High glucose induces alternative activation of macrophages via PI3K/Akt signaling pathway

Objective: It has been proved that lactate-4.25% dialysate could result in peritoneal fibrosis by inducing alternative activation of macrophages in our previous study, but the mechanism of high glucose-induced alternative activation has not been elucidated. This study was, therefore, to investigate the mechanism by high glucose stimuli.

Methods: In this study, Raw264.7 (murine macrophage cell line) cells were cultured and stimulated by 4.25% glucose medium, and mannitol medium was used as osmotic pressure control. Cells were harvested at 0?h, 4?h, 8?h, and 12?h to examine the expression of Arg-1, CD206, and p-Akt. After blocking PI3K by LY294002, the expression of Arg-1, CD206, and p-Akt was examined again.

Results: The expression of Arg-1 and CD206 was increased in a time-dependent manner induced by high glucose medium. On the contrary, there was mainly no Agr-1 or CD206 expressed in cells cultured in the mannitol medium with the same osmotic pressure. What’s more, Akt was phosphorylated at the eighth hour stimulated by high glucose medium, and LY294002 inhibited the expression of Arg-1 and CD206 by blocking the phosphorylation of Akt.

Conclusions: Our study indicated that high glucose rather than high osmotic pressure induced M2 phenotype via PI3K/Akt signaling pathway.     

Pristimerin-induced uveal melanoma cell death via inhibiting PI3K/Akt/FoxO3a signalling pathway

Uveal melanoma (UM) is a highly invasive intraocular malignancy with high mortality. Presently, there is no FDA-approved standard for the treatment of metastatic UM. Pristimerin is a natural quinine methide triterpenoid compound with anti-angiogenic, anti-cancer and anti-inflammatory activities. However, Pristimerin potential cytotoxic effect on UM was poorly investigated. In the present study, we found the migration and invasion of UM-1 cells were inhibited by Pristimerin which also caused a rapid increase of ROS, decreased mitochondrial membrane potential, induced the accumulation of cells in G0/G1 phase, ending with apoptotic cell death. Pristimerin inhibited Akt and FoxO3a phosphorylation and induced nuclear accumulation of FoxO3a in UM-1 cells, increased the expression of pro-apoptotic proteins Bim、p27^Kip1, cleaved caspase-3, PARP and Bax, and decreased the expression of Cyclin D1 and Bcl-2. LY294002 or Akt-siRNA inhibited the PI3K/Akt/FoxO3a pathway and promoted the Pristimerin-induced apoptosis, while Pristimerin effects were partially abolished in FoxO3a knockdown UM-1 cell cultures. Taken together, present results showed that Pristimerin induced apoptotic cell death through inhibition of PI3K/Akt/FoxO3a pathway in UM-1 cells. These findings indicate that Pristimerin may be considered as a potential chemotherapeutic agent for patients with UM.     

缺氧诱导因子1与PI3K/Akt/mTOR信号转导通路

缺氧诱导因子1（HIF-1）是参与缺氧调节的核心因子,可调控一系列缺氧诱导基因的表达,与机体许多生理和病理过程也密切相关。尽管一些研究显示缺氧和非缺氧性刺激可通过PI3K/Akt/mTOR信号途径诱导HIF-1的表达和活性,PI3K信号途径是否参与对HIF-1的调节仍然是个有争议的研究热点。明确HIF-1和PI3K的相互作用关系,能进一步为肿瘤等相关疾病的防治提供新的思路和方法。本文主要就HIF-1和PI3K/Akt/mTOR关系作一简要综述。     

Apelin induces vascular smooth muscle cells migration via a PI3K/Akt/FoxO3a/MMP-2 pathway

