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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)
Malignant Melanoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
The mitogen-activated protein kinase (MAPK) signaling pathway is a key intracellular signaling pathway involved in cell growth, differentiation, and survival. Genetic mutations affecting key components of this pathway have been implicated in many different tumors including melanoma. Activation of the pathway occurs upon ligand-cell surface receptor tyrosine kinase binding. This causes downstream activation of Ras, a G protein with multiple isoforms, the most important in melanoma being NRAS. Phosphorylation and activation of the RAF proteins then occurs as a consequence of RAS activation. The RAF proteins, BRAF and CRAF, dimerize to activate extracellular signal-regulated kinase (ERK) which in turn activates downstream pathways to promote cell growth, differentiation, and survival.
MAPK signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Archana Devi, Bhavana Kushwaha, Gopal Gupta
Mitogen-activated Ser/Thr protein kinases (MAPKs) are the most conserved classical pathways of signal transduction associated with an array of physiological activities such as proliferation, growth, migration, differentiation and cell survival (14–16). Mammalian cells express four MAPK families: the classical extracellular signal-regulated MAP kinase (ERK1/2), the stress-activated protein kinase/c-Jun N-terminal protein kinases (SAPK-JNK), the p38 protein kinase (α, β, γ and δ) and the ERK5, which are activated by a specific MAPK kinase or MAPKK or MAP2K (17). All MAPKKs show redundancy for activation that adds up to the complexity and diversity in MAPK signaling cascades. Various signals from cell surface receptors are transduced directly or by means of small proteins, to a number of protein kinases that amplify these cues and lead to a physiological response in the cell (Table 10.1).
Papain exerts an anti-atherosclerosis effect with suppressed MPA-mediated foam cell formation by regulating the MAPK and PI3K/Akt-NF-κB pathways
Published in Expert Opinion on Therapeutic Targets, 2023
Xianming Fei, Lianlian Pan, Wufen Yuan, Yan Zhao, Lei Jiang, Qinghua Huang, Yan Wu, Guoqing Ru
Nuclear factor-κB (NF-κB, p65) signaling is an important regulator of endothelial cell adhesion molecules in vascular inflammation. Monocyte-endothelial cell adhesion is a major promoter of inflammatory vascular diseases such as atherosclerosis [8,9]. Besides, activation of PI3K: phosphoInositide-3 Kinase (PI3K)/Akt (protein kinase B, PKB) signaling induces monocyte chemotaxis, macrophage migration, increased intracellular lipid accumulation, neovascularization, and lesion dysfunction, all of which are associated with plaque formation [9,10]. The mitogen-activated protein kinase (MAPK) signaling pathway has been implicated in a variety of biological processes, such as tissue development, cell proliferation, apoptosis, inflammation, and cancer. What’s more, MAPK is activated by various extracellular inducers of inflammation, which are highly abundant in atherosclerotic and calcific aortic valve disease lesions [11,12].
S-Propargyl-cysteine prevents concanavalin A-induced immunological liver injury in mice
Published in Pharmaceutical Biology, 2022
Beilei Ma, Yicheng Mao, Lingling Chang, Tao Dai, Xiaoming Xin, Fenfen Ma, Zhijun Wang, Zhuqing Shen, Qibing Mei, Yizhun Zhu
Previous studies have established that the release of inflammatory cytokines leads to liver injury after the Con A injection. The mitogen-activated protein kinase (MAPK) signalling pathway has previously been described to regulate the production of inflammatory cytokines. In this pathway, activation of c-Jun N-terminal kinase (JNK) and protein kinase B (Akt) has been reported to play an important role in hepatitis and determine the fate of the hepatocytes (death or survival). In this study, western blot analysis of phosphorylated JNK (p-JNK) and phosphorylated Akt (p-Akt) revealed increased expressions of these proteins in the livers of mice intoxicated with Con A after 12 h. On the contrary, SPRC (10 mg/kg) administration reduced the expressions of p-JNK (p < 0.01 vs. Con A) and p-Akt (p < 0.05 vs. Con A). This result indicated that SPRC pre-treatment suppressed the activation of the MAPK pathway (Figure 4). However, this suppression was reversed by the CSE inhibitor PAG.
Antioxidant and Immunomodulatory Properties of Partially purified Exopolysaccharide from Lactobacillus Casei Isolated from Chinese Northeast Sauerkraut
Published in Immunological Investigations, 2022
Xiaoqing Xu, Yu Qiao, Qing Peng, Bo Shi, Vermont P. Dia
ROS are highly reactive-free radicals or nonradical molecules that are generated by many potential cellular sources such as nicotinamide adenine dinucleotide phosphate oxidases (NOX) and others (Kim et al. 2017). Macrophages generate ROS when they take part in host cell defense mechanisms and studies have demonstrated that ROS are involved in cell signaling activation and gene expression regulation (Hancock et al. 2001). Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway was involved in regulating transcription of DNA, cytokine production, and cell survival, which can be activated by ROS, TNF-α, IL-1β, LPS, and others (Chandel et al. 2000). Mitogen-activated protein kinase (MAPK) is a signaling pathway involved in regulating cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis (Pearson et al. 2001). C-jun N-terminal kinases (JNKs) is a main branch of MAPK, activated by translocation from the cytoplasm into the nucleus of the cells. Some studies showed that ROS production was responsible for the activation of NF-κB and p38 MAPK signaling pathways, which promoted the expression of pro-inflammatory genes in macrophages (Rendra et al. 2019). It also has been proven that NF-κB and MAPK signaling pathways play a key role in regulating immune response by polysaccharides (Wang et al. 2019a). Therefore, NF-κB and MAPK are essential transcription factors in regulating the immune and inflammatory responses.