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Nanoparticle–Based RNA (siRNA) Combination Therapy Toward Overcoming Drug Resistance in Cancer
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
Autophagy is considered to be a cytoprotective process involved in the normal turnover of long-lived proteins and whole organelles to maintain a healthy cellular status [157]. However, recent data strongly demonstrate that autophagy is intimately linked to apoptosis or necrosis and serves both pro-survival and pro-death functions. Autophagy regulation requires an orchestrated interplay between many signaling molecules, including mammalian target of rapamycin (mTOR) kinase, which has the most potent impact on autophagy [158,159]. Once activated, mTOR inhibits autophagy via the phosphorylation of autophagy-related proteins. AMP activated protein kinase (AMPK) activation can lead to autophagy by negatively regulating mTOR [160,161]. The tumor suppressor protein p53 can trigger autophagy by phosphorylating AMPK and further inhibiting the mTOR signaling pathway [160]. Beclin-1 also plays a critical role in autophagosome formation and crosstalk between autophagy and apoptosis [161]. The BH3 domain-mediated binding of Beclin-1 to B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-XL) inhibits autophagy. However, the c-Jun N-terminal kinase (JNK) 1- or extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Bcl-2 or death-associated protein kinase-mediated phosphorylation of Beclin-1 induces the dissociation of the Beclin-1–Bcl-2/Bcl-XL complex, thus inhibiting autophagy [161–165]. Intracellular calcium ions (Ca2+) can regulate the activation of JNK and the apoptotic signaling pathway [166].
Mechanical Signaling in the Urinary Bladder
Published in Jiro Nagatomi, Eno Essien Ebong, Mechanobiology Handbook, 2018
Aruna Ramachandran, Ramaswamy Krishnan, Rosalyn M. Adam
Another non-receptor kinase that has emerged as a viable therapeutic target for the treatment of fibroproliferative bladder disease is the mammalian target of rapamycin mTOR. Using the Ingenuity Pathway Analysis (IPA) software suite, Aitken and colleagues mapped a series of stretch- or hypoxia-responsive genes identified from prior analyses of BSMC to gene identifiers within the IPA database [109]. This led to the identification of networks and signaling pathways that linked the observed gene expression changes, and also identified putative chemical inhibitors that could be tested experimentally. One such agent was rapamycin, the immunosuppressant and inhibitor of mTOR. The authors proceeded to validate the relevance of the mTOR pathway to BSMC proliferation in response to both mechanical strain and hypoxia in vitro and in the ex vivo bladder injury model described earlier. Because rapamycin and its analogs (temsirolimus, everolimus) are FDA-approved and in current clinical use, it is tempting to speculate that these agents could be moved quickly into clinical use for treatment of obstructive uropathies.
Assessment of Quercetin Isolated from Enicostemma Littorale Against Few Cancer Targets: An in Silico Approach
Published in A. K. Haghi, Ana Cristina Faria Ribeiro, Lionello Pogliani, Devrim Balköse, Francisco Torrens, Omari V. Mukbaniani, Applied Chemistry and Chemical Engineering, 2017
The mammalian target of rapamycin (mTOR) also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 (FRAP1) is a protein encoded by FRAP1 gene. mTOR is a serine/ threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. mTOR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids. mTOR also senses cellular nutrient and energy levels and redox status. The mTOR pathway is dysregulated in human diseases, especially in certain cancers. Rapamycin is a bacterial product that can inhibit mTOR by associating with its intracellular receptor FKBP12. The FKBP12-rapamycin complex binds directly to the FKBP12-rapamycin binding (FRB) domain of mTOR. mTOR is the catalytic subunit of two molecular complexes.4
The effect of experimentally-induced diabetes on rat hippocampus and the potential neuroprotective effect of Cerebrolysin combined with insulin. A histological and immunohistochemical study
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Doaa El-Adli, Salwa A. Gawish, Amany AbdElFattah Mohamed AbdElFattah, Mona Fm. Soliman
In addition to mitochondrial changes and expression of caspase-3 and caspase-8 as previously explained [37], diabetic immunohistochemical changes can be correlated to dysregulation of PI3K-Akt (phosphoinositide 3-kinase/protein kinase B) signaling pathway and to increased expression of transcription factor NF-kB (nuclear factor kappa B). STZ reduces the phosphorylated form of AKT, increases the expression of iNOS (inducible nitric oxide synthase) & Nf-kB and decreases pGSK-3β (Glycogen synthase kinase-3 beta) level, leading to apoptosis [19]. TNF-α activity is related to activation of two transcription factors; NF-kB and activating protein-1. Both mediate transcription of pro-inflammatory cytokines [43]. Mammalian target of rapamycin (mTOR) is an essential molecule in the PI3K/AKT and NF-κB signaling pathway. mTOR is increased by hyperglycemia and activates NF-κB leading to synaptic dysfunction [44,45]. Overexpression of GFAP is due to astrogliosis. Astrocytes can perform anti-oxidant function, produce neuroprotective & pro-inflammatory agents and protect the surrounding healthy tissue from the spread of injury and inflammatory cells [46].
Liquidambar orientalis Mill. gum extract induces autophagy via PI3K/Akt/mTOR signaling pathway in prostate cancer cells
Published in International Journal of Environmental Health Research, 2022
Harika Atmaca, Cisil Camli Pulat, Mustafa Cittan
The signaling pathways involved in autophagy are complicated and include the PI3K/Akt/mTOR pathway that inhibits autophagy (Shao et al. 2016). Thus, we investigated this pathway in prostate cancer cells to explore the molecular mechanism underlying the autophagic cell death induced by the SLG extract. The results demonstrated decreased levels of PI3K in both prostate cancer cells treated with the IC50 values of SLG for 72 h (Figure 4). Akt is a downstream effector of PI3K that can stimulate the mTOR to regulate autophagy negatively. We thus investigated whether SLG-induced autophagy occurred through the mammalian target of rapamycin (mTOR) inhibition because mTOR acts as a well-conserved and central regulator in autophagy induction-and AKT modulates mTOR activation. Western blot analysis revealed significantly decreased levels of PI3K, p-Akt, p-mTOR and increased levels of LC3-II in SLG-treated cells, indicating that the PI3K/Akt pathway may be involved in the regulation of autophagy by SLG (Figure 4).
MicroRNA expression profiling involved in MC-LR-induced hepatotoxicity using high-throughput sequencing analysis
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Shu Yang, Lv Chen, Cong Wen, Xian Zhang, Xiangling Feng, Fei Yang
To pinpoint the target genes affected by miRNAs, GO enrichment analyses revealed that the processes significantly altered by MC-LR involved systems development, metabolism, and protein binding. Further, KEGG pathway enrichment analysis showed that the target genes of differentially expressed miRNAs in normal liver cell line predominantly participated in mTOR signaling pathway, Ras signaling pathway, Rap1 signaling pathway, HIF-1 signaling pathway, and pathways in cancer development. mTOR is a highly conserved serine/threonine kinase that regulates cell growth, cell cycle progression, and metabolism (Laplante and Sabatini 2012). mTOR signaling was found to be activated in many types of cancers (Menon and Manning 2008). It was suggested that activation of mTOR signaling was associated with advanced tumor stages and poor survival outcomes in various types of cancers, including human hepatocellular carcinoma (HCC) (Hayashi et al. 2017; Matter et al. 2014). It is of interest that in MC-LR-induced thyroid dysfunction the mTOR signaling pathway was activated in mice (Zhao et al. 2015). Similarly MC-LR was found to activate mTOR in our hepatic cell line.