Retraction Note: The helminth product ES-62 protects against septic shock via Toll-like receptor 4–dependent autophagosomal degradation of the adaptor MyD88

Puneet, Padmam; McGrath, Mairi; Tay, Hwee Kee; Al-Riyami, Lamyaa; Rzepecka, Justyna; Moochhala, Shabbir; Pervaiz, Shazib; Harnett, Margaret M.; Harnett, William; Melendez, Alirio J.

doi:10.1038/ni0811-804a

Cited by 3 publications

(1 citation statement)

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“…Our results suggest the possible mechanism of rSj-Cys involved in the alleviation of septic cardiomyopathy is that treatment of rSj-Cys stimulates Tregs and/or cardiomyocytes to produce regulatory cytokines such as IL-10 and TGF-β, the latter suppress the production of pro-inflammatory cytokines via inhibiting TLR4/MyD88 activation signal pathway as other helminth derived proteins did [65,66,67,68].…”

Section: Ef% Fs% and E/a Ratio Of Left Ventricle (Lv)mentioning

confidence: 99%

Therapeutic efficacy of Schistosoma japonicum cystatin on sepsis-induced cardiomyopathy in a mouse model

Gao

Xie

et al. 2019

Preprint

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BackgroundMyocardial dysfunction is one of the most common complications of multiple organ failure in septic shock and significantly increases mortality in patients with sepsis. In spite of many studies have confirmed that helminth-derived proteins have strong immunomodulatory functions and could be used to treat inflammatory diseases, there is no report on the therapeutic effect of Schistosoma japonicum-produced cystatin (Sj-Cys) on the sepsis-induced cardiac dysfunction. MethodsA model of sepsis-induced myocardial injury was established by cecal ligation and puncture (CLP) in mouse. Upon CLP operation, each mouse was intraperitoneally treated with 10 µg of recombinant Sj-Cys (rSj-Cys). Twelve hours after CLP operation, the systolic and diastolic functions of left ventricular were examined by echocardiography. The levels of myoglobin (Mb), cardiac troponin I (cTnI), N-terminal pro-Brain Natriuretic peptide (NT-proBNP) in sera and the activity of myeloperoxidase (MPO) in cardiac tissues were examined as biomarkers for heart injury. The heart tissue was collected for checking pathological changes and pro-inflammatory cytokine levels. To address the signaling pathway involved in the anti-inflammatory effects of rSj-Cys, myeloid differentiation factor 88 (MyD88) was determined by Western blot in heart tissue of mice with sepsis and LPS-stimulated H9C2 cardiomyocyte cells. In addition, the therapeutic effects of rSj-Cys on LPS-induced cardiomyocyte apoptosis were also detected in H9C2 cells. The pro-inflammatory cytokines TNF-α and IL-6 and regulatory cytokines IL-10 and TGF-β were measured in sera and their mRNA levels in heart tissue of rSj-Cys-treated mice. ResultsAfter being treated with rSj-Cys, the sepsis-induced heart malfunction was largely improved. The inflammation and injury of heart tissue were also significantly alleviated characterized by significantly decreased infiltration of inflammatory cells in cardiac tissues and fiber swelling, reduced levels of Mb, cTnI and NT-proBNP in sera and MPO activity in heart tissue. The therapeutic efficacy of rSj-Cys is associated with down-regulated pro-inflammatory cytokines (TNF-α, IL-6) and up-regulated regulatory inflammatory cytokines (IL-10, TGF-β), possibly through inhibiting LPS-TLR4- MyD88 signal pathway. ConclusionsRecombinant Sj-Cys significantly reduced sepsis-induced cardiomyopathy and could be considered as be a potential therapeutic agent for the prevention and treatment of sepsis associated cardiac dysfunction.

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Section: Ef% Fs% and E/a Ratio Of Left Ventricle (Lv)mentioning

confidence: 99%

Therapeutic efficacy of Schistosoma japonicum cystatin on sepsis-induced cardiomyopathy in a mouse model

Gao

Xie

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

Therapeutic efficacy of Schistosoma japonicum cystatin on sepsis-induced cardiomyopathy in a mouse model

