scholarly journals Pathology and Anticatalytic Treatment of Exacerbated COVID-19

2022 ◽  
Author(s):  
Jong-hoon Lee ◽  
Seongcheol Cho ◽  
Badar Kanwar ◽  
Keum-ho Lee ◽  
Tuan Ngoc Minh Nguyen ◽  
...  
Keyword(s):  
Spike Protein ◽  
Inflammasome Activation ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Genetic Pathway ◽  
Angiotensin Converting Enzyme 2 ◽  
Protein Levels ◽  
Neuropilin 1 ◽  
Immune Mediated ◽  
Memory Engram

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated inflammasome diseases. Moreover, its pathophysiology involves the angiotensin-converting enzyme 2 (ACE2) receptor, Toll-like receptor 4 (TLR4) pathway, neuropilin‑1 pathway, inflammasome activation pathway, sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein 1 (SAMHD1) tetramerization pathway, cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway, spike protein/inflammasome-genetic pathway, and immunological memory engram pathway. Therefore, it is necessary to prescribe anticatalytic treatments to alleviate the SARS-CoV-2 inflammasome, immunologic engram, and spike protein levels.

scholarly journals Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome

2020 ◽  
Author(s):  
Andrea Frustaci ◽  
Maria Alfarano ◽  
Romina Verardo ◽  
Chiara Agrati ◽  
Rita Casetti ◽  
...  
Keyword(s):  
Hospital Mortality ◽  
Hypereosinophilic Syndrome ◽  
Left Ventricular ◽  
Response To Therapy ◽  
Left Ventricular Ejection ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Ventricular Ejection Fraction ◽  
Immune Mediated ◽  
Coronary Vasculitis

Abstract Aims  Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported. Methods and results  Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients. Conclusion  Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression.

Abstract 1766: Diet-Induced Obesity Causes Inflammation by Activating Toll-Like Receptor 4 Signaling and Downregulates AMPK in Heart

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hwi Jin Ko ◽  
Dae Young Jung ◽  
Zhexi Ma ◽  
Jason K Kim
Keyword(s):  
Glucose Metabolism ◽  
Whole Body ◽  
Chow Diet ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Myocardial Glucose Metabolism ◽  
Cardiac Inflammation ◽  
Protein Levels ◽  
Diet Induced Obesity

Increasing evidence implicates the role of inflammation in diabetes and complications. Macrophages are shown to infiltrate adipose tissue in obesity, and inflammatory cytokines alter glucose metabolism in peripheral organs. Male C57BL/6 mice were fed high-fat diet (HFD; 55% fat by calories) or chow diet for 6 weeks, and heart samples were taken for analysis (n = 5~7). Chronic HFD increased whole body fat mass, measured by 1 H-MRS, by 3-fold, and elevated plasma IL-6 and TNF-α levels by 40%. Diet-induced obesity caused inflammation in heart and increased macrophage-specific CD68 levels by 5-fold (Fig. 1) (* P < 0.05 vs Chow). Diet-induced cardiac inflammation was associated with significant increases in toll-like receptor 4 (TLR4) and MyD88 levels in heart (Fig. 2). HFD also increased cardiomyocyte SOCS3 levels by more than 3-fold (Fig. 3). Myocardial glucose metabolism was measured using intravenous injection of 2-[ 14 C]deoxyglucose in awake mice (n = 6). Chronic HFD reduced myocardial glucose uptake by 50%, and this was associated with significant reductions in total GLUT4 and GLUT1 protein levels. Further, Thr 172 phosphorylation of AMPK, a critical regulator of energy balance, was markedly reduced in heart following HFD (Fig. 4). These results demonstrate that diet-induced obesity causes macrophage infiltration and inflammation in heart by increasing TLR4 signaling in cardiomyocytes. Similar to the effects of inflammation on peripheral glucose metabolism, diet-induced cardiac inflammation reduced myocardial glucose metabolism by downregulating AMPK and GLUT protein levels. Thus, our findings underscore an important role of inflammation in diabetic heart.

