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Tanshinone IIA (TS IIA) and Astragaloside IV (AS IV) are natural herbal products which exert anti-inflammatory and anti-oxidant effects in order to eliminate unstable plaque in atherosclerosis. However, the combined effect of these two drugs on atherosclerotic plaque vulnerability and its molecular mechanism remains unclear. In the current study, we evaluate the effects of TS IIA and AS IV on atherosclerotic unstable plaque stability, and then further explore the mechanism of TS IIA and AS IV intervention on unstable plaque in vivo and in vitro. Histological characterization of atherosclerotic plaques was measured by Hematoxylin-Eosin (HE), Masson’s Trichrome and Oil Red O staining. Cellular lipid droplet was measured by Oil Red O staining. The size of atherosclerotic lesion areas and content of lipids and collagen in the right common carotid arteries of apoE-/- mice were examined by Hematoxylin-Eosin (HE), Oil-red O, and Masson staining, respectively. The protein expression levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α and C-reactive protein (CRP) in ApoE−/− mice and RAW264.7 cells were determined by enzyme-linked immunosorbent assay. The protein expression levels of matrix metalloproteinase-9 (MMP-9) and endothelial nitric oxide synthase (eNOS) in ApoE−/− mice and RAW264.7 cells were determined by western blotting. In addition, the PI3K/AKT and TRL4/NF-κB signaling were determined by western blotting. Our results revealed that the combination of TS IIA and AS IV significantly decreased lipid areas, increased collagen content and thickened fibrous cap in the right common carotid arteries compared with ApoE (-/-) mice model group. TS IIA and AS IV visibly reduced the cytoplasmic lipid droplet accumulation induced by oxLDL in RAW 264.7 macrophages. The ApoE−/− mice model group and oxLDL -stimulated RAW 264.7 macrophages treated with TS IIA and AS IV showed a downregulation in IL-6, MMP-9, TNF-α and CRP protein expression and upregulation in eNOS protein expression. Furthermore, TSIIA and AS IV may activate PI3K/AKT signaling and suppress TLR4/NF-κB signaling in vivo and in vitro. Additionally, blocking the PI3K/Akt signaling enhanced the translocation of NF-κB to the nucleus, TLR4, IL-6, MMP-9, TNF-α and CRP expression and inhibited eNOS expression in TS IIA and AS IV-treated RAW 264.7 macrophages. Therefore, the present study implicates that TS IIA and AS IV reinforces plaque stability via PI3K/AKT and TLR4/NF-κB signaling. TS IIA and AS IV administration may provide the basis for a potential therapeutic approach for the inhibition of vulnerable atherosclerotic plaques.

Accidental phosgene exposure can result in acute lung injury (ALI). Mesenchymal stem cells (MSCs) have been found to alleviate phosgene-induced ALI. However, the mechanism of MSCs underlying such protective effect remains largely unexplored. Exosomes, important components of microenvironment, are closely associated with intercellular information transfer. In the present study, we isolated lung exosomes in rats after phosgene exposure by ultracentrifugation and explored their effects on MSCs in vitro. ALI exosomes were elliptical in shape and 50–200 nm in size. ALI exosomes could promote proliferation and migration of MSCs. Moreover, ALI exosomes increased the secretion of IL-10, leading to enhanced immunoregulatory properties of MSCs. The paracrine factors, VEGF, HGF, LL-37 and Ang-1, were also augmented by ALI exosomes. However, ALI exosomes had no effect on differentiation of MSCs towards lung alveolar cells. To identify the effective miRNAs in ALI exosomes, we performed miRNA profile analysis. MiR-28-5p was considered as a possible effective molecule. We further studied the effect of miR-28-5p on MSCs. MiR-28-5p mimic promoted proliferation, migration, immunomodulation of MSCs. MiR-28-5p mimic promoted the paracrine of VEGF, HGF, LL-37 and Ang-1. Besides, we explored molecular mechanism of miR-28-5p in MSCs. PI3K/Akt signaling pathway was found significantly augmented by miR-28-5p mimic, indicating the activation in this process. Taken together, our findings could help identify the effects of lung-derived exosomes on MSCs, and the effective molecule in exosomes, miR-28-5p, activated MSCs through PI3K/Akt signaling pathway.

