Recombinant SARS-CoV-2 Spike Protein Stimulates Secretion of Chymase, Tryptase, and IL-1β from Human Mast Cells, Augmented by IL-33

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(11), P. 9487 - 9487

Published: May 30, 2023

SARS-CoV-2 infects cells via its spike (S) protein binding to surface receptor angiotensin-converting enzyme 2 (ACE2) and results in the production of multiple proinflammatory cytokines, especially lungs, leading what is known as COVID-19. However, cell source mechanism secretion such cytokines have not been adequately characterized. In this study, we used human cultured mast that are plentiful lungs showed recombinant full-length S (1-10 ng/mL), but receptor-binding domain (RBD), stimulates cytokine interleukin-1β (IL-1β) well proteolytic enzymes chymase tryptase. The IL-1β, chymase, tryptase augmented by co-administration interleukin-33 (IL-33) (30 ng/mL). This effect mediated toll-like 4 (TLR4) for IL-1β ACE2 These provide evidence contributes inflammation stimulating through different receptors could lead new targeted treatment approaches.

Language: Английский

---

Recombinant SARS-CoV-2 Spike Protein and Its Receptor Binding Domain Stimulate Release of Different Pro-Inflammatory Mediators via Activation of Distinct Receptors on Human Microglia Cells

Molecular Neurobiology, Journal Year: 2023, Volume and Issue: 60(11), P. 6704 - 6714

Published: July 21, 2023

Language: Английский

---

Special Issue “The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0”

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9709 - 9709

Published: Sept. 7, 2024

Toll-like receptors (TLRs) are key players in the innate immune system, host’ first-line defense against pathogens [...]

Language: Английский

---

The Yin and Yang of TLR4 in COVID-19

Cytokine & Growth Factor Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

---

AICpred: Machine Learning-Based Prediction of Potential Anti-Inflammatory Compounds Targeting TLR4-MyD88 Binding Mechanism

Information, Journal Year: 2025, Volume and Issue: 16(1), P. 34 - 34

Published: Jan. 7, 2025

Toll-like receptor 4 (TLR4) has been implicated in the production of uncontrolled inflammation within body, known as cytokine storm. Studies that employ machine learning (ML) prediction potential inhibitors TLR4 are limited. This study introduces AICpred, a robust, free, user-friendly, and easily accessible learning-based web application for predicting against by targeting TLR4-myeloid differentiation primary response 88 (MyD88) interaction. MyD88 is crucial adaptor protein TLR4-induced hyper-inflammation pathway. Predictive models were trained using random forest, adaptive boosting (AdaBoost), eXtreme gradient (XGBoost), k-nearest neighbours (KNN), decision tree models. To handle imbalance training data, resampling techniques such under-sampling, synthetic minority oversampling technique, selection 5000 instances majority class employed. A 10-fold cross-validation strategy was used to evaluate model performance based on metrics including accuracy, balanced recall. The XGBoost demonstrated superior with recall scores 0.994, 0.958, 0.917, respectively, test. AdaBoost also excelled accuracies ranging from 0.981 0.992, between 0.921 0.944, 0.845 0.891 both test datasets. deployed AICpred screen compounds have reported positive effects mitigating hyperinflammation-associated storm, which key factor COVID-19. predicted Baricitinib, Ibrutinib, Nezulcitinib, MCC950, Acalabrutinib anti-TLR4 probability above 0.90. Additionally, inhibit TLR4, TAK-242 (Resatorvid) benzisothiazole derivative (M62812), bioactive agents applicability domain probabilities 0.80. Computationally inferred can be explored starting skeletons therapeutic hyperinflammation. These predictions must consolidated experimental screening enhance further optimisation compounds. first its kind inhibition TLR4-MyD88 binding freely available at http://197.255.126.13:8080.

Language: Английский

---

Role of toll-like receptors in post-COVID-19 associated neurodegenerative disorders?

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 12

Published: March 26, 2025

In the intricate realm of interactions between hosts and pathogens, Toll-like receptors (TLRs), which play a crucial role in innate immune response, possess ability to identify specific molecular signatures. This includes components originating from pathogens such as SARS-CoV-2, well resulting damage-associated patterns (DAMPs), endogenous molecules released after cellular damage. A developing perspective suggests that TLRs central neuroinflammation, fundamental factor neurodegenerative conditions like Alzheimer’s Parkinson’s disease (PD). comprehensive review consolidates current research investigating potential interplay TLRs, their signaling mechanisms, processes neurodegeneration following SARS-CoV-2 infection with an aim elucidate involvement long-term neurological complications COVID-19 explore targeting means implementing intervention strategies for prevention or treatment COVID-19-associated brain outcomes.