scholarly journals A Multifunctional Peptide From Bacillus Fermented Soybean for Effective Inhibition of SARS-CoV-2 S1 Receptor Binding Domain and Modulation of Toll Like Receptor 4: A Molecular Docking Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Srichandan Padhi ◽  
Samurailatpam Sanjukta ◽  
Rounak Chourasia ◽  
Rajendra K. Labala ◽  
Sudhir P. Singh ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
In Silico ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Angiotensin Converting Enzyme 2 ◽  
Fermented Soybean

Fermented soybean products are traditionally consumed and popular in many Asian countries and the northeastern part of India. To search for potential agents for the interruption of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike glycoprotein 1 (S1) and human angiotensin-converting enzyme 2 (ACE2) receptor interactions, the in silico antiviral prospective of peptides identified from the proteome of kinema was investigated. Soybean was fermented using Bacillus licheniformis KN1G, Bacillus amyloliquefaciens KN2G and two different strains of Bacillus subtilis (KN2B and KN2M). The peptides were screened in silico for possible antiviral activity using two different web servers (AVPpred and meta-iAVP), and binding interactions of selected 44 peptides were further explored against the receptor-binding domain (RBD) of the S1 protein (PDB ID: 6M0J) by molecular docking using ZDOCK. The results showed that a peptide ALPEEVIQHTFNLKSQ (P13) belonging to B. licheniformis KN1G fermented kinema was able to make contacts with the binding motif of RBD by blocking specific residues designated as critical (GLN493, ASN501) in the binding of human angiotensin-converting enzyme 2 (ACE2) cell receptor. The selected peptide was also observed to have a significant affinity towards human toll like receptor 4 (TLR4)/Myeloid Differentiation factor 2 (MD2) (PDB ID: 3FXI) complex known for its essential role in cytokine storm. The energy properties of the docked complexes were analyzed through the Generalized Born model and Solvent Accessibility method (MM/GBSA) using HawkDock server. The results showed peptidyl amino acids GLU5, GLN8, PHE11, and LEU13 contributed most to P13-RBD binding. Similarly, ARG90, PHE121, LEU61, PHE126, and ILE94 were appeared to be significant in P13-TLR4/MD2 complex. The findings of the study suggest that the peptides from fermented soy prepared using B. licheniformis KN1G have better potential to be used as antiviral agents. The specific peptide ALPEEVIQHTFNLKSQ could be synthesized and used in combination with experimental studies to validate its effect on SARS-CoV-2-hACE2 interaction and modulation of TLR4 activity. Subsequently, the protein hydrolysate comprising these peptides could be used as prophylaxis against viral diseases, including COVID-19.

scholarly journals Mutating novel interaction sites in NRP1 reduces SARS-CoV-2 spike protein internalization

2021 ◽  
Author(s):  
Debjani Pal ◽  
Kuntal De ◽  
Tomithy Yates ◽  
Wellington Muchero
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Ribosomal Protein ◽  
Protein S ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Interaction Sites ◽  
Viral Binding ◽  
Expression Of Genes ◽  
Neuropilin 1

The global pandemic of Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 has become a severe global health problem because of its rapid spread. Both angiotensin-converting enzyme 2 and neuropilin 1 provide initial viral binding sites for SARS-CoV-2. Here, we show that three cysteine residues located in a1/a2 and b1 domains of neuropilin 1 are necessary for SARS-CoV-2 spike protein internalization in human cells. Mutating cysteines C82, C104, and C147 altered neuropilin 1 stability and binding ability as well as cellular internalization and lysosomal translocation of the spike protein. This resulted in up to 4 times reduction in spike protein load in cells for the original, alpha, and delta SARS-CoV-2 variants even in the presence of the endogenous angiotensin-converting enzyme 2 receptors. Transcriptome analysis of cells transfected with mutated NRP1 revealed significantly reduced expression of genes involved in viral infection and replication, including eight members of the ribosomal protein L, ten members of ribosomal protein S, and five members of the proteasome β subunit family proteins. We also observed higher expression of genes involved in the suppression of inflammation and endoplasmic reticulum-associated degradation. These observations suggest that these cysteines offer viable targets for therapies against COVID-19.

