scholarly journals Toll-like receptors activation, signaling, and targeting: an overview

2019 ◽  
Vol 43 (1) ◽  
Author(s):  
Salwa Refat El-Zayat ◽  
Hiba Sibaii ◽  
Fathia A. Mannaa
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Inflammatory Diseases ◽  
Host Cells ◽  
Signaling Cascades ◽  
Innate Immune Responses ◽  
Toll Like Receptors ◽  
Tlr Signaling ◽  
Dying Cells

Abstract Background Toll-like receptors (TLRs) are an important family of receptors that constitute the first line of defense system against microbes. They can recognize both invading pathogens and endogenous danger molecules released from dying cells and damaged tissues and play a key role in linking innate and adaptive immunity. TLRs are widely distributed in both immune and other body cells. The expressions and locations of TLRs are regulated in response to specific molecules derived from pathogens or damaged host cells. The binding of ligands to TLR activates specific intracellular signaling cascades that initiate host defense reactions. Such binding is ligand-dependent and cell type-dependent and leads to production of pro-inflammatory cytokines and type 1 interferon. TLR-dependent signaling pathways are tightly increased during innate immune responses by a variety of negative regulators. Overactivation of TLRs can ultimately lead to disruption of immune homeostasis and thus increase the risk for inflammatory diseases and autoimmune disorders. Antagonists/inhibitors targeting the TLR signaling pathways have emerged as novel therapeutics to treat these diseases. Aim of work The present review summarizes the structure, characterizations, and signaling of TLRs and their regulators, as well as describes the implication of TLRs in many diseases with a brief idea about the inhibitors that target TLR signaling pathways. Conclusion We conclude that TLRs are the main elements of our immune system, and they should be maintained functioning to keep the integrity of innate immunity. Targeting of TLR signaling represents a new challenge for treatment of many diseases.

scholarly journals Prospects for use of peptides and their derivatives, structurally corresponding to the G protein-coupled receptors, in medicine

2015 ◽  
Vol 61 (1) ◽  
pp. 19-29 ◽  
Author(s):  
A.O. Shpakov ◽  
E.A. Shpakova
Keyword(s):  
G Protein ◽  
Intracellular Signaling ◽  
High Efficiency ◽  
Clinical Medicine ◽  
Inflammatory Diseases ◽  
G Protein Coupled Receptors ◽  
Signaling Cascades ◽  
G Protein Coupled

The regulation of signaling pathways involved in the control of many physiological functions is carried out via the heterotrimeric G protein-coupled receptors (GPCR). The search of effective and selective regulators of GPCR and intracellular signaling cascades coupled with them is one of the important problems of modern fundamental and clinical medicine. Recently data suggest that synthetic peptides and their derivatives, structurally corresponding to the intracellular and transmembrane regions of GPCR, can interact with high efficiency and selectivity with homologous receptors and influence, thus, the functional activity of intracellular signaling cascades and fundamental cellular processes controlled by them. GPCR-peptides are active in both in vitro and in vivo. They regulate hematopoiesis, angiogenesis and cell proliferation, inhibit tumor growth and metastasis, and prevent the inflammatory diseases and septic shock. These data show greatest prospects in the development of the new generations of drugs based on GPCR-derived peptides, capable of regulating the important functions of the organism.

scholarly journals Visfatin: A Possible Role in Cardiovasculo-Metabolic Disorders

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2444
Author(s):  
Ali Dakroub ◽  
Suzanne A. Nasser ◽  
Nour Younis ◽  
Humna Bhagani ◽  
Yusra Al-Dhaheri ◽  
...  
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Intracellular Signaling ◽  
Skeletal Muscles ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Signaling Cascades ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Enhancing Factor ◽  
Cell Colony

Visfatin/NAMPT (nicotinamide phosphoribosyltransferase) is an adipocytokine with several intriguing properties. It was first identified as pre-B-cell colony-enhancing factor but turned out to possess enzymatic functions in nicotinamide adenine dinucleotide biosynthesis, with ubiquitous expression in skeletal muscles, liver, cardiomyocytes, and brain cells. Visfatin exists in an intracellular (iNAMPT) and extracellular (eNAMPT) form. Intracellularly, visfatin/iNAMPT plays a regulatory role in NAD+ biosynthesis and thereby affects many NAD-dependent proteins such as sirtuins, PARPs, MARTs and CD38/157. Extracellularly, visfatin is associated with many hormone-like signaling pathways and activates some intracellular signaling cascades. Importantly, eNAMPT has been associated with several metabolic disorders including obesity and type 1 and 2 diabetes. In this review, a brief overview about visfatin is presented with special emphasis on its relevance to metabolic diseases. Visfatin/NAMPT appears to be a unique molecule with clinical significance with a prospective promising diagnostic, prognostic, and therapeutic applications in many cardiovasculo-metabolic disorders.

