Plasma RIPK3 And HMGB1 Predict Severe COVID-19 Progression In ICU Patients: A Single-Center Cohort Study

Abstract Background: Severe progression of coronavirus disease 2019 (COVID‑19) causes respiratory failure and critical illness. Recently, these pathologies have been associated with necroptosis, a receptor‑interacting serine/threonine‑protein kinase 3 (RIPK3) dependent regulated form of inflammatory cell death. Investigations of indicator necroptosis proteins like RIPK3, mixed lineage kinase domain‑like pseudokinase (MLKL), receptor‑interacting serine/threonine‑protein kinases 1 (RIPK1), and high‑mobility group box 1 (HMGB1) in clinical COVID‑19 manifestations are lacking.Methods: A prospective prolonged cohort study including 46 intensive care unit (ICU) patients classified with moderate and severe COVID‑19 was conducted with daily measured plasma levels of indicator necroptosis proteins like RIPK3, MLKL, RIPK1, and HMGB1 by enzyme‑linked immunosorbent assay (ELISA). On this basis, a multiple logistic (regression) classification for the prediction of severe COVID‑19 progression was performed. Results: We found significantly elevated RIPK3, MLKL, HMGB1, and RIPK1 levels in COVID‑19 patients admitted to the ICU compared to healthy controls throughout the ongoing disease, indicating necroptotic processes. Above all, with combined measurements of RIPK3 and HMGB1 plasma levels, we were able to time‑independently predict COVID‑19 severity with 84% accuracy, 90% sensitivity, and 76% specificity.Conclusion: We suggest that HMGB1 and RIPK3 are potential biomarkers to identify high‑risk COVID‑19 patients and developed a classifier for COVID‑19 severity.

Download Full-text

Association of plasma level of high-mobility group box-1 with necroptosis and sepsis outcomes

Scientific Reports ◽

10.1038/s41598-021-88970-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hongseok Yoo ◽

Yunjoo Im ◽

Ryoung-Eun Ko ◽

Jin Young Lee ◽

Junseon Park ◽

...

Keyword(s):

Plasma Levels ◽

Validation Cohort ◽

High Mobility ◽

Kinase Domain ◽

High Mobility Group ◽

Rank Test ◽

Enzyme Linked Immunosorbent Assay ◽

Derivation Cohort ◽

The Difference

AbstractThe role of high-mobility group box-1 (HMGB1) in outcome prediction in sepsis is controversial. Furthermore, its association with necroptosis, a programmed cell necrosis mechanism, is still unclear. The purpose of this study is to identify the association between the plasma levels of HMGB1 and the severity and clinical outcomes of sepsis, and to examine the correlation between HMGB1 and key executors of necroptosis including receptor-interacting kinase 3 (RIPK3) and mixed lineage kinase domain-like- (MLKL) proteins. Plasma HMGB1, RIPK3, and MLKL levels were measured with the enzyme-linked immunosorbent assay from the derivation cohort of 188 prospectively enrolled, critically-ill patients between April 2014 and December 2016, and from the validation cohort of 77 patients with sepsis between January 2017 and January 2019. In the derivation cohort, the plasma HMGB1 levels of the control (n = 46, 24.5%), sepsis (n = 58, 30.9%), and septic shock (n = 84, 44.7%) groups were significantly increased (P < 0.001). A difference in mortality between high (≥ 5.9 ng/mL) and low (< 5.9 ng/mL) HMGB1 levels was observed up to 90 days (Log-rank test, P = 0.009). There were positive linear correlations of plasma HMGB1 with RIPK3 (R2 = 0.61, P < 0.001) and MLKL (R2 = 0.7890, P < 0.001). The difference in mortality and correlation of HMGB1 levels with RIPK3 and MLKL were confirmed in the validation cohort. Plasma levels of HMGB1 were associated with the severity and mortality attributed to sepsis. They were correlated with RIPK3 and MLKL, thus suggesting an association of HMGB1 with necroptosis.