Inflammation and coagulation are two important processes implicated in venous thromboembolism (VTE). 15-epi-lipoxin A4 (15-epi-LXA4) is the epimer of LXA4, a small lipid molecule, is known to play a key role in the resolution of inflammation. This study aimed to demonstrate whether 15-epi-LXA4 could suppress the inflammatory factor tumor necrosis factor-alpha (TNF-α)-induced upregulation of tissue factor (TF), an important regulator of the blood coagulation cascade, and evaluated the possible underlying mechanisms. We found that 15-epi-LXA4 not only reduced the up-regulation of mRNA and antigens, but also lowered the activity of TF (elevated by TNF-α) in primary culture of human umbilical vein endothelial cells (pc-HUVECs). In addition, 15-epi-LXA4 suppressed the activation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, induced by TNF-α, in pc-HUVECs. 15-epi-LXA4 also inhibited the binding of NF-κB on the TF promoter, which is otherwise enhanced by TNF-α. The role of 15-epi-LXA4 in regulating TNF-α-induced effects was enhanced by the PI3K inhibitor and prevented by the PI3K activator. In conclusion, 15-epi-LXA4 lowered the TNF-α-induced high TF expression and activity by suppressing PI3K/AKT signaling activation, thereby reducing the binding capacity of NF-κB on the TF promoter in pc-HUVECs.

CEMIP is a cell migration-inducing protein that is closely associated with carcinogenesis. However, the function of CEMIP has not been reported in ovarian cancer. Here we show that CEMIP expression level in ovarian cancer tissues was higher than that in normal ovaries. Silencing of CEMIP in ovarian cancer cell lines A2780 and OVCAR3 significantly decreased cell proliferation, cell migration and invasion capacity, while the proportion of apoptotic cells was increased. In addition, Western blotting demonstrated that knockdown of CEMIP inhibited activation of the PI3K/AKT signaling pathway. Altogether, these data suggest that CEMIP may promote the development of ovarian cancer by regulating PI3K/AKT signaling.

Myocardial ischemic/reperfusion (I/R) injury often leads to irreversible myocardial cell death and even heart failure, with limited therapeutic possibilities. In the present study, we evaluated the protective effects of shikonin (SHK) against hypoxia/reoxygenation (H/R)-induced cardiomyocyte damage and explored the underlying mechanisms. H9C2 cardiomyocytes were pretreated with different doses of SHK prior to H/R exposure. We observed that SHK pretreatment significantly increased cell viability, attenuated LDH release, and suppressed cardiomyocyte apoptosis induced by H/R exposure. SHK pretreatment also restored the loss of mitochondrial membrane potential (MMP) and cytochrome c release. In addition, SHK significantly enhanced the phosphorylation of Akt and GSK-3β in H/R-treated H9C2 cells. These protective effects of SHK were partially reversed by LY294002, a specific PI3K/Akt inhibitor. Therefore, our findings suggested that SHK might be a promising agent for myocardial I/R injury, and PI3K/Akt signaling plays a crucial role during this process. [ABSTRACT FROM AUTHOR]

