Biology subjects

Brinkley, G.

Publications and source records attributed to Brinkley, G..

2 recordsLinked to original sources

bioRxiv2021

Controlled and Selective Photo-oxidation of Amyloid-β Fibrils by Oligomeric p-Phenylene Ethynylenes

Photodynamic therapy (PDT) has been explored as a therapeutic strategy to clear toxic amyloid aggregates involved in neurodegenerative disorders such as Alzheimers disease. A major limitation of PDT is off-target oxidation, which can be lethal for the surrounding cells. We have shown that a novel class of oligo-p-phenylene ethynylene-based compounds (OPEs) exhibit selective binding and fluorescence turn-on in the presence of pre-fibrillar and fibrillar aggregates of disease-relevant proteins such as amyloid-{beta} (A{beta}) and -synuclein. Concomitant with fluorescence turn-on, OPE also photosensitizes singlet oxygen under illumination through the generation of a triplet state, pointing to the potential application of OPEs as photosensitizers in PDT. Herein, we investigated the photosensitizing activity of an anionic OPE for the photo-oxidation of toxic A{beta} aggregates and compared its efficacy to the well-known but non-selective photosensitizer methylene blue (MB). Our results show that while MB photo-oxidized both monomeric and fibrillar conformers of A{beta}40, OPE oxidized only A{beta}40 fibrils, targeting two histidine residues on the fibril surface and a methionine residue located in the fibril core. Oxidized fibrils were shorter and more dispersed, but retained the characteristic {beta}-sheet rich fibrillar structure and the ability to seed further fibril growth. Importantly, the oxidized fibrils displayed low toxicity. We have thus discovered a class of novel theranostics for the simultaneous detection and oxidization of amyloid aggregates. Importantly, the selectivity of OPEs photosensitizing activity overcomes the limitation of off-target oxidation of currently available photosensitizers, and represents a significant advancement of PDT as a viable strategy to treat neurodegenerative disorders.

neuroscience↗

bioRxiv2021

TGF-B signaling suppresses TCA cycle metabolism in renal cancer.

The Warburg effect is one of most-well studied metabolic phenomenon in cancer cells. For the most part, these studies have focused on enhanced rates of glycolysis observed in various models. The presumption has been that mitochondrial metabolism is suppressed. However, recent studies indicate that the extent of mitochondrial metabolism is far more heterogeneous in tumors than originally presumed. One tumor type with suppression of mitochondrial metabolism is renal cell carcinoma (RCC). Prior studies indicate that suppressed TCA cycle enzyme mRNA expression is associated with aggressive RCC. Yet, the mechanisms that regulate the TCA cycle in RCC remain uncharacterized. Here, we demonstrate that loss of TCA cycle enzyme expression is retained in RCC metastatic tissues. Moreover, proteomic analysis demonstrates that reduced TCA cycle enzyme expression is far more pronounced in RCC relative to other tumor types. Loss of TCA cycle enzyme expression is correlated with reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1) which is also lost in RCC tissues. PGC-1 re-expression in RCC cells restores the expression of TCA cycle enzymes in vitro and in vivo and leads to enhanced glucose carbon incorporation into TCA cycle intermediates. Mechanistically, TGF-{beta} signaling, in concert with histone deacetylase 7 (HDAC7), suppresses TCA cycle enzyme expression. In turn, pharmacologic inhibition of TGF-{beta} restores expression of TCA cycle enzyme expression and suppresses tumor growth in an orthotopic model of RCC. Taken together, our findings reveal a novel role for the TGF-{beta} /HDAC7 axis in global suppression of TCA cycle enzymes in RCC and provide novel insight into the molecular basis of altered mitochondrial metabolism in this malignancy.

cancer biology↗