Apelin is an adipokine that has a critical role in the development of atherosclerosis, which may offer potential for therapy. Because migration of vascular smooth muscle cells (VSMCs) is a key event in the development of atherosclerosis, understanding its effect on the atherosclerotic vasculature is needed. Here we investigated the effect of apelin on VSMC migration and the possible signaling mechanism. In cultured rat VSMCs, apelin dose- and time-dependently promoted VSMC migration. Apelin increased the phosphorylation of Akt, whereas LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), and an Akt1/2 kinase inhibitor blocked the apelin-induced VSMC migration. Apelin dose-dependently induced phosphorylation of Forkhead box O3a (FoxO3a) and promoted its translocation from the nucleus to cytoplasm, which were blocked by LY294002 and Akt1/2 kinase inhibitor. Furthermore, apelin increased matrix metalloproteinase 2 (MMP-2) expression and gelatinolytic activity. Overexpression of a constitutively active, phosphorylation-resistant mutant, TM-FoxO3a, in VSMCs abrogated the effect of apelin on MMP-2 expression and VSMC migration. ARP101, an inhibitor of MMP-2, suppressed apelin-induced VSMC migration. Moreover, the levels of apelin, phosphorylated Akt, FoxO3a, and MMP-2 were higher in human carotid-artery atherosclerotic plaque than in adjacent normal vessels. We demonstrate that PI3K/Akt/FoxO3a signaling may be involved in apelin inducing VSMC migration. Phosphorylation of FoxO3a plays a central role in mediating the apelin-induced MMP-2 activation and VSMC migration.     

PI3K/Akt信号通路与肺纤维化

肺纤维化(pulmonary fibrosis)是进行性、致命性的疾病。其致病机制不明,治疗效果差。PI3K/Akt信号通路主要与细胞的生长、增殖、分化、凋亡及血管形成等有关。近年来,随着对PI3K/Akt信号通路的深入研究,发现其活化后可激活下游中的一些因子参与肺纤维化,且与其他通路协同作用促进肺纤维化的形成。因此该通路有可能成为治疗肺纤维化的新靶点。将PI3K/Akt信号通路参与肺纤维化形成的研究进展作一综述。     

Roxarsone induces angiogenesis via PI3K/Akt signaling

Background

3-Nitro-4-hydroxy phenyl arsenic acid, roxarsone, is widely used as an organic arsenic feed additive for livestock and poultry, which may increase the level of arsenic in the environment and the risk of exposure to arsenic in human. Little information is focused on the angiogenesis roxarsone-induced and its mechanism at present. This paper aims to study the role of PI3K/Akt signaling in roxarsone-induced angiogenesis in rat vascular endothelial cells and a mouse B16–F10 melanoma xenograft model.

Results

The results showed that treatment with 0.1–10.0 µmol/L roxarsone resulted in an increase in the OD rate in the MTT assay, the number of BrdU-positive cells in the proliferation assay, the migration distance in the scratch test and the number of meshes in tube formation assay. Further, treatment with 1.0 µmol/L roxarsone was associated with significantly higher phosphorylation of PI3K/Akt and expression of VEGF than the control treatment. The PI3K inhibitor was found to significantly combat the effects of 1.0 µmol/L roxarsone. Furthermore, roxarsone treatment was observed to increase the weight and volume of B16–F10 xenografts and VEGF expression and PI3K/Akt phosphorylation in a dose-dependent manner, with the 25 mg/kg dose having significant effects.

Conclusions

These results demonstrate that roxarsone has the ability to promote growth and tube formation in vascular endothelial cells and the growth of mouse B16–F10 xenografts. Further, the findings also indicate that PI3K/Akt signaling plays a regulatory role in roxarsone-induced angiogenesis in vivo and in vitro.

     

TLR2 protects cisplatin-induced acute kidney injury associated with autophagy via PI3K/Akt signaling pathway

Toll-like receptors (TLRs), which are essential components of the innate immune response, play an important role in acute kidney injury (AKI). Toll-like receptor 2 (TLR2) is constitutively expressed in tubular epithelial cells of the kidney and participates in cisplatin-induced AKI. The autophagy is a dynamic catabolic process that maintains intracellular homeostasis, which is involved in the pathogenesis of AKI. Recent studies demonstrate that PI3K/Akt signaling pathway regulates autophagy in response to various stimuli. Therefore, we propose that cisplatin might activate TLR2, which subsequently phosphorylates PI3K/Akt, leading to enhanced autophagy of renal tubular epithelial cells and protecting cisplatin-induced AKI. We found that TLR2 expression was significantly increased in the kidney after the cisplatin treatment. TLR2-deficient mice exacerbated renal injury in cisplatin-induced AKI, with higher serum creatinine and blood urea nitrogen, more severe morphological injury compared with that of wild-type mice. In vitro, we found that inhibition of TLR2 reduced tubular epithelial cell autophagy after the cisplatin treatment. Mechanistically, TLR2 inhibited autophagy via activating PI3K/Akt signaling pathway in renal tubular epithelial cells after the cisplatin treatment. Take together, these results suggest that TLR2 may protect cisplatin-induced AKI by activating autophagy via PI3K/Akt signaling pathway.     

