Toll-like receptor 4 (TLR4) inhibitors: Current research and prospective

European Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 235, P. 114291 - 114291

Published: March 14, 2022

Language: Английский

---

Role of SARS-CoV-2 Spike-Protein-Induced Activation of Microglia and Mast Cells in the Pathogenesis of Neuro-COVID

Cells, Journal Year: 2023, Volume and Issue: 12(5), P. 688 - 688

Published: Feb. 22, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes disease 2019 (COVID-19). About 45% of COVID-19 patients experience several symptoms a few months after the initial infection and develop post-acute sequelae SARS-CoV-2 (PASC), referred to as “Long-COVID,” characterized by persistent physical mental fatigue. However, exact pathogenetic mechanisms affecting brain are still not well-understood. There is increasing evidence neurovascular inflammation in brain. precise role neuroinflammatory response that contributes severity long COVID pathogenesis clearly understood. Here, we review reports spike protein can cause blood–brain barrier (BBB) dysfunction damage neurons either directly, or via activation mast cells microglia release various molecules. Moreover, provide recent novel flavanol eriodictyol particularly suited for development an effective treatment alone together with oleuropein sulforaphane (ViralProtek®), all which have potent anti-viral anti-inflammatory actions.

Language: Английский

---

SARS-CoV-2 S protein activates NLRP3 inflammasome and deregulates coagulation factors in endothelial and immune cells

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 15, 2024

Abstract Background Hyperinflammation, hypercoagulation and endothelial injury are major findings in acute post-COVID-19. The SARS-CoV-2 S protein has been detected as an isolated element human tissues reservoirs is the main product of mRNA COVID-19 vaccines. We investigated whether alone triggers pro-inflammatory pro-coagulant responses primary cultures two cell types deeply affected by SARS-CoV-2, such monocytes cells. Methods In umbilical vein cells (HUVEC) monocytes, components NF-κB NLRP3 inflammasome system, well coagulation regulators, were assessed qRT-PCR, Western blot, flow cytometry, or indirect immunofluorescence. Results activated NF-κB, promoted cytokines release, triggered priming activation system resulting mature IL-1β formation both types. This was paralleled enhanced production factors von Willebrand factor (vWF), VIII tissue factor, that mediated, at least part, IL-1β. Additionally, failed to enhance ADAMTS-13 levels counteract activity vWF multimers. Monocytes HUVEC barely expressed angiotensin-converting enzyme-2. Pharmacological approaches gene silencing showed TLR4 receptors mediated effects but not HUVEC. Conclusion behaves a stimulus Interfering with signaling pathways evoked may help preventing immune vascular complications driven viral element.

Language: Английский

---

Exploiting viral sensing mediated by Toll-like receptors to design innovative vaccines

npj Vaccines, Journal Year: 2021, Volume and Issue: 6(1)

Published: Oct. 28, 2021

Abstract Toll-like receptors (TLRs) are transmembrane proteins belonging to the family of pattern-recognition receptors. They function as sensors invading pathogens through recognition pathogen-associated molecular patterns. After their engagement by microbial ligands, TLRs trigger downstream signaling pathways that culminate into transcriptional upregulation genes involved in immune defense. Here we provide an updated overview on members TLR and focus role antiviral response. Understanding innate sensing viruses triggered these would useful knowledge prompt development vaccines able elicit effective long-lasting responses. We describe mechanisms developed viral escape from surveillance mediated finally discuss how TLR/virus interplay might be exploited guide design innovative vaccine platforms.

Language: Английский

---

Toll-Like Receptors as a Therapeutic Target in the Era of Immunotherapies

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Oct. 4, 2021

Toll-like receptors (TLRs) are the pattern recognition receptors, which activated by foreign and host molecules in order to initiate immune response. They play a crucial role regulation of innate immunity, several studies have shown their importance bacterial, viral, fungal infections, autoimmune diseases, cancers. The consensus view from an immunological perspective is that TLR agonists can serve either as possible therapeutic agent or vaccine adjuvant toward cancers infectious diseases inhibitors may be promising approach treatment some cancers, viral infections. These notions based on fact stimulate secretion proinflammatory cytokines general, development responses. Some TLR-based inhibitory agents efficacious preclinical models now entered clinical trials. Therefore, TLRs seem hold potential perfect target era immunotherapies. We offer therapeutics sheds light usefulness combination therapies. also highlight various discovery phase

Language: Английский

---

Activation of TLR4 by viral glycoproteins: A double-edged sword?

Frontiers in Microbiology, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 29, 2022

Recognition of viral infection by pattern recognition receptors is paramount for a successful immune response to infection. However, an unbalanced proinflammatory can be detrimental the host. Recently, multiple studies have identified that SARS-CoV-2 spike protein activates Toll-like receptor 4 (TLR4), resulting in induction cytokine expression. Activation TLR4 glycoproteins has also been observed context other models, including respiratory syncytial virus (RSV), dengue (DENV) and Ebola (EBOV). mechanisms involved virus-TLR4 interactions remained unclear. Here, we review act as pathogen-associated molecular patterns induce via TLR4. We explore current understanding underlying how are recognized discuss contribution activation pathogenesis. identify contentious findings research gaps highlight importance glycoprotein-mediated potential therapeutic approaches.

