Discovery of a Potential Plasma Protein Biomarker Panel for Acute-on-Chronic Liver Failure Induced by Hepatitis B Virus

Zhou, Nan; Wang, Kuifeng; Fang, Shanhua; Zhao, Xiaoyu; Huang, Tingting; Chen, Huazhong; Yan, Fei; Tang, Yongzhi; Zhou, Hu; Zhu, Jiansheng

doi:10.3389/fphys.2017.01009

Cited by 25 publications

(24 citation statements)

References 67 publications

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“…8). The broad range of affected pathways is similar to proteomic surveys of acute-on-chronic liver failure, which causes sweeping changes in the plasma proteome 24,25 and an in vitro model of mycotoxin-induced hepatocyte toxicity that found non-housekeeping pathway proteins to be affected most 26 .…”

Section: Discussionmentioning

confidence: 61%

Hemoadsorption Improves Survival of Rats Exposed to an Acutely Lethal Dose of Aflatoxin B1

Ruggeberg

O’Sullivan

Kovacs

et al. 2020

Sci Rep

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Mycotoxins, such as aflatoxin B 1 (AFB 1), pose a serious threat as biological weapons due to their high toxicity, environmental stability, easy accessibility and lack of effective therapeutics. This study investigated if blood purification therapy with CytoSorb (CS) porous polymer beads could improve survival after a lethal aflatoxin dose (LD 90). The effective treatment window and potential therapeutic mechanisms were also investigated. Sprague Dawley rats received a lethal dose of AFB 1 (0.5-1.0 mg/ kg) intravenously and hemoperfusion with a cS or control device was initiated immediately, or after 30, 90, or 240-minute delays and conducted for 4 hours. The CS device removes AFB 1 from circulation and significantly improves survival when initiated within 90 minutes of toxin administration. Treated subjects exhibited improved liver morphology and health scores. changes in the levels of cytokines, leukocytes and platelets indicate a moderately-severe inflammatory response to acute toxin exposure. Quantitative proteomic analysis showed significant changes in the level of a broad spectrum of plasma proteins including serine protease/endopeptidase inhibitors, coagulation factors, complement proteins, carbonic anhydrases, and redox enzymes that ostensibly contribute to the therapeutic effect. Together, these results suggest that hemoadsorption with cS could be a viable countermeasure against acute mycotoxin exposure. Aflatoxins are toxic secondary fungal metabolites (mycotoxins) produced by fungus from the genus Aspergillus that cause severe acute reactions that can be lethal. Aspergillus species are important human pathogens and the toxic metabolites appear to act as virulence factors to suppress the immune system in invasive aspergillosis 1. Aflatoxins cause damage to the liver resulting in hemorrhagic liver necrosis, steatosis, bile duct proliferation and subsequent organ failure and have been detected in pulmonary lesions of immune-compromised patients with systemic aspergillosis 2. Aflatoxin B 1 (AFB 1), the most potent toxin of the 14 naturally occurring aflatoxin variants, is extremely cytotoxic, genotoxic, and carcinogenic 3,4. In the liver, cytochrome P450-modified AFB 1 forms DNA adducts that lead to impaired cellular function, carcinogenesis and/or cell death and organ failure 5,6. Acute aflatoxin poisoning from mold contaminated foods has been linked with numerous deaths in several instances 7,8. Importantly, mycotoxins pose a serious threat as potential biowarfare agents due to their inherent stability and ease of manufacture. The toxins can be readily weaponized into aerosol form and dispersed over a wide area to elicit mass casualties through both inhalation and dermal exposure 9. There have been several reported incidents of use of mycotoxins as bioweapons in Southeast Asia and the Gulf States 10,11. Early symptoms of mycotoxin exposure in bio-warfare manifest rapidly in minutes to hours and can include burning, pain, wheezing, nausea, vomiting, tearing, weakness, bleeding and a host of other symptoms...

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Section: Discussionmentioning

confidence: 61%

Hemoadsorption Improves Survival of Rats Exposed to an Acutely Lethal Dose of Aflatoxin B1

Ruggeberg

O’Sullivan

Kovacs

et al. 2020

Sci Rep

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“…Of those, 2,234 were quantified across all of the 25 samples, indicating that each protein generated expression information for different treatment statuses (Table S1 ). We also performed t -test analysis between any two groups to identify differentially expressed proteins that were potential targets of Andro-S. To determine potential targets of Andro-S, we filtered proteins according to the following four criteria (Smith et al, 2015 ; Xia et al, 2017 ; Zhang et al, 2017 ; Zhou et al, 2017 ): (1) significant over- or under-expression in the model group relative to the control group (Student's t -test P < 0.05); (2) significant over- or under-expression in high-dose treatment group compared with the model group (Student's t -test P < 0.05); (3) no significant changes in expression levels in the control group compared to the blank (Student's t -test P > 0.05) and (4) model group vs. control group or high-dose treatment group vs. model group (one-way analysis of variance (ANOVA) followed by Tukey test correction P < 0.05). A total of 31 proteins were identified as potential differentially expressed proteins based on these criteria (Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

