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Molecular Mechanisms of Brain Insulin Signaling 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Simran Chopra, Robert Hauffe, André Kleinridders
To exert its effects in the CNS, insulin is transported across the blood-brain barrier by saturable insulin transporters (8–10) and is released into the cerebrospinal fluid (CSF) where it is distributed to insulin-sensitive brain regions. Upon insulin binding to the IR, the IR changes its conformation to bring kinase domains of the IR in proximity to tyrosine phosphorylation sites on the β-chain, allowing the autophosphorylation of at least eight tyrosine residues (11). This then leads to the activation of insulin receptor substrate (IRS) proteins and subsequently of two general downstream signaling arms through (i) the phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB, also called AKT) axis, and (ii) the mitogen-activated protein kinase (MAPK), discussed in detail below (Figure 1.1)
Synthetic Compounds vs. Phytochemicals for the Treatment of Human Cutaneous Malignant Melanoma
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Jacqueline Maphutha, Namrita Lall
Euplotin C (EC), isolated from Euplotes crassus Dujardin, induced apoptosis in three malignant melanoma cell lines (A375, MeWo and 501 Mel) with 50% minimum inhibitory concentrations (IC50) of 3.53 ± 0.19, 2.68 ± 0.29 and 3.56 ± 0.38 µM, respectively. Western blotting analysis revealed that EC inhibited protein kinase B (p-Akt) by 68% and BRAF by 27% (Carpi et al., 2018). Bornyl cis-4-hydroxycinnamate (BCH), isolated from Piper betle L., reduced the viability of two malignant melanoma cell lines (A375 and A2058) at a concentration of 12 µM. Western blotting analysis revealed that the levels of p-PI3K and p-Akt were significantly reduced at 6 µM. Furthermore, BCH reduced the expression of extracellular signal regulated kinase (ERK), c-Jun N-terminal kinases (JNK) and p38 MAPK (MAPK pathway related proteins) (Yang et al., 2018). Isoangustone A (IA), isolated from Glycyrrhiza glabra L., inhibited the growth of the malignant melanoma cell line (SK-MEL28) by 67%. Through an in vitro PI3K assay and Western blotting, PI3K was significantly inhibited in comparison to the positive control, LY294002. Furthermore, IA inhibited p-Akt and molecular targets in the MAPK pathway (MKK4 and MKK7) (Song et al., 2013).
1,3-Diphenyl-2-Propene-1-One-Based Natural Product Antidiabetic Molecules as Inhibitors of Protein Tyrosine Phosphatase-1B (PTP-1B)
Published in Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Applied Pharmaceutical Practice and Nutraceuticals, 2021
Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Vivek Asati
The kinase enzyme, phosphoinositide 3-kinases (PI3K) downstream the metabolic signaling by phosphorylating the substrate PI to phosphatidylinositol biphosphate (PIP2), thereby activates the protein 3-phosphoinositide-dependent protein kinase-1 (PDK1).16 This cascade activates protein kinase-B (PKB) which is a sole component in the enrichment of glucose uptake by stimulating insulin-dependent GLUT4 translocation (Fig. 7.1).17
Bioactivity and mechanisms of flavonoids in decreasing insulin resistance
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Min Zhou, William H. Konigsberg, Canhua Hao, Yinbo Pan, Jie Sun, Xiaojing Wang
PI3K is a heterodimer with serine kinase activity capable of inducing the production of a second messenger phosphatidylinositol trisphosphate (PIP3), which interacts with other signalling proteins. As an important effector molecule, PI3K is a key regulatory node in converting extracellular signals activated by insulin and/or growth factors into intracellular activities13. The serine/threonine protein kinase Akt (Protein Kinase B, PKB) is composed of three isoforms, Akt1, Akt2, and Akt3. Among all isoforms of Akt, Akt2 is the most important isoform in insulin-mediated glucose uptake and lipid metabolism4. Phosphoinositide-dependent protein kinase-1 (PDK1) activates Akt by phosphorylating the threonine residue of Akt; subsequently, mammalian target of rapamycin complex 2 (mTORC2) completes the activation process of Akt by phosphorylating the serine residue of Akt3. Akt inhibits lipid breakdown by activating mTORC1 and promotes lipid synthesis by regulating sterol regulatory element-binding protein (SREBP) substrates. Activation of S6K1 by mTORC1 not only increases mRNA production and translation, but also participates in negative feedback regulation of insulin signalling through serine/threonine phosphorylation of IRS14. Targeting mTOR can disable the negative feedback loop, thereby reversing IR and helping to prevent and/or treat diabetes.
