Abstract 13458: Caspase Recruitment Domain-Containing Protein 9 Deficiency Mitigates Obesity-Induced Cardiac Dysfunction

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Li Cao ◽  
Xing Qin ◽  
Tiantian Zheng ◽  
Sreejayan Nair ◽  
Jun Ren ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
P38 Mapk ◽  
Inflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Adaptor Protein ◽  
Heart Tissue ◽  
Macrophage Infiltration ◽  
Low Grade ◽  
Caspase Recruitment Domain ◽  
Pro Inflammatory Cytokines

Obesity has become an epidemic and is associated with cardiovascular anomalies. Obesity-induced low-grade chronic inflammation and macrophage infiltration into the heart plays a critical role in the development of cardiac dysfunction. Because the adaptor protein caspase recruitment domain-containing protein 9 (CARD9) regulates the innate immunity in macrophages via activation of pro-inflammatory cytokines, we hypothesized that CARD9 mediates chronic inflammation and plays a detrimental role in obesity-associated cardiac dysfunction. Male C57BL/6 wild-type (WT) and CARD9 knockout (CARD9-/-) mice were fed normal chow (ND, 12% fat) or a Western diet (WD, 45% fat) for 5 months starting at 4 weeks of age. At the end of 5-month WD feeding, cardiac geometry and function were evaluated using echocardiography. Immunofluorescence assay was performed to detect macrophage infiltration in the heart. Heart tissue homogenates, plasma, and supernatants from cultured macrophages were collected to measure the activities of pro-inflammatory cytokines by ELISA kits. Western immunoblotting analyses were performed on isolated peritoneal macrophages and heart tissue to dissect the pro-inflammatory signaling pathways. WD feeding induced insulin resistance and glucose intolerance in the WT mice and the effects were attenuated in the CARD9-/- mice. Myocardial fractional shortening and ejection fraction were significantly compromised in the WD-fed WT mice and CARD9 knockout preserved cardiac function. CARD9 knockout also significantly decreased the number of infiltrated macrophages in the heart. In addition, myocardium-, plasma- and macrophage-derived cytokines IL-6, IL-1β and TNFα were attenuated in the CARD9-/- mice compared to the WT mice. WD feeding resulted in increased protein phosphorylation levels of p38 MAPK in the heart and macrophages which were suppressed in the CARD9-/- mice. Taken together, these results suggest that CARD9 knockout ameliorates obesity-induced cardiac dysfunction, potentially through reduction of macrophage infiltration and suppression of p38 MAPK phosphorylation in the heart.

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

2019 ◽  
Author(s):  
Shifang Gao ◽  
Huihui Li ◽  
Hong Xie ◽  
Shili Wu ◽  
Yuan Yuan ◽  
...  
Keyword(s):  
Schistosoma Japonicum ◽  
Inflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Therapeutic Efficacy ◽  
Heart Tissue ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Cardiac Tissues ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Abstract 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.

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

2020 ◽  
Author(s):  
Shifang Gao ◽  
Huihui Li ◽  
Hong Xie ◽  
Shili Wu ◽  
Yuan Yuan ◽  
...  
Keyword(s):  
Schistosoma Japonicum ◽  
Inflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Therapeutic Efficacy ◽  
Heart Tissue ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Cardiac Tissues ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Abstract 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. 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. Methods A 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 (r Sj -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, macrophages and pro-inflammatory cytokine levels. To address the signaling pathway involved in the anti-inflammatory effects of r Sj -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 r Sj -Cys on LPS-induced cardiomyocyte apoptosis were also detected in H9C2 cells.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 r Sj -Cys-treated mice. Results After being treated with r Sj -Cys, the sepsis-induced heart malfunction was largely improved. The inflammation and injury of heart tissue were also 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 r Sj -Cys is associated with down-regulated pro-inflammatory cytokines (TNF-α, IL-6) , as well as the decreased M1 macrophages and increased M2 macrophages, possibly through inhibiting LPS-MyD88 signal pathway. Conclusions Recombinant 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.

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

2020 ◽  
Author(s):  
Shifang Gao ◽  
Huihui Li ◽  
Hong Xie ◽  
Shili Wu ◽  
Yuan Yuan ◽  
...  
Keyword(s):  
Schistosoma Japonicum ◽  
Inflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Therapeutic Efficacy ◽  
Heart Tissue ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Cardiac Tissues ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Abstract 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. 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. Methods A 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 (r Sj -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, macrophages and pro-inflammatory cytokine levels. To address the signaling pathway involved in the anti-inflammatory effects of r Sj -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 r Sj -Cys on LPS-induced cardiomyocyte apoptosis were also detected in H9C2 cells.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 r Sj -Cys-treated mice. Results After being treated with r Sj -Cys, the sepsis-induced heart malfunction was largely improved. The inflammation and injury of heart tissue were also 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 r Sj -Cys is associated with down-regulated pro-inflammatory cytokines (TNF-α, IL-6) , as well as the decreased M1 macrophages and increased M2 macrophages, possibly through inhibiting LPS-MyD88 signal pathway. Conclusions Recombinant 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.