Andrographolide Sulfonate Attenuates Acute Lung Injury by Reducing Expression of Myeloperoxidase and Neutrophil-Derived Proteases in Mice

et al. 2018

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Andrographolide sulfonate (Andro-S), a sulfonation derivative of andrographolide, is known to be effective in treating inflammation-related diseases, while the underlying mechanisms and global protein alterations in response to Andro-S remain unknown. This study aimed to investigate the pharmacological effects and potential targets of Andro-S in a murine model of acute lung injury (ALI). ALI was induced by aerosolized lipopolysaccharide (LPS) exposure before treatment with Andro-S. Inflammatory state of each treatment group was determined by histological analysis and quantification of inflammatory markers. Differentially expressed proteins in lung tissues were identified by an iTRAQ-based quantitative proteomic approach and further confirmed by immunohistochemistry analysis. Administration of Andro-S alleviated LPS-induced histological changes in the lung and reduced the expression of inflammatory markers in serum, bronchoalveolar fluid and lung tissues. Proteomic analysis identified 31 differentially expressed proteins from a total of 2,234 quantified proteins in the lung. According to bioinformatics analysis, neutrophil elastase (ELANE), cathepsin G (CTSG) and myeloperoxidase (MPO), three neutrophil-derived proteases related to immune system process and defense responses to fungi were chosen as potential targets of Andro-S. Further immunohistochemistry analysis confirmed the inhibitory effects of Andro-S on LPS-induced ELANE, CTSG and MPO up-regulation. These results indicate that Andro-S suppressed the severity of LPS-induced ALI, possibly by attenuating the expression of and neutrophil-derived proteases.

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“…A few studies utilized proteomic approaches to identify biomarkers for HBV-ACLF (15)(16)(17). However, these studies were conducted with small sample sizes, and, consequently, the results were inconclusive.…”

Section: Discussionmentioning

confidence: 99%

Plasminogen as a prognostic biomarker for HBV-related acute-on-chronic liver failure

Wu¹,

Zhang²,

Xie³

et al. 2020

Journal of Clinical Investigation

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viduals infected with HBV worldwide (4). In most Asian countries, HBV-related ACLF (HBV-ACLF) accounts for over 70% of ACLF cases (5, 6). Reports have shown that the patient's condition at admission is linked to the outcome of ACLF (1, 7); thus, biomarkers that enable early and accurate risk stratification are needed. Additionally, ACLF is a highly dynamic process; therefore, sequential assessments of biomarkers that reflect the course of liver failure during hospitalization may enhance the management of patients with ACLF (7-9). However, to our knowledge, no biomarker has satisfactorily addressed these challenges. Patients with CLD who experience an episode of acute hepatic insult causing liver dysfunction are considered to have acute BACKGROUND. HBV-related acute-on-chronic liver failure (HBV-ACLF) is hallmarked by high short-term mortality rates, calling for accurate prognostic biomarkers for initial risk stratification. METHODS. Three tandem mass tag-labeled (TMT-labeled) quantitative proteomic studies were performed on 10 patients with HBV-related acute hepatic decompensation and on 20 patients with HBV-ACLF. Candidate biomarkers were preliminarily verified in a cross-sectional cohort (n = 144) and further confirmed in 2 prospective cohorts (n = 207 and n = 148). RESULTS. Plasminogen, a potential prognostic biomarker for HBV-ACLF, was identified by TMT quantitative proteomics and preliminarily verified in the cross-sectional cohort. Further validation with a prospective cohort (n = 207) showed that plasminogen levels at admission were significantly lower (P < 0.001) in HBV-ACLF nonsurvivors than in survivors. The cumulative survival duration of patients with high plasminogen levels was significantly longer (P < 0.001) than that of patients with low plasminogen levels. During hospitalization, plasminogen levels significantly decreased (P = 0.008) in the deterioration group but significantly increased (P < 0.001) in the improvement group. Additionally, plasminogen levels gradually increased in survivors but gradually decreased in nonsurvivors. The P5 score, a prognostic panel incorporating plasminogen levels, hepatic encephalopathy occurrence, age, international normalized ratio (INR), and total bilirubin, was significantly superior to the Child-Pugh, Model for End-stage Liver Disease (MELD), Chronic Liver Failure Consortium ACLF (CLIF-C ACLF), Chinese Group on the Study of Severe Hepatitis B (COSSH), and HINT (a prognostic score based on hepatic encephalopathy occurrence, INR, neutrophil count, and thyroid-stimulating hormone) scores (all P < 0.05). The performances of the plasminogen level and P5 score were validated in a second multicenter, prospective cohort (n = 148). CONCLUSIONS. Plasminogen is a promising prognostic biomarker for HBV-ACLF, and sequential plasminogen measurements could profile the clinical course of HBV-ACLF. P5 is a high-performance prognostic score for HBV-ACLF.

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Discovery of a Potential Plasma Protein Biomarker Panel for Acute-on-Chronic Liver Failure Induced by Hepatitis B Virus

Cited by 25 publications

References 67 publications

Hemoadsorption Improves Survival of Rats Exposed to an Acutely Lethal Dose of Aflatoxin B1

Hemoadsorption Improves Survival of Rats Exposed to an Acutely Lethal Dose of Aflatoxin B1

Andrographolide Sulfonate Attenuates Acute Lung Injury by Reducing Expression of Myeloperoxidase and Neutrophil-Derived Proteases in Mice

Plasminogen as a prognostic biomarker for HBV-related acute-on-chronic liver failure

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