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Introduction
Published in James E. Ferrell, Systems Biology of Cell Signaling, 2021
Positive feedback (Figure 1.12c) is also common. For example, in the EGFR system, Sos activates the Ras GTPases. In turn, active Ras can bind to and allosterically activate Sos (Figure 1.3). This constitutes a short, simple positive feedback loop. There are longer positive feedback loops built into the system as well. For example, EGFR activation leads to the rapid and reversible activation of ADAM proteases, including ADAM17. ADAM17 functions as a “sheddase,” and it can cleave the membrane-bound precursor forms of several EGFR ligands, including TGFα, to release active, diffusible growth factors that can reinforce EGFR activation and spread it to neighboring cells (Figure 1.3). The details of ADAM17 activation are not yet worked out; PKC is a likely intermediary, although how it regulates ADAM17 is not clear. Nevertheless, it is clear that the EGFR and ADAM17 are part of a long positive feedback loop, with each protein activating the other, and it is clear that this loop is important in the overall functioning of the EGFR signal transduction system.
Neuroprotective effect of quercetin through targeting key genes involved in aluminum chloride induced Alzheimer’s disease in rats
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Hala A Elreedy, Asmaa M. Elfiky, Asmaa Ahmed Mahmoud, Khadiga S. Ibrahim, Mohamed A Ghazy
Additionally, most information on APP’s non-amyloidogenic cleavage is yet unclear, mostly with relation to pharmacological approaches that could impact various signaling pathways. Three of the zinc-dependent transmembrane-dependent metalloproteinases, ADAM 10, ADAM 17 and ADAM 9, exhibit α-secretase activity [47]. According to our research, a significant reduction in ADAM 10 and ADAM 17 was observed inside the hippocampus tissue in AlCl3 group compared to normal control. These results are similar with [5]. In contrast, ADAM 17 was significantly increased in the co-administration of AlCl3 with Q at 50 mg kg-1 to the AlCl3-induced AD rats. On the other hand, the effect of quercetin did not show any significant changes to ADAM 10 in the co-administration of AlCl3 with Q 50 mg/kg bwt to the AlCl3 -induced AD rats. The last findings may explain the mechanism of quercetin to regulate ADAM17 activity. ADAM17 effects on other mediators directly or indirectly reduce Aβ. Previous studies demonstrated that ADAM17 can enhance pro-inflammatory cytokines of microglia, for instance tumor necrosis factor-α, fractalkine, and interleukin-8 (IL-8), and stimulate IL-1, IL −6, and Notch receptor that provoke phagocytosis leading to Aβ degradation [48,49]. In contrast to ADAM17, ADAM 10 directly mediated APP cleavage, in this study the targeting of quercetin was shown to be nonspecific to ADAM10. Suggesting that both enzymes, ADAM 10 and BACE1, compete with one another to cleave APP, thus, quercetin targeting BACE-1 activity may inhibit neurotoxic amyloid generation via the amyloid pathway.
Neuroprotective role of herbal alternatives in circumventing Alzheimer’s disease through multi-targeting approach - a review
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Sunil K Ravi, Balenahalli Narasingappa Ramesh, Shilpa Kj, Jagadesha Poyya, Jyothsna Karanth, N.G Raju, Chandrashekhar G Joshi
α-secretase enzyme proteolytically cleaves the APP via the non-amyloidogenic pathway at L688 residue located within the Aβ sequence and thereby preventing the formation of Aβ (Figure 2). The first enzyme for α-secretase was proposed in 1998, when ADAM17, also known as tumor necrosis factor-converting enzyme (TACE), was reported to possess α-secretase activity [118]. Later, ADAM9 and ADAM10 were also shown to have α secretase activity [119]. These three proteins belong to the ADAM (a disintegrin and metalloprotease) family. It is reported that mutations in ADAM10 alter the processing of APP and lead to AD by increasing Aβ levels [120]. Thus, a promising yet underestimated approach to overcome AD would be, activating α-secretase processing of βAPP.
Understanding the role of genetic susceptibility (ACE2 and TMPRSS2) in COVID-19
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Abdullahi Tunde Aborode, Sherifdeen Bamidele Onigbinde, Khadijah Omoshalewa Sanusi, Noah Alaba, Aderinola H. Rasaq-Lawal, Babatunde Samuel Obadawo, Allison Olatoyosi, Saidat Omowunmi Adeniran-Obey, Victor Onwukwe, Uchenna Asogwa, Ridwan Iyanu Arinola, Seun Idowu Imani, Ayoola S. Fasawe, Ibukunoluwa Sodiya, Sherif Babatunde Adeyemi, Gaber El-Saber Batiha
Additionally, estrogens boost the expression of ADAM17 and ADAM10, two putative shedders responsible for numerous ectodomain cleavages in atherosclerosis, implying a protective role for females against cardiovascular events. This mechanism may account for the observed COVID-19 sex discrepancy [29]. Russo et al. [37] reported that low levels of androgens might adequately maintain TMPRSS2 manifestation in women.