Flavopiridol inhibits lipopolysaccharide-induced TNF-α production through inactivation of nuclear factor-κB and mitogen-activated protein kinases in the MyD88-dependent pathway

Haque, Abedul; Koide, Naoki; Iftakhar-E-Khuda, Imtiaz; Noman, Abu Shadat Mohammod; Odkhuu, Erdenezaya; Badamtseren, Battuvshin; Naiki, Yoshikazu; Komatsu, Takayuki; Yoshida, Tomoaki; Yokochi, Takashi

doi:10.1111/j.1348-0421.2010.00304.x

Cited by 19 publications

(16 citation statements)

References 28 publications

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“…Thus, the “modulation of transcription elongation by CDK9” has been highlighted as a “unique negative regulatory checkpoint within the human innate immune system” [79]. Regarding a putative role for CDK9 in the activation of macrophages, Haque et al [80] recently demonstrated that flavopiridol reduces the production of TNFα and NO as well as the activation of NF-κB, IKK, p38 MAPK, JNK, and ERK in LPS-activated RAW cells (mouse leukemic/monocyte macrophage cell line). This suggests an anti-inflammatory potential of flavopiridol in the context of LPS-associated immune responses.…”

Section: The Involvement Of Cdk9 In Inflammatory Processesmentioning

confidence: 99%

Perspective of Cyclin-dependent kinase 9 (CDK9) as a Drug Target

Kryštof¹,

Baumli²,

Fürst³

2012

CPD

106

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Deregulation of cyclin-dependent kinases (CDKs) has been associated with many cancer types and has evoked an interest in chemical inhibitors with possible therapeutic benefit. While most known inhibitors display broad selectivity towards multiple CDKs, recent work highlights CDK9 as the critical target responsible for the anticancer activity of clinically evaluated drugs. In this review, we discuss recent findings provided by structural biologists that may allow further development of highly specific inhibitors of CDK9 towards applications in cancer therapy. We also highlight the role of CDK9 in inflammatory processes and diseases.

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Section: The Involvement Of Cdk9 In Inflammatory Processesmentioning

confidence: 99%

Perspective of Cyclin-dependent kinase 9 (CDK9) as a Drug Target

Kryštof¹,

Baumli²,

Fürst³

2012

CPD

106

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“…The MyD88-dependent pathway plays a critical role in the regulation of macrophage activation, thereby promoting the activation of MAPKs and NF- κ B. It is known that LPS-induced activation of MAPKs and NF- κ B leads to the expression of several proinflammatory mediators in macrophages [23, 24]. We demonstrated that V. axillare extracts significantly suppressed LPS-induced phosphorylation of p65 and I κ B- α in RAW264.7 macrophages, which was consistent with our in vivo data.…”

Section: Discussionmentioning

confidence: 99%

Veronicastrum axillare Alleviates Lipopolysaccharide-Induced Acute Lung Injury via Suppression of Proinflammatory Mediators and Downregulation of the NF-κB Signaling Pathway

Wang

Yang

et al. 2016

Mediators of Inflammation

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Veronicastrum axillare is a traditional medical plant in China which is widely used in folk medicine due to its versatile biological activities, especially for its anti-inflammatory effects. However, the detailed mechanism underlying this action is not clear. Here, we studied the protective effects of V. axillare against acute lung injury (ALI), and we further explored the pharmacological mechanisms of this action. We found that pretreatment with V. axillare suppressed the release of proinflammatory cytokines in the serum of ALI mice. Histological analysis of lung tissue demonstrated that V. axillare inhibited LPS-induced lung injury, improved lung morphology, and reduced the activation of nuclear factor-κB (NF-κB) in the lungs. Furthermore, the anti-inflammatory actions of V. axillare were investigated in vitro. We observed that V. axillare suppressed the mRNA expression of interleukin-1β (IL-1β), IL-6, monocyte chemotactic protein-1 (MCP-1), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α) in RAW264.7 cells challenged with LPS. Furthermore, pretreatment of V. axillare in vitro reduced the phosphorylation of p65 and IκB-α which is activated by LPS. In conclusion, our data firstly demonstrated that the anti-inflammatory effects of V. axillare against ALI were achieved through downregulation of the NF-κB signaling pathway, thereby reducing the production of inflammatory mediators.

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“…However, it did not affect TLR4 gene expression when murine bone marrow-derived DCs were in resting conditions [ 58 ], which is in agreement with other studies where the flavonoid is not able to modify TLRs in the absence of stimulatory conditions. On the contrary, a semi-synthetic flavonoid called flavopiridol did not alter the TLR4 cell surface expression in LPS-stimulated RAW 264.7 macrophages [ 69 ].…”

Section: Mechanisms Of Modifying “Cross-talk” By Flavonoidsmentioning

confidence: 99%

“…Baicalin may inhibit P. gingivalis LPS-induced activation of NF-κB, p38 MAPK and JNK [ 60 ], and same inflammatory pathway when the study was performed in isquemic neurons [ 86 ]. The flavonol flavopiridol—quercetin analogue—was also able to regulate the downstream TLR2 and TLR3 pathways through the MyD88-dependent pathway but not the independent pathway, as was demonstrated by in vitro studies showing inhibition of the activation of NF-κB and MAPKs but not TRAF6 [ 69 ]. Flavanones such as naringenin inhibited TLR2 pathways by the modulation of IκB degradation and JNK phosphorylation [ 57 ], and also down-regulated the induced increase of phosporylation of p38 MAPK in macrophages infected with Chlamyidia trachomatis [ 56 ].…”

Section: Mechanisms Of Modifying “Cross-talk” By Flavonoidsmentioning

confidence: 99%

Flavonoids Affect Host-Microbiota Crosstalk through TLR Modulation

et al. 2014

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Interaction between host cells and microbes is known as crosstalk. Among other mechanisms, this takes place when certain molecules of the micro-organisms are recognized by the toll-like receptors (TLRs) in the body cells, mainly in the intestinal epithelial cells and in the immune cells. TLRs belong to the pattern-recognition receptors and represent the first line of defense against pathogens, playing a pivotal role in both innate and adaptive immunity. Dysregulation in the activity of such receptors can lead to the development of chronic and severe inflammation as well as immunological disorders. Among components present in the diet, flavonoids have been suggested as antioxidant dietary factors able to modulate TLR-mediated signaling pathways. This review focuses on the molecular targets involved in the modulatory action of flavonoids on TLR-mediated signaling pathways, providing an overview of the mechanisms involved in such action. Particular flavonoids have been able to modify the composition of the microbiota, to modulate TLR gene and protein expression, and to regulate the downstream signaling molecules involved in the TLR pathway. These synergistic mechanisms suggest the role of some flavonoids in the preventive effect on certain chronic diseases.

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Flavopiridol inhibits lipopolysaccharide-induced TNF-α production through inactivation of nuclear factor-κB and mitogen-activated protein kinases in the MyD88-dependent pathway

Cited by 19 publications

References 28 publications

Perspective of Cyclin-dependent kinase 9 (CDK9) as a Drug Target

Perspective of Cyclin-dependent kinase 9 (CDK9) as a Drug Target

Veronicastrum axillare Alleviates Lipopolysaccharide-Induced Acute Lung Injury via Suppression of Proinflammatory Mediators and Downregulation of the NF-κB Signaling Pathway

Flavonoids Affect Host-Microbiota Crosstalk through TLR Modulation

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