Gao

Xie

et al. 2020

Parasites Vectors

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Background: Myocardial dysfunction is one of the most common complications of multiple organ failure in septic shock and significantly increases mortality in patients with sepsis. Although many studies having confirmed that helminthderived proteins have strong immunomodulatory functions and could treat inflammatory diseases, there is no report on the therapeutic effect of Schistosoma japonicum-produced cystatin (Sj-Cys) on sepsis-induced cardiac dysfunction. Methods: A model of sepsis-induced myocardial injury was established by cecal ligation and puncture (CLP) in mice. Upon CLP operation, each mouse was intraperitoneally treated with 10 µg of recombinant Sj-Cys (rSj-Cys). Twelve hours after CLP, the systolic and diastolic functions of the left ventricular were examined by echocardiography. The levels of myoglobin (Mb), cardiac troponin I (cTnI), N-terminal pro-Brain Natriuretic peptide (NT-proBNP) in sera, and the activity of myeloperoxidase (MPO) in cardiac tissues were examined as biomarkers for heart injury. The heart tissue was collected for checking pathological changes, macrophages and pro-inflammatory cytokine levels. To address the signaling pathway involved in the anti-inflammatory effects of rSj-Cys, myeloid differentiation factor 88 (MyD88) was determined in heart tissue of mice with sepsis and LPS-stimulated H9C2 cardiomyocytes. In addition, the therapeutic effects of rSj-Cys on LPS-induced cardiomyocyte apoptosis were also detected. The levels of M1 biomarker iNOS and M2 biomarker Arg-1 were detected in heart tissue. The pro-inflammatory cytokines TNF-α and IL-6, and regulatory cytokines IL-10 and TGF-β were measured in sera and their mRNA levels in heart tissue of rSj-Cys-treated mice. Results: After rSj-Cys treatment, the sepsis-induced heart malfunction was largely improved. The inflammation and injury of heart tissue were significantly alleviated, characterized as significantly decreased infiltration of inflammatory cells in cardiac tissues and fiber swelling, reduced levels of Mb, cTnI and NT-proBNP in sera, and MPO activity in heart tissue. The therapeutic efficacy of rSj-Cys is associated with downregulated pro-inflammatory cytokines (TNF-α and IL-6) and upregulated regulatory inflammatory cytokines (IL-10 and TGF-β), possibly through inhibiting the LPS-MyD88 signal pathway. Conclusions: RSj-Cys significantly reduced sepsis-induced cardiomyopathy and could be considered as a potential therapeutic agent for the prevention and treatment of sepsis associated cardiac dysfunction.

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Signatures of Environmental Genetic Adaptation Pinpoint Pathogens as the Main Selective Pressure through Human Evolution

et al. 2011

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Previous genome-wide scans of positive natural selection in humans have identified a number of non-neutrally evolving genes that play important roles in skin pigmentation, metabolism, or immune function. Recent studies have also shown that a genome-wide pattern of local adaptation can be detected by identifying correlations between patterns of allele frequencies and environmental variables. Despite these observations, the degree to which natural selection is primarily driven by adaptation to local environments, and the role of pathogens or other ecological factors as selective agents, is still under debate. To address this issue, we correlated the spatial allele frequency distribution of a large sample of SNPs from 55 distinct human populations to a set of environmental factors that describe local geographical features such as climate, diet regimes, and pathogen loads. In concordance with previous studies, we detected a significant enrichment of genic SNPs, and particularly non-synonymous SNPs associated with local adaptation. Furthermore, we show that the diversity of the local pathogenic environment is the predominant driver of local adaptation, and that climate, at least as measured here, only plays a relatively minor role. While background demography by far makes the strongest contribution in explaining the genetic variance among populations, we detected about 100 genes which show an unexpectedly strong correlation between allele frequencies and pathogenic environment, after correcting for demography. Conversely, for diet regimes and climatic conditions, no genes show a similar correlation between the environmental factor and allele frequencies. This result is validated using low-coverage sequencing data for multiple populations. Among the loci targeted by pathogen-driven selection, we found an enrichment of genes associated to autoimmune diseases, such as celiac disease, type 1 diabetes, and multiples sclerosis, which lends credence to the hypothesis that some susceptibility alleles for autoimmune diseases may be maintained in human population due to past selective processes.

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Retraction Note: The helminth product ES-62 protects against septic shock via Toll-like receptor 4–dependent autophagosomal degradation of the adaptor MyD88

Cited by 3 publications

References 1 publication

Therapeutic efficacy of Schistosoma japonicum cystatin on sepsis-induced cardiomyopathy in a mouse model

Therapeutic efficacy of Schistosoma japonicum cystatin on sepsis-induced cardiomyopathy in a mouse model

Therapeutic efficacy of Schistosoma japonicum cystatin on sepsis-induced cardiomyopathy in a mouse model

Signatures of Environmental Genetic Adaptation Pinpoint Pathogens as the Main Selective Pressure through Human Evolution

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