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Greener Organic Transformations by Plant-Derived Water Extract Ashes
Published in Ahindra Nag, Greener Synthesis of Organic Compounds, Drugs and Natural Products, 2022
Among these energetic conversions, the SMCR has been exploited as the most straightforward methodology which has increased interest both in academia and industry.80,81 Biaryls are the essential building blocks in several natural products,82 drug molecules,81e,83 (Figure 10.4) chiral ligands, and catalysts84 as well as in engineering materials such as polymers, liquid crystals, and molecular wires.85 The biaryl core fragments drug molecules are the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib,86 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pitavastatin,87 the Janus kinase (JAK) inhibitor baricitinib,88 and the third epidermal growth factor receptor (EGFR) inhibitor osimertinib.89
Insights from ‘Omics on the Exposure and Effects of Engineered Nanomaterials on Aquatic Organisms
Published in Julián Blasco, Ilaria Corsi, Ecotoxicology of Nanoparticles in Aquatic Systems, 2019
Kim et al. (2017) used a combined transcriptomic and metabolomics investigation of UV activated TiO2 NPs to determine the mechanisms responsible for reproductive impairment in C. elegans. They revealed that several genes in the Janus kinase/Signal transducers and activators of transcription (JAK/STAT) pathway were specifically affected by the TiO2 NP + UV treatment. In addition, decreased glutathione levels seen through metabolomics analysis suggested a role for oxidative stress in initiating this signaling pathway. These holistic investigations motivated the investigators to study components of the JAK/STAT and transforming growth factor β (TGFβ) pathway, which is involved in regulation of growth and reproduction, through functional genetic assays. Loss of JAK/STAT function rescued the mutants from TiO2 NP + UV toxicity, thus confirming an essential role of this pathway in the toxic response of these NPs. These authors used a “middle-out approach” for AOP generation (Villeneuve et al. 2014b) by identifying a KE (i.e., JAK/STAT pathway initiation) in their transcriptomic study and using additional functional genetics and pharmacological approaches to anchor the KE to reproductive effects (Fig. 3B, Kim et al. 2017). This AOP is currently under construction at http://aopwiki.org (AOP:208, accessed January 20, 2018).
Current and Rising Concepts in Immunotherapy: Biopharmaceuti cals versus Nanomedicines
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
The presence of inflammatory cytokines in serum secreted by immune cells is known to affect reactions in the whole body. Interleukin 1 β (IL1β) and TNF are two essential cytokines that affect many inflammatory diseases. Blocking of TNF represents a promising therapeutic option for inflammatory disorders such as hepatitis, rheumatoid arthritis, inflammatory bowel disease, or graft versus host disease [44]. Anti-inflammatory cytokines directly suppress inflammatory mediators; for example, IL10 suppresses IL6 and TNFα production [45]. Cytokines of M1-MΦ, specifically TNF, are targeted by pharmaceuticals such as etanercept, which has been approved since 1998. Many other pharmaceuticals inhibit TNF to overcome the negative side effects of the cytokine on healthy tissue which occurs in dysregulated inflammatory disease such as arthritis [46]. It is a matter of fact that the TNF blockers indirectly target MΦ (and neutrophil)-derived cytokines [4]. Recently, novel small molecule-based drugs which block the route of action of cytokines have been marketed. In particular, tyrosine kinase inhibitors have entered the sector of anti-inflammatories. The novel class of Janus kinase (JAK) inhibitors intend to block cytokine signaling, including that of TNF. For instance, Tofacitinib, a pan-JAK inhibitor, received approval for several inflammatory diseases such as inflammatory bowel diseases [47], psoriasis [48], and arthritis [49].
A new mixed-ligand Co(II) coordination polymer: treatment activity on ulcerative colitis by inhibiting the JAK2/STAT3 signaling pathway in the colonic epithelial cells
Published in Inorganic and Nano-Metal Chemistry, 2021
Yan Tan, Hong-Yu Yun, Jing Tang, Du-Xiong Cai, Xiao-Ning Sun
JAKs (Janus kinases) contain tandem C-terminal pseudokinase (JH2) and tyrosine kinase (JH1) domains. Here we choose JAK2 (5UT1) as the probe protein for the investigation of the biological activity of the complex. The molecular docking results suggest that the interactions between the complex and the protein are originated from both the carboxylate oxygen and nitrogen atom of six-membered ring. As depicted in Figure 5, where the docking configurations with relative lower binding energies are displayed. In Figure 5a, we can see that two binding interactions are formed, one is between the nitrogen atom and residue ASP-569 (2.5 angstrom), the other is between the oxygen atom and residue HIS-538 (2.0 angstrom), the binding energy is –8.58 kcal/mol. In Figure 5b, the binding interactions are formed between oxygen atoms to residues LYS-607 (2.1 Å) and SER-602 (2.5 Å), the nitrogen atoms are not involved in this binding configuration, the binding energy is –7.89 kcal/mol. Similar to the second configuration, in Figure 5c, it is also seen that only the oxygen atoms are participating into the binding interactions, the binding distances are 1.7 Å to residue PHE-537 and 2.0 Å to residue SER-605, the binding energy is about −7.88 kcal/mol. In Figure 5d, the oxygen atom from the carboxy group has formed two interactions to residues LYS-539 (2.8 Å) and PHE-537 (1.8 Å), the binding energy is –7.61 kcal/mol. Together with the experiment results, the molecular docking results shed light on the understanding of the interacting forms between the complex and the protein.