High Molecular Weight Kininogen Fragments Stimulate the Secretion of Interleukin-1β through the NFκ B, JNK and p38 MAP Kinase Signaling Pathways in Monocytes.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1644-1644
Author(s):  
Mohammad M. Khan ◽  
Harland N. Bradford ◽  
Irma Isordia-Salas ◽  
Yuchuan Liu ◽  
Yi Wu ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Signaling Pathways ◽  
High Molecular Weight ◽  
Intracellular Signaling ◽  
Inflammatory Diseases ◽  
Specific Inhibitor ◽  
P38 Map Kinase ◽  
High Molecular Weight Kininogen ◽  
Recombinant Peptide ◽  
Domain 3

Abstract Plasma high molecular weight kininogen (HK) is cleaved in inflammatory diseases by kallikrein to cleaved HK (HKa). We have reported that HKa releases cytokines (TNFα , IL-1β , IL-6) and chemokines (IL-8 and MCP-1) from isolated human peripheral blood monocytes. At a concentration of 600nM, Glutathione -S- transferase (GST) fusion proteins of kininogen domain 3 (D3), E7P - an active fragment of domain 3 (aaG255-Q292), HK domain 5 (D5), and D5 recombinant peptide HG (aa K420-D474) each stimulated secretion of IL-1β from monocytes. Receptors on monocytes including Mac-1, LFA-1, uPAR and gC1qR are required for IL-1β secretion from monocytes. We now report the signaling pathways and evidence for synthesis of IL-1 β in monocytes stimulated by HKa. Inhibitors of signaling pathways initiated by NFkB, JNK and p38, but not ERK, decreased IL-1b release from monocytes. A specific inhibitor of NFkB, MG-132 (1, 10 and 100 μM) significantly reduced IL-1β release from monocytes by 69.7, 67.3, 88.5% respectively, when stimulated by GST-E7P. The release of IL-1β by LPS (10 μg/ml), was blocked 83.4% by MG-132 (100 μM). A specific inhibitor of JNK, SP 600125 (1, 10 and 100 μM) significantly reduced IL-1β release from monocytes by 55.7, 76.3, 78.9% respectively, when stimulated by GST-E7P. The release of IL-1β by LPS (10 μg/ml), was blocked 90.23% by SP 600125 (100 μM). A specific inhibitor of p38, SB202190 (1,10 and 100 μM) significantly reduced IL-1β release from monocytes by 27.8, 14.2, 91.0% respectively, when stimulated by E7P. The release of IL-1β by LPS (10 μg/ml), was blocked 76.8 % by SB202190 (100 μM). In contrast, the ERK activation inhibitor U0126 (1, 10 and 100 μM) failed to inhibit GST-E7P-induced release of IL-1β from monocytes but the release of IL-1β with LPS (10 μg/ml), was blocked by 77.4% at 100 μM. After monocytes (4 X 106/ml) were treated with HKa (600 nM) or LPS (10 ng/ml), total RNA was extracted and RT-PCR reactions for expression of IL-1β and gC1qR mRNA using specific primers were carried out. PCR products was separated in 4% ethidium bromide-stained agarose gels and photographed. No IL-1b mRNA was detected prior to exposure to HKa or LPS but both were detected at 1 hour. In contrast, gC1qR mRNA was present without stimulation by HKa. HKa domains 3 and 5 may contribute to the pathogenesis of inflammatory diseases by stimulating the synthesis and release of IL-1β from human monocytes using intracellular signaling pathways initiated by uPAR, β 2 integrins and gC1qR receptors.

scholarly journals Coxsackievirus B3 Replication Is Reduced by Inhibition of the Extracellular Signal-Regulated Kinase (ERK) Signaling Pathway

2002 ◽  
Vol 76 (7) ◽  
pp. 3365-3373 ◽  
Author(s):  
Honglin Luo ◽  
Bobby Yanagawa ◽  
Jingchun Zhang ◽  
Zongshu Luo ◽  
Mary Zhang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Late Phase ◽  
Viral Myocarditis ◽  
Coxsackievirus B3 ◽  
Host Cells ◽  
Virus Protein ◽  
Signaling Mechanism ◽  
Intracellular Signaling Pathways ◽  
Cvb3 Infection

