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Role of Vasoactive Intestinal Peptide in Myocardial Ischemia Reperfusion Injury
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Dipak K. Das, Nilanjana Maulik, Richard M. Engelman
The accumulated data indicate that the physiological action of VIP is mediated through the adenylyl cyclase system (83). The a-adrenergic agonists were shown to act synergistically with VIP in cerebral cortex (84). In type I astrocytes from rat cerebral cortex, VIP at concentrations below 1 nm evoked an increase in intracellular Ca2+ concentration (85). Treatment of these astrocytes with 0.1 nM VIP together with an α-adrenergic receptor agonist, phenylephrine, at subthreshold concentrations produced a large increase in intracellular Ca2+ concentration and oscillations. VIP (0.1 nM) and phenylephrine were found to increase cellular levels of inositol phosphates. These observations suggested a calcium-mediated second messenger system for the high-affinity VIP receptor in astrocytes and that α-adrenergic receptors act synergistically with the VIP receptor to augment an intracellular Ca2+ signal.
Role of cAMP, Calcium, and Protein Phosphorylation in Sperm Motility
Published in Claude Gagnon, Controls of Sperm Motility, 2020
The important role that calcium plays in regulating sperm movement appears to be carefully coordinated not only with respect to the levels of calcium required to induce changes in motility, but also temporally in relation to sperm maturation, ejaculation, transit through the female tract, capacitation, and fertilization. With respect to protein phosphorylation, considerable attention has been paid to the possible role of protein kinase C and the inositol phosphate pathways in these processes.75 With respect to sperm, there is abundant evidence to support the role of polyphosphoinositide cleavage and coupled calcium release in the induction of the acrosome reaction.76-78 However, whether protein kinase C is involved in these processes is a question of controversy. Earlier work by Lee et al.79 suggested that protein kinase C was involved in the induction of the acrosome reaction in mouse sperm based on stimulation of the reaction by phorbol esters. On the other hand, more recent work by Roldan and Harrison80 suggests that in ram sperm, there is no active protein kinase C. Their conclusion is based upon: (1) a lack of effect of phorbol esters on protein phosphorylation, (2) no increase in phosphorylation coupled to calcium-ionophore-induced acrosomal loss, (3) no effect of phorbol ester on calcium-ionophore-induced acrosomal loss, and (4) no specific binding of 3H-phorbol ester to sperm protein. Thus, the possible role of protein kinase C in these processes requires more study.
Endothelin and Cardiac Hypertrophy
Published in Malcolm J. Lewis, Ajay M. Shah, Endothelial Modulation of Cardiac Function, 2020
ET-1 also stimulates phospholipase C-mediated breakdown of phosphoinositide (Resink et al., 1988) and increases cytosolic free Ca2+ levels, as a result of Ca2+ influx and mobilization (Hirata et al., 1988) in vascular smooth muscle cells and recent studies have shown that ET-1 induces Ca2+ influx as well as intracellular Ca2+ mobilization resulting from IP3 generation in rat atrial cells (Vigne et al., 1990). In addition, ET-1 increased accumulation of total inositol phosphates in rat cardiomyocytes (Shubeita et al., 1990; Ito et al., 1991). Hypertrophy of cardiomyocytes can also be provoked by TPA and the Ca2+ionophore ionomycin in a similar manner to ET-1. These studies therefore suggest that the activation of PKC and/or Ca2+ mobilization resulting from receptor-mediated phosphoinositide breakdown might be involved in the mechanism of the ET-1-induced hypertrophy of cardiomyocytes.
miR-100-5p is upregulated in multiple myeloma and involves in the pathogenesis of multiple myeloma through targeting MTMR3
Published in Hematology, 2023
Xiaofang Wei, Youfan Feng, Yuan Fu, Fei Liu, QiaoLin Chen, Wenjie Zhang, Yangyang Zhao, Xiujuan Huang, Yang Chen, Qingfen Li, Qike Zhang
Furthermore, protein network interaction analysis was performed to find out the major interacting proteins of these five targets and KEGG pathway analysis was performed to predicate the main cellular pathways these genes enriched. The results showed that the corresponding genes were obviously enriched in multiple pathways, especially inositol phosphate metabolism and phosphatidylinositol signaling system. Inositol phosphates are signaling molecules observed in all eukaryotes [30], and its metabolism involves several biological processes including but not limited to necroptosis [31], intracellular calcium signaling [32], and transcription [33]. Wei et al. have found that inositol phosphate metabolism is one of the most impaction metabolic pathways in early breast cancer [34], and Zhu et al. have suggested inositol phosphate metabolism as one of the most influential pathways contributing to colorectal cancer [35]. However, the influence of inositol phosphate metabolism in MM needs to be elucidated. Whereas, phosphatidylinositol signaling system, such as phosphatidylinositol 3-kinase signaling pathway, were extensively reported to be associated with the pathogenesis of MM [36,37].
TNP and its analogs: Modulation of IP6K and CYP3A4 inhibition
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Seulgi Lee, Bernie Byeonghoon Park, Hongmok Kwon, Vitchan Kim, Jang Su Jeon, Rowoon Lee, Milan Subedi, Taehyeong Lim, Hyunsoo Ha, Dongju An, Jaehoon Kim, Donghak Kim, Sang Kyum Kim, Seyun Kim, Youngjoo Byun
Inositol phosphates (IPs) have been recognised as second messengers that are involved in various biological processes ranging from growth to apoptosis1,2. Of these, inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5PP-IP5, abbreviated 5-IP7) harbour ‘high-energy’ diphosphate groups at 1- or 5-position of inositol hexakisphosphate (IP6, phytic acid). 5-IP7 is known to serve as a key signalling molecule critical for controlling insulin secretion, vesicle trafficking, growth signalling, telomere length regulation, migration, and cellular energy dynamics3–6. In mammals including humans, biosynthesis of 5-IP7 is catalysed by a family of three isoforms of IP6 kinases (IP6K1, IP6K2, and IP6K3). IP6Ks utilise ATP and IP6 to form a phosphoester bond, thereby 5-IP7 is produced7.
TGR5 agonists for diabetes treatment: a patent review and clinical advancements (2012-present)
Published in Expert Opinion on Therapeutic Patents, 2022
Rachana S. Bhimanwar, Amit Mittal
A series of bicyclic antidiabetic compounds (general structure 16) that act as TGR5 agonists were designed and synthesized by Merck Sharp Corp. in 2020. Different bicyclic rings such as isochromon, chromane, thiochromane, and naphthalene were tested with various substitutions at the A and B groups to design different compounds. Using HEK transfected with hTGR5 cells, the human IP1 assay was performed in vitro. A 384-well plate is incubated for 16 hours, and then fluorescence was measured for each test compound and extrapolated on the standard curve of inositol phosphate. Based on the activity analysis of representative compounds 16a-16e (Figure 15), the isochromone and naphthalene scaffold was a superior option with an EC50 value less than 1 µM compared to other scaffolds discussed in this patent. Compound 16a with isochromon scaffold showed potent agonistic activity with EC50 of 0.21 nM [43].