Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies. The Yes‐associated protein‐1 (YAP) plays a critical role in cell proliferation, apoptosis and angiogenesis. Verteporfin is a photosensitizer used in photodynamic therapy and also a small molecular inhibitor of the Hippo‐YAP pathway. However, little is known about whether verteporfin could inhibit YAP activity in PDAC cells. Our present results showed that verteporfin suppressed the proliferation of human PDAC PANC‐1 and SW1990 cells by arresting cells at the G1 phase, and inducing apoptosis in dose‐ and time‐dependent manners. Verteporfin also inhibited the tumor growth on the PDAC xenograft model. Treatment with verteporfin led to downregulation of cyclinD1 and cyclinE1, modulation of Bcl‐2 family proteins and activation of PARP. In addition, verteporfin exhibited an inhibitory effect on angiogenesis and vasculogenic mimicry via suppressing Ang2, MMP2, VE‐cadherin, and α‐SMA expression in vitro and in vivo. Mechanism studies demonstrated that verteporfin impaired YAP and TEAD interaction to suppress the expression of targeted genes. Our results provide a foundation for repurposing verteporfin as a promising anti‐tumor drug in the treatment of pancreatic cancer by targeting the Hippo pathway.

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Tumor hypoxia and hypoxia-related sorafenib resistance adversely affected the prognosis of HCC patients. Hypoxia-inducible factor (HIF) s are defined as the central transcriptional mediator of hypoxic response. Recent efforts have identified HIF-2α that has been involved in sorafenib resistance. However, the regulatory mechanisms of HIF-2α activity in HCC remain obscure. Here, using both in vitro and in vivo HCC models, we show that the cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) axis is a driver of HIF-2α expression and activity, which then promotes HCC growth, metastasis and angiogenesis. We further show that COX-2 specific inhibitors synergistically enhanced the antitumour activity of sorafenib treatment by regulating the HIF-2α level and activity. These observations support further clinical developments of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment.Research.

Magnetic resonance sequences may be designed to evaluate the diffusion movements of the protons (diffusion-weighted images, DWI). In these images, a bright signal identifies a region where the diffusion along a spatial axis is restricted. The contents of a cystic lesion frequently have the signal intensities of a generic homogeneous hyperproteinic fluid (hypointensity in T1-, hyperintensity in T2-weighted images). DWI may give further information about the microscopic organisation of these fluids: a hyperintense signal indicates the presence of a restricted diffusion, due to some kind of microscopic organisation, at the cellular or macromolecular level. This may provide additional information useful for clinical purposes. We obtained DWI in 24 consecutive patients with intracranial cystic lesions, (19 intra-axial: five abscesses, five gliomas, six metastases, two demyelinating lesions, one neurocysticercosis; five extraaxial: two arachnoid cysts, two epidermoid cysts, one cholesteatoma). We found a strongly hyperintense signal, indicating restricted diffusion, in brain abscesses, epidermoid cysts and cholesteatoma; all the remaining lesions were hypointense or mildly hyperintense. We found these data useful in critical diagnoses, such as in differentiating abscesses from tumours, and in identifying elusive tumours such as epidermoid cysts.

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Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the general population; yet, the precise mechanisms resulting in AF are not fully understood. Caveolin-1 (Cav-1), the principal structural component of caveolae organelles in cardiac fibroblasts, is involved in several cardiovascular conditions; however, the study on its function in atrium, in particular, in AF, is still lacking. This report examines the hypothesis that Cav-1 confers an anti-AF effect by mediating atrial structural remodeling through its anti-fibrotic action. We evaluated the expression of Cav-1, transforming growth factor-β1 (TGF-β1), and fibrosis in atrial specimens of 13 patients with AF and 10 subjects with sinus rhythm, and found that the expression of Cav-1 was significantly downregulated, whereas TGF-β1 level, collagens I/III contents and atrial fibrosis were markedly increased, in AF. Western blot analysis demonstrated that treatment of human atrial fibroblasts (HAFs) with TGF-β1 resulted in a concentration- and time-dependent repression of Cav-1. Downregulation of Cav-1 with siRNA increased the TGF-β1-induced activation of Smad signal pathway and collagens production in HAFs. Furthermore, incubation of HAFs with the peptides derived from Cav-1 to achieve Cav-1 gain-of-function abolished the TGF-β1-induced production of collagens I/III and decreases of MMP-2/-9 expression. Therefore it was concluded that Cav-1 is an important anti-AF signaling mediator by conferring its anti-fibrotic effects in atrium.

Curcumin, a naturally occurring polyphenolic compound present in turmeric (Curcuma longa), exerts antitumor effects in various types of malignancy. However, the precise mechanisms responsible for the effects of curcumin on retinoblastoma (RB) cells have not been fully explored. In the present study, the molecular mechanisms by which curcumin exerts its anticancer effects in RB Y79 cells were investigated. The results showed that curcumin reduced cell viability in Y79 cells. Curcumin induced G1 phase arrest through downregulating the expression of cyclin D3 and cyclin-dependent kinase (CDK)2/6 and upregulating the expression of CDK inhibitor proteins p21 and p27. Curcumin-induced apoptosis of Y79 cells occurred through the activation of caspases-9/-3. Moreover, flow cytometric analysis showed that curcumin induced mitochondrial membrane potential (∆Ψm) collapse in Y79 cells. We also found that curcumin induced the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). JNK and p38 MAPK inhibitors significantly suppressed curcumin‑induced activation of caspases-9/-3 and inhibited the apoptosis of Y79 cells. Taken together, our results suggest that curcumin induced the apoptosis of Y79 cells through the activation of JNK and p38 MAPK pathways. These findings provide a novel treatment strategy for human RB.

Angiogenesis is required for the invasion, metastasis and chemoresistance of tumor cells. In addition to vascular endothelial cell growth factor (VEGF), angiopoietin-2 (Ang2) is considered to be a promising target for anti-angiogenic therapy. The T7 peptide, an active fragment of full-length tumstatin [the noncollagenous 1 domain of the type IV collagen α3 chain, α3(IV)NC1], has equivalent anti-angiogenic activity to that of full-length tumstatin. This study aimed to explore the mechanisms of the T7 peptide in the regulation of Ang2 expression in endothelial cells (ECs) as well as inhibition of angiogenesis and invasion of hepatocellular carcinoma cells. We also examined the role of autophagy in angiogenesis. Human umbilical vein endothelial cells (HUVECs) were incubated with endothelial cell medium (ECM)-2 in a hypoxia chamber to mimic hypoxic conditions. The recombinant T7 peptide inhibited the cell viability, tube formation and induced apoptosis of the HUVECs. The T7 peptide downregulated the protein expression of Ang2 by inhibiting phosphorylation of AKT under hypoxic conditions. The migration of HUVECs and invasion of HepG2 cells were inhibited by the T7 peptide via inhibition of Ang2 expression. EC autophagy was induced by the T7 peptide. Inhibition of autophagy enhanced the anti‑angiogenic activity of the T7 peptide by increasing EC apoptosis. In vivo, immunohistochemistry of VE-cadherin and CD31 showed that angiogenesis was decreased significantly by the T7 peptide in a nude mouse xenogeneic tumor model. In conclusion, the T7 peptide inhibited angiogenesis and exerted its antitumor effects by inhibition of Ang2, phosphorylation of AKT and matrix metalloproteinase-2 (MMP-2) regulated by Ang2. Furthermore, inhibition of autophagy may significantly enhance the anti-angiogenic activity of the T7 peptide.