Cooperative Research in Biosciences (CICbioGUNE), Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, 48009, Spain
| | - Elijah T Roberts
- Department of Chemistry, University of Georgia, Athens, GA 30602, United States
| | - Deepak James
- Department of Chemistry, Michigan State University, East Lansing, Michigan, 48824, United States
| | - Nuno M S Almeida
- Department of Chemistry, Michigan State University, East Lansing, Michigan, 48824, United States
| | - Narasimhan Loganathan
- Department of Chemistry, Michigan State University, East Lansing, Michigan, 48824, United States
| | - Fei Fan
- Department of Chemistry, Michigan State University, East Lansing, Michigan, 48824, United States
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan, 48824, United States
| | - Angela K Wilson
- Department of Chemistry, Michigan State University, East Lansing, Michigan, 48824, United States
| | - I Jonathan Amster
- Department of Chemistry, University of Georgia, Athens, GA 30602, United States
| | - Kelley W Moremen
- Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, United States
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, United States
| | - Jian Liu
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, 27599, United States
| | - Jesús Jiménez-Barbero
- Chemical Glycobiology Lab, Center for Cooperative Research in Biosciences (CICbioGUNE), Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, 48009, Spain
- Department of Inorganic & Organic Chemistry, Faculty of Science and Technology, University of the Basque Country, EHU-UPV, Leioa, 48940, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Madrid, 28029, Spain
| | - Xuefei Huang
- Department of Chemistry, Michigan State University, East Lansing, Michigan, 48824, United States
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan, 48824, United States
- Department of Biomedical Engineering, Michigan State University, East Lansing, Michigan, 48824, United States
| |
Collapse
|
|
7
|
Wu L, Xu D, Liu Y, Li W, Jiang W, Tao X, Zhang J, Yu Z, Gao F, Chen W, Lin Z, Shan Y. Ulinastatin shortens the length of ICU stay in critical patients with organ failure: A 7-year real-world study. Sci Prog 2024; 107:368504241272696. [PMID: 39140832 PMCID: PMC11325468 DOI: 10.1177/00368504241272696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2024]
Abstract
BACKGROUND Ulinastatin has been applied in a series of diseases associated with inflammation but its clinical effects remain somewhat elusive. OBJECTIVE We aimed to investigate the potential effects of ulinastatin on organ failure patients admitted to the intensive care unit (ICU). METHODS This is a single-center retrospective study on organ failure patients from 2013 to 2019. Patients were divided into two groups according to using ulinastatin or not during hospitalization. Propensity score matching was applied to reduce bias. The outcomes of interest were 28-day all-cause mortality, length of ICU stay, and mechanical ventilation duration. RESULTS Of the 841 patients who fulfilled the entry criteria, 247 received ulinastatin. A propensity-matched cohort of 608 patients was created. No significant differences in 28-day mortality between the two groups. Sequential organ failure assessment (SOFA) was identified as the independent risk factor associated with mortality. In the subgroup with SOFA ≤ 10, patients received ulinastatin experienced significantly shorter time in ICU (10.0 d [interquartile range, IQR: 7.0∼20.0] vs 15.0 d [IQR: 7.0∼25.0]; p = .004) and on mechanical ventilation (222 h [IQR:114∼349] vs 251 h [IQR: 123∼499]; P = .01), but the 28-day mortality revealed no obvious difference (10.5% vs 9.4%; p = .74). CONCLUSION Ulinastatin was beneficial in treating patients in ICU with organ failure, mainly by reducing the length of ICU stay and duration of mechanical ventilation.
Collapse
Affiliation(s)
- Lixue Wu
- Department of Emergency and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, China
- Department of Emergency and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Deduo Xu
- Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yanru Liu
- Department of Pharmacy, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Wenfang Li
- Department of Emergency and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Weiwei Jiang
- Department of Emergency and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xia Tao
- Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Jinyuan Zhang
- Beijing Medicinovo Technology Co., Ltd, Beijing, China
| | - Ze Yu
- Beijing Medicinovo Technology Co., Ltd, Beijing, China
| | - Fei Gao
- Beijing Medicinovo Technology Co., Ltd, Beijing, China
| | - Wansheng Chen
- Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, China
- The SATCM Key Laboratory for New Resources & Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhaofen Lin
- Department of Emergency and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yi Shan
- Department of Emergency and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, China
| |
Collapse
|
|
8
|
Forget MF, Wang HT, Carignan R, Dessureault A, Gravel M, Bienvenue J, Bouchard M, Durivage C, Coveney R, Munshi L. Critically Ill Older Adults' Representation in Intervention Trials: A Systematic Review. Crit Care Explor 2024; 6:e1107. [PMID: 38919511 PMCID: PMC11196082 DOI: 10.1097/cce.0000000000001107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2024] Open
Abstract
OBJECTIVES Older adults may be under-represented in critical care research, and results may not apply to this specific population. Our primary objective was to evaluate the prevalence of inclusion of older adults across critical care trials focused on common ICU conditions or interventions. Our secondary objective was to evaluate whether older age was used as a stratification variable for randomization or outcome analysis. DESIGN SETTING AND SUBJECTS We performed a systematic review of previously published systematic reviews of randomized controlled trials (RCTs) in critical care. We searched PubMed, Ovid, CENTRAL, and Cochrane from 2009 to 2022. Systematic reviews of any interventions across five topics: acute respiratory distress syndrome (ARDS), sepsis/shock, nutrition, sedation, and mobilization were eligible. MAIN RESULTS We identified 216 systematic reviews and included a total of 253 RCTs and 113,090 patients. We extracted baseline characteristics and the reported proportion of older adults. We assessed whether any upper age limit was an exclusion criterion for trials, whether age was used for stratification during randomization or data analysis, and if age-specific subgroup analysis was present. The most prevalent topic was sepsis (78 trials, 31%), followed by nutrition (62 trials, 25%), ARDS (39 trials, 15%), mobilization (38 trials, 15%), and sedation (36 trials, 14%). Eighteen trials (7%) had exclusion criteria based on older age. Age distribution with information on older adults prevalence was given in six trials (2%). Age was considered in the analysis of ten trials (5%) using analytic methods to evaluate the outcome stratified by age. Conclusions In this systematic review, the proportion of older critically ill patients is undetermined, and it is unclear how age is or is not an effect modifier or to what extent the results are valid for older adult groups. Reporting age is important to guide clinicians in personalizing care. These results highlight the importance of incorporating older critically ill patients in future trials to ensure the results are generalizable to this growing population.
Collapse
Affiliation(s)
- Marie-France Forget
- Department of Medicine, Division of Geriatric Medicine, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada
| | - Han Ting Wang
- Department of Medicine, Division of Critical Care Medicine, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada
| | - Raphaelle Carignan
- Department of Medicine, Division of Internal Medicine, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada
| | - Alexandre Dessureault
- Department of Medicine, Division of Internal Medicine, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada
| | - Mathieu Gravel
- Department of Medicine, Faculty of Medicine, Université de Laval, Québec, QC, Canada
| | - Jeanne Bienvenue
- Department of Medicine, Division of Internal Medicine, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada
| | - Maude Bouchard
- Department of Medicine, Division of Internal Medicine, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada
| | - Camille Durivage
- Department of Medicine, Division of Internal Medicine, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada
| | - Richard Coveney
- Teaching Division/Library, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’île-de-Montréal, Montréal, QC, Canada
| | - Laveena Munshi
- Interdepartmental Division of Critical Care, Sinai Health System, University of Toronto, Toronto, ON, Canada
| |
Collapse
|
|
9
|
Park SJ, Park SY, Kang SY, Kim JH, Heo JY, Yoo JY. The effect of ulinastatin on acute kidney injury in patients undergoing off-pump cardiac bypass surgery. J Cardiothorac Surg 2024; 19:96. [PMID: 38360763 PMCID: PMC10870510 DOI: 10.1186/s13019-024-02562-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 01/30/2024] [Indexed: 02/17/2024] Open
Abstract
BACKGROUND Ulinastatin, an anti-inflammatory and antioxidant trypsin inhibitor, has shown potential in mitigating acute kidney injury (AKI) and reducing serum creatinine levels after various surgeries. This retrospective study aimed to evaluate the effects of ulinastatin on AKI in patients undergoing off-pump coronary artery bypass (OPCAB) surgery. METHODS We hypothesized that the administration of ulinastatin could prevent AKI in OPCAB. Electrical medical records were reviewed to identify OPCAB patients between January 2015 and June 2020. The utilization of ulinastatin was randomly determined and applied during this period. Acute kidney injury was defined according to the KDIGO guideline, and its incidence was compared between the ulinastatin administration group and the control group. To investigate the effect of ulinastatin on renal function, multivariate logistic regression analysis was used to calculate propensity scores for each group. RESULTS A total 454 OPCAB were performed, and after following inclusion and exclusion process, 100 patients were identified in the ulinastatin group and 303 patients in the control group. Using 1:2 propensity score matching, we analyzed 100 and 200 patients in the ulinastatin and control groups. The incidence of AKI was similar between the groups (2.5% for the control group, 2.0% for the ulinastatin group, p > 0.999). However, the serum creatinine value on the first post-operative day were significantly lower in the ulinastatin group compared to the control group (0.774 ± 0.179 mg/dL vs 0.823 ± 0.216 mg/dL, P = 0.040), while no significant differences were observed for the other time points (P > 0.05). The length of ICU stay day was significantly shorter in the ulinastatin group (2.91 ± 2.81 day vs 5.22 ± 7.45 day, respectively, P < 0.001). CONCLUSIONS Ulinastatin did not have a significant effect on the incidence of AKI; it demonstrated the ability to reduce post-operative serum creatine levels at first post-operative day and shorten the length of ICU stay.
Collapse
Affiliation(s)
- Soo Jung Park
- Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-Gu, Suwon, Korea
| | - Sung Yong Park
- Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-Gu, Suwon, Korea
| | - Se Yoon Kang
- Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-Gu, Suwon, Korea
| | - Ji Ho Kim
- Department of Medical Sciences, Ajou University School of Medicine, Suwon, Korea
| | - Ji Yeong Heo
- Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-Gu, Suwon, Korea
| | - Ji Young Yoo
- Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-Gu, Suwon, Korea.
| |
Collapse
|
|
10
|
Yu T, Yan J, Wang R, Zhang L, Hu X, Xu J, Li F, Sun Q. Integrative Multiomics Profiling Unveils the Protective Function of Ulinastatin against Dextran Sulfate Sodium-Induced Colitis. Antioxidants (Basel) 2024; 13:214. [PMID: 38397811 PMCID: PMC10886110 DOI: 10.3390/antiox13020214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/30/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Ulcerative colitis is an inflammatory bowel disease with multiple pathogeneses. Here, we aimed to study the therapeutic role of ulinastatin (UTI), an anti-inflammatory bioagent, and its associated mechanisms in treating colitis. Dextran sulfate sodium was administrated to induce colitis in mice, and a subgroup of colitis mice was treated with UTI. The gut barrier defect and inflammatory manifestations of colitis were determined via histological and molecular experiments. In addition, transcriptomics, metagenomics, and metabolomics were employed to explore the possible mechanisms underlying the effects of UTI. We found that UTI significantly alleviated the inflammatory manifestations and intestinal barrier damage in the mice with colitis. Transcriptome sequencing revealed a correlation between the UTI treatment and JAK-STAT signaling pathway. UTI up-regulated the expression of SOCS1, which subsequently inhibited the phosphorylation of JAK2 and STAT3, thus limiting the action of inflammatory mediators. In addition, 16S rRNA sequencing illustrated that UTI maintained a more stable intestinal flora, protecting the gut from dysbiosis in colitis. Moreover, metabolomics analysis demonstrated that UTI indeed facilitated the production of some bile acids and short-chain fatty acids, which supported intestinal homeostasis. Our data provide evidence that UTI is effective in treating colitis and support the potential use of UTI treatment for patients with ulcerative colitis.
