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DNA Damage Response Research, Inherent and Future Nano-Based Interfaces for Personalized Medicine
Published in Yubing Xie, The Nanobiotechnology Handbook, 2012
Madhu Dyavaiah, Lauren Endres, Yiching Hsieh, William Towns, Thomas J. Begley
p53 is another effector protein that has multiple roles in response to DNA damage. It activates the transcription of genes that participate in DNA repair, cell-cycle regulation, senescence, or apoptosis, depending on the type or the sources of DNA damage. Mdm2 is a negative regulator of p53 by ubiquitin-mediated proteasome degradation. Upon DNA damage, ATM, ATR, and DNA-PK can phosphorylate p53 at serine 15, while CHK1 and CHK2 can phosphorylate p53 at serine 20. Once activated, p53 can transcriptionally regulate the expression of the cyclin-dependent kinase (CDK) inhibitor p21, as well as of the proapoptotic BCL2-associated X protein (BAX) and p53 upregulated modulator of apoptosis (PUMA) proteins that induce cell-cycle arrest, senescence, or apoptosis. Moreover, p53 promotes DNA repair and deoxyribonucleoside triphosphate (dNTP) synthesis (Chen et al. 2005, Shieh et al. 1997, 2000). The preponderance of cancer-associated mutations that disrupt p53’s ability to bind DNA and activate gene transcription underscore the importance of this p53 function in mediating tumor suppression. DNA damage also induces modifications of Mdm2 leading to Mdm2 destabilization and degradation, which effectively reduce its negative regulatory effect on p53 (Wade et al. 2010). This, in combination with p53 N-terminal phosphorylation events and p53 binding to other cellular cofactors, leads to p53 stabilization and transcriptional activation.
The therapeutic effect of nano-zinc on the optic nerve of offspring rats and their mothers treated with lipopolysaccharides
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Eman Mohammed Emara, Hassan Ih El-Sayyad, Amr M Mowafy, Heba a El-Ghaweet
These findings are consistent with other studies that reported that ZnO NPs increase antioxidant activity, diminish free radical levels produced by Aflatoxin B1 and haves teratogenic, carcinogenic, mutagenic and immunosuppressive effects in humans and animals when giving Aflatoxins-contaminated feedstuff [41]. In addition, studies showed that ZnO NPs have anticancer effects that can kill cancer cells by inducing oxidative stress in the cancer cells [42], by the activation of DNA repair and by inhibiting both apoptosis and cancer cell growth [43]. In vitro, nanoscale zinc oxide organizes neuronal excitability, enhances glutamate secretion and alters the balance of neurotransmitter and neuronal excitability in the CNS after LPS injections; so ZnO NPs therapy can improve behavioral and electrophysiological abnormalities induced by LPS [44].
Pleural mesothelioma and lung cancer: the role of asbestos exposure and genetic variants in selected iron metabolism and inflammation genes
Published in Journal of Toxicology and Environmental Health, Part A, 2019
F. Celsi, S. Crovella, R. R. Moura, M. Schneider, F. Vita, L. Finotto, G. Zabucchi, P. Zacchi, V. Borelli
Recently, a screening of a cohort of mesothelioma patients with a family history of cancer showed the presence of BAP1 (BRCA associated protein 1) mutations in a minority of patients (Ohar et al. 2016), a result further confirmed by two whole-genome investigations accomplished in different geographic areas (Betti et al. 2017; Bueno et al. 2016). Mutations in the tumor suppressor gene BAP1 (truncation, deletions, somatic variants including large deletions, and/or chromosomal loss) associated with different types of cancer, including MPM, reviewed in Betti et al. (2019), and LC (Carbone et al. 2013), supporting the concept that a common mutation might trigger diverse malignancies. BAP1 plays an important role in chromatin modulation, transcriptional regulation, cell proliferation, DNA repair, cell death, and glucidic metabolism. Interestingly, Zhang et al. (2018) reported that cells with reduced BAP1 activity also display impaired ferroptosis, providing a possible link between Fe and BAP1 pathways in the development of asbestos-related malignancies. Many other genes were identified as involved in predisposition to MPM, which are predominantly involved in DNA repair (Betti et al. 2019). These findings suggest that the contribution of the BAP1 failure (and also that of the other genes) may follow the damage initiated by other pathways triggered by asbestos, such as those Fe-mediated. It is likely that it is the synergic (rare) combination of these pathways to determine the predisposition. External pollutants, such as asbestos and cigarette smoke, increase Fe loads in the lungs (Ghio et al. 2008; Pascolo et al. 2016), induce oxidative stress and inflammation, tipping the point toward cancer development. In this context, alterations of genes involved in Fe-metabolism might either elevate or decrease the toxicity of this metal thus possibly either inducing or protecting from the neoplastic transformation.
Recent advances and therapeutic journey of pyridine-based Cu(II) complexes as potent anticancer agents: a review (2015–2022)
Published in Journal of Coordination Chemistry, 2023
Heterocyclic compounds are cyclic organic compounds with at least one hetero atom (oxygen, nitrogen, sulphur, etc.) [1–4]. These compounds constitute the largest family of organic compounds, and about one-third of organic chemistry publications are in this field. Various biological molecules such as DNA, RNA, hemoglobin, chlorophyll, vitamins, enzyme, and natural products contain a heterocyclic ring in their major skeleton [5–14]. Heterocyclic compounds have diverse applications in various fields, including medicinal chemistry, biochemistry, analytical chemistry, catalysis, and many other fields [3, 15–23]. Pyridine derivatives (Figure 1) have excellent biological activities such as antiviral, antiarthritic, antibacterial, anticonvulsant, antithrombotic, ulcerogenic, antiglycation, antifungal, antioxidant, analgesic, anticancer, anti-inflammatory, and antiparkinsonian activity [34–37]. However, most organic compounds have limited bioavailability due to their rapid metabolism, low-intestinal absorption, and hydrophobic nature. Therefore, it is important to enhance the solubility and bioavailability to enhance the pharmacological effects of these active compounds [38–41]. One strategy is complex formation of these compounds with various metal ions [42–47]. Metal-based drugs like cisplatin are well known and effective antitumor agents. This platinum-based drug has been used for the treatment of various types of cancer including ovarian, lung, head, neck, testicular, and bladder cancers. It is also effective against germ cell tumors, sarcomas, lymphmas, and carinomas. Cisplatin interacts with the purine bases, interfering with DNA repair mechanism, causing DNA damage, and inducing apoptosis in cancer cells. However, their negative side effects including hemorrhage, gastrointestinal disorders, hearing loss, allergic reactions, kidney problems, and decreased immunity to infections, critical issues in their clinical use. These problems drive research and development of new metal-based drugs, in many cases divergent from the Pt metal-based complexes. Non-platinum metal complexes possess excellent potential toward cancer cells. Copper is less toxic than non-endogenous heavy metals and biocompatible, which makes it a remarkable candidate for cancer treatment due to its bioavailability and the observation of increased levels of copper in cancer tissue.