The extracellular matrix protein fibulin-3/EFEMP1 promotes pleural mesothelioma growth by activation of PI3K/Akt signaling.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited therapeutic options. The extracellular matrix protein fibulin-3/EFEMP1 accumulates in the pleural effusions of MPM patients and has been proposed as a prognostic biomarker of these tumors. However, it is entirely unknown whether fibulin-3 plays a functional role on MPM growth and progression. Here, we demonstrate that fibulin-3 is upregulated in MPM tissue, promotes the malignant behavior of MPM cells, and can be targeted to reduce tumor progression. Overexpression of fibulin-3 increased the viability, clonogenic capacity and invasion of mesothelial cells, whereas fibulin-3 knockdown decreased these phenotypic traits as well as chemoresistance in MPM cells. At the molecular level, fibulin-3 activated PI3K/Akt signaling and increased the expression of a PI3K-dependent gene signature associated with cell adhesion, motility, and invasion. These pro-tumoral effects of fibulin-3 on MPM cells were disrupted by PI3K inhibition as well as by a novel, function-blocking, anti-fibulin-3 chimeric antibody. Anti-fibulin-3 antibody therapy tested in two orthotopic models of MPM inhibited fibulin-3 signaling, resulting in decreased tumor cell proliferation, reduced tumor growth, and extended animal survival. Taken together, these results demonstrate for the first time that fibulin-3 is not only a prognostic factor of MPM but also a relevant molecular target in these tumors. Further development of anti-fibulin-3 approaches are proposed to increase early detection and therapeutic impact against MPM.

Kaempferol conjugated gold nanoclusters enabled efficient for anticancer therapeutics to A549 lung cancer cells.

Background: Kaempferol (K) is a recognized anticancer drug that can conjugate with small-size gold nanoclusters (AuNCs). Materials and methods: K-AuNCs were synthesized and their use as an anticancer drug was explored using A549 lung cancer cells. Colony formation and cell migration assays were carried out. The morphology of the K-AuNCs treated A549 cells was explored using bio-atomic force microscopy. Results: The K-AuNCs were 1-3 nm in diameter and emitted strong fluorescent at 650 nm following excitation at 550 nm. The stretching and bending nature of the K-AuNCs were analyzed by the Fourier transform infrared spectroscopy. The presence of kaempferol in the AuNCs were confirmed by the PL spectroscopy. Conclusion: The synthesized K-AuNCs mainly targeted and damaged the nuclei of the cancer cells. This composite nanocluster was less toxicity to the normal human cell and higher toxicity to the A549 lunch cancer cell and these material is potential for anticancer drug delivery and bio imaging applications.

Microglial AGE-albumin is critical for neuronal death in Parkinson's disease: a possible implication for theranostics.

Advanced glycation end products (AGEs) are known to play an important role in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD), by inducing protein aggregation and cross-link, formation of Lewy body, and neuronal death. In this study, we observed that AGE-albumin, the most abundant AGE product in the human PD brain, is synthesized in activated microglial cells and accumulates in the extracellular space. AGE-albumin synthesis in human-activated microglial cells is distinctly inhibited by ascorbic acid and cytochalasin treatment. Accumulated AGE-albumin upregulates the receptor to AGE, leading to apoptosis of human primary dopamine (DA) neurons. In animal experiments, we observed reduced DA neuronal cell death by treatment with soluble receptor to AGE. Our study provides evidence that activated microglial cells are one of the main contributors in AGE-albumin accumulation, deleterious to DA neurons in human and animal PD brains. Finally, activated microglial AGE-albumin could be used as a diagnostic and therapeutic biomarker with high sensitivity for neurodegenerative disorders, including PD.