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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Despite less success, research is still ongoing into the discovery of clinically useful inhibitors of the cell-cycle proteins (e.g., CDK inhibitors). Finally, some exciting new drug targets are at the research stage such as the Hedgehog signaling pathway and the Inhibition of Apoptosis (IAP) proteins.
Neuroprotective Role of Quercetin in Alzheimer’s Disease
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
Several lines of evidence have shown that quercetin increases the life span of Drosophila and also climbing ability in AD flies. Studies have also shown that quercetin protects cell cycle proteins, which are perturbed due to Aβ aggregation (Kong et al., 2016; Li et al., 2019). A three-month quercetin treatment significantly reduced extracellular β-amyloidosis and improved microglial and astroglial activation in the brain, as observed by reduced levels of Aβ1-40, Aβ1-42 and beta-amyloid cleaving enzyme1 (BACE1) -induced cleavage of APP in a triple transgenic AD mouse model (Sabogal-Guaqueta et al., 2015; Li et al., 2019). With robust antioxidant action, quercetin mitigated Aβ plaque accumulation and interleukin-1β (IL-1β)/ cyclooxygenase-2 (COX-2)/ inducible nitric oxide synthase (iNOS) proinflammatory signaling in the hippocampal CA-1 region of triple transgenic AD mice (Vargas-Restrepo et al., 2018; Li et al., 2019).
Herbal Therapy for Cancer
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Several research groups have investigated the effects of RES on breast cancer cells in vitro and in vivo. However, recent evidence indicates that RES may inhibit cancer progression through modulation of microRNAs (miRNAs). Resveratrol appears to regulate apoptotic and cell cycle machinery in breast cancer cells by modulating key tumor-suppressive miRNAs including miR-125b-5p, miR-200c-3p, miR-409-3p, miR-122-5p, and miR-542-3p. In another study, RES-mediated miRNA modulation has been said to regulate key anti-apoptotic and cell cycle proteins including bcl-2, and CDKs, which are critical for its activity (Venkatadri et al. 2016). Resveratrol inhibited breast cancer cell proliferation by stimulating SIRT-1. Activation of the AMPK pathway leads to mTOR activation, which stimulates the cell proliferation. It was observed that RES can block AMPK phosphorylation (overexpressed in tumor cells) by SIRT-1 activity (Lin et al. 2010). In a study using breast cancer cells, RES has been reported to upregulate the pro-apoptotic gene expression (BAD, p53, TP53I3, p21, c-fos, and COX-2) and significantly reduced proliferation (Chin et al. 2014). In synergistic studies, RES appears to improve the anticancer effects of doxorubicin in combination, through inhibiting breast cancer cell proliferation and invasion, and inducing apoptosis via suppression of chronic inflammation and autophagy (Rai et al. 2016).
The FnBPA from methicillin-resistant Staphylococcus aureus promoted development of oral squamous cell carcinoma
Published in Journal of Oral Microbiology, 2022
Li-Xin Kong, Zheng Wang, Yu-Ke Shou, Xue-Dong Zhou, Ya-Wen Zong, Ting Tong, Min Liao, Qi Han, Yan Li, Lei Cheng, Biao Ren
The mammalian cell cycle contains four distinct phases (G0/G1, S, G2 and M), which ensure duplication of genetic material and cell division [37]. Cancer is characterized by uncontrolled proliferation resulting from aberrant activity of various cell cycle proteins, such as CDK4 and CDK6 [38]. Therefore, exploring the cyclic changes of cancer is considered potential targets to judge its proliferation and development prognosis. Numerous studies have found that failure of the G1/S phase and S-phase checkpoints to act properly is particularly deleterious because it may directly elicit chromosomal aberrations and the accumulation of deleterious mutations, which increase the likelihood of the occurrence of cancer [39,40]. In our study, after treatment with MRSA for 24 h, the number of cells in the S phase increased, indicating that MRSA promoted oral squamous cell carcinoma cells into S phase, thereby shortening the time of cell cycle and increasing the proliferation rate.
Low-dose CDK4/6 inhibitors induce presentation of pathway specific MHC ligands as potential targets for cancer immunotherapy
Published in OncoImmunology, 2021
Angel Charles, Christopher M. Bourne, Tanya Korontsvit, Zita E. H. Aretz, Sung Soo Mun, Tao Dao, Martin G. Klatt, David A. Scheinberg
Next, we sought to determine if increased Cyclin D1 presentation in cells treated with CDK4/6i could be attributed to an increase in protein degradation through the multi-ubiquitin pathway. We immunoprecipitated multi-ubiquitinated proteins and then performed a western blot for Cyclin D1 at different time points. Similarly to the results observed for overall protein levels the amount of ubiquitinated cyclin D1 increased in CDK4/6i treated MCF7 and T47D cells compared to DMSO in a time dependent manner as indicated by higher molecular weight bands at later time points (Figure 4d arrows). Taken together, these results support a model whereby CDK4/6i led to compensatory upregulation of cell cycle proteins, followed by their degradation and presentation on HLA (Figure 5).
Effect of nitric oxide reduction on arterial thrombosis
Published in Scandinavian Cardiovascular Journal, 2019
Dario Costa, Giuditta Benincasa, Roberta Lucchese, Teresa Infante, Giovanni Francesco Nicoletti, Claudio Napoli
NO decreased in case of reduced eNOS enzymatic activity and NO bioavailability [2,7]. In ECs, different stimuli such as the binding of agonists to vascular endothelial grow factor receptor (VEGFR), estrogen receptor (ER) or GPCRs (acetylcholine, bradykinin) and shear stress lead to the activation of eNOS. Once produced, NO has an average half-life of a few seconds [38]. So it can only act as an autocrine or paracrine signaling molecule on nearby cells and tissues. NO directly activates the soluble isoenzyme of guanylate cyclaseby binding to its heme moiety, resulting in increased concentrations of cyclic guanosine monophosphate (cGMP) in target cells (Figure 1). NO plays a crucial role also in the inhibition of VSMC proliferation through GMP-dependent and GMP-independent mechanisms [39,40]. The first pathway involves the activation of specific cAMP-dependent protein kinases A (PKA). This protein may stimulate Ca2+ transport at the plasma membrane and sarcoplasmic reticulum, resulting in a marked reduction of Ca2+ concentrations. It has been observed that phosphorilation of a vasodilator-stimulated phosphoprotein (VASP) leads to the inhibition of epidermal growth factor receptor (EGFR) signaling pathway [41]. In addition, NO may directly interact with cell cycle proteins. In the GMP-independent pathway, NO directly inhibits the activity of arginase and ornithine decarboxylase [42]. Furthermore, NO seems to interfere with polyamine production causing inhibition of cell proliferation [40].