Collapse
Affiliation(s)
- Tianyu Yu
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (T.Y.); (J.Y.); (L.Z.); (X.H.)
| | - Jun Yan
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (T.Y.); (J.Y.); (L.Z.); (X.H.)
| | - Ruochen Wang
- Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China;
| | - Lei Zhang
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (T.Y.); (J.Y.); (L.Z.); (X.H.)
| | - Xiake Hu
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (T.Y.); (J.Y.); (L.Z.); (X.H.)
| | - Jiaxi Xu
- Department of Physiology and Pathophysiology, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China;
| | - Fanni Li
- Department of Talent Highland, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Qi Sun
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (T.Y.); (J.Y.); (L.Z.); (X.H.)
| |
Collapse
|
|
11
|
Giamarellos-Bourboulis EJ, Aschenbrenner AC, Bauer M, Bock C, Calandra T, Gat-Viks I, Kyriazopoulou E, Lupse M, Monneret G, Pickkers P, Schultze JL, van der Poll T, van de Veerdonk FL, Vlaar APJ, Weis S, Wiersinga WJ, Netea MG. The pathophysiology of sepsis and precision-medicine-based immunotherapy. Nat Immunol 2024; 25:19-28. [PMID: 38168953 DOI: 10.1038/s41590-023-01660-5] [Citation(s) in RCA: 102] [Impact Index Per Article: 102.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 09/21/2023] [Indexed: 01/05/2024]
Abstract
Sepsis remains a major cause of morbidity and mortality in both low- and high-income countries. Antibiotic therapy and supportive care have significantly improved survival following sepsis in the twentieth century, but further progress has been challenging. Immunotherapy trials for sepsis, mainly aimed at suppressing the immune response, from the 1990s and 2000s, have largely failed, in part owing to unresolved patient heterogeneity in the underlying immune disbalance. The past decade has brought the promise to break this blockade through technological developments based on omics-based technologies and systems medicine that can provide a much larger data space to describe in greater detail the immune endotypes in sepsis. Patient stratification opens new avenues towards precision medicine approaches that aim to apply immunotherapies to sepsis, on the basis of precise biomarkers and molecular mechanisms defining specific immune endotypes. This approach has the potential to lead to the establishment of immunotherapy as a successful pillar in the treatment of sepsis for future generations.
Collapse
Affiliation(s)
- Evangelos J Giamarellos-Bourboulis
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece
- Hellenic Institute for the Study of Sepsis, Athens, Greece
| | - Anna C Aschenbrenner
- Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Michael Bauer
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
| | - Christoph Bock
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Medical University of Vienna, Institute of Artificial Intelligence, Center for Medical Data Science, Vienna, Austria
| | - Thierry Calandra
- Service of Immunology and Allergy and Center of Human Immunology Lausanne, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Irit Gat-Viks
- The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Evdoxia Kyriazopoulou
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece
- Hellenic Institute for the Study of Sepsis, Athens, Greece
| | - Mihaela Lupse
- Infectious Diseases Hospital, University of Medicine and Pharmacy 'Iuliu Hatieganu', Cluj-Napoca, Romania
| | - Guillaume Monneret
- Joint Research Unit HCL-bioMérieux, EA 7426 'Pathophysiology of Injury-Induced Immunosuppression' (Université Claude Bernard Lyon 1 - Hospices Civils de Lyon, bioMérieux), Lyon, France
- Immunology Laboratory, Edouard Herriot Hospital - Hospices Civils de Lyon, Lyon, France
| | - Peter Pickkers
- Department of Intensive Care, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Joachim L Schultze
- Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
- PRECISE Platform for Single Cell Genomics and Epigenomics, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and the University of Bonn, Bonn, Germany
- Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Tom van der Poll
- Division of Infectious Diseases, Amsterdam University Medical Centers (Amsterdam UMC), Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, The Netherlands
| | - Frank L van de Veerdonk
- Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Alexander P J Vlaar
- Department of Intensive Care and Laboratory of Experimental Intensive Care and Anesthesiology L.E.C.A. Amsterdam Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Sebastian Weis
- Institute for Infectious Disease and Infection Control, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
- Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute-HKI, Jena, Germany
| | - W Joost Wiersinga
- Division of Infectious Diseases, Amsterdam University Medical Centers (Amsterdam UMC), Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, The Netherlands
| | - Mihai G Netea
- Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
- Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
| |
Collapse
|
|
12
|
Cao M, Wang G, Xie J. Immune dysregulation in sepsis: experiences, lessons and perspectives. Cell Death Discov 2023; 9:465. [PMID: 38114466 PMCID: PMC10730904 DOI: 10.1038/s41420-023-01766-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 12/03/2023] [Accepted: 12/06/2023] [Indexed: 12/21/2023] Open
Abstract
Sepsis is a life-threatening organ dysfunction syndrome caused by dysregulated host responses to infection. Not only does sepsis pose a serious hazard to human health, but it also imposes a substantial economic burden on the healthcare system. The cornerstones of current treatment for sepsis remain source control, fluid resuscitation, and rapid administration of antibiotics, etc. To date, no drugs have been approved for treating sepsis, and most clinical trials of potential therapies have failed to reduce mortality. The immune response caused by the pathogen is complex, resulting in a dysregulated innate and adaptive immune response that, if not promptly controlled, can lead to excessive inflammation, immunosuppression, and failure to re-establish immune homeostasis. The impaired immune response in patients with sepsis and the potential immunotherapy to modulate the immune response causing excessive inflammation or enhancing immunity suggest the importance of demonstrating individualized therapy. Here, we review the immune dysfunction caused by sepsis, where immune cell production, effector cell function, and survival are directly affected during sepsis. In addition, we discuss potential immunotherapy in septic patients and highlight the need for precise treatment according to clinical and immune stratification.
Collapse
Affiliation(s)
- Min Cao
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Guozheng Wang
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, L69 7BE, UK
- Coagulation, Liverpool University Hospitals NHS Foundation Trust, Liverpool, L7 8XP, UK
| | - Jianfeng Xie
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
| |
Collapse
|
|
13
|
Tao YN, Han Q, Jiao W, Yang LK, Wang F, Xue S, Shen M, Wang YH. Effects of ulinastatin therapy in deep vein thrombosis prevention after brain tumor surgery: A single-center randomized controlled trial. World J Clin Cases 2023; 11:7583-7592. [DOI: 10.12998/wjcc.v11.i31.7583] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 10/11/2023] [Accepted: 10/23/2023] [Indexed: 11/06/2023] Open
Abstract
BACKGROUND Venous thromboembolism (VTE) is a common neurosurgical complication after brain tumor resection, and its prophylaxis has been widely studied. There are no effective drugs in the clinical management of venous thromboembolism, and there is an absence of evidence-based medicine concerning the treatment of severe multiple traumas.
AIM To explore whether ulinastatin (UTI) can prevent VTE after brain tumor resection.
METHODS The present research included patients who underwent brain tumor resection. Patients received UTIs (400,000 IU) or placebos utilizing computer-based random sequencing (in a 1:1 ratio). The primary outcome measures were the incidence of VTE, coagulation function, pulmonary emboli, liver function, renal function, and drug-related adverse effects.
RESULTS A total of 405 patients were evaluated between January 2019 and December 2021, and 361 of these were initially enrolled in the study to form intention-to-treat, which was given UTI (n = 180) or placebo (n = 181) treatment in a random manner. There were no statistically significant differences in baseline clinical data between the two groups. The incidence of VTE in the UTI group was remarkably improved compared with that in the placebo group. UTI can improve coagulation dysfunction, pulmonary emboli, liver function, and renal function. No significant difference was identified between the two groups in the side effects of UTI-induced diarrhea, vomiting, hospital stays, or hospitalization costs. The incidence of allergies was higher in the UTI group than in the placebo group.
CONCLUSION The findings from the present research indicated that UTI can decrease the incidence of VTE and clinical outcomes of patients after brain tumor resection and has fewer adverse reactions.
Collapse
Affiliation(s)
- Yun-Na Tao
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Qian Han
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Wei Jiao
- Nursing, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Li-Kun Yang
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Fang Wang
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Shan Xue
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Meng Shen
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Yu-Hai Wang
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| |
Collapse
|
|
14
|
Wang SQ, Jiao W, Zhang J, Zhang JF, Tao YN, Jiang Q, Yu F. Ulinastatin in the treatment of severe acute pancreatitis: A single-center randomized controlled trial. World J Clin Cases 2023; 11:4601-4611. [PMID: 37469723 PMCID: PMC10353502 DOI: 10.12998/wjcc.v11.i19.4601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/16/2023] [Accepted: 06/02/2023] [Indexed: 06/30/2023] Open
Abstract
BACKGROUND Severe acute pancreatitis (AP) is one of the most common diseases of the gastrointestinal tract and carries a significant financial burden with high disability and mortality. There are no effective drugs in the clinical management of severe AP, and there is an absence of evidence-based medicine concerning the treatment of severe AP.
AIM To explore whether ulinastatin (UTI) can improve the outcome of severe AP.
METHODS The present research included patients who were hospitalized in intensive critical care units (ICUs) after being diagnosed with severe AP. Patients received UTI (400000 IU) or placebos utilizing computer-based random sequencing (in a 1:1 ratio). The primary outcome measures were 7-d mortality, clinical efficacy, inflammatory response, coagulation function, infection, liver function, renal function, and drug-related adverse effects were evaluated.
RESULTS A total of 181 individuals were classified into two groups, namely, the placebo group (n = 90) and the UTI group (n = 91). There were no statistically significant differences in baseline clinical data between the two groups. The 7-d mortality and clinical efficacy in the UTI group were remarkably improved compared with those in the placebo group. UTI can protect against hyperinflammation and improve coagulation dysfunction, infection, liver function, and renal function. UTI patients had markedly decreased hospital stays and hospitalization expenditures compared with the placebo group.
CONCLUSION The findings from the present research indicated that UTI can improve the clinical outcomes of patients with severe AP and has fewer adverse reactions.
Collapse
Affiliation(s)
- Su-Qin Wang
- Department of General Surgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Wei Jiao
- Department of Nursing, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Jing Zhang
- Department of Nursing, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Ju-Fen Zhang
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Yun-Na Tao
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Qing Jiang
- Department of General Surgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Feng Yu
- Department of General Surgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| |
Collapse
|
|
15
|
Qin N, Wang J, Peng X, Wang L. Pathogenesis and Management of Acute Necrotizing Encephalopathy. Expert Rev Neurother 2023; 23:641-650. [PMID: 37309119 DOI: 10.1080/14737175.2023.2224503] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 06/08/2023] [Indexed: 06/14/2023]
Abstract
INTRODUCTION During the COVID-19 pandemic, many cases of acute necrotizing encephalopathy (ANE) secondary to COVID-19 have been reported. ANE is characterized by a rapid onset, a fulminant course, and low morbidity and fatality rates. Therefore, clinicians need to be vigilant for such disorders, especially during the influenza virus and COVID-19 epidemics. AREAS COVERED The authors summarize the most recent studies on the clinical spectrum and treatment essentials of ANE to provide references for prompt diagnosis and improved treatment of this rare but fatal disease. EXPERT OPINION ANE is a type of necrotizing lesion of the brain parenchyma. There are two major types of reported cases. One is isolated and sporadic ANE, which is primarily caused by viral infections, particularly influenza and HHV-6 virus. The other type is familial recurrent ANE, which is caused by RANBP2 gene mutations. ANE patients have rapid progression and a very poor prognosis, with acute brain dysfunction occurring within days of viral infection and requiring admission to the intensive care unit. Clinicians still need to investigate and find solutions for the problems of early detection and treatment of ANE.
Collapse
Affiliation(s)
- Ningxiang Qin
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Wang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xi Peng
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Liang Wang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
16
|
Xu H, Jiao W, Zhang Y, Deng X, Dai R, Chen L. Effects of ulinastatin therapy in emergency severe multiple trauma: A single-center randomized controlled trial. Medicine (Baltimore) 2023; 102:e32905. [PMID: 36800599 PMCID: PMC9935977 DOI: 10.1097/md.0000000000032905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/19/2023] Open
Abstract
BACKGROUND Severe multiple traumas are one of the most common diseases and carry a significant financial burden with high disability and mortality. There are no effective drugs in the clinical management of severe multiple traumas, and there is an absence of evidence-based medicine concerning the treatment of severe multiple traumas. METHODS The present study explored whether ulinastatin (UTI) can improve the outcome of severe multiple traumas. The present research included patients who were hospitalized in intensive care units after being diagnosed with severe multiple trauma. Patients received UTIs (400,000 IU) or placebos utilizing computer-based random sequencing (in a 1:1 ratio). The primary outcome measures were 30-day mortality, multiple organ dysfunction syndrome, inflammatory response, coagulation function, infection, liver function, renal function, and drug-related adverse effects. RESULTS A total of 239 individuals were classified into 2 groups, namely, the placebo group (n = 120) and the UTI group (n = 119). There were no statistically significant differences in baseline clinical data between the 2 groups. The 30-day mortality and multiple organ dysfunction syndrome in the UTI group were remarkably improved compared with those in the placebo group. UTI can protect against hyperinflammation and improve coagulation dysfunction, infection, liver function, and renal function. UTI patients had markedly decreased hospitalization expenditures compared with the placebo group. CONCLUSION The findings from the present research indicated that UTIs can improve the clinical outcomes of patients with severe multiple traumas and have fewer adverse reactions.
