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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).
Responses to Muscular Exercise, Heat Shock Proteins as Regulators of Inflammation, and Mitochondrial Quality Control
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Alex T. Von Schulze, Paige C. Geiger
Like HSP70, HSP25 is known to inhibit the activation of the pro-inflammatory transcriptional complex, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). HSP25-induced NF-κB inhibition is thought to occur by preventing the degradation NF-κB's upstream inhibitory regulator, the IκB kinase (IKK) complex (25, 45). It is believed that HSP25 blocks the phosphorylation of IKKβ, whose phosphorylation is critical for the degradation of the IKK complex (68). This inhibition of the IκB kinase complex formation (IKKα and IKKβ) causes a decrease in the phosphorylation of NF-κB inhibitor, IκB, which ultimately suppresses the activation of the NF-κB signalling pathway (45). As with HSP70, HSP25 can shift the cell away from inflammatory signalling. However, shifts in signalling are not the only ways that HSPs can prevent cell death and restore homeostasis.
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).
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).
Small-molecule inhibitors and the salivary gland epithelium in Sjögren’s syndrome
Published in Expert Opinion on Investigational Drugs, 2019
Sarah Pringle, Xiaoyan Wang, Hendrika Bootsma, Fred K. L. Spijkervet, Arjan Vissink, Frans G. M. Kroese
The nuclear factor kappa B (NFκB) family is a group of transcription factors, capable of activating an array of inflammatory downstream targets, when permitted to translocate to the nucleus. Their activation can be achieved through both a canonical or non-canonical pathway. The five members of the NFκB family (RelA, RelB, c-Rel, NFκB1, and NFκB2) form homo- or heterodimers with each other, together with the inhibitory molecule IκB. The canonical NFκB pathway is activated by proinflammatory cytokines such as IL-1β and TNFα, that bind to their respective receptors and also by binding of (PAMPS) to the TLRs. Engagement of both types of receptors triggers activity of the IKK (IκB kinase) complex, culminating in phosphorylation IκB proteins in the inhibitory NFκB complex. Phosphorylated IκB is then degraded, and released NKκB translocate to the nucleus and activate target gene transcription. The non-canonical pathway operates via a slightly different mechanism, and given the expression of CD40 on ductal epithelial cells, is also likely to be operational in pSS. For the purpose of this review however and considering which drugs are currently in clinical trials for pSS treatment, we will focus only on the canonical pathway.