Last update 01 Nov 2024

IKKβ x NF-κB x RELA

Last update 01 Nov 2024

Basic Info

Related Targets

IKKβNF-κBRELA

Drugs associated with IKKβ x NF-κB x RELA

SpiD3(University of Nebraska)

Target

IKKβ x NF-κB x RELA

Mechanism

IKKβ inhibitors [+2]

Active Org.

University of Nebraska

Originator Org.

University of Nebraska

Active Indication

Lymphoid Leukemia

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with IKKβ x NF-κB x RELA

100 Translational Medicine associated with IKKβ x NF-κB x RELA

0 Patents (Medical) associated with IKKβ x NF-κB x RELA

164

Literatures (Medical) associated with IKKβ x NF-κB x RELA

01 Aug 2024·Kidney International

The glycolytic enzyme PFKFB3 drives kidney fibrosis through promoting histone lactylation-mediated NF-κB family activation

Article

Author: Jiang, Simin ; Fu, Dongying ; Li, Guanglan ; Chen, Wei ; Wu, Kefei ; Zhou, Yi ; Xu, Yiping ; Li, Hongyu ; Mao, Haiping ; Liu, Qinghua ; Lu, Miaoqing ; Zhou, Yiming ; Lu, Xiaohui ; Luo, Dan ; Li, Yi ; Wang, Yating

Persistently elevated glycolysis in kidney has been demonstrated to promote chronic kidney disease (CKD). However, the underlying mechanism remains largely unclear. Here, we observed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic enzyme, was remarkably induced in kidney proximal tubular cells (PTCs) following ischemia-reperfusion injury (IRI) in mice, as well as in multiple etiologies of patients with CKD. PFKFB3 expression was positively correlated with the severity of kidney fibrosis. Moreover, patients with CKD and mice exhibited increased urinary lactate/creatine levels and kidney lactate, respectively. PTC-specific deletion of PFKFB3 significantly reduced kidney lactate levels, mitigated inflammation and fibrosis, and preserved kidney function in the IRI mouse model. Similar protective effects were observed in mice with heterozygous deficiency of PFKFB3 or those treated with a PFKFB3 inhibitor. Mechanistically, lactate derived from PFKFB3-mediated tubular glycolytic reprogramming markedly enhanced histone lactylation, particularly H4K12la, which was enriched at the promoter of NF-κB signaling genes like Ikbkb, Rela, and Relb, activating their transcription and facilitating the inflammatory response. Further, PTC-specific deletion of PFKFB3 inhibited the activation of IKKβ, I κ B α, and p65 in the IRI kidneys. Moreover, increased H4K12la levels were positively correlated with kidney inflammation and fibrosis in patients with CKD. These findings suggest that tubular PFKFB3 may play a dual role in enhancing NF-κB signaling by promoting both H4K12la-mediated gene transcription and its activation. Thus, targeting the PFKFB3-mediated NF-κB signaling pathway in kidney tubular cells could be a novel strategy for CKD therapy.

01 Jul 2024·Journal of Ethnopharmacology

Mechanism of Astragalus mongholicus Bunge ameliorating cerebral ischemia-reperfusion injury: Based on network pharmacology analysis and experimental verification

Article

Author: Li, Rui ; Luo, Shengyong ; Lou, Qi ; Li, Yincan ; Ma, Zheng ; Yang, Haoran ; Wang, Yijun ; Ji, Tingting ; Yang, Wulin ; Zhu, Yu ; Qian, Can

