• The Korean Journal of Pain
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• v.34 no.2
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• pp.176-184
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• 2021

Background: Diabetes-related neuropathic pain frequently occurs, and the underpinning mechanism remains elusive. The periaqueductal gray (PAG) exhibits descending inhibitory effects on central pain transmission. The current work aimed to examine whether inflammatory cytokines regulate mechanical allodynia and thermal hyperalgesia induced by diabetes through the phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathway in the PAG. Methods: Streptozotocin (STZ) was administered intraperitoneally to mimic allodynia and hyperalgesia evoked by diabetes in rats. Behavioral assays were carried out for determining mechanical pain and thermal hypersensitivity. Immunoblot and ELISA were performed to examine PAG protein amounts of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), as well as their corresponding receptors in STZ rats, and the expression of PI3K/protein kinase B (Akt)/mTOR signaling effectors. Results: Increased PAG p-PI3K/p-Akt/p-mTOR protein amounts were observed in STZ-induced animals, a PI3K-mTOR pathway inhibition in the PAG attenuated neuropathic pain responses. Moreover, the PAG concentrations of IL-1β, IL-6, and TNF-α and their receptors (namely, IL-1R, IL-6R, and tumor necrosis factor receptor [TNFR] subtype TNFR1, respectively) were increased in the STZ rats. Additionally, inhibiting IL-1R, IL-6R, and TNFR1 ameliorated mechanical allodynia and thermal hyperalgesia in STZ rats, alongside the downregulation of PI3K-mTOR signaling. Conclusions: Overall, the current study suggests that upregulated proinflammatory cytokines and their receptors in the PAG activate PI3K-mTOR signaling, thereby producing a de-inhibition effect on descending pathways in modulating pain transmission, and eventually contributing to neuropathic pain.

• Development and Reproduction
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• v.15 no.3
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• pp.197-204
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• 2011

Egg activation is a crucial step that initiates embryo development upon breaking the meiotic arrest. In mammalian, egg activation is accomplished by fusion with sperm, which induces the repeated intracellular $Ca^{2+}$- increases ($[Ca^{2+}]_i$ oscillation). Researches in mammals support the view of the $[Ca^{2+}]_i$ oscillation and egg activation is triggered by a protein factor from sperm that causes $[Ca^{2+}]_i$ release from endoplasmic reticulum, intracellular $[Ca^{2+}]_i$ store, by persistently activation of phosphoinositide pathway. It represents that the sperm factor generates production of inositol trisphosphate ($IP_3$). Recently a sperm specific form of phospholipase C zeta, referred to as PLCZ was identified. In this paper, we confer the evidence that PLCZ represent the sperm factor that induces $[Ca^{2+}]_i$ oscillation and egg activation and discuss the correlation of PLCZ and infertility.

• Journal of environmental and Sanitary engineering
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• v.16 no.3
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• pp.14-21
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• 2001

The effects of sodium molybdate(Mo) on phospholipid metabolism in sciatic nerve isolated from lead-intoxicated rat were investigated. Four weeks aged albino rats were divided into four groups : normal control group, lead(10 ppm)-treated group, Mo(1 mg/kg)-treated group, lead and Mo-treated group. As a result of the study, Mo significantly increased the rate of incorporation of $2-[^3H]$myo-inositol into polyphosphinositides in lead-intoxicated rat. Mo also increased the rate of phosphatidylcholine metabolism in normal and lead-intoxicated rats. However, Mo did not affect the metabolism of phosphatidylserine and phosphatidylethanola-mine in normal and lead-intoxicated status. These results suggest that Mo might improve lead-intoxicated status by principally enhancing the metabolism of myo-inositol-related phospholipids and by partly phosphatidylcholine in sciatic nerve.

• BMB Reports
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• v.42 no.1
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• pp.1-5
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• 2009

Synaptic vesicles (SVs) are key structures for synaptic transmission in neurons. Numerous membrane-associated proteins are sorted from the Golgi complex to the axon and the presynaptic terminal. Protein-protein and protein-lipid interactions are involved with SV targeting in neurons. Interestingly, many SV proteins have lipid binding capability, primarily with either cholesterol or phosphoinositides (PIs). As examples, the major SV protein synaptophysin can bind to cholesterol, a major lipid component in SVs, while several other SV proteins, including synaptotagmin, can bind to PIs. Thus, lipid-protein binding plays a key role for the SV targeting of synaptic proteins. In addition, numerous SV proteins can be palmitoylated. Palmitoylation is thought to be another synaptic targeting signal. Here, we briefly describe the relationship between lipid binding and SV targeting.