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

2020 ◽  
Author(s):  
Shifang Gao ◽  
Huihui Li ◽  
Hong Xie ◽  
Shili Wu ◽  
Yuan Yuan ◽  
...  
Keyword(s):  
Schistosoma Japonicum ◽  
Inflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Therapeutic Efficacy ◽  
Heart Tissue ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Cardiac Tissues ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Abstract 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. 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. Methods A 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 (r Sj -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, macrophages and pro-inflammatory cytokine levels. To address the signaling pathway involved in the anti-inflammatory effects of r Sj -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 r Sj -Cys on LPS-induced cardiomyocyte apoptosis were also detected in H9C2 cells.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 r Sj -Cys-treated mice. Results After being treated with r Sj -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 r Sj -Cys is associated with down-regulated pro-inflammatory cytokines (TNF-α, IL-6) , as well as the decreased M1 macrophages and increased M2 macrophages, possibly through inhibiting LPS-MyD88 signal pathway. Conclusions Recombinant 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.

scholarly journals Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 653
Author(s):  
Seth O. Asiedu ◽  
Samuel K. Kwofie ◽  
Emmanuel Broni ◽  
Michael D. Wilson
Keyword(s):  
Molecular Docking ◽  
P38 Mapk ◽  
Inflammatory Cytokines ◽  
Binding Energies ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Activity ◽  
Computational Techniques ◽  
Cytokine Storm ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

Role of p38 MAPK and pro‐inflammatory cytokines expression in glutamate‐induced neuronal death of neonatal rats

2008 ◽  
Vol 26 (5) ◽  
pp. 487-495 ◽  
Author(s):  
V. Chaparro‐Huerta ◽  
M.E. Flores‐Soto ◽  
G. Gudiño‐Cabrera ◽  
M.C. Rivera‐Cervantes ◽  
O.K. Bitzer‐Quintero ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Inflammatory Cytokines ◽  
Neuronal Death ◽  
Neonatal Rats ◽  
Pro Inflammatory Cytokines

Glyoxal and Methylglyoxal as E-cigarette Vapor Ingredients-Induced Pro-Inflammatory Cytokine and Mucins Expression in Human Nasal Epithelial Cells

2020 ◽  
pp. 194589242094696
Author(s):  
Soyoung Kwak ◽  
Yoon Seok Choi ◽  
Hyung Gyun Na ◽  
Chang Hoon Bae ◽  
Si-Youn Song ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Inflammatory Cytokines ◽  
Water Soluble ◽  
Nasal Epithelial Cells ◽  
Airway Diseases ◽  
Human Nasal Epithelial Cells ◽  
Specific Inhibitors ◽  
Pro Inflammatory Cytokines

Background Glyoxal (GO), and methylglyoxal (MGO) are among the most toxic compounds emitted by electronic cigarette (E-cig) and regular tobacco cigarette smoke. Airway diseases presented mucus over production as their major pathophysiologic feature. However, the effects of GO and MGO on pro-inflammatory cytokines and mucin expression in human nasal epithelial cells, as well as the underlying signaling pathway, have not yet been studied. Objective This study is to determine whether GO and MGO induce pro-inflammatory cytokines, and MUC5AC/5B expression via mitogen-activated protein kinase (MAPK)s and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways. Methods The effect of GO, and MGO on pro-inflammatory cytokines, mucins expression and the signalling pathway of GO and MGO were investigated using water-soluble tetrazolium salt-1, enzyme immunoassays, and immunoblot analysis with specific inhibitors and small interfering RNA. Results GO and MGO did not affect cell viability up to 2 mM in human nasal epithelial cells. GO and MGO increased production of pro-inflammatory such as interleukin (IL)-1β and IL-6) and MUC5AC/5B. Additionally, GO and MGO significantly activated extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK, and NF-κB. Whether ERK1/2, p38 MAPK, and NF-κB signaling pathway were involved in GO and MGO-induced production of pro-inflammatory cytokines (IL-1β and IL-6) and MUC5AC/5B, we used specific inhibitors and siRNA transfection. These significantly repressed GO- and MGO-induced expression of pro-inflammatory cytokines (IL-1β and IL-6) and MUC5AC/5B. Conclusions GO and MGO induced pro-inflammatory cytokines and MUC5AC/5B expression via ERK1/2, p38 MAPK, and NF-κB in human nasal epithelial cells. These results suggested that GO and MGO may be involved in mucus hypersecretion-related airway diseases.

scholarly journals Alzheimer's disease and periodontitis - an elusive link

2014 ◽  
Vol 60 (2) ◽  
pp. 173-180 ◽  
Author(s):  
Abhijit N. Gurav
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Cytokines ◽  
Critical Role ◽  
Anaerobic Bacteria ◽  
Systemic Infection ◽  
Low Grade ◽  
Inflammatory Status ◽  
Pro Inflammatory Cytokines

Alzheimer's disease is the preeminent cause and commonest form of dementia. It is clinically characterized by a progressive descent in the cognitive function, which commences with deterioration in memory. The exact etiology and pathophysiologic mechanism of Alzheimer's disease is still not fully understood. However it is hypothesized that, neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease. Alzheimer's disease is marked by salient inflammatory features, characterized by microglial activation and escalation in the levels of pro-inflammatory cytokines in the affected regions. Studies have suggested a probable role of systemic infection conducing to inflammatory status of the central nervous system. Periodontitis is common oral infection affiliated with gram negative, anaerobic bacteria, capable of orchestrating localized and systemic infections in the subject. Periodontitis is known to elicit a "low grade systemic inflammation" by release of pro-inflammatory cytokines into systemic circulation. This review elucidates the possible role of periodontitis in exacerbating Alzheimer's disease. Periodontitis may bear the potential to affect the onset and progression of Alzheimer's disease. Periodontitis shares the two important features of Alzheimer's disease namely oxidative damage and inflammation, which are exhibited in the brain pathology of Alzheimer's disease. Periodontitis can be treated and hence it is a modifiable risk factor for Alzheimer's disease.

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