Download Full-text

Increased Levels of PTX3 in Human Plasma in Septic Patients with DIC

Blood ◽

10.1182/blood.v118.21.4347.4347 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4347-4347

Author(s):

Kazuo Kawasugi ◽

Tadashi Yamamoto ◽

Ryosuke Shirasaki ◽

Haruko Tashiro ◽

Naoki Shirafuji

Keyword(s):

Human Plasma ◽

Plasma Levels ◽

Conflicts Of Interest ◽

High Mobility ◽

Whole Body ◽

Enzyme Linked Immunosorbent Assay ◽

Inflammatory Activation ◽

Threatening Condition ◽

Inflammatory State ◽

Life Threatening

Abstract Abstract 4347 Sepsis is a life-threatening condition that is characterized by a whole-body inflammatory state (called a systemic inflammatory response syndrome, SIRS). Long pentraxin PTX3 is an inflammatory mediator and a component of the humoral arm of innate immunity produced by neutrophils, macrophages, myeloid dendritic and endothelial cells. During sepsis a massive inflammatory activation and coagulation/fibrinolysis dysfunction occur. However, little is known about PTX3 in septic patients with DIC. Therefore, we measured PTX3s in the plasma from septic patients with DIC (n=20). Also, we investigated PTX3 in the plasma from septic patients without DIC (n=8) and acute promyelocytic leukemia (APL)-induced DIC (n=5). PTX3 in the plasma from human were measured using enzyme-linked immunosorbent assay (ELISA) kits (Perseus Proteomics Inc, Japan). The thrombin antithrombin complexes (TAT) levels were higher in both DIC patients as reported by others. We detected high levels of PTX3 in the plasma of all septic patients with DIC. Also, plasma levels of PTX3 were positive in septic patients without DIC. However, plasma levels of PTX3 were significantly higher in septic patients with DIC than in septic patients without DIC. Plasma levels of PTX3 ware significantly correlated with severity of septic DIC (platelet count and TAT level). We did not find any difference plasma levels of PTX3 in the APL patients with DIC. Moreover, high-mobility group box 1 (HMGB1) concentrations in the human plasma were determined using ELISA kit (Shino-Test, Japan). Plasma levels of HMBG1 were positive for 14 cases in 20 septic patients with DIC. Also, we did not find any difference plasma levels of HMGB1 in the APL patients with DIC. These results suggest that assess of PTX3 and HMBG1 in the plasma may be helpful in the making the diagnosis in septic patients with DIC. However, PTX3 seemed to be a better biomarker than HMGB1. It appears that PTX3 may contribute to the severity of septic DIC. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Plasma levels of high mobility group box 1 increase in patients with posttraumatic stress disorder after severe blunt chest trauma: a prospective cohort study

Journal of Surgical Research ◽

10.1016/j.jss.2014.06.020 ◽

2015 ◽

Vol 193 (1) ◽

pp. 308-315 ◽

Cited By ~ 6

Author(s):

Xiao-Wen Wang ◽

Avash Karki ◽

Ding-Yuan Du ◽

Xing-Ji Zhao ◽

Xiao-Yong Xiang ◽

...

Keyword(s):

Posttraumatic Stress Disorder ◽

Cohort Study ◽

Posttraumatic Stress ◽

Prospective Cohort Study ◽

Plasma Levels ◽

Prospective Cohort ◽

Blunt Chest Trauma ◽

Chest Trauma ◽

Stress Disorder ◽

High Mobility

Download Full-text

High plasma levels of high mobility group box 1 is associated with the risk of sepsis in severe blunt chest trauma patients: a prospective cohort study

Journal of Cardiothoracic Surgery ◽

10.1186/s13019-014-0133-5 ◽

2014 ◽

Vol 9 (1) ◽

Cited By ~ 21

Author(s):

Xiao-Wen Wang ◽

Avash Karki ◽

Xing-Ji Zhao ◽

Xiao-Yong Xiang ◽

Zhi-Qian Lu

Keyword(s):

Cohort Study ◽

Prospective Cohort Study ◽

Plasma Levels ◽

Prospective Cohort ◽

Blunt Chest Trauma ◽

Chest Trauma ◽

High Mobility ◽

High Plasma ◽

High Mobility Group ◽

Trauma Patients

Download Full-text

Abstract TP440: Elevated Plasma Level of Soluble Form of RAGE in Ischemic Stroke Patients With Vascular Cognitive Impairment

Stroke ◽

10.1161/str.48.suppl_1.tp440 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Sung-Chun tang ◽