Collapse
Affiliation(s)
- Haiting Xu
- Department of Emergency, The 904th Hospital of Joint Logistic Support Force, Wuxi, China
| | - Wei Jiao
- Department of Nursing, The 904th Hospital of Joint Logistic Support Force, Wuxi, China
| | - Yunfei Zhang
- Department of Emergency, The 904th Hospital of Joint Logistic Support Force, Wuxi, China
| | - Xiaoyan Deng
- Department of Emergency, The 904th Hospital of Joint Logistic Support Force, Wuxi, China
| | - Rongrong Dai
- Department of Emergency, The 904th Hospital of Joint Logistic Support Force, Wuxi, China
| | - Lei Chen
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi, China
- * Correspondence: Lei Chen, Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Xing Yuan North Road 101, Wuxi 214044, China (e-mail: )
| |
Collapse
|
|
17
|
The effects of female sexual hormones on the endothelial glycocalyx. CURRENT TOPICS IN MEMBRANES 2023; 91:89-137. [PMID: 37080682 DOI: 10.1016/bs.ctm.2023.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
Abstract
The glycocalyx is a layer composed of carbohydrate side chains bound to core proteins that lines the vascular endothelium. The integrity of the glycocalyx is essential for endothelial cells' performance and vascular homeostasis. The neuroendocrine and immune systems influence the composition, maintenance, activity and degradation of the endothelial glycocalyx. The female organism has unique characteristics, and estrogen and progesterone, the main female hormones are essential to the development and physiology of the reproductive system and to the ability to develop a fetus. Female sex hormones also exert a wide variety of effects on other organs, including the vascular endothelium. They upregulate nitric oxide synthase expression and activity, decrease oxidative stress, increase vasodilation, and protect from vascular injury. This review will discuss how female hormones and pregnancy, which prompts to high levels of estrogen and progesterone, modulate the endothelial glycocalyx. Diseases prevalent in women that alter the glycocalyx, and therapeutic forms to prevent glycocalyx degradation and potential treatments that can reconstitute its structure and function will also be discussed.
Collapse
|
|
18
|
Zhang R, Liu H, Dai D, Ding X, Wang D, Wang Y, Shi X, Zhang S, Duan X, Wang H, Luo Y, Liu S, Han B, Zhang X, Fang Y, Yang J, Xu W, Sun T. Adjunctive sepsis therapy with aminophylline (STAP): a randomized controlled trial. Chin Med J (Engl) 2022; 135:2843-2850. [PMID: 36728571 PMCID: PMC9944697 DOI: 10.1097/cm9.0000000000002282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Sepsis is a serious disease caused by infection. Aminophylline has anti-asthma and anti-inflammatory effects. We aimed to explore the safety and effect of aminophylline in sepsis. METHODS We conducted a clinical randomized controlled trial involving 100 patients diagnosed with sepsis within 48 h after intensive care unit (ICU) admission in two sites. All patients were randomized in a 1:1 ratio to receive standard therapy with or without aminophylline. The primary clinical outcome was all-cause mortality at 28 days. RESULTS From September 27, 2018 to February 12, 2020, we screened 277 septic patients and eventually enrolled 100 patients, with 50 assigned to the aminophylline group and 50 to the usual-care group. At 28 days, 7 of 50 patients (14.0%) in the aminophylline group had died, compared with 16 of 50 (32.0%) in the usual-care group ( P = 0.032). Cox regression showed that the aminophylline group had a lower hazard of death (hazard ratio = 0.312, 95% confidence interval: 0.129-0.753). Compared with the usual-care group, patients in the aminophylline group had a longer survival time ( P = 0.039 by the log-rank test). The effects of aminophylline on vasopressor dose, oxygenation index, and sequential organ failure assessment score were time-dependent with treatment. There were no significant differences in total hospitalization days, ICU hospitalization days, and rates of serious adverse events (all P > 0.05). No adverse events were observed in the trial. CONCLUSIONS Aminophylline as an adjunct therapy could significantly reduce the risk of death and prolong the survival time of patients with sepsis. TRIAL REGISTRATION ChiCTR.org.cn, ChiCTR1800019173.
Collapse
Affiliation(s)
- Ruifang Zhang
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Huan Liu
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Dongmei Dai
- Department of Intensive Care Unit, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Xianfei Ding
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Dong Wang
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Yan Wang
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Xuexiu Shi
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Shuguang Zhang
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Xiaoguang Duan
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Haixu Wang
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Yonggang Luo
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Shaohua Liu
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Bing Han
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Xiaojuan Zhang
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Yu Fang
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| | - Jing Yang
- Precision Medicine Monitoring Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Wangbin Xu
- Department of Intensive Care Unit, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Tongwen Sun
- General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, Henan 450052, China
| |
Collapse
|
|
19
|
Liu Z, Chen M, Sun Y, Li X, Cao L, Ma X. Transforming growth factor-β receptor type 2 is required for heparin-binding protein-induced acute lung injury and vascular leakage for transforming growth factor-β/Smad/Rho signaling pathway activation. FASEB J 2022; 36:e22580. [PMID: 36189652 DOI: 10.1096/fj.202200228rrrrr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 09/12/2022] [Accepted: 09/19/2022] [Indexed: 11/11/2022]
Abstract
Heparin-binding protein (HBP), as a granule protein secreted by polymorphonuclear neutrophils, participates in the pathophysiological process of sepsis. It has been reported that HBP is a biomarker of sepsis related to the severity of septic shock and organ dysfunction. HBP binds to vascular endothelial cells as a primary target site. However, it is still unclear whether HBP-binding protein receptors exist on the surface of endothelial cells. The effect of HBP on vascular permeability in sepsis and its mechanism needs to be explored. We conducted in vivo and in vitro studies and demonstrated that HBP binds to transforming growth factor-β receptor type 2 (TGF-β-R2) as a ligand. Glutathione S-transferase pull-down analysis revealed that HBP mainly interacts with the extracellular domain of TGF-β-R2. HBP induces acute lung injury and vascular leakage via activation of the TGF-β/SMAD2/3 signaling pathway. A permeability assay suggested that TGF-β-R2 is necessary for HBP-induced increased permeability. We also defined the role of HBP and its potential membrane receptor TGF-β-R2 in the blood-gas barrier in the pathogenesis of HBP-related acute lung injury.
Collapse
Affiliation(s)
- Zixuan Liu
- Department of Critical Care Medicine, the First Hospital of China Medical University, Shenyang, China.,Department of Critical Care Medicine, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China
| | - Mingming Chen
- Department of Critical Care Medicine, the First Hospital of China Medical University, Shenyang, China
| | - Yini Sun
- Department of Critical Care Medicine, the First Hospital of China Medical University, Shenyang, China
| | - Xu Li
- Department of Critical Care Medicine, the First Hospital of China Medical University, Shenyang, China
| | - Liu Cao
- Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
| | - Xiaochun Ma
- Department of Critical Care Medicine, the First Hospital of China Medical University, Shenyang, China
| |
Collapse
|
|
20
|
Wu X, Jiao W, Chen J, Tao Y, Zhang J, Wang Y. Ulinastatin alleviates early brain injury after intracerebral hemorrhage by inhibiting oxidative stress and neuroinflammation via ROS/MAPK/Nrf2 signaling pathway. Acta Cir Bras 2022; 37:e370606. [PMID: 36074399 PMCID: PMC9448248 DOI: 10.1590/acb370606] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 05/11/2022] [Indexed: 11/26/2022] Open
Abstract
Purpose: Spontaneous intracerebral hemorrhage (ICH) is still a major public health problem, with high mortality and disability. Ulinastatin (UTI) was purified from human urine and has been reported to be anti-inflammatory, organ protective, and antioxidative stress. However, the neuroprotection of UTI in ICH has not been confirmed, and the potential mechanism is unclear. In the present study, we aimed to investigate the neuroprotection and potential molecular mechanisms of UTI in ICH-induced early brain injury in a C57BL/6 mouse model. Methods: The neurological score, brain water content, neuroinflammatory cytokine levels, oxidative stress levels, and neuronal damage were evaluated. Results: UTI treatment markedly increased the neurological score, alleviated brain edema, decreased the levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and NF-κB, decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and upregulated the levels of glutathione (GSH), superoxide dismutase (SOD), and Nrf2. This finding indicated that UTI-mediated inhibition of neuroinflammation and oxidative stress alleviated neuronal damage after ICH. The neuroprotective capacity of UTI is partly dependent on the ROS/MAPK/Nrf2 signaling pathway. Conclusions: UTI improves neurological outcomes in mice and reduces neuronal death by protecting against neural neuroinflammation and oxidative stress.
Collapse
Affiliation(s)
- Xi Wu
- BS. 904th Hospital of Joint Logistic Support Force of PLA - Anhui Medical University - Wuxi Clinical College - Department of Neurosurgery - Wuxi, China
| | - Wei Jiao
- MD. 904th Hospital of Joint Logistic Support Force of PLA - Anhui Medical University - Wuxi Clinical College - Department of Neurosurgery - Wuxi, China
| | - Junhui Chen
- BS. 904th Hospital of Joint Logistic Support Force of PLA - Anhui Medical University - Wuxi Clinical College - Department of Neurosurgery - Wuxi, China
| | - Yunna Tao
- BS. 904th Hospital of Joint Logistic Support Force of PLA - Anhui Medical University - Wuxi Clinical College - Department of Neurosurgery - Wuxi, China
| | - Jing Zhang
- BS. 904th Hospital of Joint Logistic Support Force of PLA - Anhui Medical University - Wuxi Clinical College - Department of Neurosurgery - Wuxi, China
| | - Yuhai Wang
- PhD. 904th Hospital of Joint Logistic Support Force of PLA - Anhui Medical University - Wuxi Clinical College - Department of Neurosurgery - Wuxi, China
| |
Collapse
|
|
21
|
Liu H, Qian SC, Shao YF, Li HY, On behalf of the Additive Anti-inflammatory Action for Aortopathy & Arteriopathy (5A) Investigators Group. Anti-Inflammatory Effect of Ulinastatin on the Association Between Inflammatory Phenotypes in Acute Type A Aortic Dissection. J Inflamm Res 2022; 15:3709-3718. [PMID: 35783246 PMCID: PMC9248951 DOI: 10.2147/jir.s369703] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/21/2022] [Indexed: 11/23/2022] Open
Abstract
Background Acute type A aortic dissection (ATAAD) is a heterogeneous systemic inflammatory response syndrome. Identification of distinct inflammatory phenotypes may allow more precise therapy and improved care. We aim to investigate whether distinct inflammatory subphenotypes exist in ATAAD patients and respond differently to pharmacotherapies. Methods Retrospective analysis of data sets was conducted from the Additive Anti-inflammatory Actions for Aortopathy & Arteriopathy (5A) III study. Inflammatory subphenotypes were derived among 2008 ATAAD patients who received surgical repair at 11 Chinese hospitals (2016–2020) using latent class analysis applied to 14 laboratory signatures within 6 hours of hospital admission. Outcomes included operative mortality (Society of Thoracic Surgeons definition), derived subphenotype frequency, and the potential consequences of phenotype frequency distributions on the treatment effects. Results The median (interquartile range) age of patients was 54 (45–62) years, and 1423 (70.9%) were male. A two-class (two subphenotype) model was an improvement over a one-class model (P<·001), with 1451 (72.3%) patients in the hypoinflammatory subphenotype group and 557 (27.7%) in the hyperinflammatory subphenotype group. Patients with the hyperinflammatory subphenotype had higher operative mortality (71 [12.7%] vs 127 [8.8%]; P=0·007) than did those with the hypoinflammatory subphenotype. Furthermore, the interaction between ulinastatin treatment and subphenotype is not significant for operative mortality (P=0.15) but for ventilator time (P=0·04). Conclusion Two subphenotypes of ATAAD were identified in the 5A cohort that correlated with clinical outcomes, with significant interaction effect between anti-inflammatory treatment and subphenotypes for ventilator time, suggesting these phenotypes may help in understanding heterogeneity of treatment effects. Trial Registration Clinical Trials. Gov: number NCT04918108.
