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Pharmacological and Surgical Interventions to Improve Brain Insulin Resistance
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Linus Haberbosch, Lukas Maurer, Reiner Jumpertz-von Schwartzenberg
Especially, the successful application of GLP-1-RA to modulate peripheral insulin secretion and action in patients with type 2 diabetes has attracted great attention within this context (3). GLP-1-RA increases glucose-dependent insulin secretion (incretin effect) of the beta cells. This effect is dependent on adenylate cyclase (ADCY) turn-over of ATP to cAMP which can activate exchange protein activated by cAMP (EPAC) leading to increased insulin granule exocytosis. Besides EPAC activation, insulin secretion can also be mediated by a protein kinase A-dependent pathway (Figure 13.1). However, GLP-1 agonism not only triggers insulin secretion but also induces insulin gene transcription and biosynthesis to replenish insulin stores of the beta cells. Insulin gene transcription and its biosynthesis are mediated by protein kinase A (PKA) dependent and independent signaling cascades, both stimulating the insulin transcription factor PDX-1 (Figure 13.1). The PKA-independent pathway of PDX-1 activation is mediated via phosphoinositide 3-kinase (PI-3K) and insulin receptor substrate 2 (IRS-2) activation (Figure 13.1).
Ischemic Inhibition of Calcium Slow Current in the Heart
Published in Samuel Sideman, Rafael Beyar, Analysis and Simulation of the Cardiac System — Ischemia, 2020
A test of whether the regulatory effect of cAMP is exerted by means of the cAMP-dependent protein kinase and phosphorylation was made by intracellular injection of the catalytic subunit (protein) of the cAMP-dependent protein kinase. Such injections induced and enhanced the slow APs6 and potentiated Isi.12 Another direct test of the phosphorylation hypothesis was done by intracellular injection (by the liposome method) of an inhibitor (protein) of the cAMP-dependent protein kinase into cultured chick heart cells.6 It was found that the inhibitor depressed and abolished the slow APs (Figure 8). Although some depolarization also occurred concomitantly, it was shown that the slow channels were blocked at larger take-off potentials produced by application of repolarizing current pulses. The effect of the inhibitor was rapidly reversed by injection of the catalytic subunit of the cAMP-dependent protein kinase. Thus, these results further support the phosphorylation hypothesis.
The Neurobiology of Central Sensitization
Published in Robert M. Bennett, The Clinical Neurobiology of Fibromyalgia and Myofascial Pain, 2020
The applicability of the entire signalling cascade described in CA1 is likely limited to a subpopulation of neurons in the dorsal horn. Administering exogenous CAMKII has been shown to enhance AMPA responses of dorsal horn neurons but expression of endogenous CAMKIIa is highly restricted within the dorsal horn. A protein kinase which is a
Therapeutic perspectives on the metabolism of lymphocytes in patients with rheumatoid arthritis and systemic lupus erythematosus
Published in Expert Review of Clinical Immunology, 2021
The glycolytic system is the major metabolic process involved in generating energy in immune cells. When T cells are exposed to specific antigens, co-stimulatory molecules activate PI3K and upregulate the expression of glucose transporter 1 (GLUT1), resulting in enhanced glucose uptake [26]. AMP-activated protein kinase (AMPK) plays an important role in the regulation of glucose metabolism. Activation of AMPK enhances glycolysis by increasing the expression of GULT and promoting glucose utilization [27]. Furthermore, the glycolytic system is more enhanced in the Th1, Th17, Tfh, and CD8+ cells compared to that in the quiescent cells [28,29] and is particularly important for Th1 and Th17 cell differentiation [29,30]. Overexpression of the GLUT1 gene in mouse T cells leads to increased glucose uptake and production of IL-2 and IFN-γ [31]. Deletion of GLUT1 decreases the utilization of glucose in the CD4 + T cells and suppresses their differentiation into effector T cells [32]. Blockade of the glycolytic system promotes Treg cell differentiation [29]. High expression of Glut1 is associated with Th cell activation and production of IL-17, which is associated with the disease severity of active SLE [33,34]. HIF1α is activated by mTOR and is involved in the differentiation of Th1, Th17, and CD8+ cells via enhanced glucose metabolism. HIF1α activity is promoted to induce Th1 and Th17 cell differentiation via glucolysis downstream of TCR signaling [35,36].
Systematic analysis of miRNAs in patients with postmenopausal osteoporosis
Published in Gynecological Endocrinology, 2020
Yulin Li, Zhongju Shi, Shiqing Feng
In our study, the functions of these differentially expressed miRNAs were also predicted via GO enrichment analysis. Consistent with previous studies, the miRNAs were involved in some key processes in PMOP. NF-κB was showed to regulate transcriptional activation of E2-ERα stimulated transient receptor potential vanilloid 5 expression, which is related to osteoclasts formation, bone resorption activity, and osteoclasts apoptosis [18]. Protein kinase A is considered as a regulator of some cellular functions, including sugar metabolism, immune response, and osteoblast differentiation [19–21]. A recent study found that linarin could induce the osteogenic differentiation and mineralization of osteoblastic cells via PKA signaling [19]. Furthermore, the promotion of osteoclasts apoptosis by estrogen is considered as the main reason in estrogen protecting from bone loss [22]. Therefore, the current study may provide more understanding of the effects of miRNAs on PMOP.
Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Daseul Im, Hyungwoo Moon, Jinwoong Kim, Youri Oh, Miyoung Jang, Jung-Mi Hah
Protein kinase inhibitors can be classified as type I, II, III, IV and V9 based on their binding mode. Among these inhibitors, type II kinase inhibitor can take advantage of selectivity acquisition and exhibits promising potency due to additional interaction with the DFG pocket adjacent to the ATP-binding pocket on top of the hinge hydrogen bond in the ATP site10. Previously, we reported very potent type II FMS inhibitors11 and selective benzimidazole-incorporated FLT3 inhibitors12. Here, we demonstrate that the amide or urea between the middle phenyl ring and the secondary hydrophobic aromatic ring can be rigidified further, introducing a quinazoline structure as a bioisostere (Figure 2). The quinazoline structures are well-known privileged structures in medicinal chemistry, exhibiting diverse biological activities13. However, this is the first attempt to incorporate one in type II PKI modification. Introducing quinazoline into type II FMS kinase inhibitor, we could discover a novel FLT3 inhibitor with excellent selective profile.