• The Korean Journal of Physiology and Pharmacology
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• v.27 no.4
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• pp.345-356
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• 2023

This study aimed to assess the effects of exogenous hydrogen sulfide (H₂S) on abdominal aorta coarctation (AAC) induced myocardial fibrosis (MF) and autophagy in rats. Forty-four Sprague-Dawley rats were randomly divided into control group, AAC group, AAC + H₂S group, and H₂S control group. After a model of rats with AAC was built surgically, AAC + H₂S group and H₂S group were injected intraperitoneally with H₂S (100 µmol/kg) daily. The rats in the control group and the AAC group were injected with the same amount of PBS. We observed that H₂S can improve left ventricular function and the deposition of myocardial collagen fibers, inhibit pyroptosis, down-regulate the expression of P-eif2α in myocardial tissue, and inhibit cell autophagy by activating the phosphatidylinositol 3-kinase (PI3K)/AKT1 signaling pathway (p < 0.05). In addition, angiotensin II (1 µM) H9c2 cardiomyocytes were injured in vitro experiments, and it was also observed that pyroptosis was inhibited after H₂S (400 µmol/kg) intervention, the expression of P-eif2α in cardiomyocytes was significantly down-regulated, and the PI3K/AKT1 signaling pathway was activated at the same time. Therefore, increasing the expression of P-eif2α reverses the activation of the PI3K/AKT1 signaling pathway by H₂S. In conclusion, these findings suggest that exogenous H₂S can ameliorate MF in rats with AAC by inhibiting pyroptosis, and the mechanism may be associated with inhibiting the phosphorylation of eif2α and activating the PI3K/AKT1 signaling pathway to inhibit excessive cell autophagy.

• Biomolecules & Therapeutics
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• v.22 no.4
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• pp.308-313
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• 2014

Activator protein-1 (AP-1) is an inducible transcription factor that contributes to the generation of chronic inflammation in response to oxidative and electrophilic stress. Previous studies have demonstrated that the PI3K/Akt1 pathway plays an important role in the transcriptional regulation of AP-1 expression. Although the histone post-translational modifications (PTMs) are assumed to affect the AP-1 transcriptional regulation by the PI3K/Akt pathway, the detailed mechanisms are completely unknown. In the present study, we show that heterochromatin 1 gamma ($HP1{\gamma}$) plays a negative role in TPA-induced c-Jun and c-Fos expression. We show that TPA-induced Akt1 directly phosphorylates $HP1{\gamma}$, abrogates its suppressive function and increases the interaction between histone H3 and 14-3-$3{\varepsilon}$. Collectively, these our data illustrate that the activation of PI3K/Akt pathway may play a permissive role in the recruitment of histone readers or other coactivators on the chromatin, thereby affecting the degree of AP-1 transcription.

• Journal of Life Science
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• v.32 no.2
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• pp.86-93
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• 2022

Lupeol is a type of pentacyclic triterpene and has been reported to have pharmacological activities against various diseases; however, the effect of lupeol on glucose absorption has not been elucidated yet. This study aimed to investigate the effect of lupeol on glucose uptake in 3T3-L1 adipocytes. Lupeol significantly facilitated glucose uptake by translocating glucose transporter type 4 (GLUT4) to the plasma membrane of the 3T3-L1 adipocytes, which was related to activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and 5 'adenosine monophosphate-activated protein kinase (AMPK) pathways. In the PI3K/AKT pathway, lupeol stimulates the phosphorylation of insulin receptor substrate 1 (IRS-1), which activates PI3K. Its activation by lupeol promotes the phosphorylation of AKT, but not the atypical protein kinase C isoforms ζ and λ. Lupeol also promoted the phosphorylation of AMPK. The activation of AMPK increased the expressions of the plasma membrane GLUT4 and the intracellular glucose uptake. The increase in the glucose uptake by lupeol was suppressed by wortmannin (PI3K inhibitor) and compound C (AMPK inhibitor) in the 3T3-L1 adipocytes. The results indicate that lupeol can facilitate glucose uptake by increasing insulin sensitivity through the stimulation of the expression of plasma membrane glucose transporter type 4 via the PI3K/AKT and AMPK pathways in the 3T3-L1 adipocytes.