Collapse
Affiliation(s)
- Hong Liu
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Si-chong Qian
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People’s Republic of China
| | - Yong-feng Shao
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China
- Correspondence: Yong-feng Shao, Department of Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China, Email
| | - Hai-yang Li
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People’s Republic of China
- Hai-yang Li, Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People’s Republic of China, Email
| | | |
Collapse
|
|
22
|
Shukla P, Mandalla A, Elrick MJ, Venkatesan A. Clinical Manifestations and Pathogenesis of Acute Necrotizing Encephalopathy: The Interface Between Systemic Infection and Neurologic Injury. Front Neurol 2022; 12:628811. [PMID: 35058867 PMCID: PMC8764155 DOI: 10.3389/fneur.2021.628811] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 12/02/2021] [Indexed: 12/17/2022] Open
Abstract
Acute necrotizing encephalopathy (ANE) is a devastating neurologic condition that can arise following a variety of systemic infections, including influenza and SARS-CoV-2. Affected individuals typically present with rapid changes in consciousness, focal neurological deficits, and seizures. Neuroimaging reveals symmetric, bilateral deep gray matter lesions, often involving the thalami, with evidence of necrosis and/or hemorrhage. The clinical and radiologic picture must be distinguished from direct infection of the central nervous system by some viruses, and from metabolic and mitochondrial disorders. Outcomes following ANE are poor overall and worse in those with brainstem involvement. Specific management is often directed toward modulating immune responses given the potential role of systemic inflammation and cytokine storm in potentiating neurologic injury in ANE, though benefits of such approaches remain unclear. The finding that many patients have mutations in the nucleoporin gene RANBP2, which encodes a multifunctional protein that plays a key role in nucleocytoplasmic transport, may allow for the development of disease models that provide insights into pathogenic mechanisms and novel therapeutic approaches.
Collapse
Affiliation(s)
- Priya Shukla
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Abby Mandalla
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Matthew J Elrick
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Arun Venkatesan
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| |
Collapse
|
|
23
|
Huang H, Hu PF, Sun LL, Guo YB, Wang Q, Liu ZM, Yin JZ, Shi PM, Yuan ZL, Xie WF. Treatment of patients with Covid-19 with a high dose of ulinastatin. Exp Ther Med 2022; 23:121. [PMID: 34970344 PMCID: PMC8713169 DOI: 10.3892/etm.2021.11044] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 10/07/2021] [Indexed: 01/08/2023] Open
Abstract
Currently, there are no specific therapeutic agents available for the treatment of coronavirus disease 2019 (Covid-19). The present study aimed to assess the efficacy of high-dose ulinastatin for the treatment of patients with Covid-19. A total of 12 patients hospitalized with confirmed severe acute respiratory syndrome coronavirus 2 infection were treated with a high dose of ulinastatin alongside standard care. Changes in clinical manifestations, laboratory examinations and chest images were retrospectively analyzed. A total of 10 patients with severe Covid-19 and two patients with moderate Covid-19 received ulinastatin treatment. The average age of the patients was 68.0±11.9 years (age range, 48-87 years). In total, nine of the 12 patients (75.0%) had one or more comorbidities. The most common symptoms on admission were fever (8/12, 66.7%), cough (5/12, 41.7%) and dyspnea (5/12, 41.7%). The percentage of lymphocytes was decreased in 41.7% of patients (5/12) and 58.3% of patients (7/12) had elevated hypersensitive C-reactive protein (CRP) levels (mean, 49.70±77.70 mg/l). The white blood cell levels and the percentage of lymphocytes returned to normal in all of the patients, and CRP was significantly decreased and returned to normal in 83.3% of patients (10/12; mean, 6.87±6.63 mg/l) on day 7 after ulinastatin treatment. Clinical symptoms were relieved synchronously. The peripheral oxygen saturation improved and 66.7% of the patients (8/12) did not require further oxygen therapy 7 days after ulinastatin treatment. No patients required intensive care unit admission or mechanical ventilation. All patients revealed different degrees of absorption of pulmonary lesions after treatment. Compared with the standard care group, ulinastatin treatment significantly prevented illness deterioration. In conclusion, these preliminary data revealed that high-dose ulinastatin treatment was safe and exhibited a potential beneficial effect for patients with Covid-19.
Collapse
Affiliation(s)
- Hai Huang
- Department of Pulmonary and Critical Care Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Ping-Fang Hu
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Liang-Liang Sun
- Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Yi-Bin Guo
- Department of Health Statistics, Second Military Medical University, Shanghai 200433, P.R. China
| | - Qiong Wang
- Department of Pulmonary and Critical Care Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Zhi-Min Liu
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Ji-Zhong Yin
- Department of Pulmonary and Critical Care Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Pei-Mei Shi
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Zong-Li Yuan
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Wei-Fen Xie
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| |
Collapse
|
|
24
|
Wang L, Jiao W, Wu J, Zhang J, Tang M, Chen Y. Ulinastatin alleviates early brain injury after intracerebral hemorrhage by inhibiting necroptosis and neuroinflammation via MAPK/NF-κB signaling pathway. Acta Cir Bras 2022; 37:e370301. [PMID: 35584533 PMCID: PMC9109988 DOI: 10.1590/acb370301] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 02/14/2022] [Indexed: 11/22/2022] Open
Abstract
Purpose: Spontaneous intracerebral hemorrhage (ICH) is a major public health problem
with a huge economic burden worldwide. Ulinastatin (UTI), a serine protease
inhibitor, has been reported to be anti-inflammatory, immune regulation, and
organ protection by reducing reactive oxygen species production, and
inflammation. Necroptosis is a programmed cell death mechanism that plays a
vital role in neuronal cell death after ICH. However, the neuroprotection of
UTI in ICH has not been confirmed, and the potential mechanism is unclear.
The present study aimed to investigate the neuroprotection and potential
molecular mechanisms of UTI in ICH-induced EBI in a C57BL/6 mouse model. Methods: The neurological score, brain water content, neuroinflammatory cytokine
levels, and neuronal damage were evaluated. The anti-inflammation
effectiveness of UTI in ICH patients also was evaluated. Results: UTI treatment markedly increased the neurological score, alleviate the brain
edema, decreased the inflammatory cytokine TNF-α, interleukin‑1β (IL‑1β),
IL‑6, NF‑κB levels, and RIP1/RIP3, which indicated that UTI-mediated
inhibition of neuroinflammation, and necroptosis alleviated neuronal damage
after ICH. UTI also can decrease the inflammatory cytokine of ICH patients.
The neuroprotective capacity of UTI is partly dependent on the MAPK/NF-κB
signaling pathway. Conclusions: UTI improves neurological outcomes in mice and reduces neuronal death by
protecting against neural neuroinflammation, and necroptosis.
Collapse
Affiliation(s)
- Li Wang
- Anhui Medical University, China
| | | | | | | | | | | |
Collapse
|
|
25
|
Feng X, Ma W, Chen J, Jiao W, Wang Y. Ulinastatin alleviates early brain injury after traumatic brain injury by inhibiting oxidative stress and apoptosis. Acta Cir Bras 2022; 37:e370108. [PMID: 35475892 PMCID: PMC9020790 DOI: 10.1590/acb370108] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 12/19/2021] [Indexed: 12/11/2022] Open
Abstract
Purpose: Traumatic brain injury (TBI) remains a major public health problem and cause of death. Ulinastatin (UTI), a serine protease inhibitor, has been reported to have an anti-inflammatory effect and play a role in immunoregulation and organ protection by reducing reactive oxygen species (ROS) production, oxidative stress and inflammation. However, the neuroprotective of UTI in TBI has not been confirmed. Therefore, this study aimed to investigate the neuroprotection and potential molecular mechanisms of UTI in TBI-induced EBI in a C57BL/6 mouse model. Methods: The neurological score and brain water content were evaluated. Enzyme-linked immunosorbent assay was used to detect neuroinflammatory cytokine levels, ROS and malondialdehyde detection to evaluate oxidative stress levels, and TUNEL staining and western blotting to examine neuronal damages and their related mechanisms. Results: Treatment with UTI markedly increased the neurological score; alleviated brain oedema; decreased the inflammatory cytokine tumour necrosis factor a, interleukin-1β (IL-1β), IL-6 and nuclear factor kappa B (NF-kB) levels; inhibited oxidative stress; decreased caspase-3 and Bax protein expressions; and increased the Bcl-2 levels, indicating that UTI-mediated inhibition of neuroinflammation, oxidative stress and apoptosis ameliorated neuronal death after TBI. The neuroprotective capacity of UTI is partly dependent on the TLR4/NF-kB/p65 signalling pathway. Conclusions: Therefore, this study reveals that UTI improves neurological outcomes in mice and reduces neuronal death by protecting against neural neuroinflammation, oxidative stress and apoptosis.
Collapse
Affiliation(s)
- Xiaoyan Feng
- Wuxi Clinical College of Anhui Medical University, China
| | - Weiwei Ma
- Wuxi Clinical College of Anhui Medical University, China
| | - Junhui Chen
- Wuxi Clinical College of Anhui Medical University, China
| | - Wei Jiao
- Wuxi Clinical College of Anhui Medical University, China
| | - Yuhai Wang
- Wuxi Clinical College of Anhui Medical University, China
| |
Collapse
|
|
26
|
Emerging role of long non-coding RNAs in endothelial dysfunction and their molecular mechanisms. Biomed Pharmacother 2021; 145:112421. [PMID: 34798473 DOI: 10.1016/j.biopha.2021.112421] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/10/2021] [Accepted: 11/10/2021] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are the novel class of transcripts involved in transcriptional, post-transcriptional, translational, and post-translational regulation of physiology and the pathology of diseases. Studies have evidenced that the impairment of endothelium is a critical event in the pathogenesis of atherosclerosis and its complications. Endothelial dysfunction is characterized by an imbalance in vasodilation and vasoconstriction, oxidative stress, proinflammatory factors, and nitric oxide bioavailability. Disruption of the endothelial barrier permeability, the first step in developing atherosclerotic lesions is a consequence of endothelial dysfunction. Though several factors interfere with the normal functioning of the endothelium, intrinsic epigenetic mechanisms governing endothelial function are regulated by lncRNAs and perturbations contribute to the pathogenesis of the disease. This review comprehensively addresses the biogenesis of lncRNA and molecular mechanisms underlying and regulation in endothelial function. An insight correlating lncRNAs and endothelial dysfunction-associated diseases can positively impact the development of novel biomarkers and therapeutic targets in endothelial dysfunction-associated diseases and treatment strategies.
Collapse
|
|
27
|
McCullough LD, Roy-O'Reilly M, Lai YJ, Patrizz A, Xu Y, Lee J, Holmes A, Kraushaar DC, Chauhan A, Sansing LH, Stonestreet BS, Zhu L, Kofler J, Lim YP, Venna VR. Exogenous inter-α inhibitor proteins prevent cell death and improve ischemic stroke outcomes in mice. J Clin Invest 2021; 131:144898. [PMID: 34580244 DOI: 10.1172/jci144898] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 07/12/2021] [Indexed: 12/14/2022] Open
Abstract
Inter-α inhibitor proteins (IAIPs) are a family of endogenous plasma and extracellular matrix molecules. IAIPs suppress proinflammatory cytokines, limit excess complement activation, and bind extracellular histones to form IAIP-histone complexes, leading to neutralization of histone-associated cytotoxicity in models of sepsis. Many of these detrimental processes also play critical roles in the pathophysiology of ischemic stroke. In this study, we first assessed the clinical relevance of IAIPs in stroke and then tested the therapeutic efficacy of exogenous IAIPs in several experimental stroke models. IAIP levels were reduced in both ischemic stroke patients and in mice subjected to experimental ischemic stroke when compared with controls. Post-stroke administration of IAIP significantly improved stroke outcomes across multiple stroke models, even when given 6 hours after stroke onset. Importantly, the beneficial effects of delayed IAIP treatment were observed in both young and aged mice. Using targeted gene expression analysis, we identified a receptor for complement activation, C5aR1, that was highly suppressed in both the blood and brain of IAIP-treated animals. Subsequent experiments using C5aR1-knockout mice demonstrated that the beneficial effects of IAIPs are mediated in part by C5aR1. These results indicate that IAIP is a potential therapeutic candidate for the treatment of ischemic stroke.
