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Role of Vitamin D and Antioxidant Functional Foods in the Prevention and Treatment of Alzheimer’s Disease Pathology
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
New tools for the study of the molecular pathways affected by this disease include genome-wide association studies and genetic sequencing. Some of the gene families being identified as relevant in disease pathogenesis by these methods include APOE, BIN1, CLU, and CD33. Involved biological pathways include immune response (ABCA7, CD33, CLU, CR1. HLA locus, MEF2C, PTK2B, TREM2), lipid metabolism (ABCA), and endocytosis (BIN1, CD2AP, EPHA1, PICAALM, SORL1) pathways (Verheijen & Sleegers, 2018).
The Neurobiology of Central Sensitization
Published in Robert M. Bennett, The Clinical Neurobiology of Fibromyalgia and Myofascial Pain, 2020
candidate to substitute for CAMKII is protein kinase C [PKC] which potentiates synaptic transmission in dorsal horn neurons and elsewhere. In CA1 PKC has been implicated in initiating LTP but recent evidence indicates that it is likely upstream of Src and its effects mediated via the protein tyrosine kinase [CAK|3/Pyk2] (II). In the dorsal horn PKC could play a dual role, phosphorylating AMPA receptors and stimulating CAK|i/Pyk2-Src signalling, or alternatively, phosphorylation of AMPA receptors may be produced by an as yet unidentified serine/ threonine kinase.
Acute Lymphoblastic Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The 2016 classification highlights the unique association between low hypodiploid ALL and germline TP53 mutations and includes four new provisional entities: B-ALL with intrachromosomal amplification of chromosome 21 (iAMP21), in which the RUNX1 gene reveals >5 copies of the gene (or >3 extra copies on a single chromosome 21), and B-ALL with translocations involving tyrosine kinases or cytokine receptors (‘BCR-ABL1-like’). This subtype is particular important due to the poor prognosis and potential responses to TKI therapies, including ABL1 TKIs (Table 5.2). Patients with BCR-ABL1-like ALL may involve rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP or TYK2, and sequence mutations involving FLT3, IL7R or SH2B3. They can also show loss of IKZF1 and CDKN2A/B, which can occur at high frequency in other types of ALL also. The new T-ALL entities are early thymic precursor (ETP)-ALL, which is characterized by the frequent presence of myeloid-associated mutations, such as FLT3, NRAS/KRAS, DNMT3A, IDH1 and IDH2, compared to the presence of NOTCH1 or CDKN2A/B in ‘typical’ T-ALL.
Review of the mechanism underlying mefloquine-induced neurotoxicity
Published in Critical Reviews in Toxicology, 2021
Airton C. Martins, Monica M. B. Paoliello, Anca O. Docea, Abel Santamaria, Alexey A. Tinkov, Anatoly V. Skalny, Michael Aschner
GSH is the main non-enzymatic cellular antioxidant with wide effects as a mediator in xenobiotic metabolism, cellular signaling and reactions of exchange between thiol and disulfide groups (Paul et al. 2018). F-2-soPs is a product of lipid peroxidation derived from arachidonic acid that is used as a marker for lipid peroxidation (Montine et al. 2005). Pyk2 is a member of focal adhesion kinase (FAK) family and a mediator in many signaling pathways implicated in the survival of neuronal synapsis. It acts through activation of MAP kinase signaling pathway and calcium-induced regulation of ion channels. Pyk2 expression is activated mainly by stress stimuli (Montalban et al. 2019). Hood et al. (2010) investigated the effect of mefloquine (1–10 μM) on primary rat cortical neurons and showed a dose-dependent increase in oxidative stress level translated by a decrease in glutathione (GSH) levels and an increase of F2-isoprostanes (F-2-isoPs) levels associated with the degeneration of the dendritic spines. Further studies showed that these effects are in part modulated by Pyk2 (cell-adhesion kinase β, CAKβ). Therefore, suppression of PyK2 may decrease the cytotoxic effects of mefloquine, but its efficacy in mefloquine—oxidative stress suppression is low and only occurs under conditions where greater than 35% of Pyk2 expression is downregulated (Milatovic et al. 2011).
FAK inhibitors in Cancer, a patent review
Published in Expert Opinion on Therapeutic Patents, 2018
Peng-Cheng Lv, Ai-Qin Jiang, Wei-Ming Zhang, Hai-Liang Zhu
Proline-rich tyrosine kinase 2 (Pyk2) is a non-receptor cytoplasmic tyrosine kinase within the FAK subfamily. Both Pyk2 and FAK are involved in multiple signaling pathways that regulate cell migration, proliferation, and survival [15,29]. The catalytic domains of Pyk2 and FAK kinases have 73% sequence similarity. The similarity is slightly higher (78%) for residues generally thought to form the ATP binding sites of these two enzymes [30]. Consequently, the discovery of a small molecule inhibitor selective for Pyk2 has been challenging. Farand et al. initiated efforts toward that goal for proof-of-concept studies and focused their attention on diaminopyrimidine-based inhibitors 10 (PF-431,396, Scheme 2), 11 (PF-562,271) and 12. Compound 11 (PF-562,271) was described as a potent, ATP-competitive and reversible FAK inhibitor (IC50 = 1.5 nM) with a 9-fold selectivity over Pyk2 (IC50 = 13 nM) [31–35]. The newly synthesized acyclic diaminopyrimidines 13 and 14 showed IC50 of 3.3 nM and 177 nM against FAK, and IC50 of 256 nM and 201 nM against Pyk2, respectively [36].
Pyk2 inhibitor prevents epithelial hyperpermeability induced by HMGB1 and inflammatory cytokines in Caco-2 cells
Published in Tissue Barriers, 2021
Takumi Konno, Takayuki Kohno, Maki Miyakawa, Hiroki Tanaka, Takashi Kojima
Protein tyrosine kinase 2β (Pyk2), which is also known as FAK2/RAFTK, is a member of the focal adhesion PTK family. Pyk2/FAK2 can be activated by a variety of extracellular signals that elevate the intracellular calcium concentration and by stress signals.12 Pyk2 phosphorylates angulin-1/LSR and enhances localization of angulin-1/LSR and TRIC at tTJs.11 PF431396 (PF43), which is an inhibitor of Pyk2, suppresses the recruitment of LSR and TRIC from tTJs to bTJs and cytoplasmic regions.11 However, the effects of PF43 on the epithelial barrier and permeability remain unknown.