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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
Mechanistically, the activation of NF‑κB depends on the degradation of the specific inhibitor of NF‑κB, i.e., IκB, followed by the phosphorylation by IκB kinase (IKK) complex (Karin, 1999). HDAC1 and HDAC2 interacts with NF-κB family proteins by binding with the co-repressor protein p65 (RELA) and p50 (NFκB1) and downregulate NF-κB-mediated gene transcription. HDAC3-mediated deacetylation of p65 results in shuttling of the NF-κB complex from the nucleus to the cytoplasm, thus controlling the pro-inflammatory response. NF-κB activation is also dependent on HDAC3 in the regulation of target genes IκB-α, IL-2, IL-6 promoter hyperacetylation (Leus et al., 2016).
Garcinia indica (Kokum) and Ilex aquifolium (European Holly)
Published in Azamal Husen, Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
Dicson Sheeja Malar, Mani Iyer Prasanth, Tewin Tencomnao, James Michael Brimson, Anchalee Prasansuklab
Garcinol treatment significantly inhibited the growth and proliferation and colony formation of oral squamous cell carcinoma cells with a concomitant induction of apoptosis and cell cycle arrest. It exerts anti-proliferative, pro-apoptotic, cell-cycle regulatory, and anti-angiogenic effects by reducing the expression of STAT-3, c-Src, JAK1, and JAK2, NK-κB, and COX-2 besides inhibiting VEGF expression (Aggarwal and Das, 2016). Inhibition of NK-κB by garcinol was mediated through the suppression of TGF-β activated kinase 1 (TAK1) and inhibitor of IkB kinase (IKK) activation (Li et al., 2013a). Further, garcinol also targets cancer cell energy producing pathway mitochondrial respiration by inhibiting ATP production, maximal respiration, spare respiration capacity, and basal respiration. Garcinol treatment reflexively boosted glycolysis apart from the upregulation of glucose transporter 1 and 4, and HIF-1α, AKT, and PTEN (Zhang et al., 2019a).
Innate and Adaptive Immune Dysfunction and Necrotizing Enterocolitis
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Paula Osterhout, Christina S. Kim, Erika C. Claud
NF-κB represents a group of structurally related proteins that activate transcription of a wide variety of genes involved in inflammatory and immune responses. In its resting state, NF-κB dimers are bound in the cytoplasm to proteins that inhibit κB (IκB) (22–24). Cell stimulation can trigger signal transduction pathways leading to the activation of IκB kinase (IKK), which then phosphorylates IκB, targeting it for degradation by the proteasome. The NF-κB, thus liberated, moves to the nucleus, where it activates the transcription of genes including cytokines like IL-6 and TNFα, chemokines like IL-8, adhesion molecules, and regulators of apoptosis. When appropriately activated, NF-κB can serve to protect the host against stressors or infection.
Hepatoprotective effect of protocatechuic acid against type 2 diabetes-induced liver injury
Published in Pharmaceutical Biology, 2023
Kaixia Xu, Guang Lu, Qianjin Feng, Shuangchao Chen, Yonghui Wang
Once the NF-κB signaling pathway is activated, the IκB kinase IKK will be activated for phosphorylating and ubiquitinating the NF-κB inhibitory protein IκBα, thereby decreasing the cytoplasmic IκBα content. Hence, the NF-κB p65 subunit enters the nucleus from suppressed to activated condition, and promotes the expression of multiple inflammatory factors, resulting in liver disorder (Zheng et al. 2020). In IR/type 2 diabetic (IR/D) rats, the activation of NF-κB is proved to promote the transcription of inflammatory cytokines including IL-1β, which is involved in the development of IR/D by suppressing the translocation of GLUT4 (Abo El-Nasr et al. 2020; Elias-Oliveira et al. 2020; Esmaeilzadeh et al. 2020). Also, the current review states NF-κB as a promising therapeutic target for the probable management of type 2 diabetes (Meyerovich et al. 2018; Bhardwaj et al. 2020). In mammals, the Wnt/β-catenin signaling pathway is mainly composed of Wnt signaling transduction in the membrane, regulation of β-catenin stabilization in the cytoplasm and activation of Wnt target genes in the nucleus (Huang et al. 2019). The Wnt1/β-catenin pathway plays a critical role in liver diseases and can regulate the oxidative stress in hepatic fibrosis (Hasan et al. 2017). Furthermore, NF-κB upregulation and Wnt1/β-catenin pathway inhibition in IR/D rats are blocked by gallic acid (Bashar et al. 2021).
Picroside II alleviates DSS-induced ulcerative colitis by suppressing the production of NLRP3 inflammasomes through NF-κB signaling pathway
Published in Immunopharmacology and Immunotoxicology, 2022
Huixiang Yao, Jun Yan, Li Yin, Wei Chen
Nuclear factor-κB (NF-κB) is identified as a dominating transcription factor of inflammation [18]. NF-κB mainly comprises the p60/p65 heterodimer, which is generally bound with its inhibitory kappa B (IκB) as an inactive complex sequestered in the cytoplasm. However, IκB can be subsequently phosphorylated, ubiquitinated and degraded due to the activation of IκB kinase (IKK) after being stimulated by different factors, such as IL-1β, tumor necrosis factor-α (TNF-α) and LPS. Then, the liberated NF-κB is translocated into the nucleus to modulate the secretion and production of a variety of pro-inflammatory factors [19]. The previous study has been shown that NF-κB can modulate the expression of NLRP3 and is also identified as the first signal to reflect the activation of the NLRP3 inflammasome [20]. Therefore, these findings led us to conclude that the role of NLRP3 inflammasome is closely associated with NF-κB.
Recent trends in the development of Toll-like receptor 7/8-targeting therapeutics
Published in Expert Opinion on Drug Discovery, 2021
Xuan Huang, Xiaoyong Zhang, Mengji Lu
Members of the TLR family have common intracellular signaling pathways. The signaling pathways are not identical, however, due to different linker proteins that determine their various biological effects. ssRNA has been identified as a common natural ligand of TLR7 and TLR8 [46,47]. Therefore, TLR7 and TLR8 activation patterns are similar. The transduction pathway induces the expression of common genes, but each TLR has its own characteristics with respect to specific adapter proteins. Once they have been activated by their ligands, the myeloid differentiation primary response protein 88 (MyD88)-dependent pathway is activated [48]. MyD88 is the main linker protein in the signal transduction pathway [49,50]. It recruits the IL-1 receptor-associated kinase (IRAK) family of proteins along with the adapter protein TNF receptor-associated factor-6. Phosphorylation of IRAK proteins passes the signal to the transforming growth factor-β-activated kinase-1 complex, which subsequently activates the IκB kinase complex. The activated IκB kinase complex phosphorylates IκB and ‘marks’ it for degradation. Phosphorylated IκB induces the release of nuclear factor-kappa B and its translocation to the nucleus, which results in the production and release of proinflammatory cytokines and chemokines [51,52] (Figure 1).