Reversal Effect of Thalidomide on Established Hepatic Cirrhosis in Rats via Inhibition of Nuclear Factor-κB/Inhibitor of Nuclear Factor-κB Pathway

Lv, Ping; Luo, Haitao; Zhou, Xiao‐Ping; Xiao, Yan-Jv; Paul, Shelley Chireyath; Si, Xiaoyan; Zhou, Yanhong

doi:10.1016/j.arcmed.2006.09.006

Cited by 29 publications

(24 citation statements)

References 33 publications

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“…8 It has been reported that thalidomide blocks NF-kB activation through suppression of IKK activity, 18 and subsequently by the inhibition of IkB degradation. 27 The present study also confirmed that thalidomide inhibited NF-kB activation in LPS-stimulated RAW 264.7 cells and that the inactivation of NF-kB was due to the inhibition of phosphorylation of IKK-a, IKK-b and IkB-a by thalidomide. Moreover, we provide new evidence that thalidomide inhibits LPS-induced phosphorylation of AKT, which is an upstream molecule of IKK and causes the activation of IKK.…”

Section: Discussionsupporting

confidence: 86%

Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor-α production via down-regulation of MyD88 expression

et al. 2009

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The effect of thalidomide on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-a production was studied by using RAW 264.7 murine macrophage-like cells. Thalidomide significantly inhibited LPS-induced TNF-a production. Thalidomide prevented the activation of nuclear factor (NF)-kB by down-regulating phosphorylation of inhibitory kB factor (IkB), and IkB kinase (IKK)-a and IKK-b Moreover, thalidomide inhibited LPS-induced phosphorylation of AKT, p38 and stress-activated protein kinase (SAPK)/JNK. The expression of myeloid differentiation factor 88 (MyD88) protein and mRNA was markedly reduced in thalidomide-treated RAW 264.7 cells but there was no significant alteration in the expression of interleukin-1 receptor-associated kinase (IRAK) 1 and TNF receptor-associated factor (TRAF) 6 in the cells. Thalidomide did not affect the cell surface expression of Toll-like receptor (TLR) 4 and CD14, suggesting the impairment of intracellular LPS signalling in thalidomide-treated RAW 264.7 cells. Thalidomide significantly inhibited the TNF-a production in response to palmitoyl-Cys(RS)-2,3-di(palmitoyloxy) propyl)-Ala-Gly-OH (Pam 3 Cys) as a MyD88-dependent TLR2 ligand. Therefore, it is suggested that thalidomide might impair LPS signalling via down-regulation of MyD88 protein and mRNA and inhibit LPS-induced TNF-a production. The putative mechanism of thalidomide-induced MyD88 down-regulation is discussed.

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Section: Discussionsupporting

confidence: 86%

Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor-α production via down-regulation of MyD88 expression

et al. 2009

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“…12 NF-B is activated in HSCs in response to carbon tetrachloride injury and stimulates expression of proinflammatory molecules (IL-6, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1) and antiapoptotic factors (growth arrest and DNA damage-inducible gene 45␤) required for HSC function and survival during the fibrogenic response. 13 The induction of hepatocyte NF-B during liver injury has been reported by many laboratories in response to alcohol, endotoxin, TNF-␣, and cholestasis (bile duct ligation). 11,14,15 Activation of hepatocyte NF-B is generally perceived as a protective response that limits apoptotic loss of the parenchyma and promotes regeneration of hepatocyte mass by stimulating hepatocyte proliferation.…”

Section: The Inflammation-fibrosis-cancer Axismentioning

confidence: 97%

“…46 In vivo studies have demonstrated the ability of NF-B inhibitors such as gliotoxin, sulfasalazine, and thalidomide to promote HM apoptosis and stimulate resolution of fibrosis and regeneration of normal liver tissue. 13,46,47 Angiotensin blockade, an antifibrotic strategy currently in clinical trials, may also act by inhibiting NF-B activity. 48 It would now be of interest to determine the effects of selective and/or inducible knockout of IKK/NF-B in HMs in the context of models of inflammation-driven HCC to establish if targeting the NF-B activity of HMs will be of therapeutic benefit.…”

Section: Nf-b As a Tumor Suppressor In Hepatocytesmentioning

confidence: 99%

Nuclear factor‐κB and the hepatic inflammation‐fibrosis‐cancer axis†

2007

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Nuclear factor-B (NF-B) is a transcriptional regulator of genes involved in immunity, inflammatory response, cell fate, and function. Recent attention has focused on the pathophysiological role of NF-B in the diseased liver. In vivo studies using rodent models of liver disease and cell-targeted perturbation of NF-B activity have revealed complex and multicellular functions in hepatic inflammation, fibrosis, and the development of hepatocellular carcinoma-a process we have termed the "inflammation-fibrosis-cancer axis". This review summarizes the current state of knowledge and provides insight into the vast complexity of the hepatic NF-B signaling system, which should provide a rich source of new therapeutic targets. (HEPATOLOGY 2007;46:590-597.)

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“…They concluded that thalidomide treatment is strongly correlated with decreased micro vessel density; however, they did not determine whether the reduction in microvascular density is one of the main results of thalidomide antiangiogenic activity or if it was a secondary process to reduce tumor burden. In a rat model of hepatic cirrhosis, Lv et al (41) reported that thalidomide was able to downregulate NF-κB-induced expression of adhesion molecules (such as intercellular adhesion molecule-1) and activation of hepatic stellate cells via inhibiting the degradation of IκB to reverse the disease. In the setting of hereditary hemorrhagic telangiectasia, thalidomide treatment stimulated mural cell coverage and restored vessel wall defects via increasing the platelet-derived growth factor-B expression in endothelial cells and stimulating mural cell activation (42).…”

Section: Biological Effect Implementationmentioning

confidence: 99%

Thalidomide and its analogues: A review of the potential for immunomodulation of fibrosis diseases and opthalmopathy (Review)

et al. 2017

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Abstract. The US Food and Drug Administration approved thalidomide and its analogues for the treatment of erythema nodosum leprosum, in spite of the notoriety of reports of severe birth defects in the middle of the last century. As immunomodulatory drugs, thalidomide and its analogues have been used to effectively treat various diseases. In the present review, preclinical data about the effects of thalidomide and its analogues on the immune system are integrated, including the effects of cytokines on transdifferentiation, the anti-inflammatory effect, immune cell function regulation and angiogenesis. The present review also investigates the latest developments of thalidomide as a therapeutic option for the treatment of idiopathic pulmonary fibrosis, skin fibrosis, and ophthalmopathies.

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Reversal Effect of Thalidomide on Established Hepatic Cirrhosis in Rats via Inhibition of Nuclear Factor-κB/Inhibitor of Nuclear Factor-κB Pathway

Cited by 29 publications

References 33 publications

Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor-α production via down-regulation of MyD88 expression

Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor-α production via down-regulation of MyD88 expression

Nuclear factor‐κB and the hepatic inflammation‐fibrosis‐cancer axis†

Thalidomide and its analogues: A review of the potential for immunomodulation of fibrosis diseases and opthalmopathy (Review)

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