Language: Английский

---

Ginkgo biloba in the management of the COVID‐19 severity

Archiv der Pharmazie, Journal Year: 2022, Volume and Issue: 355(10)

Published: June 7, 2022

Abstract The severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection is linked with inflammatory disorders and the development of oxidative stress in extreme cases. Therefore, anti‐inflammatory antioxidant drugs may alleviate these complications. Ginkgo biloba L. folium extract (EGb) a herbal medicine containing various active constituents. This review aims to provide critical discussion on potential role EGb management coronavirus disease 2019 (COVID‐19). antiviral effect mediated by different mechanisms, including blocking SARS‐CoV‐2 3‐chymotrypsin‐like protease that provides trans‐variant effectiveness. Moreover, impedes pulmonary through diminution neutrophil elastase activity, release proinflammatory cytokines, platelet aggregation, thrombosis. Thus, can attenuate lung injury distress COVID‐19. In conclusion, offers being used as adjuvant symptomatic therapy. Nanosystems enabling targeted delivery, personalization, booster effects opportunity for use modern phytotherapy.

Language: Английский

---

In Silico Analyses Indicate a Lower Potency for Dimerization of TLR4/MD-2 as the Reason for the Lower Pathogenicity of Omicron Compared to Wild-Type Virus and Earlier SARS-CoV-2 Variants

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(10), P. 5451 - 5451

Published: May 17, 2024

The SARS-CoV-2 Omicron variants have replaced all earlier variants, due to increased infectivity and effective evasion from infection- vaccination-induced neutralizing antibodies. Compared of concern (VoCs), the show high TMPRSS2-independent replication in upper airway organs, but lower lungs mortality rates. shift cellular tropism towards pathogenicity was hypothesized correlate with a toll-like receptor (TLR) activation, although underlying molecular mechanisms remained undefined. In silico analyses presented here indicate that spike protein has potency induce dimerization TLR4/MD-2 compared wild type virus despite comparable binding activity TLR4. A model illustrating consequences different potencies vs. wild-type for TLR4 activation is presented. Further clear tendency decreasing potential during evolution via Alpha Gamma Delta variants.

Language: Английский

---

Interplay of TLR4 and SARS-CoV-2: Unveiling the Complex Mechanisms of Inflammation and Severity in COVID-19 Infections

Journal of Inflammation Research, Journal Year: 2024, Volume and Issue: Volume 17, P. 5077 - 5091

Published: July 1, 2024

Abstract: The late 2019 emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), causative agent COVID-19, caused profound and unprecedented disruption to global socio-economic structure, negatively affecting millions lives worldwide. A typical hallmark severe COVID-19 is hyper inflammation due aberrant cytokine release (cytokine storm) by innate immune cells. Recent studies have revealed that SARS-CoV-2, through its spike (S) protein, can activate body's cells via Toll-Like Receptors (TLRs), particularly TLR4. In silico demonstrated S protein binds with high affinity TLR4, triggering downstream signaling processes result in pro-inflammatory release. Compared other TLRs, such as TLR2, TLR4 plays a more significant role initiating sustaining inflammatory response associated COVID-19. Furthermore, interactions between virus target enhance cellular expression making susceptible viral subsequent inflammation. This increased upon entry creates feedback loop, where heightened levels lead amplified responses, contributing severity disease. Additionally, TLR4's potent activation pathways sets it apart from underscoring pivotal pathogenesis this review, we thoroughly explore multitude regulatory SARS-CoV-2 employs incite We specifically focus on critical impact compared highlighting how exacerbate By delving into mechanisms TLR4-mediated inflammation, aim shed light potential therapeutic targets could mitigate damage Understanding unique context infection pave way for novel treatment strategies inhibit receptor's activity, thereby reducing overall disease burden improving patient outcomes. Keywords: storm, toll-like receptor 4, hyperinflammation, ACE2 receptors, immunity

Language: Английский

---

Role of milk glycome in prevention, treatment, and recovery of COVID-19

Frontiers in Nutrition, Journal Year: 2022, Volume and Issue: 9

Published: Nov. 8, 2022

Milk contains all essential macro and micro-nutrients for the development of newborn. Its high therapeutic antimicrobial content provides an important function prevention, treatment, recovery certain diseases throughout life. The bioactive components found in milk are mostly decorated with glycans, which provide proper formation modulate biological functions glycosylated compounds. glycome consists free glycolipids, N- O- proteins. Recent studies have shown that both glycans glycan-containing molecules antiviral characteristics based on different mechanisms such as signaling, microbiome modulation, natural decoy strategy, immunomodulatory action. In this review, we discuss recent clinical potential conjugated glycans' role COVID-19.

Language: Английский

---