scholarly journals Regulatory Role of rno-miR-30b-5p in IL-10 and Toll-like Receptor 4 Expressions of T Lymphocytes in Experimental Autoimmune Uveitis In Vitro

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Yuanyuan Sun ◽  
Dadong Guo ◽  
Bin Liu ◽  
Xuewei Yin ◽  
Huixia Wei ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Protein Levels ◽  
Eye Tissues ◽  
Spleen And Lymph Nodes ◽  
Experimental Autoimmune

Uveitis is a serious eye disease that usually damages young adult’s health. MicroRNAs (miRNAs) are a class of small noncoding RNAs which regulate messenger RNA (mRNA) expression. It is predicted that rno-miR-30b-5p can regulate the expressions of interleukin-10 (IL-10) and Toll-like receptor 4 (TLR4). In this study, the regulatory role of rno-miR-30b-5p in IL-10 and TLR4 gene expressions was validated using luciferase activity assay. Further, the inflammatory manifestation of the anterior segment and pathological examination of the eye were explored in experimental autoimmune uveitis (EAU) rats. Meanwhile, the levels of rno-miR-30b-5p in eye tissues, spleen, and lymph nodes were measured using quantitative PCR (Q-PCR). IL-10 and TLR4 in spleen and lymph nodes were further separately determined by using Q-PCR and Enzyme-Linked Immunosorbent Assay (ELISA). Moreover, rno-miR-30b-5p mimic and its inhibitor were separately transfected into purified T cells, and the levels of IL-10 and TLR4 were detected using PCR, flow cytometry, and ELISA techniques. Results indicate that rno-miR-30b-5p was downregulated in spleen, lymph nodes, and eye tissues whereas the expressions of IL-10 and TLR4 at mRNA and protein levels were upregulated. The levels of IL-10 and TLR4 were negatively correlated to rno-miR-30b-5p levels. The result of in vitro cell transfection experiment indicates that IL-10 and TLR4 expressions were inhibited at mRNA and protein levels after T cells incubated with rno-miR-30b-5p mimic. However, the IL-10 and TLR4 mRNA levels were upregulated in purified T cells from spleen and lymph nodes after treatment with miR-30b-5p antagonist. In addition, there was no evident change of IL-10 and TLR4 proteins in spleen and lymph node T cells between EAU control and negative treatment groups. Flow cytometry analysis revealed that rno-miR-30b-5p mimic could reduce the number of both IL-10 and TLR4 positive cells, whereas rno-miR-30b-5p inhibitor could increase the number of IL-10 and TLR4 positive cells. Our study demonstrates that rno-miR-30b-5p influences the development of uveitis by regulating the level of IL-10 and TLR4 positive cells, thereby playing a role in the pathogenesis of uveitis.

scholarly journals Role of Toll-Like Receptor 4 on Lupus Lung Injury and Atherosclerosis in LPS-Challenge ApoE−/−Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Jing-qin Ni ◽  
Qiufang Ouyang ◽  
Ling Lin ◽  
Ziyang Huang ◽  
Huixia Lu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Interleukin 1 ◽  
Intima Media Thickness ◽  
Immunofluorescent Staining ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Serum Autoantibody ◽  
Lps Challenge ◽  
Immune Mediated

To investigate the pathologic mechanisms of toll-like receptor 4 (TLR4) in lung injury and atherosclerosis, ApoE−/−or wild-type mice were intraperitoneally administered saline, lipopolysaccharides (LPS), or LPS plus TAK-242 (TLR4 inhibitor), respectively, twice a week for 4 weeks. Serum autoantibody of antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA), and cytokines of interferon-gamma (IFN-γ), tumor necrosis factor (TNF-α), and interleukin-1 (IL-1β) were assessed by ELISA. Hematoxylin and eosin (HE) and Perl's stains for lung pathomorphology as well as HE staining for atherosclerosis were employed. TLR4 in macrophages was detected by double immunofluorescent staining. While protein expressions of TLR4, nuclear factor-kappa B p65 (NF-κB p65), and B cell activating factor belonging to the TNF family (BAFF) were examined by immunohistochemistry. We found that serum autoantibody (ANA and anti-dsDNA), cytokines (IFN-γ, TNF-α, IL-1β), lung inflammation, and intima-media thickness in brachiocephalic artery were obviously increased after LPS challenge in both genotypes, but to a lesser extent in wild-type strains. And those alterations were alleviated by coadministration of LPS and TAK-242. Mechanistically, upregulation of TLR4, NF-κb, and BAFF was involved. We concluded that TLR4/NF-κb/BAFF in macrophages might be a possible common autoimmune pathway that caused lung injury and atherosclerosis. TLR4 signal will be a therapeutic target in atherosclerosis and immune-mediated lung injury.

