TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis
Toll-Like Receptor 4 (TLR4) signal pathway plays an important role in initiating the innate immune response and its activation by bacterial endotoxin is responsible for chronic and acute inflammatory disorders that are becoming more and more frequent in developed countries. Modulation of the TLR4 pa...
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doaj-139828354a7640cdb446ffc223be8bd22020-11-24T21:59:43ZengMDPI AGVaccines2076-393X2017-10-01543410.3390/vaccines5040034vaccines5040034TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and SepsisNikolay N. Kuzmich0Konstantin V. Sivak1Vladimir N. Chubarev2Yuri B. Porozov3Tatiana N. Savateeva-Lyubimova4Francesco Peri5Department of Drug Safety, Research Institute of Influenza, WHO National Influenza Centre of Russia, 15/17 Professor Popov St, Saint-Petersburg 197376, RussiaDepartment of Drug Safety, Research Institute of Influenza, WHO National Influenza Centre of Russia, 15/17 Professor Popov St, Saint-Petersburg 197376, RussiaDepartment of Pharmacology, Institute of Pharmacy and Translational medicine, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya St., Moscow 119991, RussiaLaboratory of Bioinformatics, Institute of Pharmacy and Translational medicine, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya St., Moscow 119991, RussiaDepartment of Drug Safety, Research Institute of Influenza, WHO National Influenza Centre of Russia, 15/17 Professor Popov St, Saint-Petersburg 197376, RussiaDepartment of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, Milano 20126, ItalyToll-Like Receptor 4 (TLR4) signal pathway plays an important role in initiating the innate immune response and its activation by bacterial endotoxin is responsible for chronic and acute inflammatory disorders that are becoming more and more frequent in developed countries. Modulation of the TLR4 pathway is a potential strategy to specifically target these pathologies. Among the diseases caused by TLR4 abnormal activation by bacterial endotoxin, sepsis is the most dangerous one because it is a life-threatening acute system inflammatory condition that still lacks specific pharmacological treatment. Here, we review molecules at a preclinical or clinical phase of development, that are active in inhibiting the TLR4-MyD88 and TLR4-TRIF pathways in animal models. These are low-molecular weight compounds of natural and synthetic origin that can be considered leads for drug development. The results of in vivo studies in the sepsis model and the mechanisms of action of drug leads are presented and critically discussed, evidencing the differences in treatment results from rodents to humans.https://www.mdpi.com/2076-393X/5/4/34TLR4sepsisLPSCD14MD-2in vivo studiesPAMPDAMP |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nikolay N. Kuzmich Konstantin V. Sivak Vladimir N. Chubarev Yuri B. Porozov Tatiana N. Savateeva-Lyubimova Francesco Peri |
spellingShingle |
Nikolay N. Kuzmich Konstantin V. Sivak Vladimir N. Chubarev Yuri B. Porozov Tatiana N. Savateeva-Lyubimova Francesco Peri TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis Vaccines TLR4 sepsis LPS CD14 MD-2 in vivo studies PAMP DAMP |
author_facet |
Nikolay N. Kuzmich Konstantin V. Sivak Vladimir N. Chubarev Yuri B. Porozov Tatiana N. Savateeva-Lyubimova Francesco Peri |
author_sort |
Nikolay N. Kuzmich |
title |
TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis |
title_short |
TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis |
title_full |
TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis |
title_fullStr |
TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis |
title_full_unstemmed |
TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis |
title_sort |
tlr4 signaling pathway modulators as potential therapeutics in inflammation and sepsis |
publisher |
MDPI AG |
series |
Vaccines |
issn |
2076-393X |
publishDate |
2017-10-01 |
description |
Toll-Like Receptor 4 (TLR4) signal pathway plays an important role in initiating the innate immune response and its activation by bacterial endotoxin is responsible for chronic and acute inflammatory disorders that are becoming more and more frequent in developed countries. Modulation of the TLR4 pathway is a potential strategy to specifically target these pathologies. Among the diseases caused by TLR4 abnormal activation by bacterial endotoxin, sepsis is the most dangerous one because it is a life-threatening acute system inflammatory condition that still lacks specific pharmacological treatment. Here, we review molecules at a preclinical or clinical phase of development, that are active in inhibiting the TLR4-MyD88 and TLR4-TRIF pathways in animal models. These are low-molecular weight compounds of natural and synthetic origin that can be considered leads for drug development. The results of in vivo studies in the sepsis model and the mechanisms of action of drug leads are presented and critically discussed, evidencing the differences in treatment results from rodents to humans. |
topic |
TLR4 sepsis LPS CD14 MD-2 in vivo studies PAMP DAMP |
url |
https://www.mdpi.com/2076-393X/5/4/34 |
work_keys_str_mv |
AT nikolaynkuzmich tlr4signalingpathwaymodulatorsaspotentialtherapeuticsininflammationandsepsis AT konstantinvsivak tlr4signalingpathwaymodulatorsaspotentialtherapeuticsininflammationandsepsis AT vladimirnchubarev tlr4signalingpathwaymodulatorsaspotentialtherapeuticsininflammationandsepsis AT yuribporozov tlr4signalingpathwaymodulatorsaspotentialtherapeuticsininflammationandsepsis AT tatianansavateevalyubimova tlr4signalingpathwaymodulatorsaspotentialtherapeuticsininflammationandsepsis AT francescoperi tlr4signalingpathwaymodulatorsaspotentialtherapeuticsininflammationandsepsis |
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