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Hypothalamic Neuronal Circuits Are Modulated by Insulin and Impact Metabolism 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Tadeu de Oliveira Diz, Sabela Casado, Rubén Nogueiras, Sulay Tovar
The mammalian target of rapamycin (mTOR) is a serine-threonine-kinase that, when activated, generates that is able to activate an important cascade pathway found in different cell types and involved in different roles, from cell growth to energy homeostasis (131). The mTOR is characterized by having two complexes, mTORC1 and mTORC2, which have different constitutions and act in different ways and in different locations (132). The activity of the mTORC1 complex in the hypothalamus depends on insulin binding with its receptor in the plasma membrane. Upon activation of IRS1, PI3K is stimulated and consequently phosphorylates PDK1 and AKT. Then, AKT is responsible for phosphorylating the TSC1-TSC2 (Tuberous sclerosis proteins 1 and 2) complex, leading to its inactivation and thus enabling the Rheb-GTP (Ras homolog enriched in brain) activity on mTORC1 (133, 134). With mTORC1 activated, the S6K1 (Ribosomal protein S6 kinase β-1) protein becomes a target for phosphorylation to generate a cellular response.
Medical Therapies
Published in Nazar N. Amso, Saikat Banerjee, Endometriosis, 2022
Simone Ferrero, Fabio Barra, Giulio Evangelisti, Matteo Tantari
Mammalian target of rapamycin (mTOR) is a protein kinase that controls cellular growth, proliferation, and survival (113). In fact, it has been suggested that PI3K/AKT/mTOR pathway may significantly modulate survival, proliferation of endometriotic cells and angiogenesis in endometriotic implants, and that it may also be involved in resistance to progestins (114,115). Rapamycin, a bacterial macrolide, is known to inhibit this pathway and antiangiogenic activity (116). In the animal model, rapamycin succeeded in decreasing the size of the endometriotic implants by inhibiting VEGF-induced angiogenesis, as indicated by the suppression of endothelial cell sprouting in vitro and the reduction of micro vessel density in implants (117). Temsirolimus, an inhibitor of mTOR/AKT pathway, demonstrated to decrease endometriotic cell proliferation in mouse models (118).
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
Curcumin, isolated from Curcuma longa L., inhibited the proliferation of human malignant melanoma cells (A375 and C8161) in a dose- and time-dependent manner. The whole-cell lysates of human cutaneous malignant melanoma cell lines (A375 and C8161) treated with curcumin were analyzed through Western blotting. This analysis revealed that p-Akt and p-mTOR were downregulated, suggesting that the induction of autophagy was through the inhibition of the PI3K/Akt/mTOR pathway (Zhao et al., 2016). The inhibition of JNK and ERK 1/2 was evaluated through Western blotting using whole-cell lysates from A375 cells treated with natural borneol and curcumin. The phosphorylation of JNK and ERK 1/2 was significantly reduced by the combination of natural borneol and curcumin (Chen et al., 2014).
The therapeutic prospect of zinc oxide nanoparticles in experimentally induced diabetic nephropathy
Published in Tissue Barriers, 2023
Samia A. Abd El-Baset, Nehad F. Mazen, Rehab S. Abdul-Maksoud, Asmaa A. A. Kattaia
Several factors are included in the pathogenesis of DN e.g., genetic factors, hemodynamics, oxidative stress, and inflammation.51,52 Autophagy is implicated in the pathogenesis of DN. It maintains the homeostasis of intracellular environment by degradation of proteins and peroxidases.53 Diabetes affects podocyte autophagy through autophagy-related (Atg) protein conjugation system and mTOR regulation.54 Induction of mTOR plays a crucial role in inhibition of pathways of autophagy.17 According to the results of our work, the diabetic group showed an intense mTOR immune reaction in both tubular and glomerular cells. Apoptosis is also enhanced as evidenced by the significant increase in p53 immune expression. Bhang et al.55 reported that activation of mTOR aggravates podocyte apoptosis and facilitates the advance of DN. The loss of podocytes by apoptosis impairs the glomerular filtration barrier and characterizes the early stages of DN.
T-cell acute lymphoblastic leukemia: promising experimental drugs in clinical development
Published in Expert Opinion on Investigational Drugs, 2023
High Pl3K-AKT-mTOR signaling is frequently observed in T-ALL and can be caused by cellular events involving mutations in Pl3K or AKT, mutations and deletions of PTEN, or IL7R signaling mutations. These mutations are particularly observed in the TAL1 subgroup. Pl3K inhibitors have shown efficacy in growth cell inhibition and survival of T-ALL cell lines and in vitro studies in synergy with various chemotherapeutic agents [51]. Recently, dual Pl3K/mTOR inhibitors have also shown synergistic efficacy with chemotherapeutic agents [52]. Another synergistic approach targets both PI3K and NOTCH1 through treatment with PI3K/mTOR inhibition by upregulating NOTCH1 target genes such as MYC. The first generation of mTOR inhibitors, including rapamycin (sirolimus), RAD001 (everolimus), and CCI-779 (temsirolimus), has demonstrated efficacy in T-ALL [53]. However, the second generation of inhibitors was shown more efficient by interfering with more downstream Pl3K-AKT-mTOR signaling effectors (Figure 1). Dual inhibitors demonstrated more efficacy than Pl3K- or mTOR only inhibitors. Direct AKT inhibition also showed efficacy. Inhibitors, such as MK-2206 and AZD5363, demonstrate cytotoxic effect against T-ALL cells and synergy with steroids in cell samples from patients with T-ALL [54,55]. Current ongoing trials are indicated in Table 3.
Polyphyllin II induced apoptosis of NSCLC cells by inhibiting autophagy through the mTOR pathway
Published in Pharmaceutical Biology, 2022
Yuhan Jiao, Ming Xin, Juanjuan Xu, Xindong Xiang, Xuan Li, Jingjing Jiang, Xiuqin Jia
Autophagy is a dynamic process in which part of the cytoplasm is isolated in autophagosomes and then degraded when fused with lysosomes (Chifenti et al. 2013). It is generally believed that LC3-II, as the key autophagy marker, is essential for the formation of autophagosomes (Kabeya et al. 2000). The p62 is negatively correlated with autophagy activity as an autophagy marker. The protein binds to LC3 directly and is degraded during autophagy (Klionsky et al. 2021). In our research, we studied the transformation of LC3-I to LC3-II, and found that the protein level of LC3-II/LC3-I ratio was increased significantly, while p62 was decreased when cells were exposed to PPII (Figure 3(A)). Overall, PPII treatment increased the formation of autophagosomes and autophagic flux. The formation of autophagic vacuoles was detected by MDC staining (Figure 3(B)), and autophagy flux was detected by the dual fluorescence mRFP-GFP-LC3 system. These results further confirmed that PPII induced autophagy (Figure 4). As is well known, cell signalling pathways are involved in the regulation of autophagy, such as the mTOR signalling pathway, which plays an important role in regulating autophagy of cancer cells. Inhibition of mTOR can trigger autophagy and increase autophagy-related protein levels (Callens et al. 2021). Our results showed that p-mTOR was decreased with increasing concentration of PPII (Figure 5), indicating that PPII may induced autophagy by down-regulating the mTOR signalling pathway.