Collapse
Affiliation(s)
- Louise D McCullough
- Department of Neurology, McGovern Medical School at University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Meaghan Roy-O'Reilly
- Department of Neurology, McGovern Medical School at University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Yun-Ju Lai
- Department of Neurology, McGovern Medical School at University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Anthony Patrizz
- Department of Neurology, McGovern Medical School at University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Yan Xu
- Department of Neurology, McGovern Medical School at University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Juneyoung Lee
- Department of Neurology, McGovern Medical School at University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Aleah Holmes
- Department of Neurology, McGovern Medical School at University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Daniel C Kraushaar
- Genomic and RNA Profiling Core, Baylor College of Medicine, Houston, Texas, USA
| | - Anjali Chauhan
- Department of Neurology, McGovern Medical School at University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Lauren H Sansing
- Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Barbara S Stonestreet
- Department of Pediatrics, Women and Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Liang Zhu
- Biostatistics and Epidemiology Research Design Core, Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Julia Kofler
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Yow-Pin Lim
- ProThera Biologics Inc., Providence, Rhode Island, USA.,Department of Pathology and Laboratory Medicine, The Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Venugopal Reddy Venna
- Department of Neurology, McGovern Medical School at University of Texas Health Science Center at Houston, Houston, Texas, USA
| |
Collapse
|
|
28
|
Mehta Y, Dixit SB, Zirpe K, Sud R, Gopal PB, Koul PA, Mishra VK, Ansari AS, Chamle VS. Therapeutic Approaches in Modulating the Inflammatory and Immunological Response in Patients With Sepsis, Acute Respiratory Distress Syndrome, and Pancreatitis: An Expert Opinion Review. Cureus 2021; 13:e18393. [PMID: 34692364 PMCID: PMC8526068 DOI: 10.7759/cureus.18393] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/30/2021] [Indexed: 12/15/2022] Open
Abstract
Immunomodulation has long been an adjunct approach in treating critically ill patients with sepsis, acute respiratory distress syndrome (ARDS), and acute pancreatitis (AP). Hyperactive immune response with immunopathogenesis leads to organ dysfunction and alters the clinical outcomes in critically ill. Though the immune response in the critically ill might have been overlooked, it has gathered greater attention during this novel coronavirus disease 2019 (COVID-19) pandemic. Modulating hyperactive immune response, the cytokine storm, especially with steroids, has shown to improve the outcomes in COVID-19 patients. In this review, we find that immune response pathogenesis in critically ill patients with sepsis, ARDS, and AP is nearly similar. The use of immunomodulators such as steroids, broad-spectrum serine protease inhibitors such as ulinastatin, thymosin alpha, intravenous immunoglobulins, and therapies such as CytoSorb and therapeutic plasma exchange may help in improving the clinical outcomes in these conditions. As the experience of the majority of physicians in using such therapeutics may be limited, we provide our expert comments regarding immunomodulation to optimize outcomes in patients with sepsis/septic shock, ARDS, and AP.
Collapse
Affiliation(s)
- Yatin Mehta
- Institute of Critical Care and Anesthesiology, Medanta - The Medicity, Gurugram, IND
| | | | - Kapil Zirpe
- Neurocritical Care, Grant Medical Foundation, Ruby Hall Clinic, Pune, IND
| | - Randhir Sud
- Institute of Digestive & Hepatobiliary Sciences, Medanta - The Medicity, Gurugram, IND
| | - Palepu B Gopal
- Department of Critical Care, Continental Hospitals, Hyderabad, IND
| | - Parvaiz A Koul
- Department of Pulmonary Medicine, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, IND
| | - Vijay K Mishra
- Medica Institute of Critical Care, Bhagwan Mahavir Medica Superspecialty Hospital, Ranchi, IND
| | - Abdul S Ansari
- Department of Critical Care Services, Nanavati Super Specialty Hospital, Mumbai, IND
| | | |
Collapse
|
|
29
|
Qiu J, Xiao X, Gao X, Zhang Y. Ulinastatin protects against sepsis‑induced myocardial injury by inhibiting NLRP3 inflammasome activation. Mol Med Rep 2021; 24:730. [PMID: 34414461 PMCID: PMC8404092 DOI: 10.3892/mmr.2021.12369] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 07/22/2021] [Indexed: 11/29/2022] Open
Abstract
Myocardial injury is the primary manifestation of multiple organ dysfunction during sepsis, however, the mechanisms underlying sepsis-induced myocardial injury remain unclear. Similarly, no effective therapeutics have yet been developed for myocardial injury. In the present study, the role of the NOD-like receptor 3 (NLRP3) inflammasome on cardiac function were characterized and the effects of different ulinastatin (UTI) doses in protecting a septic rat model from myocardial injury were elucidated. To evaluate UTI efficacy on cardiac function, its effects on anti-inflammatory mediators were analyzed and its cardioprotective effects were investigated. It was demonstrated that circulatory levels of tumor necrosis factor-α and interleukin-1β were elevated during sepsis. It was also observed that NLRP3 and caspase-1 expression enhanced post-cecal ligation and puncture (CLP), and that high UTI levels protected against myocardial injury induced by sepsis. To the best of our knowledge, this is the first study to demonstrate that the mechanisms underpinning UTI-mediated myocardial protection were due to the downregulation of the NLRP3/caspase-1/IL-1β signaling pathway. Based on these findings, it is proposed that UTI exerts beneficial effects during sepsis-induced myocardial injury.
Collapse
Affiliation(s)
- Juanjuan Qiu
- Centralab, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Xiaoguang Xiao
- Clinical Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Xue Gao
- Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Yongli Zhang
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| |
Collapse
|
|
30
|
Beltrán-García J, Osca-Verdegal R, Nácher-Sendra E, Cardona-Monzonís A, Sanchis-Gomar F, Carbonell N, Pallardó FV, Lavie CJ, García-Giménez JL. Role of non-coding RNAs as biomarkers of deleterious cardiovascular effects in sepsis. Prog Cardiovasc Dis 2021; 68:70-77. [PMID: 34265333 DOI: 10.1016/j.pcad.2021.07.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 07/05/2021] [Indexed: 12/15/2022]
Abstract
The mechanisms occurring during sepsis that produce an increased risk of cardiovascular (CV) disease (CVD) are poorly understood. Even less information exists regarding CV dysfunction as a complication of sepsis, particularly for sepsis-induced cardiomyopathy. However, recent research has demonstrated that non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, play a crucial role in genetic reprogramming, gene regulation, and inflammation during the development of CVD. Here we describe experimental findings showing the importance of non-coding RNAs mediating relevant mechanisms underlying CV dysfunction after sepsis, so contributing to sepsis-induced cardiomyopathy. Importantly, non-coding RNAs are critical novel regulators of CVD risk factors. Thus, they are potential candidates to improve diagnostics and prognosis of sepsis-induced cardiomyopathy and other CVD events occurring after sepsis and set the basis to design novel therapeutic strategies.
Collapse
Affiliation(s)
- Jesús Beltrán-García
- Center for Biomedical Research Network on Rare Diseases (CIBERER), Carlos III Health Institute, Valencia 900225235, Spain; INCLIVA Biomedical Research Institute, Valencia, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain
| | - Rebeca Osca-Verdegal
- Center for Biomedical Research Network on Rare Diseases (CIBERER), Carlos III Health Institute, Valencia 900225235, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain
| | - Elena Nácher-Sendra
- INCLIVA Biomedical Research Institute, Valencia, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain
| | - Alejandro Cardona-Monzonís
- EpiDisease S.L. (Spin-Off CIBER-ISCIII), Parc Científic de la Universitat de València, Paterna, 46980 Valencia, Spain
| | - Fabian Sanchis-Gomar
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Nieves Carbonell
- INCLIVA Biomedical Research Institute, Valencia, Spain; Intensive Care Unit, Clinical University Hospital of Valencia, Valencia 46010, Spain
| | - Federico V Pallardó
- Center for Biomedical Research Network on Rare Diseases (CIBERER), Carlos III Health Institute, Valencia 900225235, Spain; INCLIVA Biomedical Research Institute, Valencia, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain
| | - Carl J Lavie
- John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA, USA
| | - José Luis García-Giménez
- Center for Biomedical Research Network on Rare Diseases (CIBERER), Carlos III Health Institute, Valencia 900225235, Spain; INCLIVA Biomedical Research Institute, Valencia, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain; EpiDisease S.L. (Spin-Off CIBER-ISCIII), Parc Científic de la Universitat de València, Paterna, 46980 Valencia, Spain.
| |
Collapse
|
|
31
|
Dong R, Zhang X, Zhao Z. Ulinastatin as an Adjuvant Therapy to Restricting Volumes of Resuscitation Fluid Strategy for Patients with Septic Shock after Initial Management. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:4231454. [PMID: 34221069 PMCID: PMC8221865 DOI: 10.1155/2021/4231454] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 06/09/2021] [Indexed: 12/29/2022]
Abstract
Septic shock is the most serious complication of sepsis, leading to unacceptably high morbidity and mortality worldwide. Fluid resuscitation using crystalloids has become the mainstay of early and aggressive treatment of severe sepsis and septic shock, while increased daily fluid balances from day 2 until day 7 have been related with increased mortality. Recently, pharmacological management has been recommended to combine with appropriate fluid resuscitation for the treatment of septic shock. In this study, we compared the clinical efficacy of restricting volumes of resuscitation fluid strategy with or without intravenous infusion of ulinastatin (UTI) in treating patients with septic shock and additionally examined the patient's changes of the extravascular lung water index (EVLWI), pulmonary vascular permeability index (PVPI), systemic vascular resistance index (SVRI), cardiac function, lactic acid (LA) level, coagulation function, and renal function. The study included 182 patients with septic shock, among which 89 patients had undergone restricting volumes of resuscitation fluid strategy with intravenous infusion of UTI and 93 patients had undergone restricting volumes of resuscitation fluid strategy alone. It was found that patients with septic shock after restricting volumes of resuscitation fluid strategy with intravenous infusion of UTI showed an increased SVRI concomitant with declined PVPI and EVLWI, increased mean artery pressure (MAP), cardiac output (CO), left ventricular ejection fraction (LVEF), stroke volume (SV), and heart rate (HR), declined levels of cardiac troponin I (cTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and C-reactive protein (CRP), reduced LA level along with shortened prothrombin time (PT) and partially activated thrombin time (PATT), and decreased levels of blood urea nitrogen (BUN), creatinine (Cr), and uric acid (UA) when comparable to those after restricting volumes of resuscitation fluid strategy alone (P < 0.05). We also observed fewer scores of the Acute Physiology and Chronic Health Evaluation (APACHE II) and the sequential organ failure assessment (SOFA) in patients undergoing restricting volumes of resuscitation fluid strategy with intravenous infusion of UTI than those undergoing restricting volumes of resuscitation fluid strategy alone (P < 0.05). According to the above data, it is concluded that UTI as an adjuvant therapy for restricting volumes of resuscitation fluid strategy in treating septic shock may decrease the LA level, attenuate the inflammatory response, reduce vascular permeability, prevent pulmonary edema, and restore cardiac and renal functions.
Collapse
Affiliation(s)
- Rensong Dong
- Department of Pharmacy, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xi Zhang
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zhi Zhao
- Department of Pharmacy, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| |
Collapse
|
|
32
|
Abstract
The recent outbreak of COVID-19 has affected human lives severely. The human-to-human transmission of this viral disease has become deadly due to the unavailability of COVID-19 specific drugs. Here, an overview of various attempts made to design different therapeutic agents against various structural and non-structural proteins of SARS-CoV-2 has been summarized. Emphasis has been made to highlight the mechanisms of drug action and ways to design better inhibitors of these proteins. The roles of anti-oxidants and vitamins in suppressing COVID-19 are also discussed.
