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Metallopharmaceuticals
Published in Varma H. Rambaran, Nalini K. Singh, Alternative Medicines for Diabetes Management, 2023
Varma H. Rambaran, Nalini K. Singh
The intracellular action of chromium is still ungrounded, but studies have shown plausible evidence that, like vanadium, it binds to both IRTK and PTP-1B (Mechanisms 1 and 2) (R. A. Anderson 1998). Other studies have shown that it also assists in the promotion of insulin-induced glucose uptake via amplifying the activation of Akt (Mechanism 3) (Figure 4.6) (Peng and Yang 2015).
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.
Neurodegeneration in Diabetes Mellitus
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Narsingh Verma, Smriti Rastogi
GSK3b is a member of the proline directed serine–threonine kinase family and plays a central role in insulin signaling pathway. It phosphorylates τ protein. GSK3b function is controlled by phosphorylation at different sites. AKT is a major GSK3b inhibitor being activated upon disturbed insulin signaling pathway in Alzheimer’s and diabetes.16
Network pharmacology approach and experimental verification of Dan-Shen Decoction in the treatment of ischemic heart disease
Published in Pharmaceutical Biology, 2023
Difei Gong, Tianyi Yuan, Ranran Wang, Shuchan Sun, Awaguli Dawuti, Shoubao Wang, Guanhua Du, Lianhua Fang
The PPI network showed the potential interaction between the 122 targets, and then we selected 15 hub genes from this network based on the degree value. Among them, AKT1 is a serine/threonine protein kinase that is involved in various biological processes such as cell proliferation, metabolism, insulin signalling and angiogenesis (Chen et al. 2017). Recent studies have found that AKT is involved in regulating the biological process of cardiomyocyte apoptosis in the IHD model (Han et al. 2018; Huangfu et al. 2020). The JAK2/STAT3 signalling pathway is thought to be an important anti-IHD pathway because it can regulate myocardial apoptosis and reduce mitochondrial oxidative stress injury (Chen et al. 2020; Lan et al. 2019). Furthermore, the JNK signalling pathway is a critical cellular transduction channel for cardiomyocyte death and plays an important role in the development of cardiac ischemia–reperfusion. Studies have found that salvianolic acid A may increase the expression of thioredoxin (Trx) and inhibit the activation of JNK to reduce apoptosis and inflammation after MI (Zhou et al. 2020).
AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis
Published in Hematology, 2023
Yunjian Li, Liang Du, Kaiqin Ye, Xiao Sun, Lei Hu, Shan Gao, Haiming Dai
PI3K/AKT signaling plays important role in regulating cellular functions. Moreover, activation of PI3K/AKT/mTOR signaling contributes to the pathogenesis of many cancer types. For example, PI3Ks have been reported to be involved in cell growth, proliferation, differentiation and intracellular trafficking, which in turn contribute to cancer development [58]. AKT is functionally activated or deactivated through phosphorylation or dephosphorylation, resulting in different consequences in controlling cell metabolism, growth, proliferation, and survival [59]. The activated AKTs affect cellular proliferation or survival through multiple downstream signaling pathways, such as activating the pathway for the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), or suppression of the p53 pathway [60]. Gsk690690 and MK-2206 are AKT inhibitors that effectively inhibit AKT1, AKT2, and AKT3. In particular, MK-2206 is an allosteric inhibitor of AKT with activity against all three AKT isoforms but has more inhibition against AKT1 and AKT2 [61]. MK-2206 has been under clinical trials for endometrial cancer [62], uterine serous carcinoma [63], and breast cancer [64].
Neuroprotective effect of Morin via TrkB/Akt pathway against diabetes mediated oxidative stress and apoptosis in neuronal cells
Published in Toxicology Mechanisms and Methods, 2022
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that released from the central nervous system plays an important role in cell proliferation, synaptic function, morphogenesis, neurotransmission and protect neuronal cells from oxidative stress-mediated via TrkB (Tyrosine kinase receptor B) pathway (Murillo Ortíz et al. 2016). TrkB is a member of the tropomyosin-related kinase family. BDNF has high affinity to the TrkB receptor. It promotes cell survival, synaptic plasticity, development and differentiation of neurons. Binding BDNF to TrkB receptor elicits various intracellular signaling pathways, including phosphatidylinositol 3-kinase (PI3K)-Akt pathway (Meng et al. 2017; Baek and Kim 2020). Akt, a serine/threonine-protein kinase B (PKB), is the primary protein effector downstream of the PI3K signaling pathway. Akt has a vital role in glucose metabolism by regulating the biological function of insulin (Meng et al. 2017). Akt persuade the translocation of glucose transporter type 4 (GLUT4) to the plasma membrane, thereby mediating glucose uptake. Besides, Akt phosphorylates and inhibits the activity of glycogen synthase kinase 3 (GSK3), which enhance the activity of glycogen synthase and stimulates glycogen synthesis. As well, Akt being the major apoptosis-inhibiting protein, previous experimental studies have shown that the Akt signaling pathway is concerned with the pathophysiological processes of diabetes mellitus and its complications (He et al. 2017; Meng et al. 2017; Lu et al. 2017; Sifuentes-Franco et al. 2018).