• The Korean Journal of Physiology and Pharmacology
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• v.12 no.2
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• pp.37-41
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• 2008

Melatonin has been reported to protect neurons from a variety of neurotoxicity. However, the underlying mechanism by which melatonin exerts its neuroprotective property has not yet been clearly understood. We previously demonstrated that melatonin protected kainic acid-induced neuronal cell death in mouse hippocampus, accompanied by sustained activation of Akt, a critical mediator of neuronal survival. To further elucidate the neuroprotective action of melatonin, we examined in the present study the causal mechanism how Akt signaling pathway is regulated by melatonin in a rat primary astrocyte culture model. Melatonin resulted in increased astrocytic Akt phosphorylation, which was significantly decreased with wortmannin, a specific inhibitor of PI3K, suggesting that activation of Akt by melatonin is mediated through the PI3K-Akt signaling pathway. Furthermore, increased Akt activation was also significantly decreased with luzindole, a non-selective melatonin receptor antagonist. As downstream signaling pathway of Akt activation, increased levels of CREB phoshorylation and GDNF expression were observed, which were also attenuated with wortmannin and luzindole. These results strongly suggest that melatonin exerts its neuroprotective property in astrocytes through the activation of plasma membrane receptors and then PI3K-Akt signaling pathway.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.6
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• pp.3631-3634
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• 2013

MicroRNAs (MiRNAs) play important roles in coordinating a variety of cellular processes and abnormal expression has been linked to the occurrence of several cancers. The miRNA miR-451 is downregulated in colorectal carcinoma (CRC) cells, suggested by several research groups including our own. In this study, synthetic miR-451 mimics were transfected into the SW620 human CRC cell line using Lipofectamine 2000 and expression of miR-451 was analyzed by real time PCR, while expression of CAB39, LKB1, AMPK, AKT, PI3K and Bcl2 was analyzed by Western blot, and cell growth was detected by MTT assay. In comparison to the controls, a significant increase in the expression of miR-451 was associated with significantly decreased expression of CAB39, LKB1, AMPK, AKT, PI3K and Bcl2. The capacity of cell proliferation was significantly decreased by miR-451 expression, which also inhibited cell growth. Our study confirmed that miR-451 has a repressive role in CRC cells by inhibiting cell growth through down-regulating the P13K/AKT pathway.

• Biomedical Science Letters
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• v.29 no.3
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• pp.184-189
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• 2023

Normal activation of platelets and their aggregation are crucial during hemostasis process. It appears excessive or abnormal aggregation of platelets may bring about cardiovascular diseases like stroke, atherosclerosis, and thrombosis. For this reason, finding a substance that can regulate platelet aggregation or suppress aggregation will aid in the prevention and treatment of cardiovascular diseases. Artemisinin, a compound derived from Artemisia or Scopolia plants, has shown potential in various areas such as anticancer and Alzheimer's disease research. However, the specific role and mechanisms by which artemisinin influences platelet activation and thrombus formation are not yet fully understood. This study investigated the effects of artemisinin on platelet activation and thrombus formation. This study examined the effect of artemisinin on regulation of U46619-induced platelet aggregation, granule secretion. In addition, the effects of artemisinin on phosphorylation of PI3K/Akt and MAPK pathway involved in platelet aggregation was studied. As a result, artemisinin significantly downregulated of PI3K/Akt and MAPK pathway. In addition, artemisinin significantly reduced granule secretion, and platelet aggregation was inhibited by artemisinin. Therefore, we suggest that artemisinin is an anti-platelet substance that regulates PI3K/Akt and MAPK pathway and is valuable as a therapeutic and preventive agent for platelet-derived cardiovascular disease.