• YAKHAK HOEJI
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• v.48 no.2
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• pp.105-110
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• 2004

Akt (or Protein Kinase B; PKB) is a serine/threonine kinase and is activated by phosphoinositide 3-kinase (PI3K) pathway. Recent evidence indicates that the abnormal activities or expression of Akt is closely associated with cancer, diabetes and neuro-degenerative diseases. These findings mean that Akt is likely to be a new therapeutic target for the treatment of disease. Here, we screened the effects of dithiolo-dithione derivatives such as SWU-20004, SWU-20009 and SWU-20025 on Akt activities. Among these compounds, only SWU-20009 (2-Thioxo-[1,3]dithiolo[4,5- $\beta$][1,4]dithiine-5,6-dicarboxylic acid dimethyl ester) inhibited the growth of KATOIII cell at micromolar range of concentration. Further investigation also revealed that SWU-20009 inhibited cellular Akt activity and induced apoptotic cell death.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.2699-2701
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• 2013

The RAS family genes encode small GTP-binding cytoplasmic proteins. Activated KRAS engages multiple effector pathways, notably the RAF-mitogen-activated protein kinase, phosphoinositide-3-kinase (PI3K) and RalGDS pathways. In the clinical field, K-ras oncogene activation is frequently found in human cancers and thus may serve as a potential diagnostic marker for cancer cells in circulation. This mini-review aims to summarise information on Ras-induced oncogenesis and the clinical significance of K-ras.

• Bulletin of the Korean Chemical Society
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• v.23 no.10
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• pp.1451-1489
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• 2002

Sphingosine is known to regulate a wide range of cell physiology including growth, differentiation, and apoptosis. In this study, we examined the effect of sphingosine on the phospholipase D (PLD) activity in rat thymocytes. Sphingosine potently stimulated PLD in the absence of extracellular calcium, while depletion of intracellular calcium by BAPTA/AM treatment completely blocked activation of PLD by sphingosine. Sphingosine-induced increase of the intracellular calcium concentration was confirmed using a fluorescent calcium indicator Fluo-3/AM. A phosphoinositide-specific phospholipase C inhibitor U73122 partially inhibited the stimulation of PLD by sphingosine. When mouse PLD2 gene was transfected into mouse thymoma EL4 cells, which lack intrinsic PLD activity, sphingosine could stimulate PLD2 significantly while overexpression of human PLD1 had no effect. Taken together, the sphingosine-stimulated PLD activity in rat thymocytes is dependent on the mobilization of intracellular calcium and appears to be due to the PLD2 isoform.

• Tuberculosis and Respiratory Diseases
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• v.43 no.2
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• pp.123-127
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• 1996

Secretion of surfactant phospholipid can be stimulated by a variety of agonists acting via at least three different signal transduction mechanisms. These include the adenylate cyclase system with activation of cAMP-dependent protein kinase; activation of protein kinase C either directly or subsequent to activation of phosphoinositide-specific phospholipase C and generation of diacylglycerols and inositol trisphosphate; and a third mechanism that involves incresed $Ca^{2+}$ levels and a calmodulin-dependent step. ATP stimulates secretion via all three mechanisms. The protein kinase C pathway is also coupled to phopholipase D which, acting on relatively abundant cellular phospholipids, generates diacylglycerols that further activate protein kinase C. Sustained protein kinase C activation can maintain phosphatidylcholine secretion for a prolonged period of time. It is likely that interactions between the different signaling pathways have an important role in the overall physiological regulation of surfactant secretion.

• Biomolecules & Therapeutics
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• v.4 no.2
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• pp.148-153
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• 1996

Activation of the T lymphocytes results in a variety of early biochemical events ultimately leading to cell proliferation and lymphokine production. Stimulation of the signal transduction cascade in T cells through the T cell receptor coincides with activation of the phosphatidylinositol-phospholipase C (PI-PLC) pathway. Therefore, we have established a model system to screen immune-simulator that can increase the hydrolysis of phosphoinositides in human T cell leukemia Jurkat cells. As a result of screening from herbal medicine extract, 4 extracts (O1ibanum, Ephedrae Herba, Real Gar, Saussureae Radix) were found 14 increase the production of inositol phosphates. All the active fraction from the four kinds of extract were fluted in a different retention time on C-18 HPLC and these active fraction also showed difference in cell specificity. And all the active fractions increased DNA synthesis in T cell. Therefore, it is suggested that the active fraction among 4 extracts might contain a compound having different properties one another.

• Journal of Integrative Natural Science
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• v.9 no.1
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• pp.41-61
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• 2016

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Phosphoinositide 3-kinases (PI3Ks) play important role in Non-Small Cell Lung Cancer. PI3Ks constitute a lipid kinase family which modulates the function of numerous substrates involved in the regulation of cell survival, cell cycle progression and cellular growth. Herein, we describe the ligand based pharmacophore combined with molecular docking studies methods to identify new potent PI3K inhibitors. Several pharmacophore models were generated and validated by Guner-Henry scoring Method. The best models were utilized as 3D pharmacophore query to screen against ZINC database (Chemical and Natural) and the retrieved hits were further validated by fitness score, Lipinski's rule of five. Finally four compounds were found to have good potential and they may act as novel lead compounds for PI3K inhibitor designing.