Collapse
|
|
33
|
Powering Bias and Clinically Important Treatment Effects in Randomized Trials of Critical Illness. Crit Care Med 2021; 48:1710-1719. [PMID: 33031148 DOI: 10.1097/ccm.0000000000004568] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVES Recurring issues in clinical trial design may bias results toward the null, yielding findings inconclusive for treatment effects. This study evaluated for powering bias among high-impact critical care trials and the associated risk of masking clinically important treatment effects. DESIGN, SETTING, AND PATIENTS Secondary analysis of multicenter randomized trials of critically ill adults in which mortality was the main endpoint. Trials were eligible for inclusion if published between 2008 and 2018 in leading journals. Analyses evaluated for accuracy of estimated control group mortality, adaptive sample size strategy, plausibility of predicted treatment effect, and results relative to the minimal clinically important difference. The main outcome was the mortality risk difference at the study-specific follow-up interval. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Of 101 included trials, 12 met statistical significance for their main endpoint, five for increased intervention-associated mortality. Most trials (77.3%) overestimated control group mortality in power calculations (observed minus predicted difference, -6.7% ± 9.8%; p < 0.01). Due to this misestimation of control group mortality, in 14 trials, the intervention would have had to prevent at least half of all deaths to achieve the hypothesized treatment effect. Seven trials prespecified adaptive sample size strategies that might have mitigated this issue. The observed risk difference for mortality fell within 5% of predicted in 20 trials, of which 16 did not reach statistical significance. Half of trials (47.0%) were powered for an absolute risk reduction greater than or equal to 10%, but this effect size was observed in only three trials with a statistically significant treatment benefit. Most trials (67.3%) could not exclude clinically important treatment benefit or harm. CONCLUSIONS The design of most high-impact critical care trials biased results toward the null by overestimating control group mortality and powering for unrealistic treatment effects. Clinically important treatment effects often cannot be excluded.
Collapse
|
|
34
|
The Effect of Ulinastatin to the Learning and Memory in Zebrafish. Neuromolecular Med 2021; 23:511-520. [PMID: 33772390 DOI: 10.1007/s12017-021-08653-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 03/10/2021] [Indexed: 10/21/2022]
Abstract
Previous study indicated that Ulinastatin (UTI) increased glutamine uptake by upregulation of glutamate transporters in astrocytes. These glutamate transporters have important role to improve cognitive function in hippocampus. In this study, we wanted to demonstrate whether UTI could improve learning and memory by using zebrafish behavior model and bio-markers. Zebrafish were 6-8 months of age and were 2.5-3.5 cm long. They were divided into four groups by control, 1X PBS-injected control, UTI 10,000, and 50,000 injected group. All PBS and UTI injected zebrafish were anesthetized by Tricainemethanesulphonate. We measured total time, distance moved, and frequency in each compartment of T-maze. We also measured the expression levels of glutamate transporter levels and cognitive bio-markers such as c-fos, c-jun, BDNF. UTI affected the learning and memory in zebrafish in a dose-dependent manner. In 50,000 unit/kg UTI-treated zebrafish, there were increases of time, distance, and frequency in target compartment. In 50,000 unit/kg UTI-treated zebrafish, there was an increase of time in target compartment. There was no difference among control, PBS-injected, and UTI 10,000 unit/kg-treated groups. EAAT4 glutamate transporter, c-fos and BDNF were significantly increased in 50,000 unit/kg UTI-treated group. UTI-enhanced learning and memory in zebrafish. The expressions of EAAT4 glutamate transporter, c- fos and BDNF in zebrafish were highly correlated may play a role.
Collapse
|
|
35
|
Kaur U, Chakrabarti SS, Ojha B, Pathak BK, Singh A, Saso L, Chakrabarti S. Targeting Host Cell Proteases to Prevent SARS-CoV-2 Invasion. Curr Drug Targets 2021; 22:192-201. [PMID: 32972339 DOI: 10.2174/1389450121666200924113243] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/16/2020] [Accepted: 08/26/2020] [Indexed: 11/22/2022]
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread worldwide and caused widespread devastation. In the absence of definitive therapy, symptomatic management remains the standard of care. Repurposing of many existing drugs, including several anti-viral drugs, is being attempted to tackle the COVID-19 pandemic. However, most of them have failed to show significant benefit in clinical trials. An attractive approach may be to target host proteases involved in SARS-CoV-2 pathogenesis. The priming of the spike (S) protein of the virus by proteolytic cleavage by the transmembrane serine protease-2 (TMPRSS2) is necessary for the fusion of the virus to the host cell after it binds to its receptor angiotensin converting enzyme-2 (ACE2). There are other proteases with varying spatiotemporal locations that may be important for viral entry and subsequent replication inside the cells, and these include trypsin, furin and cathepsins. In this report, we have discussed the tentative therapeutic role of inhibitors of TMPRSS2, cathepsin, trypsin, furin, plasmin, factor X and elastase in infection caused by SARS-CoV-2. Both available evidence, as well as hypotheses, are discussed, with emphasis on drugs which are approved for other indications such as bromhexine, ammonium chloride, nafamostat, camostat, tranexamic acid, epsilon amino-caproic acid, chloroquine, ulinastatin, aprotinin and anticoagulant drugs. Simultaneously, novel compounds being tested and problems with using these agents are also discussed.
Collapse
Affiliation(s)
- Upinder Kaur
- Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India
| | - Sankha Shubhra Chakrabarti
- Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India
| | - Bisweswar Ojha
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, India
| | - Bhairav Kumar Pathak
- Department of Biochemistry and Central Research Cell, MM Institute of Medical Sciences and Research, Maharishi Markandeshwar (deemed to be) University, Mullana, Ambala, Haryana, India
| | - Amit Singh
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, India
| | - Luciano Saso
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Sasanka Chakrabarti
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, India
| |
Collapse
|
|
36
|
Wang R, Song W, Xie C, Zhong W, Xu H, Zhou Q, Deng Y, Hong Y, Li X, Fang M. Urinary Trypsin Inhibitor Protects Tight Junctions of Septic Pulmonary Capillary Endothelial Cells by Regulating the Functions of Macrophages. J Inflamm Res 2021; 14:1973-1989. [PMID: 34045879 PMCID: PMC8149216 DOI: 10.2147/jir.s303577] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 03/19/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Our previous study found that urinary trypsin inhibitor (ulinastatin, UTI) protected tight junctions (TJs) of lung endothelia via TNF-α inhibition, thereby alleviating pulmonary capillary permeability in septic rats. As the activated macrophage is the main source of TNF-α in sepsis, we speculate that UTI may exert the above effects by regulating the functions of macrophages. METHODS Bone-marrow derived macrophages (BMDM) were divided into control, lipopolysaccharide (LPS), UTI+LPS and UTI groups. TNF-α, TGF-β, IL-10, CD86, CD206 and MCP-1 expression were assessed by Western blot. The phagocytosis and migration of BMDM were detected. Pulmonary microvascular endothelial cells (PMVECs) were cultured with the conditioned medium (CM) from each group of BMDM above. Sprague-Dawley rats were divided into sham, cecal ligation and puncture (CLP), and UTI+CLP groups. Western blot and immunofluorescence were used to detected zonula occludens-1 (ZO-1), occludin and claudin-5 expression in PMVECs, as well as TNF-α, TGF-β, iNOS, CD86 and CD206 expression in lungs. Pulmonary capillary permeability was assessed by extravasated Evans blue, lung injury score (LIS), wet-to-dry weight ratio and electron microscope. RESULTS TNF-α and CD86 expression were increased in LPS-treated BMDM, but were reversed by UTI pretreatment. TGF-β, IL-10 and CD206 expression were the opposite. UTI markedly decreased phagocytosis and migration of LPS-treated BMDM. ZO-1, occludin and claudin-5 expression were markedly decreased in PMVECs of the CM-LPS group, but significantly increased in the CM-UTI+LPS group. TNF-α, iNOS and CD86 expression were increased in the lungs of CLP-rats but decreased with UTI pretreatment, while TGF-β and CD206 expression were the opposite. UTI markedly ameliorated the lung EB leakage, improved LIS, reduced the wet-to-dry ratio and revised the damaged TJs of PMVECs in CLP-rats. CONCLUSION UTI effectively inhibits the conversion of M1 macrophage but increases M2, reduces the phagocytosis and migration, which helps to protect endothelia TJs and reduce pulmonary capillary permeability during sepsis.
Collapse
Affiliation(s)
- Ruijie Wang
- Department of Intensive Care Unit, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China
| | - Wenliang Song
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China
| | - Chengyuan Xie
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China
| | - Wenhong Zhong
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China
| | - Hui Xu
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China
- Shantou University Medical College, Shantou, People’s Republic of China
| | - Qiuping Zhou
- Department of Intensive Care Unit, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China
| | - Yiyu Deng
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China
| | - Yimei Hong
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China
| | - Xin Li
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China
| | - Ming Fang
- Department of Intensive Care Unit, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China
- Correspondence: Ming Fang Department of Intensive Care Unit, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, 510080, People’s Republic of ChinaTel +8613527774075 Email
| |
Collapse
|
|
37
|
Huang C, Huang W, Wang R, He Y. Ulinastatin Inhibits the Proliferation, Invasion and Phenotypic Switching of PDGF-BB-Induced VSMCs via Akt/eNOS/NO/cGMP Signaling Pathway. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:5505-5514. [PMID: 33363359 PMCID: PMC7753898 DOI: 10.2147/dddt.s275488] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/04/2020] [Indexed: 12/12/2022]
Abstract
Background Atherosclerosis is a chronic inflammatory disease responsible for thrombosis, blood supply disorders, myocardial infarction and strokes, eventually leading to increased deaths and reduced quality of life. As inflammation plays a vital role in the development of this disease, the present study aims to investigate whether urinary trypsin inhibitor (UTI) with anti-inflammatory property can inhibit the proliferation, invasion and phenotypic switching of PDGF-BB-induced vascular smooth muscle cells (VSMCs) and probe its potential mechanism. Methods Western blot was used to detect the expressions of the proteins related to the Akt/eNOS/NO/cGMP signaling pathway, phenotypic switching and proliferation. CCK-8 assay and EdU staining were used to detect cell proliferation of VSMCs. Transwell and wound healing assays were respectively conducted to measure the invasion and migration of VSMCs. The concentration of NO was evaluated by NO detection kit. ELISA assay analyzed the expression of cyclic GMP (cGMP). Results The expressions of p-Akt and p-eNOS were elevated by UTI treatment. Furthermore, UTI inhibited the proliferation, migration and invasion of VSMCs. UTI also increased the expressions of proteins related to phenotypic switching. The amount of NO and expression of cGMP were both elevated under UTI treatment. Conclusion UTI inhibits the proliferation, invasion and phenotypic switching of PDGF-BB-induced VSMCs via Akt/eNOS/NO/cGMP signaling pathway, which might provide a theoretical basis for the UTI treatment of atherosclerosis.
Collapse
Affiliation(s)
- Cheng Huang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510055, People's Republic of China
| | - Weihui Huang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510055, People's Republic of China
| | - Rui Wang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510055, People's Republic of China
| | - Yongli He
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510055, People's Republic of China
| |
Collapse
|
|
38
|
Meng C, Qian Y, Zhang WH, Liu Y, Song XC, Liu H, Wang X. A retrospective study of ulinastatin for the treatment of severe sepsis. Medicine (Baltimore) 2020; 99:e23361. [PMID: 33285716 PMCID: PMC7717755 DOI: 10.1097/md.0000000000023361] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
This retrospective study aimed to investigate the efficacy and safety of existing approach of ulinastatin for the treatment of severe sepsis (SS).A total of 130 eligible patients with SS were included in this study. We divided them into an intervention group (n = 65) and a control group (n = 65). Patients in both groups received conventional therapy. In addition, patients in the intervention group received ulinastatin for 7 days. Outcomes were measured by Acute Physiology and Chronic Health Evaluation II (APACHE II), Multiple Organ Failure (MOF), Glasgow Coma Scale (GCS), CD3, CD4, CD8, CD4/CD8, and adverse events. We assessed all outcomes before and after treatment.After treatment, patients in the intervention group showed better improvement in APACHE II (P < .01), MOF (P < .01), GCS (P < .01), CD3 (P = .03), CD4 (P = .03), and CD4/CD8 (P < .01), than those of patients in the control group. There are similar safety profiles between both groups.This study suggests that ulinastatin may be beneficial for SS. Future studies are still needed to warrant the results of this study.
