8 replies to this topic

[reason]

Transcription factor EB (TFEB) is a regulator of autophagy, one of the processes by which cells clear out unwanted junk and damaged components. Enhancing autophagy via TFEB for therapeutic ends has been explored in a very preliminary fashion to date, such as in the context of treating atherosclerosis. Continuing in this vein, researchers here show that manipulating TFEB can increase clearance of the α-synuclein aggregates whose increased presence is associated with the age-related diseases collectively known as synucleinopathies:

Aggregation of α-synuclein (α-syn) is associated with the development of a number of neurodegenerative diseases, including Parkinson's disease (PD). The formation of α-syn aggregates results from aberrant accumulation of misfolded α-syn and insufficient or impaired activity of the two main intracellular protein degradation systems, namely the ubiquitin-proteasome system and the autophagy-lysosomal pathway.

Novel insights into the mechanisms of autophagy regulation have emerged with the recent discovery that the transcription factor EB (TFEB) controls the coordinated activation of the CLEAR (Coordinated Lysosomal Expression and Regulation) network. TFEB regulates lysosome biogenesis as well as autophagosome formation and autophagosome-lysosome fusion, thereby promoting cellular clearance. Based on this evidence we hypothesized that TFEB activation could prevent accumulation of α-syn aggregates by enhancing autophagic clearance.

We tested this hypothesis by using a human neuroglioma stable cell line that accumulates aggregated α-syn and demonstrated that overexpression of TFEB reduces the accumulation of aggregated α-syn. Specifically, we provide evidence that the reduced accumulation of α-syn aggregates correlates with TFEB activation and with upregulation of the CLEAR network and the autophagy system. We also show that chemical activation of TFEB using 2-hydroxypropyl-β-cyclodextrin (HPβCD) mediates autophagic clearance of aggregated α-syn. These results support the role of TFEB as a therapeutic target for the treatment of PD and potentially other neurodegenerative diseases characterized by protein aggregation.

Link: http://dx.doi.org/10...al.pone.0120819

View the full article at FightAging

[Logic]

The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation

"...oblongifolin C (OC), a natural small molecule compound extracted from Garcinia yunnanensis Hu, is a potent autophagic flux inhibitor. Exposure to OC results in an increased number of autophagosomes..."

http://www.tandfonli...4161/auto.28034

 

"...accumulated amino acids inside the lysosome initiate signalling through the v-ATPase-Ragulator protein complex to Rag-GTPases, which, in turn, recruit mammalian target of rapamycin (mTOR) to the surface of the lysosomes (Sancak et al., 2008, 2010; Zoncu et al., 2011). TFEB interacts with mTOR on the lysosomal surface, where phosphorylation of multiple serine residues by mTOR prevents TFEB translocation to the nucleus...?

http://www.medscape....rticle/826577_3

 

"...Here, we demonstrated that the activation of the two major proteolytic machineries, the molecular chaperone-ubiquitin proteasome system (UPS) and the autophagy system, were simultaneously enhanced by paeoniflorin, a major component of Paeonia plants, and exerted therapeutic effects in models of spinal and bulbar muscular atrophy..."

http://hmg.oxfordjou...ddu066.full.pdf

 

The Phytoestrogen Genistein Modulates Lysosomal Metabolism and Transcription Factor EB (TFEB) Activation

"...this isoflavone can cross the blood-brain barrier, making it an especially desirable potential drug for the treatment of neurological symptoms present in most lysosomal storage diseases..."

http://www.jbc.org/c...9/24/17054.full

 

 

[niner]

The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation

"...oblongifolin C (OC), a natural small molecule compound extracted from Garcinia yunnanensis Hu, is a potent autophagic flux inhibitor. Exposure to OC results in an increased number of autophagosomes..."

http://www.tandfonli...4161/auto.28034

 

This one inhibits autophagy, rather than increases it.  That's probably not what you want unless you are using it in conjunction with fasting to treat cancer.

[ClarkSims]

 

The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation

"...oblongifolin C (OC), a natural small molecule compound extracted from Garcinia yunnanensis Hu, is a potent autophagic flux inhibitor. Exposure to OC results in an increased number of autophagosomes..."

http://www.tandfonli...4161/auto.28034

 

This one inhibits autophagy, rather than increases it.  That's probably not what you want unless you are using it in conjunction with fasting to treat cancer.

 

 

Autophagic flux is downregulation of autophagy. http://www.ncbi.nlm....pubmed/25484088
 

[ClarkSims]

This is a nice essay about protein cycling and various drugs that up regulate autophagy.

https://proteincycli...3nmvrwklbxs-15/

[resveratrol_guy]

 

The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation

"...oblongifolin C (OC), a natural small molecule compound extracted from Garcinia yunnanensis Hu, is a potent autophagic flux inhibitor. Exposure to OC results in an increased number of autophagosomes..."

http://www.tandfonli...4161/auto.28034

 

This one inhibits autophagy, rather than increases it.  That's probably not what you want unless you are using it in conjunction with fasting to treat cancer.

 

 

Why would one want to inhibit autophagy in order to treat cancer? Many cancer drugs (e.g. nilotinib) work by upregulating autophagy to such an extreme degree that the genetically deranged cancer cells end up digesting themselves, essentially.
 

[resveratrol_guy]

The Phytoestrogen Genistein Modulates Lysosomal Metabolism and Transcription Factor EB (TFEB) Activation

"...this isoflavone can cross the blood-brain barrier, making it an especially desirable potential drug for the treatment of neurological symptoms present in most lysosomal storage diseases..."

http://www.jbc.org/c...9/24/17054.full

 

I was surpised to find that for all its apparently beneficial pathway activations, genistein is available for cheap at WalMart. Unfortunately, it's a phytoestrogen. So it's unclear to me whether this stuff has a net benefit or not. The same issues seem to apply to isoflavones generally, e.g. from tofu.

[niner]

 

 

The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation

"...oblongifolin C (OC), a natural small molecule compound extracted from Garcinia yunnanensis Hu, is a potent autophagic flux inhibitor. Exposure to OC results in an increased number of autophagosomes..."

http://www.tandfonli...4161/auto.28034

 

This one inhibits autophagy, rather than increases it.  That's probably not what you want unless you are using it in conjunction with fasting to treat cancer.

 

Autophagic flux is downregulation of autophagy. http://www.ncbi.nlm....pubmed/25484088

 

That paper says: "Autophagic flux is often defined as a measure of autophagic degradation activity".  So higher flux would mean more degradation, i.e. more autophagy.  Normally, more autophagy is exactly what we want.

[niner]

 

This one inhibits autophagy, rather than increases it.  That's probably not what you want unless you are using it in conjunction with fasting to treat cancer.

 

Why would one want to inhibit autophagy in order to treat cancer? Many cancer drugs (e.g. nilotinib) work by upregulating autophagy to such an extreme degree that the genetically deranged cancer cells end up digesting themselves, essentially.

 

If you're treating cancer using a metabolic approach involving fasting, then you might want to turn down autophagy, because autophagy creates nutrients.  It's probably not a good idea;  I was just trying to think of a reason why you might want to inhibit autophagy.