ABSTRACT Coxsackievirus B3 (CVB3) is the most common human pathogen for viral myocarditis. We have previously shown that the signaling protein p21 ras GTPase-activating protein (RasGAP) is cleaved and that mitogen-activated protein kinases (MAPKs) ERK1/2 are activated in the late phase of CVB3 infection. However, the role of intracellular signaling pathways in CVB3-mediated myocarditis and the relative advantages of such pathways to host or virus remain largely unclear. In this study we extended our prior studies by examining the interaction between CVB3 replication and intracellular signaling pathways in HeLa cells. We observed that CVB3 infection induced a biphasic activation of ERK1/2, early transient activation versus late sustained activation, which were regulated by different mechanisms. Infection by UV-irradiated, inactivated virus capable of receptor binding and endocytosis triggered early ERK1/2 activation, but was insufficient to trigger late ERK1/2 activation. By using a general caspase inhibitor (zVAD.fmk) we further demonstrated that late ERK1/2 activation was not a result of CVB3-mediated caspase cleavage. Treatment of cells with U0126, a selective inhibitor of MAPK kinase (MEK), significantly inhibited CVB3 progeny release and decreased virus protein production. Furthermore, inhibition of ERK1/2 activation circumvented CVB3-induced apoptosis and viral protease-mediated RasGAP cleavage. Taken together, these data suggest that ERK1/2 activation is important for CVB3 replication and contributes to virus-mediated changes in host cells. Our findings demonstrate coxsackievirus takeover of a particular host signaling mechanism and uncover a prospective approach to stymie virus spread and preserve myocardial integrity.

Functional aspects of extracellular cyclophilins

2014 ◽  
Vol 395 (7-8) ◽  
pp. 721-735 ◽  
Author(s):  
Henrik Hoffmann ◽  
Cordelia Schiene-Fischer
Keyword(s):  
Rheumatoid Arthritis ◽  
Cardiovascular Diseases ◽  
Intracellular Signaling ◽  
Inflammatory Diseases ◽  
Cell Communication ◽  
Signaling Cascades ◽  
Specific Inhibition ◽  
Functional Aspects ◽  
Inflammatory Processes ◽  
Inflammatory Response To Injury

Abstract The cyclophilin family of peptidyl prolyl cis/trans isomerases includes several isoforms found to be secreted in response to different stimuli, thus existing both in the interior and the exterior of cells. The extracellular fractions of the cyclophilins CypA and CypB are involved in the control of cell-cell communication. By binding to the cell membrane receptor CD147 and cell surface heparans they elicit a variety of intracellular signaling cascades involved in inflammatory processes. Increased levels of cyclophilins in inflammatory tissues and body fluids are considered as an inflammatory response to injury. Thus, the extracellular portion of cyclophilins probably plays an important role in human diseases associated with acute or chronic inflammation like rheumatoid arthritis, sepsis, asthma and cardiovascular diseases. Specific inhibition of the cyclophilins in the extracellular space may open an effective therapeutic approach for treating inflammatory diseases.

scholarly journals Nanotechnology to the Rescue: Treatment Perspective for the Immune Dysregulation Observed in COVID-19

2021 ◽  
Vol 3 ◽  
Author(s):  
Angela E. Peter ◽  
B. V. Sandeep ◽  
B. Ganga Rao ◽  
V. Lakshmi Kalpana
Keyword(s):  
Drug Delivery ◽  
Signaling Pathways ◽  
Targeted Delivery ◽  
Inflammatory Diseases ◽  
Human Life ◽  
Immune Dysregulation ◽  
Current Treatment ◽  
The Body ◽  
Signaling Cascades ◽  
Great Promise

The study of the use of nanotechnology for drug delivery has been extensive. Nanomedical approaches for therapeutics; drug delivery in particular is superior to conventional methods in that it allows for controlled targeted delivery and release, higher stability, extended circulation time, minimal side-effects, and improved pharmacokinetic clearance (of the drug) form the body, to name a few. The magnitude of COVID-19, the current ongoing pandemic has been severe; it has caused widespread the loss of human life. In individuals with severe COVID-19, immune dysregulation and a rampant state of hyperinflammation is observed. This kind of an immunopathological response is detrimental and results in rapid disease progression, development of secondary infections, sepsis and can be fatal. Several studies have pin-pointed the reason for this immune dysregulation; deviations in the signaling pathways involved in the mediation and control of immune responses. In severe COVID-19 patients, many signaling cascades including JAK/STAT, NF-κB, MAPK/ERK, TGF beta, VEGF, and Notch signaling were found to be either upregulated or inactivated. Targeting these aberrant signaling pathways in conjunction with antiviral therapy will effectuate mitigation of the hyperinflammation, hypercytokinemia, and promote faster recovery. The science of the use of nanocarriers as delivery agents to modulate these signaling pathways is not new; it has already been explored for other inflammatory diseases and in particular, cancer therapy. Numerous studies have evaluated the efficacy and potential of nanomedical approaches to modulate these signaling pathways and have been met with positive results. A treatment regime, that includes nanotherapeutics and antiviral therapies will prove effective and holds great promise for the successful treatment of COVID-19. In this article, we review different nanomedical approaches already studied for targeting aberrant signaling pathways, the host immune response to SARS-CoV-2, immunopathology and the dysregulated signaling pathways observed in severe COVID-19 and the current treatment methods in use for targeting signaling cascades in COVID-19. We then conclude by suggesting that the use of nanomedical drug delivery systems for targeting signaling pathways can be extended to effectively target the aberrant signaling pathways in COVID-19 for best treatment results.