Collapse
Affiliation(s)
- Chao Meng
- Department of Critical Care Medicine, Nanjing First Hospital
| | - Yi Qian
- The State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Wen-hao Zhang
- Department of Critical Care Medicine, Nanjing First Hospital
| | - Ying Liu
- Department of Critical Care Medicine, Nanjing First Hospital
| | - Xiao-chun Song
- Department of Critical Care Medicine, Nanjing First Hospital
| | - Han Liu
- Department of Critical Care Medicine, Nanjing First Hospital
| | - Xiang Wang
- Department of Critical Care Medicine, Nanjing First Hospital
| |
Collapse
|
|
39
|
Lv H, Wei X, Yi X, Liu J, Lu P, Zhou M, An Y, Yi H. High-dose ulinastatin to prevent late-onset acute renal failure after orthotopic liver transplantation. Ren Fail 2020; 42:137-145. [PMID: 31984833 PMCID: PMC7034081 DOI: 10.1080/0886022x.2020.1717530] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose To compare the efficacy and safety of two distinct doses of ulinastatin on late-onset acute renal failure (LARF) following orthotopic liver transplantation (OLT). Methods The high-risk recipients that underwent OLT were divided into two groups according to ulinastatin dose: low-dose (LD) ulinastatin group, 0.8 million U/d; high-dose (HD) ulinastatin group, 1.6 million U/d. The primary outcome was the incidence of LARF, which was defined the newly onset acute kidney injury (AKI) stage III (KDIGO, 2012) within 7–28 post-transplant days. The second outcomes were early multiple organ retrieval assessments, length of hospital stay and safety events. Results A total of 174 recipients were included (LD ulinastatin group, n = 55; HD ulinastatin group, n = 119). There was no significant difference in the incidence of LARF between LD (8/55, 14.50%) and HD (9/119, 7.56%) ulinastatin groups (HD vs. LD, HR, 0.49; 95%CI, 0.17–1.37; p = .1295). Multivariate Cox proportion risk regression model revealed HD ulinastatin (HR, 0.57; 95%CI, 0.38–0.98; p = .0464) was an independent protective factor for LARF. Early lactate level, oxygenation, AKI stage, graft function, and sequential organ failure assessment [SOFA] score were significantly improved in HD ulinastatin group versus LD ulinastatin group. No significant adverse events were observed in either group. Conclusions Higher dose of ulinastatin (1.6 million U/d) might be preferable to prevent LARF after OLT, and it may contribute to the enhancement of early multiple organ recovery and thus attenuate the incidence of LARF.
Collapse
Affiliation(s)
- Haijin Lv
- Transplant and Surgical Intensive Care Unit, The 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Xuxia Wei
- Transplant and Surgical Intensive Care Unit, The 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Xiaomeng Yi
- Transplant and Surgical Intensive Care Unit, The 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Jianrong Liu
- Transplant and Surgical Intensive Care Unit, The 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Pinglan Lu
- Transplant and Surgical Intensive Care Unit, The 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Mi Zhou
- Transplant and Surgical Intensive Care Unit, The 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Yuling An
- Transplant and Surgical Intensive Care Unit, The 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Huimin Yi
- Transplant and Surgical Intensive Care Unit, The 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| |
Collapse
|
|
40
|
Abo El Gheit RE, Atef MM, Badawi GA, Elwan WM, Alshenawy HA, Emam MN. Role of serine protease inhibitor, ulinastatin, in rat model of hepatic encephalopathy: aquaporin 4 molecular targeting and therapeutic implication. J Physiol Biochem 2020; 76:573-586. [PMID: 32794154 DOI: 10.1007/s13105-020-00762-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 08/09/2020] [Indexed: 12/13/2022]
Abstract
Hepatic encephalopathy (HE) is a devastating neuropsychiatric presentation of the advanced hepatic insufficiency. It is associated with high morbidity and mortality. Aquaporin-4 (AQP4), the principal astrocyte water channel, is primarily involved in brain edema development. Ulinastatin (ULI) is a potent protease inhibitor, extracted from fresh human urine. We hypothesized that ULI could be neuroprotective in acute HE through molecular targeting of brain AQP4, which is known to be upregulated in HE. To induce acute liver failure (ALF), the rats were acutely intoxicated with thioacetamide (TAA). Animals were randomized into HE- and ULI-treated HE groups, with control normal group. Total bilirubin, albumin, serum aminotransferases, and serum/brain ammonia/proinflammatory cytokines, blood-brain barrier (BBB) integrity/tight junction proteins, brain water content, and neurological scores were assessed. Additionally, brain AQP4 and α-Syntrophin mRNA expression and protein levels were evaluated by quantitative real-time PCR and enzyme-linked immunosorbent assay, respectively. Brain and liver tissues were stripped and processed for further microscopic and histological analyses. ULI exerted potent dual neuro/hepato protective potential, improved neurological score, animals' survival, ameliorated brain edema, probably via anti-inflammatory activity, preserved BBB integrity, down-regulated AQP4 expression, and membrane polarization by decreased α-syntrophin level, with rescued brain bioenergetics. ULI could be tooled as a possible therapeutic option in HE in ALF.Graphical abstract The possible ULI mediated protection in TAA-induced HE rat model.
Collapse
Affiliation(s)
- Rehab E Abo El Gheit
- Physiology Department, Faculty of Medicine, Tanta University, El Geesh Street, Tanta, Egypt.
| | - Marwa Mohamed Atef
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ghada A Badawi
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Pharmaceutical Industries, Sinai University, El-Arish, Egypt
| | - Walaa M Elwan
- Histology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - H A Alshenawy
- Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Marwa Nagy Emam
- Physiology Department, Faculty of Medicine, Tanta University, El Geesh Street, Tanta, Egypt
| |
Collapse
|
|
41
|
Wang JW, Wu AS, Yue Y, Wu Y. Perioperative Ulinastatin helps preserve endothelial glycocalyx layer in periampullary carcinoma patients undergoing Traditional Whipple Procedure. Clin Hemorheol Microcirc 2020; 75:135-142. [PMID: 31903986 DOI: 10.3233/ch-190688] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Jia-Wan Wang
- Department of Anesthesiology, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China
| | - An-Shi Wu
- Department of Anesthesiology, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Yun Yue
- Department of Anesthesiology, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Yan Wu
- Department of Anesthesiology, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China
| |
Collapse
|
|
42
|
Recombinant human ulinastatin improves immune dysfunction of dendritic cells in septic mice by inhibiting endoplasmic reticulum stress-related apoptosis. Int Immunopharmacol 2020; 85:106643. [DOI: 10.1016/j.intimp.2020.106643] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/10/2020] [Accepted: 05/22/2020] [Indexed: 12/12/2022]
|
|
43
|
Wang J, Sun Y, Teng S, Li K. Prediction of sepsis mortality using metabolite biomarkers in the blood: a meta-analysis of death-related pathways and prospective validation. BMC Med 2020; 18:83. [PMID: 32290837 PMCID: PMC7157979 DOI: 10.1186/s12916-020-01546-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 03/03/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Sepsis is a leading cause of death in intensive care units (ICUs), but outcomes of individual patients are difficult to predict. The recently developed clinical metabolomics has been recognized as a promising tool in the clinical practice of critical illness. The objective of this study was to identify the unique metabolic biomarkers and their pathways in the blood of sepsis nonsurvivors and to assess the prognostic value of these pathways. METHODS We searched PubMed, EMBASE, Cochrane, Web of Science, CNKI, Wangfang Data, and CQVIP from inception until July 2019. Eligible studies included the metabolomic analysis of blood samples from sepsis patients with the outcome. The metabolic pathway was assigned to each metabolite biomarker. The meta-analysis was performed using the pooled fold changes, area under the receiver operating characteristic curve (AUROC), and vote-counting of metabolic pathways. We also conducted a prospective cohort metabolomic study to validate the findings of our meta-analysis. RESULTS The meta-analysis included 21 cohorts reported in 16 studies with 2509 metabolite comparisons in the blood of 1287 individuals. We found highly limited overlap of the reported metabolite biomarkers across studies. However, these metabolites were enriched in several death-related metabolic pathways (DRMPs) including amino acids, mitochondrial metabolism, eicosanoids, and lysophospholipids. Prediction of sepsis death using DRMPs yielded a pooled AUROC of 0.81 (95% CI 0.76-0.87), which was similar to the combined metabolite biomarkers with a merged AUROC of 0.82 (95% CI 0.78-0.86) (P > 0.05). A prospective metabolomic analysis of 188 sepsis patients (134 survivors and 54 nonsurvivors) using the metabolites from DRMPs produced an AUROC of 0.88 (95% CI 0.78-0.97). The sensitivity and specificity for the prediction of sepsis death were 80.4% (95% CI 66.9-89.4%) and 78.8% (95% CI 62.3-89.3%), respectively. CONCLUSIONS DRMP analysis minimizes the discrepancies of results obtained from different metabolomic methods and is more practical than blood metabolite biomarkers for sepsis mortality prediction. TRIAL REGISTRATION The meta-analysis was registered on OSF Registries, and the prospective cohort study was registered on the Chinese Clinical Trial Registry (ChiCTR1800015321).
Collapse
Affiliation(s)
- Jing Wang
- Department of Critical Care Medicine, Yantai Yuhuangding Hospital, Yantai, 264000, Shandong, China.,School of Medicine, University of California, San Diego, CA, 92103, USA
| | - Yizhu Sun
- Department of Critical Care Medicine, Yantai Yuhuangding Hospital, Yantai, 264000, Shandong, China
| | - Shengnan Teng
- Department of Critical Care Medicine, Yantai Yuhuangding Hospital, Yantai, 264000, Shandong, China
| | - Kefeng Li
- School of Medicine, University of California, San Diego, CA, 92103, USA.
| |
Collapse
|
|
44
|
Yang XY, Song J, Hou SK, Fan HJ, Lv Q, Liu ZQ, Ding H, Zhang YZ, Liu JY, Dong WL, Wang X. Ulinastatin ameliorates acute kidney injury induced by crush syndrome inflammation by modulating Th17/Treg cells. Int Immunopharmacol 2020; 81:106265. [PMID: 32044661 DOI: 10.1016/j.intimp.2020.106265] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 01/27/2020] [Accepted: 01/27/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Acute kidney injury (AKI) is the main complication of crush syndrome (CS), and it is also a cause of lethality in CS. However, effective treatments for AKI are still lacking. Ulinastatin (UTI) is a broad-spectrum serine protease inhibitor extracted from human urine that reportedly modulates innate immunity and pro-inflammatory responses in sepsis. Here, we explored the effect and the potential mechanism of ulinastatin on crush syndrome-induced acute kidney injury (CSAKI). METHODS A CSAKI rat model was established by using a digital crush injury device platform. Forty-six male Wistar rats were randomly divided into five groups: the normal control (n = 6), CSAKI model (n = 10), CSAKI plus UTI1 (50,000 U/kg) (n = 10), CSAKI plus UTI2 (100,000 U/kg) (n = 10) and CSAKI plus UTI3 (200,000 U/kg) (n = 10) groups. Hematoxylin-eosin (HE) staining was used to investigate the reliability of the CSAKI model. The percentage of Th17/Treg lymphocytes in peripheral blood was measured by flow cytometry, and the expression of transcription factors associated with Th17/Treg cells was evaluated by quantitative real-time polymerase chain reaction (PCR). In addition, specific cytokines released by Th17/Treg cells in serum and kidney tissues were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS Treatment with ulinastatin could significantly decrease serum BUN, CK, Scr, Mb and K+ levels compared with CSAKI group. HE staining results showed that ulinastatin could inhibit inflammatory cells infiltration, decrease sarcomere rupture in muscle tissues induced by extrusion, and alleviate the glomerular congestion and edema, as well as decrease myoglobin cast in kidney tissues. The proportion of CD4+CD25+Foxp3+ regulatory T (Treg) cells and Foxp3 expression levels were decreased in the CSAKI animals, while IL-17 expression levels were significantly increased, compared with those of the normal control group. Treatment with ulinastatin upregulated the proportion of Treg cells in CD4+ T cells and downregulated the expression of IL-17 compared with those of the CSAKI group. CONCLUSION The findings of our study indicate that UTI attenuates CS-induced AKI and alleviate the inflammatory response during the early stage. The mechanism of UTI may be due to regulating the balance between Th17/Treg cells. Our study provides a new mechanism for the beneficial effect of ulinastatin on CSAKI.