• Journal of Life Science
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• v.20 no.10
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• pp.1443-1450
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• 2010

Honokiol is a small molecular weight ligand originally isolated from the Chinese medicinal herb Magnolia officinalis, a plant used in traditional Chinese and Japanese medicine [9]. In a previous study, the effects of honokiol were shown to have anti-angiogenic, anti-invasive and anti-proliferative activities in a variety of cancers [1,3,4,11,13,17,24,29,30]. We showed previously that direct production of nitric oxide (NO) by treatment of NO donor, sodium nitroprusside (SNP), led to apoptosis in rabbit articular chondrocytes [15,16]. This study confirmed that NO-induced apoptosis was suppressed by honokiol treatment in a dose-dependent manner as determined by cell phenotype, MTT assay, Western blot analysis and FACS analysis in articular chondrocytes. Treatment of honokiol inhibited SNP-induced expression of p53 as well as DNA fragmentation in articular chondrocytes, but increased expressionof pro-caspase-3. Inhibition of SNP-induced apoptosis by honokiol treatment was rescued by LY294002, the specific inhibitors of phosphoinositide 3-kinase (PI-3K) in articular chondrocytes. Our results indicate that honokiol inhibits NO-induced apoptosis via PI-3K/AKT pathway in rabbit articular chondrocytes.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.4
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• pp.2201-2205
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• 2013

Colorectal cancer (CRC) is one of the most common cancers in many parts of the world. Its development is a multi-step process involving three distinct stages, initiation that alters the molecular message of a normal cell, followed by promotion and progression that ultimately generates a phenotypically altered transformed malignant cell. Reports have suggested an association of the phosphoinositide-3-kinase (PI3K)/Akt pathway with colon tumorigenesis. Activation of Akt signaling and impaired expression of phosphatase and tensin homolog (PTEN) (a negative regulator of Akt) has been reported in 60-70% of human colon cancers and inhibitors of PI3K/Akt signaling have been suggested as potential therapeutic agents. Around 80% of human colon tumors possess mutations in the APC gene and half of the remainder feature ${\beta}$-catenin gene mutations which affect downstream signaling of the PI3K/Akt pathway. In recent years, there has been a great focus in targeting these signaling pathways, with natural and synthetic drugs reducing the tumor burden in different experiment models. In this review we survey the role of PI3K/Akt/mTOR and Wnt signaling in CRC.

• Journal of Life Science
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• v.25 no.2
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• pp.231-236
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• 2015

Angiotensin II (AngII) is an essential hormone that affects vascular physiology. For example, stimulation of vascular smooth muscle cells (VSMCs) rapidly induces vasoconstriction and results in the up-regulation of blood pressure. Chronic stimulation of VSMCs with AngII also results in hypertrophy. In this study, we confirmed an involvement of phosphatidylinositol 3-kinase (PI3K)-dependent calcium mobilization in AngII-induced generation of reactive oxygen species (ROS). Stimulation of rat aortic smooth muscle cells (RASMCs) with AngII significantly induced the generation of ROS in a dose- and time-dependent manner. AngII-induced generation of ROS was completely abolished by pharmacological inhibition of PI3K (with LY294002), but inhibition of the ERK signaling pathway had no effect. AngII-induced calcium mobilization was completely blocked by inhibition of PI3K, whereas inhibition of the ERK signaling pathway by PD98059 was ineffective. Depletion of extracellular calcium or inhibition of the L-type calcium channel by nifedipine completely blocked AngII-induced calcium mobilization. Depletion of extracellular calcium by EGTA and incubation of RASMCs with calcium-free medium both significantly blocked AngII-induced ROS generation. Inhibition of the L-type calcium channel also significantly blocked AngII-induced ROS generation. These results suggest that AngII-induced ROS generation is regulated by calcium mobilization, which, in turn, is modulated by a PI3K/L-type calcium channel signaling pathway.

• 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.