Language: Английский

---

Human Milk Oligosaccharides: Potential Applications in COVID-19

Biomedicines, Journal Year: 2022, Volume and Issue: 10(2), P. 346 - 346

Published: Feb. 1, 2022

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has become a global health crisis with more than four million deaths worldwide. A substantial number of COVID-19 survivors continue suffering from long-COVID syndrome, long-term complication exhibiting chronic inflammation and gut dysbiosis. Much effort is being expended to improve therapeutic outcomes. Human milk oligosaccharides (hMOS) are non-digestible carbohydrates known exert benefits in breastfed infants preventing infection, maintaining immune homeostasis nurturing healthy microbiota. These beneficial effects suggest the hypothesis that hMOS might have applications as receptor decoys, immunomodulators, mucosal signaling agents, prebiotics. This review summarizes biogenesis classification, describes possible mechanisms action upon different phases SARS-CoV-2 discusses challenges opportunities research for clinical COVID-19.

Language: Английский

---

Pharmacokinetic/Pharmacodynamic Modeling of Dexamethasone Anti-Inflammatory and Immunomodulatory Effects in LPS-Challenged Rats: A Model for Cytokine Release Syndrome

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2023, Volume and Issue: 384(3), P. 455 - 472

Published: Jan. 11, 2023

Dexamethasone (DEX) is a potent synthetic glucocorticoid used for the treatment of variety inflammatory and immune-mediated disorders. The RECOVERY clinical trial revealed benefits DEX therapy in COVID-19 patients. Severe SARS-CoV-2 infection leads to an excessive reaction commonly known as cytokine release syndrome that associated with activation toll like receptor 4 (TLR4) signaling pathway. possible mechanism action related its anti-inflammatory activity arising from inhibition production but may be also attributed influence on immune cell trafficking turnover. This study, by means pharmacokinetic/pharmacodynamic modeling, aimed at comprehensive quantitative assessment effects lipopolysaccharide-challenged rats describe interrelations among relevant molecules this animal model induced TLR4 was administered range doses 0.005 2.25 mg·kg⁻¹ LPS-challenged rats. Serum DEX, corticosterone (CST), tumor necrosis factor α, interleukin-6, nitric oxide well lymphocyte granulocyte counts peripheral blood were quantified different time points. A minimal physiologically based (mPBPK/PD) proposed characterizing courses plasma investigated biomarkers. high not complete mediators CST produced vivo DEX. mPBPK/PD model, upon translation humans, help optimize patients diseases mediators, such COVID-19.

SIGNIFICANCE STATEMENT

developed concentration-time profiles inflammation, turnover Interrelations biomarkers reflected mechanistic structure. enabled potency and, dosing regimens immune-related conditions exaggerated response.

Language: Английский

---

Structure-Based Drug Design of RdRp Inhibitors against SARS-CoV-2

Topics in Current Chemistry, Journal Year: 2023, Volume and Issue: 381(5)

Published: June 15, 2023

Language: Английский

---

Pharmacogenomic Study of SARS-CoV-2 Treatments: Identifying Polymorphisms Associated with Treatment Response in COVID-19 Patients

Biomedicines, Journal Year: 2025, Volume and Issue: 13(3), P. 553 - 553

Published: Feb. 21, 2025

Background/Objectives: The COVID-19 pandemic resulted in 675 million cases and 6.9 deaths by 2022. Despite substantial declines case fatalities following widespread vaccination campaigns, the threat of future coronavirus outbreaks remains a concern. Current treatments for have been repurposed from existing therapies other infectious non-infectious diseases. Emerging evidence suggests role genetic factors both susceptibility to SARS-CoV-2 infection response treatment. However, comprehensive studies correlating clinical outcomes with variants are lacking. main aim our study is identification host biomarkers that predict outcome pharmacological treatments. Methods: In this study, we present findings GWAS candidate gene pathway enrichment analyses leveraging diverse patient samples Spanish Coalition Unlock Research Host Genetics on (SCOURGE), representing patients treated immunomodulators (n = 849), corticoids 2202), combined cohort 2487) who developed different outcomes. We assessed various phenotypes as indicators treatment response, including survival at 90 days, admission intensive care unit (ICU), radiological affectation, type ventilation. Results: identified significant polymorphisms 16 genes (TLR1, TLR6, TLR10, CYP2C19, ACE2, UGT1A1, IL-1α, ZMAT3, TLR4, MIR924HG, IFNG-AS1, ABCG1, RBFOX1, ABCB11, TLR5, ANK3) may modulate corticoid immunomodulator patients. Enrichment revealed overrepresentation involved innate immune system, drug ADME, viral infection, programmed cell death pathways associated phenotypes. Conclusions: Our provides an initial framework understanding determinants patients, offering insights could inform precision medicine approaches epidemics.

Language: Английский

---