ETHNOPHARMACOLOGICAL RELEVANCEAstragalus mongholicus Bunge (AMB) is a herb with wide application in traditional Chinese medicine, exerting a wealth of pharmacological effects. AMB has been proven to have an evident therapeutic effect on ischemic cerebrovascular diseases, including cerebral ischemia-reperfusion injury (CIRI). However, the specific mechanism underlying AMB in CIRI remains unclear.AIM OF THE STUDYThis study aimed to investigate the potential role of AMB in CIRI through a comprehensive approach of network pharmacology and in vivo experimental research.METHODSThe intersection genes of drugs and diseases were obtained through analysis of the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and Gene Expression Omnibus (GEO) database. The protein-protein interaction (PPI) network was created through the string website. Meanwhile, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was carried out using R studio, and thereafter the key genes were screened. Then, the molecular docking prediction was made between the main active ingredients and target genes, and hub genes with high binding energy were obtained. In addition, molecular dynamic (MD) simulation was used to validate the result of molecular docking. Based on the results of network pharmacology, we used animal experiments to verify the predicted hub genes. First, the rat middle cerebral artery occlusion and reperfusion (MACO/R) model was established and the effective dose of AMB in CIRI was determined by behavioral detection and 2,3,5-Triphenyltetrazolium chloride (TTC) staining. Then the target proteins corresponding to the hub genes were measured by Western blot. Moreover, the level of neuronal death was measured using hematoxylin and eosin (HE) and Nissl staining.RESULTSBased on the analysis of the TCMSP database and GEO database, a total of 62 intersection target genes of diseases and drugs were obtained. The KEGG enrichment analysis showed that the therapeutic effect of AMB on CIRI might be realized through the advanced glycation endproduct-the receptor of advanced glycation endproduct (AGE-RAGE) signaling pathway in diabetic complications, nuclear factor kappa-B (NF-κB) signaling pathway and other pathways. Molecular docking results showed that the active ingredients of AMB had good binding potential with hub genes that included Prkcb, Ikbkb, Gsk3b, Fos and Rela. Animal experiments showed that AWE (60 g/kg) could alleviate CIRI by regulating the phosphorylation of PKCβ, IKKβ, GSK3β, c-Fos and NF-κB p65 proteins.CONCLUSIONAMB exerts multi-target and multi-pathway effects against CIRI, and the underlying mechanism may be related to anti-apoptosis, anti-inflammation, anti-oxidative stress and inhibiting calcium overload.

01 May 2024·Anti-Cancer Agents in Medicinal Chemistry

Indirubin, an Active Component of Indigo Naturalis, Exhibits Inhibitory Effects on Leukemia Cells via Targeting HSP90AA1 and PI3K/Akt Pathway

Article

Author: Yao, Yuanzhi ; Wei, Lin ; Mou, Hai ; Li, Xiaoying ; Yang, Xiaoqin

Background::This research intended to predict the active ingredients and key target genes of Indigo Naturalis in treating human chronic myeloid leukemia (CML) using network pharmacology and conduct the invitro verification.Methods::The active components of Indigo Naturalis and the corresponding targets and leukemia-associated genes were gathered through public databases. The core targets and pathways of Indigo Naturalis were predicted through protein-protein interaction (PPI) network, gene ontology (GO) function, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Next, after intersecting with leukemia-related genes, the direct core target gene of Indigo Naturalis active components was identified. Subsequently, HL-60 cells were stimulated with indirubin (IND) and then examined for cell proliferation using CCK-8 assay and cell cycle, cell apoptosis, and mitochondrial membrane potential using flow cytometry. The content of apoptosis-associated proteins (Cleaved Caspase 9, Cleaved Caspase 7, Cleaved Caspase 3, and Cleaved parp) were detected using Western blot, HSP90AA1 protein, and PI3K/Akt signaling (PI3K, p-PI3K, Akt, and p-Akt) within HL-60 cells.Results::A total of 9 active components of Indigo Naturalis were screened. The top 10 core target genes (TNF, PTGS2, RELA, MAPK14, IFNG, PPARG, NOS2, IKBKB, HSP90AA1, and NOS3) of Indigo Naturalis active components within the PPI network were identified. According to the KEGG enrichment analysis, these targets were associated with leukemia-related pathways (such as acute myeloid leukemia and CML). After intersecting with leukemia-related genes, it was found that IND participated in the most pairs of target information and was at the core of the target network; HSP90AA1 was the direct core gene of IND. Furthermore, the in-vitro cell experiments verified that IND could inhibit the proliferation, elicit G2/M-phase cell cycle arrest, enhance the apoptosis of HL-60 cells, reduce mitochondrial membrane potential, and promote apoptosis-related protein levels. Under IND treatment, HSP90AA1 overexpression notably promoted cell proliferation and inhibited apoptosis. Additionally, IND exerted tumor suppressor effects on leukemia cells by inhibiting HSP90AA1 expression.Conclusion::IND, an active component of Indigo Naturalis, could inhibit CML progression, which may be achieved via inhibiting HSP90AA1 and PI3K/Akt signaling expression levels.

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