scholarly journals Targeting Toll-like receptor 4 with CLI-095 (TAK-242) enhances the antimetastatic effect of the estrogen receptor antagonist fulvestrant on non-small cell lung cancer

2020 ◽  
Vol 22 (11) ◽  
pp. 2074-2086
Author(s):  
S. Fan ◽  
Y. Liao ◽  
W. Qiu ◽  
L. Li ◽  
D. Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Metastatic Lymph Node ◽  
Small Cell ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Small Cell Lung ◽  
Toll Like Receptor 4 ◽  
Protein Levels ◽  
Antimetastatic Effect ◽  
Primary Nsclc

Abstract Purpose Estrogen plays a critical role in the invasiveness and metastasis of non-small cell lung cancer (NSCLC) through estrogen receptor β (ERβ). However, the antimetastatic effect of the ERβ antagonist fulvestrant was still limited in NSCLC patients. Recently, Toll-like receptor 4 (TLR4) signaling was implicated in NSCLC metastasis. Our present study aimed to evaluate the synergistic antimetastatic effect of a combination of fulvestrant and the TLR4-specific inhibitor CLI-095 (TAK-242) on human NSCLC cells. Methods The expression levels of ERβ and TLR4 were detected by immunohistochemical (IHC) analysis of 180 primary NSCLC and 30 corresponding metastatic lymph node samples. The association between ERβ and TLR4 expression was analyzed. The aggressiveness of NSCLC cells treated with fulvestrant, CLI-095 or the drug combination and formation status of their invadopodia, invasion-associated structures, were investigated. The protein levels in NSCLC cells in different groups were determined by Western blot and immunofluorescence analyses. Results Here, a positive correlation between ERβ and TLR4 expression was observed in both primary NSCLC tissue (Spearman’s Rho correlation coefficient = 0.411, p < 0.001) and metastatic lymph node tissue (Spearman’s Rho correlation coefficient = 0.374, p = 0.009). The protein levels of ERβ in NSCLC cell lines were decreased by fulvestrant, and this suppressive effect was significantly enhanced when fulvestrant was combined with CLI-095 (p < 0.05). Both the migration and invasion of NSCLC cells were suppressed by fulvestrant or CLI-095 alone, and the combination of fulvestrant + CLI-095 showed the strongest inhibitory effect (p < 0.05). In addition, the results demonstrated that CLI-095 also helped fulvestrant restrict the formation and function of invadopodia in NSCLC cells (p < 0.05). Conclusions Collectively, our study results suggested that CLI-095 enhances the antimetastatic effect of fulvestrant on NSCLC and provided support for further investigation of the antitumor activity of combined therapy with antiestrogen and anti-TLR4 agents in the clinic.

scholarly journals Targeting Toll-like receptor 4 with CLI-095 (TAK-242) enhances the antimetastatic effect of the estrogen receptor antagonist fulvestrant on non-small cell lung cancer

2019 ◽  
Author(s):  
Sheng fan ◽  
Wenlin Qiu ◽  
Lequn Li ◽  
Dong Li ◽  
Yongde Liao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Metastatic Lymph Node ◽  
Small Cell ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Small Cell Lung ◽  
Toll Like Receptor 4 ◽  
Protein Levels ◽  
Antimetastatic Effect ◽  
Primary Nsclc

