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Phytoconstituents from Neem with Multiple Activities
Published in Bhupinder Singh, Om Prakash Katare, Eliana B. Souto, NanoAgroceuticals & NanoPhytoChemicals, 2018
Suman Chaudhary, Rupinder Kaur Kanwar, Teenu Sharma, Bhupinder Singh, Jagat Rakesh Kanwar
The bioactivity of neem seed oil is mainly attributed to its rich content of azadirachtin. Azadirachtin, along with nimbolide, exerts significant cytotoxic effects on the viability of the human cervical cancer cell line (HeLa). It induces p53-dependent p21 accumulation, along with cell-cycle arrest at the G0/G1 phase, and causes decrease in cell-cycle regulatory proteins including cyclin b, PCNA, and cyclin D1. Further, it causes modifications in the nuclear morphology and induces apoptotic signals via a mitochondrial pathway (Priyadarsini et al., 2010). However, both azadirachtin and nimbolide are capable of causing toxicity since a high dose of azadirachtin (LD50 > 5000 mg/kg bw) and intraperitoneal or intravenous administration of nimbolide can cause acute toxicity in experimental animals (Glinsukon et al., 1986; Raizada et al., 2001). Another study, conducted on the bioinsecticide azadirachtin A, indicated that it is not genotoxic and has an antiproliferative effect on the Chinese hamster ovary cells (CHO) and on human lymphocytes. It modulates the first and second (M1 and M2) division metaphases, thus interfering with the cell-cycle progression (Mosesso et al., 2012). Nonetheless, extensive investigations are required on the precise molecular mechanisms, pharmacokinetics, and toxicity of these neem limonoids to explore the therapeutic and preventive potential of neem in humans.
Carcinogenesis of Depleted Uranium: Studies in Animals
Published in Alexandra C. Miller, Depleted Uranium, 2006
Gene changes in the tumors induced by DU and Thorotrast®, a radioactive compound, were compared looking for a similarity that might indicate a radiation mechanism for DU carcinogenesis. The specific gene changes sought were the expression of p53, MDM2, p21 or c-myc, and the mutation of K-ras. P53 was chosen because of its relatively high frequency of mutation in human soft tissue sarcomas and in rodent soft tissue sarcomas induced with materials placed subcutaneously. The regulation of cell growth by p53 depends on activating transcription of MDM2 by p53. Overexpression of p53 was detected by immunohistochemistry (16). Overexpression of the MDM2 gene interferes with transcriptional activation of wild-type p53, thereby abrogating normal p53 function. In addition to this close correlation, several studies of human soft tissue sarcomas have reported the overexpression of MDM2. Expression of MDM2 was detected by immunohistochemistry (17). P21 protein is important in regulation of the cell cycle and falls in the p53 activation pathway. Expression of p21 was detected by immunohistochemistry (Santa Cruz Biotechnology, Santa Cruz, CA). The c-myc oncogene was selected based on evidence from both humans and rodents that c-myc expression may be an aid in separating the radiation-induction mechanism from other mechanisms of cancer induction C-myc expression was detected by immunohistochemistry (Santa Cruz Biotechnology). In vitro studies with DU suggest that K-ras may be important in carcinogenesis. For example, DU causes transformation of human osteoblasts and expression of high levels of K-ras by these cells (18). In rats, pellets of DU embedded in the muscles caused increased levels of K-ras in the muscles (19). K-ras codon 12 mutations were detected by a restriction fragment length polymorphism analysis using the BstN1 test. (16).
Exposure to long-term evolution radiofrequency electromagnetic fields decreases neuroblastoma cell proliferation via Akt/mTOR-mediated cellular senescence
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Ju Hwan Kim, Sangbong Jeon, Hyung-Do Choi, Jae-Hun Lee, Jun-Sang Bae, Nam Kim, Hyung-Gun Kim, Kyu-Bong Kim, Hak Rim Kim
Activated p53 then binds to the p21 promoter, thereby inactivating cyclin-CDKs in the G1 and S phases of the cell cycle. p21 is a cyclin-dependent kinase inhibitor (CKI) that binds to and inhibits the activity of cyclin-CDK2, CDK1, and CDK4/6 complexes, and therefore plays a crucial role in regulation of cell cycle progression at the G1 and S phases (Abbas and Dutta 2009; Wade Harper et al. 1993). In addition, p27 is another CKI called cyclin-dependent kinase inhibitor p27 (also known as KIP1), which inhibits activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, thus controlling cell cycle progression at the G1 phase (Chiarle, Pagano, and Inghirami 2000). In the present study, the cyclin-dependent kinase inhibitor p27 (p27KIP1) was also increased in SH-SY5Y cells after RF-EMF exposure (Figure 5c). Therefore, elevated p21 and p27 modified cyclin-CDK complexes, which blocked cell cycle progression at the G1 phase in SH-SY5Y cells after RF-EMF exposure (Figure 2).
Impact of stainless-steel welding fumes on proteins and non-coding RNAs regulating DNA damage response in the respiratory tract of Sprague-Dawley rats
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Jayaraman Krishnaraj, Abdul Basit Baba, Periasamy Viswanathan, Veeran Veeravarmal, Viswalingam Balasubramanian, Siddavaram Nagini
ATM is known to activate DNA damage checkpoints enabling DNA repair. ATM is critical for cyclin D1 phosphorylation (Hitomi et al. 2008). Reciprocally, cyclin D1 collaborates with molecular pathways of DNA repair by sustained activation of ATM, DNA-PKCs, and Rad51 (Marampon et al. 2016). P21 has a dual role in cell fate based upon its subcellular localization. While nuclear p21 halts cell cycle progression, p21 in the cytosol promotes cell survival (Letchoumy et al. 2007). In the present study, ATM activation correlated with cell cycle arrest and apoptosis up to 8 weeks of exposure but subsequently shifts in favor of a pro-survival phenotype indicating that longer exposure leads to resumption of cell cycle progression despite cells suffering extensive DNA damage probably due to failed apoptosis. Persistent DNA damage coupled to deficient DNA repair with failure of apoptosis may induce senescence that is deleterious to genomic stability (d’Adda di Fagagna 2008).