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Pharmacokinetic-Pharmacodynamic Correlations of Corticosteroids
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Helmut Möllmann, Stefan Baibach, Günther Hochhaus, Jürgen Barth, Hartmut Derendorf
The activated complex is then able to translocate into the nucleus. Because of its large size, translocation is probably not by simple diffusion.141 In the nucleus, binding on specific sequences (glucocorticoid response elements, GRE) in chromatin takes place.142 The hormone-receptor-GRE complex regulates the transcription rate of specific genes, resulting in a modulated, or increased m-RNA production. The final step is modulation, stimulation, or inhibition of protein and therefore enzyme synthesis. The induction time of m-RNA varies greatly. Rapidly induced m-RNA could be detected in isolated rat thymus cells 15 to 30 min after DEX administration, whereas slower induction occurred after 1 to 2 h.143
Formation of Peptide Bonds — Proteases as “Activating Systems”
Published in Willi Kullmann, Enzymatic Peptide Synthesis, 1987
The activated acyl-protease complexes of both the ester and the anhydride type are at a high energy level and can therefore readily undergo deacylation by a nucleophilic attack. Frequently the nucleophile is a water molecule and the activated complex is hydrolyzed, i.e., the acyl group is transferred to the water molecule, and the commonly known proteolysis takes place (Figures 4a and b). Less commonly, where the nucleophile is the α-amino group of an amino acid residue, the activated complex is aminolyzed, i.e., the acyl group is transferred to the amino acid, and synthesis of a peptide bond takes place (Figures 4a and b). In fact, the partition of the acyl-protease complexes between hydrolytic and aminolytic cleavage does not only depend on the concentrations of the deacylating agents and consequently peptide bond synthesis is not as unfavored as it may first appear. If the opposite were true then the rate of proteolysis would of course significantly outstrip proteosynthesis in an aqueous solution. However, the ratio of hydrolysis to aminolysis is also strongly influenced by the nucleophilic strength of the competitors; and in this respect the amino acids — especially C-terminally protected ones — have an unequivocal advantage over water. To give an example: due to its strongly nucleophilic character, the leucine amide (0.25 M) is able to deacylate an acyl-chymotrypsin complex 20 times faster than water (55 M).21 As a consequence, in this case proteosynthesis would largely predominate over proteolysis in a kinetically controlled reaction (cf. Chapter 5, Section III).
The Reactivity Of Copper Sites In The “Blue” Copper Proteins
Published in René Lontie, Copper Proteins and Copper Enzymes, 1984
Quantum mechanical tunneling has also been invoked to explain biochemical electron-transfer processes.14–16 (For a comprehensive presentation and discussion of the present state of tunneling theory as applied to biochemistry, see Reference 16.) In principle, at least short-range electron tunneling may occur whenever energy barriers are involved in electron transfer. The electron transfer rate constant, k, is related to a “tunneling” matrix element, Tab, the magnitude of which depends on the extent of electronic overlap of the donor and acceptor wave functions. Tab is small because of the exponential decrease of the wave functions in the region of the energy barrier between the two redox sites. In calculating the rate of tunneling through the barrier it is assumed that the translational energy of the reactants is conserved as internal vibrational energy of the activated complex. This energy is coupled to the electronic state of the donor molecule and thus serves to reduce the height of the tunneling barrier.
Emerging drugs for EGFR-mutated non-small cell lung cancer
Published in Expert Opinion on Emerging Drugs, 2019
Vineeth Sukrithan, Lei Deng, Alexander Barbaro, Haiying Cheng
Lung cancer is the leading cause of cancer-related mortality worldwide [1]. Non-small-cell lung cancer (NSCLC) accounts for 80–85% of all lung cancers diagnosed. Molecularly targeted therapies against specific oncogenic drivers have had a significant impact on the treatment paradigm and clinical outcome in patients with NSCLC carrying these mutations [2]. One of the most commonly encountered drivers is the activating mutation in epidermal growth factor receptor (EGFR), which has been observed in approximately 17% of patients [3]. Signaling through EGFR, a member in the ErbB family of tyrosine kinase receptors, is instrumental for cell growth and proliferation [4]. Once activated by its various ligands, including epidermal growth factor (EGF) and TGF-α, it dimerizes and auto-phosphorylates intracellular tyrosine residues. This activated complex activates several signaling pathways, most notably MAPK, PI3K-AKT, and JAK-STAT [5]. The activation of these pathways drives cell growth and proliferation and inhibits apoptosis, leading to oncogenesis. Several EGFR mutations, which render this pathway constitutively active have been identified. The in-frame deletion of exon 19 and substitution of leucine for arginine in exon 21 (L858R) together account for 85–90% of all EFGR mutations [6,7]. These mutations have been the target for tyrosine kinase inhibitors (TKIs) ever since responses were initially demonstrated with targeting of mutant EGFR[8].
Optimization of siRNA delivery to target sites: issues and future directions
Published in Expert Opinion on Drug Delivery, 2018
Ikramy A. Khalil, Yuma Yamada, Hideyoshi Harashima
RNAi was first observed in C. elegans in 1998 and described as the digestion of endogenous double-stranded RNA molecules by an endo-ribonuclease enzyme (Dicer) to produce smaller molecules that are able to bind to specific mRNA molecules in the cytosol causing their cleavage [1]. Later, siRNA molecules were synthesized and the first successful siRNA-based gene silencing was reported in 2001 [24]. Research on siRNA attracted substantial interest since that time, raising great hopes that they might be potential candidates for use in the treatment of various diseases. Synthetic siRNA are short double-stranded RNA molecules composed of 21–25 nucleotides (~13 kDa) that carry ~50 negatively charged phosphate groups. When successfully delivered in a free state to the cytosol, they bind to other proteins to form an RNA-Induced Silencing Complex (RISC). The complex is activated when the sense strand of the siRNA is discarded. The antisense strand in the activated complex then binds specifically with complementary mRNA and induces its cleavage with the production of the protein encoded by this mRNA being blocked [25,26]. The activated complex continues to bind to other mRNA molecules causing a further inhibition in protein production [24].
Seminal inflammasome activity in the adult varicocele
Published in Human Fertility, 2022
Mariana Camargo, Emad Ibrahim, Paula Intasqui, Larissa B. Belardin, Mariana P. Antoniassi, Charles M. Lynne, Nancy L. Brackett, Ricardo P. Bertolla
Inflammasomes are macromolecular complexes that serve as platforms for the innate immune response (Guarda & So, 2010). This complex is formed by a cytosolic NLR-type receptor, ASC protein (caspase domain recruiter) and pro-caspase-1, which is activated by different pathways, leading to the activation of pannexin-1 and P2X7R receptors (Monie, 2013). The activated complex stimulates increased expression of inflammatory cytokines such as caspase-1, IL-1β and IL-18, responsible for tissue injury (Guarda & So, 2010; Monie, 2013). The cytokines are released into the extracellular space after their production (Matsushita et al., 2009).