Hung-Yi Chiou ◽

Chung Y. Hsu ◽

Chau-Chung Wu ◽

Jiann-Shing Jeng

Keyword(s):

Ischemic Stroke ◽

Cognitive Impairment ◽

Plasma Levels ◽

Medical Center ◽

Univariate Analysis ◽

High Mobility ◽

Vascular Cognitive Impairment ◽

Soluble Form ◽

Enzyme Linked Immunosorbent Assay ◽

Cross Sectional

Background / Purpose: Little is known about the role of receptor for advanced glycation end products (RAGE) -mediated signaling in the development of vascular cognitive impairment (VCI). The study aimed to investigate the associations of various RAGE signaling related plasma biomarkers and the development of VCI in chronic ischemic stroke (IS) patients. Methods: This cross-sectional study recruited patients with IS at an university medical center stroke clinic. VCI was defined as the scale of Clinical Dementia Ranking (CDR) ≥1. Standard enzyme-linked immunosorbent assay was used to measure the plasma concentration of soluble form of RAGE (sRAGE), endogenous soluble form of RAGE (esRAGE), high mobility group box 1 (HMGB1) and matrix metallopeptidase 9 (MMP9) in IS patients with and without VCI. Results: Between November 2014 to October 2015, a total of 172 IS patients (mean age 72.1±7.5 years, 64.5% male) were recruited, including 73 with CDR=0, 63 with CDR=0.5 and 36 with CDR ≥1. In univariate analysis, IS patients with VCI were older, and had more diabetes mellitus, fewer atrial fibrillation, and higher post-stroke modified Rankin Scales than those without. Plasma levels of sRAGE and esRAGE, but not HMGB1 or MMP9 were significantly higher in IS patients with VCI than those without (1.44±1.29 versus 1.03±0.48 and 0.39±0.40 versus 0.24±0.13 ng/ml, both p<0.01). Importantly, both parameters remained independent after adjustment for clinical variables (OR 2.683, p=0.013 and OR 39.192, p=0.006, respectively). Conclusion: Among IS patients, plasma levels of both sRAGE and esRAGE were elevated in those with VCI.

Download Full-text

Faculty Opinions recommendation of Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14267354.15779561 ◽

2012 ◽

Author(s):

Henning Walczak ◽

Maurice Darding

Keyword(s):

Kinase Domain ◽

Mixed Lineage Kinase

Download Full-text

Risk factors associated with toxoplasmosis and toxocariasis in populations of children from nine cities in southern Brazil

Journal of Helminthology ◽

10.1017/s0022149x14000212 ◽

2014 ◽

Vol 89 (4) ◽

pp. 428-432 ◽

Cited By ~ 11

Author(s):

A.A. Marchioro ◽

C.M. Colli ◽

É.C. Ferreira ◽

B.M. Viol ◽

S.M. Araújo ◽

...

Keyword(s):

Risk Factors ◽

Preventive Measures ◽

Enzyme Linked Immunosorbent Assay ◽

Multiple Logistic Regression ◽

Southern Brazil ◽

Parasite Control ◽

Igg Antibodies ◽

Positive Serology ◽

Factors Associated ◽

Epidemiological Factors

AbstractThis study investigated the epidemiological factors that contribute to the seroprevalence of Toxoplasma gondii and Toxocara spp. in children from Paraná state, Brazil. Immunoglobulin G (IgG) antibodies to T. gondii were detected using indirect immunofluorescence, and IgG antibodies to Toxocara were detected using an enzyme-linked immunosorbent assay. For each individual, a questionnaire was completed that contained epidemiological and clinical data. The data analysis was performed using multiple logistic regression. Of the 544 children investigated, 3.2% presented co-infection with T. gondii and Toxocara spp. Of this total, 7.4% were positive for antibodies to T. gondii, and 25% were positive for antibodies to Toxocara spp. The presence of antibodies to Toxocara spp. increased the risk of T. gondii infection (P= 0.029). Children who were 1–8 years of age were less infected by T. gondii than those who were 9–12 years of age. The variables that influenced positivity for anti-Toxocara spp. were the origin of the children and contact with sand. Children with positive serology for Toxocara spp. presented more eosinophilia compared with those with non-reactive serology. Infection with both parasites reveals the need for preventive measures, such as guidance about modes of infection, parasite control and monitoring recreational areas.