Collapse
Affiliation(s)
| | - Jie Song
- Department of Nephrology, Characteristic Medical Center of Chinese People's Armed Police Forces, Tianjin, China
| | - Shi-Ke Hou
- Institute of Disaster Medicine, Tianjin University, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China.
| | - Hao-Jun Fan
- Institute of Disaster Medicine, Tianjin University, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Qi Lv
- Institute of Disaster Medicine, Tianjin University, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China.
| | - Zi-Quan Liu
- Institute of Disaster Medicine, Tianjin University, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Hui Ding
- Institute of Disaster Medicine, Tianjin University, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Yong-Zhong Zhang
- Institute of Disaster Medicine, Tianjin University, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Jin-Yang Liu
- Institute of Disaster Medicine and Public Health, Characteristic Medical Center of the Chinese People's Armed Police Force (PAP), Tianjin, China
| | - Wen-Long Dong
- Institute of Disaster Medicine, Tianjin University, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Xue Wang
- Institute of Disaster Medicine and Public Health, Characteristic Medical Center of the Chinese People's Armed Police Force (PAP), Tianjin, China
| |
Collapse
|
|
45
|
Meng F, Du C, Zhang Y, Wang S, Zhou Q, Wu L, Wang Y, Yang X. Protective effect of rhubarb combined with ulinastatin for patients with sepsis. Medicine (Baltimore) 2020; 99:e18895. [PMID: 32049789 PMCID: PMC7035124 DOI: 10.1097/md.0000000000018895] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Sepsis is the leading cause of death in critically ill patients. Ulinastatin (UTI), a protease inhibitor, and rhubarb, used as a traditional Chinese medication, are proved to be effective in treating sepsis, but the effect of the combination therapy of these two drugs on sepsis remains unclear. This study aimed to investigate the effect of the combination treatment of UTI and rhubarb on sepsis patients. METHODS A total of 75 septic patients were randomly divided into control group, UTI group, Rhubarb group, and UTI plus Rhubarb group. Clinical data and score of Acute Physiology and Chronic Health Evaluation II (APACHE II) were collected; lymphocyte subtypes in the peripheral blood were analyzed before and after the 5-day treatment in the Intensive Care Unit. RESULTS All the therapeutic interventions (UTI alone, rhubarb alone, or UTI plus rhubarb) significantly reduced the levels of C-Reactive protein, white blood cell density, lactic acid, and APACH II scores, and elevated the levels of CD4/CD8, but only UTI plus rhubarb treatment obviously decreased the level of procalcitonin. CONCLUSION This study suggested that the combination of UTI and rhubarb may be a promising therapeutic scheme to ameliorate sepsis.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Yanli Wang
- Department of Mental Health, First Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | | |
Collapse
|
|
46
|
Keyal N, Nakarmi M. Hydrocortisone and ulinastatin for miliary tuberculosis-induced septic shock and adult respiratory distress syndrome in the intensive care unit. CHRISMED JOURNAL OF HEALTH AND RESEARCH 2020. [DOI: 10.4103/cjhr.cjhr_45_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
|
47
|
Ma C, Han DF, Jin H, Cheng YY, Hu HX, Wang X. A Combination of Ulinastatin and Xuebijing Amplifies Neuroprotection after Transient Cerebral Ischemia via Attenuating Apoptosis Signal Pathways in Hippocampus. Curr Pharm Des 2019; 24:5342-5347. [PMID: 30727870 DOI: 10.2174/1381612825666190206224134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 01/30/2019] [Indexed: 12/30/2022]
Abstract
BACKGROUND Ulinastatin (UTI) plays the beneficial roles in modifying cerebral ischemic injury evoked by cardiac arrest (CA). XueBiJing (XBJ), comprised of extracts from Chinese herbals, has been used for the treatment of sepsis and ischemic disorders linked to multiple organ dysfunction syndromes. The current study was to find interventions that can enhance effectiveness of these drugs and further to provide a fundamental for their rational application in clinical practice. Thus, we examined how apoptosis signal in the hippocampus is engaged in a facilitating role of UTI and XBJ in improving neural injury and neurological functions after transient cerebral ischemia. METHODS CA was induced by asphyxia followed by cardiopulmonary resuscitation in rats. Western Blot analysis and ELISA were employed to determine the protein expression of Caspase-3 and Caspase-9 in the hippocampus; and representative apoptosis pathways. The modified neurological severity score (mNSS) and spatial working memory performance were used to assess neurological deficiencies in CA rats. RESULTS CA increased Caspase-3 and Caspase-9 in the hippocampus CA1 region. A lower dose of UTI did not attenuate upregulation of apoptosis signal pathways evoked by CA. However, a systemic administration of XBJ significantly amplified the inhibitory effects of the lower dose of UTI on apoptosis signal of the hippocampus. In addition, a combination of UTI and XBJ improved mNSS and spatial working memory performance to a greater degree. CONCLUSIONS Our data indicate that a combination of XBJ and UTI plays a facilitating role in improving neuronal injury and neurological deficits observed in transient cerebral ischemia; and an inhibition of apoptosis signal pathways is involved in neuroprotective effects of united XBJ and UTI.
Collapse
Affiliation(s)
- Chi Ma
- Department of Neurosurgery, First Hospital of Jilin University, Jilin, China
| | - Dong-Feng Han
- Department of Emergency Medicine, First Hospital of Jilin University, Jilin, China
| | - Hang Jin
- Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Jilin, China
| | - Ying-Ying Cheng
- Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Jilin, China
| | - Hai-Xia Hu
- Department of Emergency Medicine, First Hospital of Jilin University, Jilin, China
| | - Xu Wang
- Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Jilin, China
| |
Collapse
|
|
48
|
Wang H, Liu B, Tang Y, Chang P, Yao L, Huang B, Lodato RF, Liu Z. Improvement of Sepsis Prognosis by Ulinastatin: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front Pharmacol 2019; 10:1370. [PMID: 31849646 PMCID: PMC6893897 DOI: 10.3389/fphar.2019.01370] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 10/29/2019] [Indexed: 01/02/2023] Open
Abstract
Background: Ulinastatin has been prescribed to treat sepsis. However, there is doubt regarding the extent of any improvement in outcomes to guide future decision making. Objectives: To evaluate the effects of ulinastatin on mortality and related outcomes in sepsis patients. Methods: Thirteen randomized controlled trials and two prospective studies published before September 1, 2018, that included 1358 patients with sepsis, severe sepsis, or septic shock were evaluated. The electronic databases searched in this study were PubMed, Medline, Embase, and China National Knowledge Infrastructure (CNKI) for Chinese Technical Periodicals. Results: Ulinastatin significantly decreased the all-cause mortality {odds ratio (OR) = 0.48, 95% confidence interval (CI) [0.35-0.66], p < 0.00001, I2 = 13%}, Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score {mean difference (MD) = -2.40, 95% CI [-4.37, -0.44], p = 0.02, I2 = 66%}, and reduced the incidence of multiple organ dysfunction syndrome (MODS) (OR = 0.3, 95% CI [0.18, 0.49], p < 0.00001, I2 = 0%). Ulinastatin also decreased the serum levels of IL-6 (MD = -88.5, 95% CI [-123.97, -53.04], p < 0.00001), TNF-α (MD = -56.22, 95% CI [-72.11, -40.33], p < 0.00001), and increased the serum levels of IL-10 (MD = 37.73, 95% CI [16.92, 58.54], p = 0.0004). Ulinastatin administration did not lead to any difference in the occurrence of adverse events. Conclusions: Ulinastatin improved all-cause mortality and other related outcomes in patients with sepsis or septic shock. The results of this meta-analysis suggest that ulinastatin may be an effective treatment for sepsis and septic shock.
Collapse
Affiliation(s)
- Huifang Wang
- Department of Intensive Care Unit, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Bin Liu
- Emergency Department, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Ying Tang
- Department of Intensive Care Unit, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Ping Chang
- Department of Intensive Care Unit, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lishuai Yao
- Department of Thoracic and Cardiovascular Surgical, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Bo Huang
- Department of Intensive Care Unit, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Robert F Lodato
- Department of Pulmonary, Critical Care, and Sleep Medicine, Medical School, University of Texas Health Science Center at Houston, TX, United States
| | - Zhanguo Liu
- Department of Intensive Care Unit, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
49
|
Ulinastatin treatment for acute respiratory distress syndrome in China: a meta-analysis of randomized controlled trials. BMC Pulm Med 2019; 19:196. [PMID: 31684936 PMCID: PMC6829844 DOI: 10.1186/s12890-019-0968-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 10/18/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Epidemiologic studies have shown inconsistent conclusions about the effect of ulinastain treatment for acute respiratory distress syndrome (ARDS). It is necessary to perform a meta-analysis of ulinastatin's randomized controlled trials (RCTS) to evaluate its efficacy for treating ARDS. METHODS We searched the published RCTs of ulinastatin treatment for ARDS from nine databases (the latest search on April 30th, 2017). Two authors independently screened citations and extracted data. The meta-analysis was performed using Rev. Man 5.3 software. RESULTS A total of 33 RCTs involving 2344 patients satisfied the selection criteria and were included in meta-analysis. The meta-analysis showed that, compared to conventional therapy, ulinastatin has a significant benefit for ARDS patients by reducing mortality (RR = 0.51, 95% CI:0.43~0.61) and ventilator associated pneumonia rate (RR = 0.50, 95% CI: 0.36~0.69), and shortening duration of mechanical ventilation (SMD = -1.29, 95% CI: -1.76~-0.83), length of intensive care unit stay (SMD = -1.38, 95% CI: -1.95~-0.80), and hospital stay (SMD = -1.70, 95% CI:-2.63~-0.77). Meanwhile, ulinastatin significantly increased the patients' oxygenation index (SMD = 2.04, 95% CI: 1.62~2.46) and decreased respiratory rate (SMD = -1.08, 95% CI: -1.29~-0.88) and serum inflammatory factors (tumor necrosis factor-α: SMD = -3.06, 95% CI:-4.34~-1.78; interleukin-1β: SMD = -3.49, 95% CI: -4.64~-2.34; interleukin-6: SMD = -2.39, 95% CI: -3.34~-1.45; interleukin-8: SMD = -2.43, 95% CI: -3.86~-1.00). CONCLUSIONS Ulinastatin seemly showed a beneficial effect for ARDS patients treatment and larger sample sized RCTs are needed to confirm our findings.
Collapse
|
|
50
|
Zhang FJ, Song HQ, Li XM. Effect of ulinastatin combined with mild therapeutic hypothermia on intestinal barrier dysfunction following cardiopulmonary resuscitation in rats. Exp Ther Med 2019; 18:3861-3868. [PMID: 31616513 PMCID: PMC6781809 DOI: 10.3892/etm.2019.8039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 08/21/2019] [Indexed: 11/23/2022] Open
Abstract
The aim of the present study was to investigate the effect of ulinastatin (UTI) alone or combined with mild therapeutic hypothermia (MTH) on intestinal barrier dysfunction following cardiopulmonary resuscitation (CPR) in rats. A total of 25 adult male Sprague-Dawley rats were randomly organized into five groups: Sham; control; UTI; MTH; and the combined group. The latter four groups were induced with the asphyxiated cardiac arrest rat model and treated with different interventions. After 6 h of treatment, the intestinal tissues of the rats were examined by electron microscopy, and the levels of intestinal malondialdehyde (MDA) and superoxide dismutase (SOD) were determined. The results of the present study indicated that the target temperature had successfully been attained in MTH and the combined group, and the other three groups of rats all survived at a normal temperature. In the rats treated with UTI or MTH, the epithelial cells exhibited pathological changes in their tight junctions and epithelial cell surface microvilli compared with the sham group. In the rats treated with a combination of UTI and MTH, whilst the epithelial cells exhibited a few slight changes, including mitochondrial edema, they were largely similar to the normal epithelial cells. However, there were significant differences in the levels of MDA and SOD between the different treatment groups. UTI combined with MTH may serve a protective role by suppressing oxidative stress in the small intestinal mucosa following CPR in rats compared with either UTI or MTH treatment alone.
Collapse
Affiliation(s)
- Fang-Jie Zhang
- Department of Emergency Medicine, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
| | - Hua-Qiang Song
- Department of Emergency Medicine, The First People's Hospital of Changde City, Changde, Hunan 415000, P.R. China
| | - Xiang-Min Li
- Department of Emergency Medicine, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
| |
Collapse
|