Overexpression of miR-181a regulates the Warburg effect in triple-negative breast cancer
Published in Climacteric, 2023
Y. Wang, H. Tahiri, C. Yang, M. Gu, X. Ruan, P. Hardy
To gain insight into the mechanisms underlying miR-181a-mediated suppression of the Warburg effect, we focused on several direct targets that have been implicated in the regulation of glycolysis in cancer cells. For example, AKT3 was identified as a direct target of miR-181a based on the presence of relevant binding sites within its 3′ untranslated region [38]. AKT3 is a member of the protein kinase B (PKB/AKT) family, which is a group of intracellular kinases that modulate cell proliferation and survival [39]. AKT3 has been identified as a critical mediator of the Warburg effect. Furthermore, both HIF-1 and PGRMC1 contribute to glucose uptake and metabolism and promote cancer cell survival and metastasis [40,41]. Thus, we performed quantitative PCR and western blot analysis to determine whether miR-181a regulates the expression of any or all of these genes upon its expression in MDA-MB-231 cells. As anticipated, overexpression of miR-181a resulted in significant reductions in the levels of AKT3, HIF-1α and PGRMC1 mRNA and protein (Figure 3). Taken together, these results suggest that miR-181a may modulate the expression of key factors associated with the AKT3/HIF-1α signaling pathway in TNBC cells, thereby suppressing the Warburg effect.
Gnetum montanum extract induces apoptosis by inhibiting the activation of AKT in SW480 human colon cancer cells
Published in Pharmaceutical Biology, 2022
Xianglong Pan, Xiaotao Hou, Fan Zhang, Peiling Tang, Wanruo Wan, Zixia Su, Yeguo Yang, Wei Wei, Zhengcai Du, Jiagang Deng, Erwei Hao
Apoptosis refers to the physiological death process of cells mediated by genes in accordance with their own pathway under a specific physiological or pathological condition to maintain the homeostasis (An et al. 2019; Ismail et al. 2019). According to Shariati and Meric-Bernstam (2019), AKT signalling pathway is closely related to cell apoptosis. AKT, also known as protein kinase B (PKB), is a serine/threonine kinase that mediates cell metabolism, proliferation, protein synthesis, survival and apoptosis (Liu et al. 2014; Manning and Toker 2017). It can be phosphorylated over 9000 proteins and it is an attractive therapeutic target in cancer (Mundi et al. 2016). Its kinase activity is positively mediated by the phosphorylation of the two key residues Thr308 and Ser473 (Liu et al. 2019). The activation of AKT signalling pathway can be governed by mainly phosphorylated AKT, glycogen synthase kinase-3β (GSK-3β), phosphoinositide dependent kinase-1 (PDK1) and Raf-1 proto-oncogene, serine/threonine kinase (c-Raf; Bamodu et al. 2020; Jiang et al. 2020). During cell cycle progression, AKT is phosphorylated and inhibits GSK-3β to prevent cyclin D1 degradation. Besides, PDK1, the 66-kD protein kinase phosphorylates AKT at Thr308. Phosphorylation of AKT negatively associated with the regulation of Raf-1 (Jun et al. 2012; Shorning et al. 2020). Numerous studies demonstrated that activation of AKT cascade often results in tumour aggressiveness and drug resistance in various types of human cancer (Chan et al. 2014; Neophytou et al. 2021).