Trop2 as an oncogene in gastric cancer by regulating PI3K/Akt signaling pathway

High Trop2 expression relates to aggressive tumor behavior and contributes to poor overall survival rates in gastric cancer (GC) patients. However, little is known about the molecular mechanism of Trop2 in the carcinogenesis of GC. We found that over-expressed Trop2 induced cell proliferation and clone formation, inhibited cell apoptosis and induced S cell cycle arrest in GC cell lines, meanwhile, knockdown Trop2 inhibited cell proliferation and clone formation, induced cell apoptosis and inhibits S cell cycle arrest in vitro. Moreover, Trop2 depletion inhibited tumor growth , the anti-tumor rate in this report being 22.53% in vivo. In addition, Trop2 activated the PI3K/Akt signaling pathway to promote GC malignant progression. These results indicated that Trop2 is a critical regulation factor in the progression of GC, which may help to lead a novel insight into understanding the mechanism of the Trop2 in the pathogenesis of GC.     

Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

This review focuses on the syntheses of PI3K/Akt/mTOR inhibitors that have been reported outside of the patent literature in the last 5 years but is largely centered on synthetic work reported in 2011 and 2012. While focused on syntheses of inhibitors, some information on in vitro and in vivo testing of compounds is also included. Many of these reported compounds are reversible, competitive adenosine triphosphate (ATP) binding inhibitors, so given the structural similarities of many of these compounds to the adenine core, this review presents recent work on inhibitors based on where the synthetic chemistry was started, that is, inhibitor syntheses which started with purines/pyrimidines are followed by inhibitor syntheses which began with pyridines, pyrazines, azoles, and triazines then moves to inhibitors which bear no structural resemblance to adenine: liphagal, wortmannin and quercetin analogs. The review then finishes with a short section on recent syntheses of phosphotidyl inositol (PI) analogs since competitive PI binding inhibitors represent an alternative to the competitive ATP binding inhibitors which have received the most attention.     

Role of PI3K/Akt signaling pathway in cardiac fibrosis

Molecular and Cellular Biochemistry - Heart failure (HF) is considered as a severe health problem worldwide, while cardiac fibrosis is one of the main driving factors for the progress of HF....     

LEM domain containing 1 promotes proliferation via activating the PI3K/Akt signaling pathway in gastric cancer

Gastric cancer (GC) is one of the most common cancers worldwide and has especially high morbidity and mortality in China. LEM domain containing 1 (LEMD1), an important cancer-testis antigen, has been reported to be overexpressed in various cancers and promotes the progression of cancers. However, the biological characteristics of LEMD1 remain to be explored in GC. The connection between LEMD1 expression and GC progression was analyzed by using The Cancer Genome Atlas datasets and our human microarray datasets. A Kaplan-Meier plot was used to analyze the relationship between LEMD1 expression and prognosis. The expression of LEMD1 was analyzed by quantitative real-time polymerase chain reaction and Western blot, and the proliferation ability of GC cells was analyzed by cell proliferation and colony formation assays and 5-ethynyl-2′-deoxyuridine analysis. The cell cycle and apoptosis were analyzed by flow cytometry. Furthermore, subcutaneously implanted tumor models in nude mice were used to demonstrate the role of LEMD1 in promoting tumor proliferation in vivo. In this study, we demonstrated that the LEMD1 expression level was increased in GC tissues and cells compared with normal tissues and GES-1. The in vivo and in vitro assays showed that LEMD1 promoted GC cell proliferation by regulating the cell cycle and apoptosis. Moreover, we showed that LEMD1 regulated cell proliferation by activating the phosphatidylinositol 3 kinase (PI3K) / protein kinase B (AKT) signaling pathway. Overall, the results of our study suggest that LEMD1 contributes to GC proliferation by regulating the cell cycle and apoptosis via activation of the PI3K/AKT signaling pathway. LEMD1 may act as a potential target for GC treatment.     

