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Probiotics Modulate Cell Signaling Pathway and Innate Cytokine Responses to Oral HRV Vaccine in HGM-Transplanted Gn Pigs
Published in Lijuan Yuan, Vaccine Efficacy Evaluation, 2022
AttHRV+LGG9X pigs had significantly higher levels of p-NF-κB than the AttHRV+LGG14X pigs, but neither pig group significantly differed from the AttHRV pigs. The result indicates that nine doses of LGG further activated the NF-κB, but 14 doses prevented the further NF-κB activation. NF-κB is located in the cytoplasm as an inactive complex bound to IκBα, which is phosphorylated and subsequently degraded, and the degradation of IκBα results in the dissociation of activated NF-κB from IκBα (Baldwin, 1996). Pre-treatment of HT29 and T84 polarized cell monolayers using purified DNA from LGG delayed NF-κB activation, stabilized levels of IκBα, and attenuated IL-8 secretion in response to stimulation by Salmonella DNA or TNF-a (Ghadimi et al., 2010). In the present study, both LGG dosing regimens significantly increased the IκBα level, which indicates that LGG may have inhibited inflammation by increasing the IκBα level to balance the activation of NF-κB (Chon et al., 2010). Therefore, the reduced transcription of TNF-α, IL-6, and IL-10 in the AttHRV+LGG14X pigs may not be due to the lack of impact of LGG on the signaling pathways, rather it reflected the active effect of the higher dose LGG in attenuation of NF-κB activation.
Role of NF-κB in Macrophage Activation
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
The activation of NF-κB is a critical step in LPS-induced macrophage activation, which depends on the activation of various genes for cytokines, cell surface molecules, and cellular enzymes. Extensive research by numerous laboratories in recent years rapidly advanced our knowledge on the structure and function of proteins of the NF-κB and IκB families. A large body of evidence clearly indicates that phosphorylation and degradation of IκBα in response to LPS are the essential events for NF-κB activation. Several important questions regarding the mechanism of LPS-triggered NF-κB activation still remain to be examined, however. Which of protein kinases so far implicated are indeed involved in LPS-triggered phosphorylation of IκBα? How are such protein kinase activities regulated by LPS? Is the proteasome system solely responsible for IκBα degradation? How is the activity of such a proteasome system regulated by LPS?
Imaging Cellular Networks and Protein-Protein Interactions In Vivo
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Snehal Naik, Britney L. Moss, David Piwnica-Worms, Andrea Pichler-Wallace
Using an IκBα-FLuc fusion reporter, IKK activity and pharmacological modulation can be monitored in real time (51). Reporter degradation was recorded in cultured cells after treatment with TNF-α, reaching a minimum value of ∼30% of initial, 20 minutes after addition of TNF-α. A slow signal rebound, up to 60% of initial at 120 minutes after addition of TNF-α was observed, which can be attributed to resynthesis of IκBα-FLuc and is in a good agreement with the previously reported ligand-induced stabilization of newly-synthesized endogenous IκBα (52). In addition, the effect of IKK or proteasome inhibitors could be tested and were shown to inhibit the TNF-α-induced degradation of IκBα-FLuc in a time- and concentration-responsive manner.
Salvianolic acid A suppresses CCl4-induced liver fibrosis through regulating the Nrf2/HO-1, NF-κB/IκBα, p38 MAPK, and JAK1/STAT3 signaling pathways
Published in Drug and Chemical Toxicology, 2023
Shengnan Li, Rong Wang, Fuxing Song, Panpan Chen, Yanqiu Gu, Chun Chen, Yongfang Yuan
As shown in Figure 4(A,B), the CCl4-administrated group presented with higher and lower levels of NF-κB protein in the nucleus and cytoplasm, than those in control group (p < 0.05), Therefore, CCl4-induced liver fibrosis may activate NF-κB and promote the disaggregation of NF-κB and IκBα dimers. These effects lead to NF-κB translocation into the nucleus and degradation of IκBα by phosphorylation, ultimately resulting in inflammation. Furthermore, SA-A administration in the CCl4-induced liver fibrosis model, decreased and increased the expression level of NF-κB in the nucleus and cytoplasm, respectively (p < 0.05), indicating that SA-A could inhibit the disaggregation of the dimers of NF-κB in liver cytoplasm and attenuate NF-κB translocation into nucleus. As shown in Figure 4(C), the CCl4 group demonstrated higher levels of p-NF-κBp65 protein than those in control group (p < 0.05) whereas SA-A suppressed the phosphorylation of NF-κBp65 dose-dependently (p < 0.05). Therefore, SA-A may affect the pathogenesis of liver fibrosis by regulating inflammation through the NF-κB/IκBα pathway, thus alleviating the symptoms of CCl4-induced liver fibrosis.
Kirenol alleviates diabetic nephropathy via regulating TGF-β/Smads and the NF-κB signal pathway
Published in Pharmaceutical Biology, 2022
Jialin Li, Jiawen Zhang, Meng Yang, Xiaocui Huang, Meng Zhang, Xiansong Fang, Suzhen Wu
DN is also driven by inflammation which was widely accepted as one of the most crucial pathogenic factors for DN. The secretion of cytokines such as TNFα and IL6 will aggravate DN-related inflammation (Li M et al. 2020). The activation of NF-κB will lead to the expression of TNFα and IL6. In the diabetic kidney, HG-induced phosphorylation and the subsequent translocation of NF-κB from the cytoplasm to the nucleus will trigger inflammation, and subsequently, produce excessive TNFα and IL6 (Aladaileh et al. 2021). IκBα is a negative regulator of the NF-κB signal pathway. IκBα binds to NF-κB in the cytoplasm and then inhibits the nucleus translocation of NF-κB under normal circumstances, and finally inhibits the expression of inflammatory factors, such as IL-6 and TNF-α (Sureshbabu et al. 2016). Multiple drugs targeting inflammatory pathways have also been used for antidiabetic cardiometabolic diseases and other diabetic complications. A study analyzed the fasting blood glucose and serum levels of TNF-α and IL-6 among T2DM patients and found a positive correlation between the fasting blood glucose level and inflammation during diabetes (Buldak et al. 2012). Alolga et al. (2020) also clarified the relationship between inflammation and diabetes. Interfering the production of cytokines such as IL-6 and TNF-α by inhibiting the activation of the inflammation pathway may stop the progression of diabetes (Tsalamandris et al. 2019).
Nuclear factor-kappa B and effector molecules in photoaging
Published in Cutaneous and Ocular Toxicology, 2022
Qiang Zhang, Shiyun Qiao, Chunsheng Yang, Guan Jiang
NF-κB has three activation pathways, namely, the canonical and two other noncanonical activation pathways13. The canonical NF-κB signalling pathway is induced by proinflammatory cytokine receptors and pattern recognition receptors and ultimately causes the transcription of proinflammatory and prosurvival genes17,24. Various stimuli activate the IKK complex19, which then phosphorylates the inhibitor protein IκBα13,19. This phosphorylation leads to the polyubiquitination of lysines and then the proteasomal degradation of 26S that targets the IκBα protein13,19. The degradation of IκBα exposes the nuclear location sequence of the NF-κB protein, and then the protein dimer translocates to the nucleus where it binds to the DNA and activates a specific set of target genes (Figure 1)13,25. One of the noncanonical signalling pathways is the activation of NF-κB by receptor tyrosine kinases at low oxygen concentrations26, and the other pathway is related to the NF-κB2/p100 dimerisation with RelB in the cytoplasm13. However, few studies have been conducted on these two activation pathways in photoaging13, and these pathways will not be discussed in this commentary.