Oridonin, a bioactive diterpenoid purified from Rabdosia rubescens , has been shown to possess anticancer capacity in several cancer types. However, its effects on oral squamous cell carcinoma (OSCC) cells remain unclear. This study aimed to investigate the anticancer ability of oridonin in OSCC cells, including proliferation, apoptosis and underlying mechanisms using the OSCC cell lines, UM1 and SCC25. The results showed that oridonin not only inhibited proliferation and clonal formation but also induced G2/M cell cycle arrest and apoptosis in UM1 and SCC25 cells in a dose-dependent manner. Western blot revealed that oridonin treatment increased the ratio of Bax/Bcl-2, and activated the cleavage of caspase-3, caspase-9 and PARP-1. Oridonin also induced G2/M phase arrest in OSCC cells via down-regulating the G2/M transition-related proteins such as cyclin B1 or up-regulating cyclin D1, cyclin D3, P21, p-CDK1 and cyclin A2. In addition, oridonin treatment significantly inhibited the phosphorylation of PI3K and Akt and inhibited tumor growth of OSCC xenograft in nude mice. Taken together, these results suggested that oridonin possesses anti-oral cancer capacity via inhibiting the PI3K/Akt signaling and induce apoptosis and G2/M-phase arrest. Therefore, oridonin may be a potential anticancer drug for the treatment of oral cancer. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a common, prevalent malignancy. Its poor prognosis is mainly related to high rate of diagnosis in non-curable stages, in which patients are suitable for palliative treatment. Placenta-specific 8 (PLAC8), also known as Onzin, is a small, highly conserved, cysteine-rich protein. In current study, we found that PLAC8 is prominently decreased in HCC tissues compared with adjacent tissues and patients with low level of PLAC8 suffered a poor prognosis. In addition, cellular function assays demonstrate that down-regulated PLAC8 promotes cell viability, proliferation and tumor formation both in vitro and in vivo . Furthermore, we validate that down-regulated PLAC8 enhances the activity of PI3K/Akt/GSK3β and Wnt/β-catenin signaling to promote cell proliferation. Moreover, we proved that highly expressed miR-185-5p targets PLAC8 in HCC tissues. In conclusion, our findings enlarged our knowledge about the roles of PLAC8 in HCC progression and miR-185-5p/PLAC8/β-catenin axis might be a novel pathway for HCC treatment. [ABSTRACT FROM AUTHOR]

Tanshinone IIA (TS IIA) and Astragaloside IV (AS IV) are natural herbal products which exert anti-inflammatory and anti-oxidant effects in order to eliminate unstable plaque in atherosclerosis. However, the combined effect of these two drugs on atherosclerotic plaque vulnerability and its molecular mechanism remains unclear. In the current study, we evaluate the effects of TS IIA and AS IV on atherosclerotic unstable plaque stability, and then further explore the mechanism of TS IIA and AS IV intervention on unstable plaque in vivo and in vitro. Histological characterization of atherosclerotic plaques was measured by Hematoxylin-Eosin (HE), Masson's Trichrome and Oil Red O staining. Cellular lipid droplet was measured by Oil Red O staining. The size of atherosclerotic lesion areas and content of lipids and collagen in the right common carotid arteries of apoE-/- mice were examined by Hematoxylin-Eosin (HE), Oil-red O, and Masson staining, respectively. The protein expression levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α and C-reactive protein (CRP) in ApoE−/− mice and RAW264.7 cells were determined by enzyme-linked immunosorbent assay. The protein expression levels of matrix metalloproteinase-9 (MMP-9) and endothelial nitric oxide synthase (eNOS) in ApoE−/− mice and RAW264.7 cells were determined by western blotting. In addition, the PI3K/AKT and TRL4/NF-κB signaling were determined by western blotting. Our results revealed that the combination of TS IIA and AS IV significantly decreased lipid areas, increased collagen content and thickened fibrous cap in the right common carotid arteries compared with ApoE (-/-) mice model group. TS IIA and AS IV visibly reduced the cytoplasmic lipid droplet accumulation induced by oxLDL in RAW 264.7 macrophages. The ApoE−/− mice model group and oxLDL -stimulated RAW 264.7 macrophages treated with TS IIA and AS IV showed a downregulation in IL-6, MMP-9, TNF-α and CRP protein expression and upregulation in eNOS protein expression. Furthermore, TSIIA and AS IV may activate PI3K/AKT signaling and suppress TLR4/NF-κB signaling in vivo and in vitro. Additionally, blocking the PI3K/Akt signaling enhanced the translocation of NF-κB to the nucleus, TLR4, IL-6, MMP-9, TNF-α and CRP expression and inhibited eNOS expression in TS IIA and AS IV-treated RAW 264.7 macrophages. Therefore, the present study implicates that TS IIA and AS IV reinforces plaque stability via PI3K/AKT and TLR4/NF-κB signaling. TS IIA and AS IV administration may provide the basis for a potential therapeutic approach for the inhibition of vulnerable atherosclerotic plaques. [ABSTRACT FROM AUTHOR]

