2 research outputs found
Synthesis and Identification of New Flavonoids Targeting Liver X Receptor β Involved Pathway as Potential Facilitators of Aβ Clearance with Reduced Lipid Accumulation
Alzheimer’s
disease (AD) is associated with impaired Aβ
degradation in the brain. Enhancing the process of Aβ clearance
is an attractive potential AD therapy. Treatment with LXR agonists
may reduce Aβ levels in vivo. However, the clinical potential
of many LXR agonists is limited because of their nonselective actions
on LXRα/β, which lead to undesired hepatic lipogenesis
via LXRα-dependent pathways. In this study, ABCA1 up-regulators
were identified from a series of flavonoids and were found to preferentially
activate LXRβ and up-regulate expression of ABCA1 and apoE in
different cell lines. Further investigations confirmed that these
compounds facilitate intracellular Aβ clearance in Aβ-loaded
BV2 cells. Administration of compound <b>19</b> reduced total
brain Aβ and plaque burden in APP/PS1 double transgenic mice,
associated with elevated ABCA1 and apoE expression. Compared with
the nonselective LXR agonists, the active compounds reported here
induced less accumulation of undesired lipids and triglycerides in
HepG2 cells
Dual Function of RGD-Modified VEGI-192 for Breast Cancer Treatment
Identification of endogenous angiogenesis inhibitors
has led to
development of an increasingly attractive strategy for cancer therapy
and other angiogenesis-driven diseases. Vascular endothelial growth
inhibitor (VEGI), a potent and relatively nontoxic endogenous angiogenesis
inhibitor, has been intensively studied, and this work shed new light
on developing promising anti-angiogenic strategies. It is well-documented
that the RGD (Arg-Gly-Asp) motif exhibits high binding affinity to
integrin α<sub>v</sub>β<sub>3</sub>, which is abundantly
expressed in cancer cells and specifically associated with angiogenesis
on tumors. Here, we designed a fusion protein containing the special
RGD-4C motif sequence and VEGI-192, aimed at offering more effective
multiple targeting to tumor cells and tumor vasculature, and higher
anti-angiogenic and antitumor efficacy. Functional tests demonstrated
that the purified recombinant human RGD-VEGI-192 protein (rhRGD-VEGI-192)
potently inhibited endothelial growth in vitro and suppressed neovascularization
in chicken chorioallantoic membrane in vivo, to a higher degree as
compared with rhVEGI-192 protein. More importantly, rhRGD-VEGI-192,
but not rhVEGI-192 protein, could potentially target MDA-MB-435 breast
tumor cells, significantly inhibiting growth of MDA-MB-435 cells in
vitro, triggered apoptosis in MDA-MB-435 cells by activation of caspase-8
as well as caspase-3, which was mediated by activating the JNK signaling
associated with upregulation of pro-apoptotic protein Puma, and consequently
led to the observed significant antitumor effect in vivo against a
human breast cancer xenograft. Our study indicated that the RGD-VEGI-192
fusion protein might represent a novel anti-angiogenic and antitumor
strategy