The addition of temozolomide (TMZ) to radiotherapy (RT) improves survival of patients with glioblastoma (GBM). However, TMZ + RT causes excess toxicity in patients. In this study, we prepared angiopep-2 (A2) modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles for TMZ delivery (A2-P(MIs)25/TMZ) to achieve synergistic effects against glioma. This A2-P(MIs)25/TMZ display highly promising advantages: (1) a hydrophobic P-(MIs)25 core where poorly water-soluble TMZ can be encapsulated; (2) nitro groups of the hydrophobic P-(MIs)25 core that are converted into hydrophilic amino groups (P(NH 2 s)25) under low oxygen conditions to mimic the oxygen-increased sensitization to RT; (3) a lipid monolayer at the interface of the core and the shell to modify the A2 (a specific ligand for low-density lipoprotein receptor-related protein-1 (LRP-1), which are expressed in the blood-brain barrier (BBB) and human glioma cells), thereby enhancing the drug encapsulation efficiency in glioma. These nanoparticles appear as a promising and robust nanoplatforms for TMZ and hypoxic cell radiosensitization delivery.
It is known that apelin has definite protective effects on various cardiovascular diseases; however, the mechanism through which hypertension with heart failure (H-HF) is affected by pyroglutamylated apelin-13 (Pyr-AP13) remain unclear. Thus, in the present study, we investigated the effects of apelin on the cardiac hemodynamics in rats with hypertension and heart failure. In our study, cardiac function, dimensions and histological determination of the fibrosis of rats with two-kidney, one-clip induced hypertension and sham-operated rats were assessed using an echocardiography system and Masson’s trichrome. The infusion of either 5% glucose injection (GS) alone or 5% GS containing Pyr-AP13 as a dose, time-matched design on the cardiac hemodynamics in H-HF rats and sham-operated rats was recorded. For the determination of the effects of potential related proteins on cardiac hemodynamics in the H-HF rats, the animals were divided into 5 groups: i) the sham-operated group (n=8); ii) H-HF (n=8); iii) H-HF with infusion of 0.1 μg dose of Pyr-AP13 (n=8) or 5% glucose (GS) (n=8); iv) H-HF with infusion of 1 μg dose of Pyr-AP13 (n=8) or 5% GS (n=8); and v) H-HF with infusion of 10 μg dose of Pyr-AP13 (n=8) or 5% GS (n=8). The concentration of cyclic adenosine 3′,5′-monophosphate (cAMP) was determined by ELISA. The expression of membrane and cytosolic proteins was evaluated by western blot analysis. Significant cardiac and perivascular fibrosis was observed in the H-HF rats. Following the infusion of Pyr-AP13, the systolic and diastolic function was significantly improved in the cardiac hemodynamic parameters in the H-HF rats treated with Pyr-AP13. The apelin receptor (APJ), which was activated by the exogenous infusion of Pyr-AP13, was partially recycled from the cytoplasm back to the plasma membrane; however, membrane APJ was eventually downregulated in the H-HF rats treated with Pyr-AP13 compared with the sham-operated group rats. Our findings suggested that a complex was formed after Pyr-AP13 combined with cellular membrane APJ receptor. However, the endogenous downregulation of the APJ receptor results in benefits from the exogenous administration of apelin.
Protocadherin-8 (PCDH8), a member of the protocadherin superfamily of proteins, is frequently lost in numerous types of cancer. However, the role that PCDH8 serves in human glioma, and the molecular mechanisms underlying this, remain unclear. Data from the present study demonstrated that the expression levels of PCDH8 mRNA and protein were significantly decreased in human glioma tissue compared with normal brain tissue. This suggested that PCDH8 is associated with the development of glioma. Thus, the role of PCDH8 in glioma cell proliferation was investigated by silencing and overexpressing PCDH8 in U251 glioma cells. Overexpression of PCDH8 significantly inhibited glioma cell proliferation, while silencing of PCDH8 using small interfering RNA promoted glioma cell proliferation. Restoration of PCDH8 decreased phosphorylated (p)-Rac-α serine/threonine-protein kinase (AKT) [Threonine (T)308/Serine (S)473] and p-glycogen synthase kinase-3β (p-GSK3β) (S9) protein expression, thereby reducing the level of β-catenin when compared with the control. By contrast, silencing of PCDH8 increased levels of p-AKT (T308/S473) and p-GSK3β (S9), thereby increasing the level of β-catenin. In conclusion, the results of the present study suggested that PCDH8 suppressed glioma cell proliferation, and that the loss of PCDH8 may stimulate the proto-oncogene Wnt/β-catenin signaling pathway and therefore promote glioma cell proliferation.
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