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Microbe-mediated Synthesis of Zinc Oxide Nanoparticles and Its Biomedical Applications
Published in Mahendra Rai, Patrycja Golińska, Microbial Nanotechnology, 2020
Happy Agarwal, Amatullah Nakara, Soumya Menon, Venkat Kumar Shanmugam
Studies have reported the formation of ROS after ZnONP internalization into the bacterial cells, primarily O2-, OH– and H2O2, which are strong oxidizing agents. This was inferred by a significant increase in the transcription levels of oxidative stress genes and stress-response genes (Xie et al. 2011). The ROS are anticipated to be produced as a result of the redox reaction of the electrons trapped at the oxygen valence sites of the NPs. The ROS further disrupts or alters protein synthesis cycle or DNA replication, causing cell death. It also causes membrane damage by creating holes on the membrane surface, which increases its overall surface area. This increased surface area assists in more absorption of ROS on the surface, causing an autocrine stimulation of ROS (Mittal et al. 2014). Bacterial cellular components such as proteins and nucleic acids promote the dissolution of ZnO by forming ionic salts with Zn2+ ions. Though Zn2+ ions are essential for microbial metabolism, an excess of Zn2+ due to internalization of the NPs disrupts the Zn2+ homeostasis of the microbe, leading to intracellular cytotoxicity (Joe et al. 2017). There is also a consequential increase in the Zn2+ levels in the bacterial cytoplasm that causes a loss of proton motive force and subsequently membrane leakage (Sirelkhatim et al. 2015). Another mechanism reported to induce bacterial cell death is the inhibition of vital enzymes involved in essential metabolic pathways. Zn2+ may distort the active site of cardinal enzymes or bind to them via various macromolecular interactions, thereby bringing about a conformational change in their structure. This inhibits or inactivates polymerases, dehydrogenases, and phosphatases, which are involved in essential metabolic pathways of the organism (Maret 2013). ZnONP concentration above threshold levels in bacterial cells has been shown to inhibit vital enzymes such as glutathione reductase and thiolperoxidase. Glutathione reductase is a crucial enzyme involved in the glutathione redox cycle that helps in maintaining glutathione balance in the cell. Reduced glutathione helps resist oxidative stress by reacting with ROS. Thiolperoxidase is responsible for catalyzing the reduction of ROS such as H2O2. By inhibiting vital enzymes, ZnONPs consequently inhibit the destruction of ROS, favoring cell death (Kumar et al. 2011, Ji et al. 2015). It is also shown that ZnONPs selectively inhibit the adenylyl cyclase pathway (cAMP-dependent pathway) in Vibrio cholerae, thereby downregulating cAMP levels. cAMP (cyclic AMP) is a secondary messenger and an ATP derivative that is involved in various intracellular signal transduction cascades like DNA transcription, regulation of gene expression and enzyme activation (Salem et al. 2015). The various mechanisms of the antibacterial activity of ZnONPs are summarized in Fig. 9.1.
Hyaluronate – parathyroid hormone peptide conjugate for transdermal treatment of osteoporosis
Published in Journal of Biomaterials Science, Polymer Edition, 2018
Minsoo Cho, Seulgi Han, Hyemin Kim, Ki Su Kim, Sei Kwang Hahn
PTH induces the expression of cAMP by stimulating G-protein coupled receptors [22,23]. The cAMP plays a key role in many biological processes as the second messenger. cAMP is used for intracellular signal transduction in many different organisms, so called the cAMP-dependent pathway [24]. PTH also affects osteoblast cells through the cAMP-dependent pathway [25–27]. As shown in Figure 4(B), PTH1–34 and HA-PTH1–34 conjugate increased the cAMP level in osteoblast cells, compared to the control group. PTH1–34 and HA-PTH1–34 conjugate treated cells expressed significantly higher level of cAMP than the control group (0.4 pmol/mL). These results reflect the hormonal stimulation of the transmembrane PTH1–34 receptors on the primary human osteoblasts and the amount of signaling to the cells. In addition, HA with a high molecular weight appeared to enhance the osteoblast differentiation, and the osteogenic and osteoinductive properties of osteboblasts [28,29]. Thus, we thought that HA-PTH1–34 conjugates could stimulate primary osteoblast cells more effectively than intact PTH1–34.