Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the Toll-like receptor 4 (TLR4) complex, a receptor of the innate immune system, may underpin the pathophysiology of many human diseases, including asthma, cardiovascular disorder, diabetes, obesity, metabolic syndrome, autoimmune disorders, neuroinflammatory disorders, schizophrenia, bipolar disorder, autism, clinical depression, chronic fatigue syndrome, alcohol abuse, and toluene inhalation. TLRs are pattern recognition receptors that recognize damage-associated molecular patterns and pathogen-associated molecular patterns, including lipopolysaccharide (LPS) from gram-negative bacteria. Here we focus on the environmental factors, which are known to trigger TLR4, e.g., ozone, atmosphere particulate matter, long-lived reactive oxygen intermediate, pentachlorophenol, ionizing radiation, and toluene. Activation of the TLR4 pathways may cause chronic inflammation and increased production of reactive oxygen and nitrogen species (ROS/RNS) and oxidative and nitrosative stress and therefore TLR-related diseases. This implies that drugs or substances that modify these pathways may prevent or improve the abovementioned diseases. Here we review some of the most promising drugs and agents that have the potential to attenuate TLR-mediated inflammation, e.g., anti-LPS strategies that aim to neutralize LPS (synthetic anti-LPS peptides and recombinant factor C) and TLR4/MyD88 antagonists, including eritoran, CyP, EM-163, epigallocatechin-3-gallate, 6-shogaol, cinnamon extract, N-acetylcysteine, melatonin, and molecular hydrogen. The authors posit that activation of the TLR radical (ROS/RNS) cycle is a common pathway underpinning many "civilization" disorders and that targeting the TLR radical cycle may be an effective method to treat many inflammatory disorders.
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PMID:Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. 2343 41

Substantial evidence indicates an association between clinical depression and altered immune function. Systemic administration of bacterial lipopolysaccharide (LPS) is commonly used to study inflammation-associated behavioral changes in rodents. In these experiments, we tested the hypothesis that peripheral immune activation leads to neuroinflammation and depressive-like behavior in mice. We report that systemic administration of LPS induced astrocyte activation in transgenic GFAP-luc mice and increased immunoreactivity against the microglial marker ionized calcium-binding adapter molecule 1 in the dentate gyrus of wild-type mice. Furthermore, LPS treatment caused a strong but transient increase in cytokine levels in the serum and brain. In addition to studying LPS-induced neuroinflammation, we tested whether sickness could be separated from depressive-like behavior by evaluating LPS-treated mice in a panel of behavioral paradigms. Our behavioral data indicate that systemic LPS administration caused sickness and mild depressive-like behavior. However, due to the overlapping time course and mild effects on depression-related behavior per se, it was not possible to separate sickness from depressive-like behavior in the present rodent model.
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PMID:Systemic immune activation leads to neuroinflammation and sickness behavior in mice. 2393 46

Mitochondria play a significant role in pathogenesis of clinical depression and their function can be impaired by inflammation and alterations in hypothalamic-pituitary-adrenal axis. Sexual context is also a relevant factor in the incidence of mood disorders, and could have a strong influence during an immune challenge. Therefore, in this study we investigated whether the effects of seven-day lipopolysaccharide (LPS) treatment on glucocorticoid receptor (GR) could be associated with apoptosis and alterations in energy metabolism in hippocampus of female and male Wistar rats with depressive-like behavior. To that end, we measured the mitochondrial levels of GR and its phosphoisoforms pGR232 and pGR246 in hippocampus of female and male rats, as well as the mRNA levels of two GR-regulated mitochondrial genes, cyclooxygenase -1 and -3 (COX-1 and -3). We also measured alterations in the extrinsic and intrinsic apoptotic pathways in mitochondria and cytosol of hippocampus of these animals, and the levels of cleaved cytosolic poly [ADP-ribose] polymerase-1 (PARP-1) protein. We discovered that even though LPS treatment induced behavioral alterations and affected corticosterone levels and apoptosis in a similar manner in both sexes, it affected mitochondrial GR differently in males and females. Namely, the treatment decreased levels of mitochondrial GR and pGR232/pGR246 ratio only in females, and these alterations were followed by decreased mRNA levels of COX-1 and COX-3 only in this sex. The alterations in COX-1 and COX-3 mRNA levels could indicate impaired oxidative metabolism and diminished mitochondrial function in hippocampus of this sex.
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PMID:Sex-specific Effects of Lipopolysaccharide on Hippocampal Mitochondrial Processes in Neuroinflammatory Model of Depression. 3303 25