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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
As in other cases, allosteric drugs may be classified as covalent (see below) or noncovalent. To the latter belong the benzodiazepines, the non-benzodiazepine Z-drugs (zopiclone, zolpidem, etc.) or barbiturate drugs, targeting the ionotropic GABA receptor and acting as positive allosteric modulator molecules that increase the activity of the GABAA receptor protein in the central nervous system (e.g., Henschel et al., 2008). Cinacalcet is a positive G-protein-coupled receptor (GPCR) modulator that enhances Ca2+ activation of calcium-sensing receptor (Brown, 2010) and is employed to treat hyperparathyroidism; the cellular mechanisms for allosteric modulation of calcium-sensing receptors has been discussed by Cavanaugh et al. (2012). Maraviroc is a negative modulator of the GPCR chemokine receptor CCR5 and used for the treatment of HIV-type 1 (Conn et al., 2009, and literature cited therein). Metabotropic glutamate receptors (mGluRs, several different groups) involved in the modulation of synaptic transmission and neuronal excitability are members of the GPCR superfamily; mGluRs are drug targets of positive allosteric modulators for treating neurological and psychiatric disorders (Alzheimer’s, anxiety, schizophrenia, etc.) as reviewed by Niswender and Conn (2010), Wood et al. (2011), or Herman et al. (2012). A recent example are allosteric BCR-ABL tyrosine kinase fusion protein inhibitors in Philadelphia chromosome-positive acute lymphoblastic leukemia, developed to overcome resistance towards drugs like imatinib and others (Hantschel, 2012). For covalent allosteric inhibitors see the next section.
Fabrication of Sr-functionalized micro/nano-hierarchical structure ceramic coatings on 3D printing titanium
Published in Surface Engineering, 2021
Yongjie Wei, Yang Hu, Mingrui Li, Dongdong Li
EDS analysis demonstrates the uniform distribution of Ca (3.85 at.-%), P (4.19 at.-%), and Sr (4.33 at.-%) in MAOs-HT-Sr@TC4 (Figure 3(a)). It has been reported that Ca can up-regulate the expression of bone-related genes [20,23]. Among the divalent cations, Sr2+ can stimulate the calcium-sensing receptor, which will further promote the proliferation and differentiation of osteoblastic cells [18,19,24]. Figure 3(b) displays the Sr2+ release profiles after immersed in deionized water. The release rate of Sr ions is very fast within the first 3 days and then keep increasing slowly for a long time. The slow and sustained release of Sr may accelerate the rate of bone-implant integration, showing great potential for clinical use. The release process of Sr from coatings could be described as follows: SrTiO3 + H2O→Sr2+ + TiO2 + 2OH−.
Enhanced osteogenesis and angiogenesis by PCL/chitosan/Sr-doped calcium phosphate electrospun nanocomposite membrane for guided bone regeneration
Published in Journal of Biomaterials Science, Polymer Edition, 2019
Huilin Ye, Junjin Zhu, Dan Deng, Shue Jin, Jidong Li, Yi Man
The SEM images and CCK-8 assays indicated that all the PCL/CS, CaP/PCL/CS and Sr-CaP/PCL/CS membranes were nontoxic to BMSCs, and contributed to cell adhesion and proliferation. The difference on the cell adhesion and proliferation among these membranes may be attributed to the addition of nanoparticles, which were similar to biological apatite and increased the surface roughness to promote cell adhesion and proliferation [57]. Our results accord with previous researches, which demonstrated that Sr2+ ions promoted cells proliferation in low concentration and inhibited in higher concentration, and specifically it indicated that cells viability increased in a range of 2 to 6 µg/mL of Sr2+ dosage [58]. The proliferation accelerating effect from Sr2+ might be attributed to the activation of the calcium-sensing receptor (CaR) [59] and significantly increasing the proportion of cells in the S and G2/M phases (proliferation index) [60].