Download Full-text

Effectiveness of Infection Preventive Behaviors on COVID-19-Like Illness Symptoms During the Winter Third Wave of the Epidemic in Japan: A 2-Month Follow-up Nationwide Cohort Study

Asia Pacific Journal of Public Health ◽

10.1177/10105395211064437 ◽

2021 ◽

pp. 101053952110644

Author(s):

Shoichi Shimizu ◽

Tomohiro Ishimaru ◽

Masako Nagata ◽

Ayako Hino ◽

Seiichiro Tateishi ◽

...

Keyword(s):

Cohort Study ◽

Face Mask ◽

Hand Washing ◽

Third Wave ◽

Multiple Logistic Regression ◽

Regression Analyses ◽

Preventive Behaviors ◽

The Third ◽

Room Ventilation

Although multilayered strategies including preventive behaviors should be adopted to mitigate coronavirus disease 2019 (COVID-19) transmission, evidence on the effectiveness of preventive behaviors against COVID-19 remains limited. This Internet-based prospective cohort study collected baseline data in November 2020 and follow-up data in February 2021, during the third wave of the epidemic in Japan. Among the 19 941 included participants, the percentages reporting that they always used a face mask, practiced hand washing/disinfection, gargling, and ensuring proper room ventilation were 85.4%, 36.0%, 51.1%, and 44.6%, respectively. Multiple logistic regression analyses revealed that less frequently practicing hand washing/disinfection (odds ratio [OR] = 1.20, 95% confidence interval [CI]: 1.10-1.32), gargling (OR = 1.20, 95% CI: 1.10-1.30), and ensuring proper room ventilation (OR = 1.38, 95% CI: 1.26-1.52) were significantly associated with self-reported COVID-19-like illness (CLI). These results suggest that personal preventive behaviors may be effective in reducing CLI, even when universal masking is practiced.

Download Full-text

DUSP1 Is a Potential Marker of Chronic Inflammation in Arabs with Cardiovascular Diseases

Disease Markers ◽

10.1155/2018/9529621 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Abdelkrim Khadir ◽

Sina Kavalakatt ◽

Mohammed Dehbi ◽

Monira Alarouj ◽

Abdullah Bennakhi ◽

...

Keyword(s):

Risk Factors ◽

Chronic Inflammation ◽

Plasma Levels ◽

Recurrent Events ◽

Multivariate Logistic Regression Analysis ◽

Least Square ◽

Enzyme Linked Immunosorbent Assay ◽

Low Grade ◽

Potential Marker ◽

Diabetes Status

Background. Cardiovascular disease (CVD) risks persist in patients despite the use of conventional treatments. This might be due to chronic inflammation as reflected in epidemiological studies associating circulating low-grade inflammatory markers with CVD recurrent events. Here, we explored this potential link by assessing plasma dual-specificity phosphatase 1 (DUSP1) levels and comparing them to high-sensitivity CRP (hsCRP) and oxidized low-density lipoprotein (oxLDL) levels and their associations to conventional CVD risk factors in confirmed CVD patients. Methods. Human adults with reported CVD (n=207) and controls (n=70) living in Kuwait were used in this study. Anthropometric and classical biochemical parameters were determined. Plasma levels of DUSP1, oxLDL, and hsCRP were measured using human enzyme-linked immunosorbent assay kits. Results. DUSP1 and hsCRP plasma levels and their least square means were higher in CVD cases, while oxLDL plasma levels were lower (p<0.05). Multivariate logistic regression analysis showed that DUSP1 and hsCRP are independently associated with CVD in the studied population, as reflected by 2-fold and 1.5-fold increased risks with increased levels of DUSP1 and hsCRP, respectively. In our study, DUSP1 levels were found to be associated with CVD despite statin treatment and diabetes status (p<0.05), whereas hsCRP mainly correlated with obesity markers. Conclusions. Circulating DUSP1 might be a predictor of chronic subclinical inflammation and residual risk in CVD patients, whereas our data suggest that the association between hsCRP and CVD is largely accounted for adiposity risk factors.

Download Full-text