scholarly journals Inflammation, Extracellular Matrix Remodeling, and Proteostasis in Tumor Microenvironment

2021 ◽  
Vol 22 (15) ◽  
pp. 8102
Author(s):  
Marina Marozzi ◽  
Arianna Parnigoni ◽  
Aide Negri ◽  
Manuela Viola ◽  
Davide Vigetti ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Host Cells ◽  
Inflammatory Factors ◽  
Matrix Remodeling ◽  
Surface Receptors ◽  
Degrading Enzymes

Cancer is a multifaceted and complex pathology characterized by uncontrolled cell proliferation and decreased apoptosis. Most cancers are recognized by an inflammatory environment rich in a myriad of factors produced by immune infiltrate cells that induce host cells to differentiate and to produce a matrix that is more favorable to tumor cells’ survival and metastasis. As a result, the extracellular matrix (ECM) is changed in terms of macromolecules content, degrading enzymes, and proteins. Altered ECM components, derived from remodeling processes, interact with a variety of surface receptors triggering intracellular signaling that, in turn, cancer cells exploit to their own benefit. This review aims to present the role of different aspects of ECM components in the tumor microenvironment. Particularly, we highlight the effect of pro- and inflammatory factors on ECM degrading enzymes, such as metalloproteases, and in a more detailed manner on hyaluronan metabolism and the signaling pathways triggered by the binding of hyaluronan with its receptors. In addition, we sought to explore the role of extracellular chaperones, especially of clusterin which is one of the most prominent in the extracellular space, in proteostasis and signaling transduction in the tumor microenvironment. Although the described tumor microenvironment components have different biological roles, they may engage common signaling pathways that favor tumor growth and metastasis.

scholarly journals Toll-Like Receptors and Dental Mesenchymal Stromal Cells

2021 ◽  
Vol 2 ◽  
Author(s):  
Oleh Andrukhov
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Inflammatory Diseases ◽  
Toll Like Receptors ◽  
Tlr Signaling ◽  
Differentiation Potential ◽  
Proinflammatory Mediators ◽  
Promising Tool ◽  
And Function

Dental mesenchymal stromal cells (MSCs) are a promising tool for clinical application in and beyond dentistry. These cells possess multilineage differentiation potential and immunomodulatory properties. Due to their localization in the oral cavity, these cells could sometimes be exposed to different bacteria and viruses. Dental MSCs express various Toll-like receptors (TLRs), and therefore, they can recognize different microorganisms. The engagement of TLRs in dental MSCs by various ligands might change their properties and function. The differentiation capacity of dental MSCs might be either inhibited or enhanced by TLRs ligands depending on their nature and concentrations. Activation of TLR signaling in dental MSCs induces the production of proinflammatory mediators. Additionally, TLR ligands alter the immunomodulatory ability of dental MSCs, but this aspect is still poorly explored. Understanding the role of TLR signaling in dental MSCs physiology is essential to assess their role in oral homeostasis, inflammatory diseases, and tissue regeneration.

scholarly journals IP3R-driven increases in mitochondrial Ca2+ promote neuronal death in NPC disease

2021 ◽  
Vol 118 (40) ◽  
pp. e2110629118
Author(s):  
Scott A. Tiscione ◽  
Maria Casas ◽  
Jonathan D. Horvath ◽  
Vincent Lam ◽  
Keiko Hino ◽  
...  
Keyword(s):  
Neuronal Death ◽  
Intracellular Signaling ◽  
Signaling Cascades ◽  
Presenilin 1 ◽  
Signaling Cascade ◽  
Molecular Pathways ◽  
Loss Of Function ◽  
Signaling Axis ◽  
Niemann Pick

Ca2+ is the most ubiquitous second messenger in neurons whose spatial and temporal elevations are tightly controlled to initiate and orchestrate diverse intracellular signaling cascades. Numerous neuropathologies result from mutations or alterations in Ca2+ handling proteins; thus, elucidating molecular pathways that shape Ca2+ signaling is imperative. Here, we report that loss-of-function, knockout, or neurodegenerative disease–causing mutations in the lysosomal cholesterol transporter, Niemann-Pick Type C1 (NPC1), initiate a damaging signaling cascade that alters the expression and nanoscale distribution of IP3R type 1 (IP3R1) in endoplasmic reticulum membranes. These alterations detrimentally increase Gq-protein coupled receptor–stimulated Ca2+ release and spontaneous IP3R1 Ca2+ activity, leading to mitochondrial Ca2+ cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IP3R1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca2+ phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IP3R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease.

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