Accidental phosgene exposure can result in acute lung injury (ALI). Mesenchymal stem cells (MSCs) have been found to alleviate phosgene-induced ALI. However, the mechanism of MSCs underlying such protective effect remains largely unexplored. Exosomes, important components of microenvironment, are closely associated with intercellular information transfer. In the present study, we isolated lung exosomes in rats after phosgene exposure by ultracentrifugation and explored their effects on MSCs in vitro. ALI exosomes were elliptical in shape and 50–200 nm in size. ALI exosomes could promote proliferation and migration of MSCs. Moreover, ALI exosomes increased the secretion of IL-10, leading to enhanced immunoregulatory properties of MSCs. The paracrine factors, VEGF, HGF, LL-37 and Ang-1, were also augmented by ALI exosomes. However, ALI exosomes had no effect on differentiation of MSCs towards lung alveolar cells. To identify the effective miRNAs in ALI exosomes, we performed miRNA profile analysis. MiR-28-5p was considered as a possible effective molecule. We further studied the effect of miR-28-5p on MSCs. MiR-28-5p mimic promoted proliferation, migration, immunomodulation of MSCs. MiR-28-5p mimic promoted the paracrine of VEGF, HGF, LL-37 and Ang-1. Besides, we explored molecular mechanism of miR-28-5p in MSCs. PI3K/Akt signaling pathway was found significantly augmented by miR-28-5p mimic, indicating the activation in this process. Taken together, our findings could help identify the effects of lung-derived exosomes on MSCs, and the effective molecule in exosomes, miR-28-5p, activated MSCs through PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Inflammation and coagulation are two important processes implicated in venous thromboembolism (VTE). 15-epi-lipoxin A 4 (15-epi-LXA 4) is the epimer of LXA 4 , a small lipid molecule, is known to play a key role in the resolution of inflammation. This study aimed to demonstrate whether 15-epi-LXA 4 could suppress the inflammatory factor tumor necrosis factor-alpha (TNF-α)-induced upregulation of tissue factor (TF), an important regulator of the blood coagulation cascade, and evaluated the possible underlying mechanisms. We found that 15-epi-LXA 4 not only reduced the up-regulation of mRNA and antigens, but also lowered the activity of TF (elevated by TNF-α) in primary culture of human umbilical vein endothelial cells (pc-HUVECs). In addition, 15-epi-LXA 4 suppressed the activation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, induced by TNF-α, in pc-HUVECs. 15-epi-LXA 4 also inhibited the binding of NF-κB on the TF promoter, which is otherwise enhanced by TNF-α. The role of 15-epi-LXA 4 in regulating TNF-α-induced effects was enhanced by the PI3K inhibitor and prevented by the PI3K activator. In conclusion, 15-epi-LXA 4 lowered the TNF-α-induced high TF expression and activity by suppressing PI3K/AKT signaling activation, thereby reducing the binding capacity of NF-κB on the TF promoter in pc-HUVECs. [ABSTRACT FROM AUTHOR]

• CEMIP knockdown reduces proliferation and increases apoptosis of ovarian cancer cells. • CEMIP knockdown significantly reduces migration and invasion capacity of ovarian cancer cells. • CEMIP silencing inhibits activation of the PI3K/AKT signaling pathway. • CEMIP may promote development of ovarian cancer via activation of PI3K/AKT signaling. CEMIP is a cell migration-inducing protein that is closely associated with carcinogenesis. However, the function of CEMIP has not been reported in ovarian cancer. Here we show that CEMIP expression level in ovarian cancer tissues was higher than that in normal ovaries. Silencing of CEMIP in ovarian cancer cell lines A2780 and OVCAR3 significantly decreased cell proliferation, cell migration and invasion capacity, while the proportion of apoptotic cells was increased. In addition, Western blotting demonstrated that knockdown of CEMIP inhibited activation of the PI3K/AKT signaling pathway. Altogether, these data suggest that CEMIP may promote the development of ovarian cancer by regulating PI3K/AKT signaling. [ABSTRACT FROM AUTHOR]