Abstract Background Estrogen plays a critical role in the invasiveness and metastasis of non-small cell lung cancer (NSCLC) through estrogen receptor β (ERβ). However, the antimetastatic effect of the ERβ antagonist fulvestrant was still limited in NSCLC patients in phase II clinical trials. Recently, Toll-like receptor 4 (TLR4) signaling was implicated in NSCLC metastasis. Our present study aimed to evaluate the synergistic antimetastatic effect of a combination of fulvestrant and the TLR4-specific inhibitor CLI-095 (TAK-242) on human NSCLC cells. Methods The expression levels of ERβ and TLR4 were detected by immunohistochemical (IHC) analysis of 180 primary NSCLC and 30 corresponding metastatic lymph node samples. The association between ERβ and TLR4 expression was analyzed. The aggressiveness of NSCLC cells treated with fulvestrant, CLI-095 or the drug combination and formation status of their invadopodia, invasion-associated structures, were investigated. The protein levels in NSCLC cells in different groups were determined by Western blot and immunofluorescence analyses. Results Here, a positive correlation between ERβ and TLR4 expression was observed in both primary NSCLC tissue (Spearman’s Rho correlation coefficient = 0.411, p<0.001) and metastatic lymph node tissue (Spearman’s Rho correlation coefficient = 0.374, p=0.009). The protein levels of ERβ in the A549 and H1793 cell lines induced by estrogen were decreased by fulvestrant, and this suppressive effect was significantly enhanced when fulvestrant was combined with CLI-095 (p<0.05 for both treatments). Both the migration and invasion of NSCLC cells were suppressed by fulvestrant or CLI-095 alone, and the combination of fulvestrant+CLI-095 showed the strongest inhibitory effect (p<0.05 for all treatments). In addition, the results demonstrated that CLI-095 also helped fulvestrant restrict the formation and function of invadopodia in NSCLC cells (p<0.05). Conclusions Collectively, our study results suggested that CLI-095 enhances the antimetastatic effect of fulvestrant on NSCLC and provided support for further investigation of the antitumor activity of combined therapy with antiestrogen and anti-TLR4 agents in the clinic.

scholarly journals Glucan phosphate inhibits HMGB-1 release from rat myocardial H9C2 cells in sepsis via TLR4/NF-кB signal pathway

2017 ◽  
Vol 40 (2) ◽  
pp. 66 ◽  
Author(s):  
Haizhu Wang ◽  
Zhifei Cui ◽  
Fei Sun ◽  
Huayong Ding
Keyword(s):  
Cultured Cells ◽  
Mrna Levels ◽  
H9c2 Cells ◽  
Toll Like Receptor ◽  
Mobility Shift ◽  
Toll Like Receptor 4 ◽  
Protein Levels ◽  
Elevated Activity ◽  
Underlying Mechanisms ◽  
Electrophoretic Mobility Shift Assays

Purpose: The effect of glucan phosphate (GP) on the release of HMGB-1 from rat myocardial cells (H9C2) during lipopolysaccharide-induced sepsis, and the underlying mechanisms, were investigated. Methods: H9C2 cells were divided into three groups: normal; lipopolysaccharide (LPS) (1 mg/ml LPS); and, LPS+GP (2 mg/ml GP). Western blot was used to determine toll-like receptor 4 (TLR4) levels, and electrophoretic mobility-shift assays (EMSA) was used to determine nuclear factor-кB (NF-кB) activity 3, 6 and 9 h after treatment. HMGB-1 mRNA levels in cultured cells were determined by real-time PCR and supernatant HMGB-1 protein levels were evaluated by ELISA at 12, 24, 36 and 48 h after treatment. Following the transfection of H9C2 cells with Ad5-IкBα, which inhibits NF-кB activity, TLR4, NF-кB and HMGB-1 levels were determined. Results: Intracellular TLR4 levels and NF-кB activity in LPS and LPS+GP groups increased 3-9 h after stimulation, but the increased levels of TLR4 and elevated activity of NF-кB were significantly lower in the LPS+GP group vs. the LPS group. HMGB-1 mRNA levels in both LPS and LPS+GP groups, increased gradually from 24 h after stimulation, but the increase was more obvious in the LPS group vs. the LPS+GP group. Supernatant HMGB-1 levels in the LPS and LPS+GP groups increased gradually from 9 h after stimulation, and also increased markedly in the LPS group. After the inhibition of NF-кB activity, LPS-induced HMGB-1 release decreased significantly (p

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