Inflammatory signaling pathways

Figure 15.3 Resveratrol modulation of pro-inflammatory signaling pathways. Resver-atrol represses transcriptional activation of various pro-inflammatory genes by inhibiting pro-inflammatory stimuli-induced activation of upstream kinases, such as MAP kinases, PI3K/Akt, IKK, PKC, etc., and blocking the DNA binding of eukaryotic transcription factors, such as NF-kB, AP-1, and STAT3.

Chronic inflammatory states associated with infection or xenobiotic chemical exposure from the environment can produce genomic lesions that, in time, can become initiated tumors. It is known that hosts do fight microbial infections by moderate production of various free radicals reactive oxygen species (ROS) [e.g., hydroxyl radical (OH ) and the superoxide radical (OT)] or reactive nitrogen species (RNS) [e.g., nitric oxide (NO ) and the strong oxidant, peroxynitrite (ONOO )]. Within limits inflammatory signaling pathways of the host can control excessive free radical concentrations by means of enzymes such as NADPH oxidase, myeloperoxidase, nitric oxide synthase, and others (Federico et al. 2007 Rakoff-Nahonm 2006). 

Hours or days after the primary injury, secondary injuries develop. Secondary injmy is caused by the release of substances that alter synaptic funchon, blood flow, ionic and neurotransmitter homeostasis, metabolic function, and inflammatory signaling pathways. This section focuses on mechanisms of neuronal loss by secondary injuries mechanisms of synaptic alterations are discussed in the next section. 

These compounds represent only some of the efforts being made to target the TLRs and their signalling pathways. Targeting TLRs holds great promise in the effort to find new therapies for infectious, allergic and inflammatory diseases, and cancer. 

Proteasomal degradation also plays an essential role in the activation of cellular signaling pathways. A prototype for this is the control of NF-kB signaling, which has a pivotal role in inflammatory responses. Upon stimulation the inhibitory IicBa protein is phos-phorylated and thereby becomes a target substrate for K48-polyubiquitination. Proteasomal degradation of IkBu releases the transcription factor NF-kB, which subsequently translocates to the nucleus and activates specific target genes. 

The inhibition of the phosphorylation of IkBoc by celastrol in the NF-kB signaling pathway is not cell specific72-75 and thus significantly broadened the potential medicinal applications of natural triterpene QMs. Celastrol 76 has been evaluated in the treatment of Crohn s disease,76 which is a chronic relapsing inflammatory bowel disease. In the peripheral blood mononuclear cells, celastrol 76 reduced the levels of... 

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