A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition

Tumor metastasis is not only a sign of disease severity but also a major factor causing treatment failure and cancer-related death. Therefore, studies on the molecular mechanisms of tumor metastasis are critical for the development of treatments and for the improvement of survival. The epithelial-mesenchymal transition (EMT) is an orderly, polygenic biological process that plays an important role in tumor cell invasion, metastasis and chemoresistance. The complex, multi-step process of EMT involves multiple regulatory mechanisms. Specifically, the PI3K/Akt signaling pathway can affect the EMT in a variety of ways to influence tumor aggressiveness. A better understanding of the regulatory mechanisms related to the EMT can provide a theoretical basis for the early prediction of tumor progression as well as targeted therapy.     

Curcumin inhibits the invasion of thyroid cancer cells via down-regulation of PI3K/Akt signaling pathway

The objectives of this study were to evaluate the in vitro anti-tumor (human thyroid cancer cell lines) potential of curcumin and to elucidate its molecular mechanisms. Here, we investigated the effects of curcumin on the cell viability, apoptosis, migration and invasion of human thyroid cancer cell lines FTC133. We also investigated the effects of curcumin on PI3K, p-Akt, MMP1/7, and COX-2 protein expressions using Western blot. Results showed that curcumin inhibited growth, cell migration and invasion in FTC133, and promoted its apoptosis. Western blot assay data demonstrated that curcumin inhibited phosphorylation of PI3K and Akt signaling pathways and subsequently attenuated MMP1/7 and COX-2 protein expressions in FTC133. In conclusion, curcumin suppresses FTC133 cell invasion and migration by inhibiting PI3K and Akt signaling pathways. Therefore, curcumin produces anti-metastatic activity in FTC133 cells.     

Muscone suppresses myocardial ischemia damage by regulating PI3K/Akt signaling pathway

Muscone is the main active compound of Moschus. In this paper, the cardioprotective effect of Muscone on acute myocardial ischemia (AMI) rats and its potential mechanisms were investigated. AMI rat models were established to evaluate the protective effect and antioxidative function of Muscone on the hearts. Moreover, Western blot analysis was conducted to quantify the phosphorylated PI3K and AKT levels in PI3K/Akt pathway for further investigating the mechanism of Muscone. Results showed that Muscone could markedly lessen the infarct size and myocardial injury, improve cardiac function, inhibit cardiomyocyte apoptosis and down-regulate serum reactive oxygen species level as indicated by the decreased MDA, BNP and c-TnI activities and the increased SOD, GSH-px, CAT activities and the expression of Bax protein. In addition, it was revealed that Muscone notably promoted the phosphorylation of PI3K and AKT. These findings denote that Muscone exerts a protective effect in heart via inhibition of oxidative stress and apoptosis, offering new insights into the treatment of CHD and the clinical application of Muscone.     

Apelin stimulates glucose uptake through the PI3K/Akt pathway and improves insulin resistance in 3T3-L1 adipocytes

Apelin, a cytokine mainly secreted by adipocytes, is closely related with insulin resistance. The underlying molecular mechanisms of how apelin affects insulin resistance, however, are poorly understood. This study aimed to investigate the effect of apelin on glucose metabolism and insulin resistance in 3T3-L1 adipocytes. After 10 ng/ml TNF-α treatment for 24 h, insulin-stimulated glucose uptake was reduced by 47% in 3T3-L1 adipocytes. Apelin treatment improved glucose uptake in a time- and dose-dependent manner. Treatment of 1,000 nM apelin for 60 min maximally augmented glucose uptake in insulin-resistant 3T3-L1 adipocytes. Furthermore, apelin pre-incubation also increased adipocytes' insulin-stimulated glucose uptake, and PI3K/Akt pathway were involved in these effects. In addition, immunocytochemistry staining and western blotting analysis indicated that apelin could increase glucose transporter 4 translocation from the cytoplasm to the plasma membrane. Apelin also increased the anti-inflammatory adipokine adiponectin mRNA expression while reducing that of pro-inflammatory adipokine interleukin-6 in insulin-resistant 3T3-L1 adipocytes. These results suggest that apelin stimulates glucose uptake through the PI3K/Akt pathway, promotes GLUT4 translocation from the cytoplasm to the plasma membrane, and modulates inflammatory responses in insulin-resistant 3T3-L1 adipocytes.     

PDGF-AA promotes cell-to-cell communication in osteocytes through PI3K/Akt signaling pathway

Osteocytes are the main sensitive cells in bone remodeling due to their potent functional cell pro-cesses from the mineralized bone matrix to the bone surface a...