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Insulin Resistance as a Risk Factor for Alzheimer's Disease
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Miren Ettcheto, Amanda Cano, Elena Sanchez-Lopez, Carme Auladell, Jaume Folch, Antoni Camins
Related to the insulin pathway, previous studies have reported that ceramides are involved in the IR onset through different processes such as the activation of the NLRP3 sensor which promotes IL-1β-induced inflammation. In consequence, plasma glucose and insulin sensitivity in individuals with T2DM is reduced, inhibiting PI3K/AKT signalling pathway (117). In addition, increased ceramide production can stress the ER contributing to the development of IR and lipolysis, leading to an increased ceramide production and enhancing neuroinflammatory processes. Therefore, the dysregulated lipid metabolism promotes an excess of ceramides generation that exacerbate IR, neuroinflammation, brain damage, and synaptic loss.
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Studies have shown that the Akt signaling cascade is frequently impaired in many tumor types due to mutations and in some may be associated with enhanced growth and invasive ability. Despite promising data from many in vitro and in vivo studies over several years, at the time of writing no Akt inhibitors have reached the approval stage, although some have reached late clinical trials. The most prominent of these are briefly described below.
Markers of Sensitivity and Resistance to EGFR Inhibitors in Colorectal Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Jose G. Monzon, Janet E. Dancey
Less common genetic alterations that may activate AKT signaling and substitute for PIK3CA mutations include amplification of insulin receptor substrate 2 (IRS2), loss of PTEN expression, or co-amplification of AKT and PAK4 [24]. The latter two alterations are downstream mediators of PI3K signaling, while IRS2 is an upstream activator of PI3K. Of these alterations, the best characterized is the inactivation of the tumor suppressor gene PTEN, which encodes a phosphatase that dephosphorylates a lipid second messenger, phosphatidyllinositol (3,4,5) triphosphate (PIP3) to phosphatidylinositol (4,5) biphosphate (PIP2). PIP3 is the primary product of PI3K activity and its production antagonizes PI3K function and activates downstream signaling components, most notably the protein kinase AKT. Hence, the dephosphorylation of PIP3 is important because it results in the inhibition of the AKT signaling pathway. Loss of PTEN activity and subsequent loss of inhibition of AKT signaling is sufficient to cause a cancer phenotype by increasing cellular proliferation and reducing cell death. The PTEN gene may be inactivated via somatic mutations, allelic losses, and epigenetic hypermethylation [27–29].
Neuroinflammation after ischemic stroke involves INPP5D expression mediated by the TMPO-AS1-PU.1 complex
Published in Neurological Research, 2023
Wenhui Luan, Zhongwen Sun, Chunmei Wu, Manli Tao, Xiaoqian Shen
Akt signaling pathway is an important survival and anti-apoptotic signal transduction pathway, which plays an important biological function in apoptosis, survival, proliferation, cytoskeleton changes and other activities [32]. Numerous studies showed that AKT pathway activation has a repairing effect on brain damage after ischemic stroke [33,34]. The gene INPP5D encodes the SH2-containing inositol 5-phosphatase 1(SHIP1), which is a negative regulator of PI3K/AKT signaling. SHIP-1 overexpression inhibits the phosphorylation of PI3K/Akt, thereby promoting phagocytosis of macrophages and promoting the transformation of macrophages to an anti-inflammatory phenotype [35]. Our study found that sh-TMPO-AS1 treatment could promote the activation of AKT in BV2 cells induced by OGD/R, and the overexpression of INPP5D could reverse the effect of sh-TMPO-AS1 treatment. Similarly, PU.1 interference could promote the activation of AKT in BV2 cells induced by OGD/R, and promote the transformation of BV2 cell phenotype from M1 to M2, and the overexpression of INPP5D could reverse the effect of PU.1 interference. In vivo, sh-TMPO-AS1 treatment improved the infarct volume of MCAO mice, and improved sensorimotor and cognitive functions, as well as neuroinflammation in the brain tissue of mice.
Buyang Huanwu decoction improves neural recovery after spinal cord injury in rats through the mTOR signaling pathway and autophagy
Published in The Journal of Spinal Cord Medicine, 2023
Ying Nie, Yujie Fan, Xi Zhang, Xiaosong Li, Jian Yin, Meili Li, Zhaoyong Hu, Liang Li, Xiaoye Wang
It is generally accepted that activating PI3K/Akt signaling pathways with downstream mTOR protein complexes helps prevent cellular death and enhance cell processes related to growth and proliferation. After SCI, the deletion of PTEN or its function promoted the activity of downstream PI3K/Akt and mTOR signaling pathways, enhanced axonal regeneration after SCI,19 decreased the atrophy of motor neurons,20 and improved nerve survival.13,21 Normally, PI3K/AKT signaling downstream mTOR is inactivated in the neurons of the spinal cord.22 However, drugs like bisperoxovanadium significantly promoted mTOR signaling pathway and inhibited autophagy, thus enhanced strong neuroprotective effects by decreasing the death of motor neurons, promoting tissue sparing, reducing cavity formation, and improving forelimb motor function in rats.14 Similarly, in the present study, BL, BM moderately, and BH significantly increased mTOR mRNA expression and protein levels, suggesting that BYHWD might exert its neuroprotective effects through mTOR signaling pathway.
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).