CGAS STING PATHWAY

[JDRhope]

My understanding to date is that neurological diseases are driven by autoimmunity and auto inflammation. Unfortunately the hyper focus on proteins and amyloids has effectively delayed a cure across all pathologies. There is hope. Let me introduce to you the CGAS Sting pathway.

nature.com/articles/s41586-...

[JDRhope]

pnas.org/doi/full/10.1073/p...

ncbi.nlm.nih.gov/pmc/articl...

It is increasingly recognized that chronic neuroinflammation is causally relevant to neurodegeneration. In Parkinson’s disease (PD), α-synuclein pathology activates inflammatory signaling that disturbs parenchymal homeostasis and disrupts neuron-glia interactions. Herein, we report that the innate immune cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) DNA-sensing pathway is activated in a mouse model of α-synucleinopathy and parkinsonism, leading to type-I interferon activation that precedes the onset of neurodegeneration. Remarkably, STING-deficient mice were protected from dopaminergic neuron loss in this model. We also show that αSyn aggregates can increase STING expression and augment canonical STING activation, suggesting a possible generalized propensity for exaggerated antiviral responses in neurological states with STING elevation. Our results suggest that STING inhibition may be therapeutic in idiopathic PD and possibly other human α-synucleinopathies.

[JDRhope]

pnas.org/doi/full/10.1073/p...

[JDRhope]

I would encourage all of you to go to your neurologists in your next appointment and ask them about the CGAS Sting Pathway. There is a clear differentiation between Sting Antagonists and Sting Agonists. The later being utilized with immunotherapies and cancer. (Most Drs seems to be somewhat familiar with this) In essence this recently discovered pathway is central in immune regulation. Hyperactivation of STING can be multifactorial caused by many things or one thing. The billion dollar question is how to inhibit this hyperactivation. There are many different applications that contribute to inhibition and there are some very big biotech companies in this area. I have spent the last months cross referencing many of the suggested treatments from synthetic to organic compounds and more to figure out how they inhibit STING. Most every single one does including IVM but not only. The UK study on URSO while no mention of STING is made in their paper, it is absolutely a STING inhibitor. I did find this curious. I hope this information assists and propels you forward to demand better treatments. ❤️

[JDRhope]

science.org/doi/full/10.112...

Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice

GBA MUTATION

[JDRhope]

journals.sagepub.com/doi/10...

3-N-butylphthalide attenuates neuroinflammation in rotenone-induced Parkinson’s disease models via the cGAS-STING pathway

”This study demonstrated that NBP reduced neuroinflammation and protected dopaminergic neurons by inhibiting activation of the cGAS-STING pathway in vitro and in vivo (Figure 8). The results showed that rotenone upregulated cGAS-STING signaling and induced an inflammatory response in BV2 cells, which was ameliorated by the STING inhibitor C-176. NBP reduced mtROS production and mitigated rotenone-induced mtDNA leakage. Moreover, NBP improved behavioral impairments and protected against rotenone-induced microglial activation and dopaminergic neuronal damage in PD mice. In addition, NBP inhibited the activation of the cGAS-STING pathway and simultaneously attenuated neuroinflammation. This was indicated by the decrease in the ratios of p-NfκB/NfκB and p-IκBα/IκBα and the production of proinflammatory cytokines (IL-1β, TNF-α, and IL-6). Our study revealed a novel mechanism by which NBP exhibits protective effects in rotenone-induced PD models.”

[104L]

biospace.com/drug-developme...

[JDRhope in reply to 104L]

Thanks for this. Disease modifying treatments in the pipeline. Now I need to cross reference. If I have anything of interest I’ll post.

[JDRhope in reply to 104L]

Some of them are mentioned here btw:

youtu.be/qFHX_d5ZBcI?si=D9U...(Not working as expected?)

[LAJ12345]

interesting. How many/which current parkinsons drugs inhibit STING if any?

Do any activate it, and what about foods and supplements?

Is there a natural inhibitor?

.

[Ghmac in reply to LAJ12345]

following

[LAJ12345]

I had a chat to chat gpt about STING to see if it knew if any natural products would be useful or what starting product they would suggest to a scientist who wanted to start with a natural compound and modify it. Here is what it said.

“

When suggesting a natural product as a potential starting point for STING inhibitor development, the choice would ideally be based on known anti-inflammatory and immune-modulating properties, as STING is a key player in the innate immune response. Here are a few natural products that might be worth investigating due to their known bioactive properties:

Curcumin (from Turmeric):

Known for its potent anti-inflammatory and immune-modulating effects.

Curcumin has been shown to interact with various molecular targets and signaling pathways involved in inflammation and immune responses.

Epigallocatechin Gallate (EGCG) (from Green Tea):

Exhibits strong anti-inflammatory and antioxidant properties.

EGCG has been studied for its effects on various signaling pathways, including those involved in immune regulation.

Resveratrol (from Grapes and Red Wine):

Known for its anti-inflammatory, antioxidant, and neuroprotective effects.

Resveratrol has been shown to modulate various molecular pathways, including those involved in inflammation and immune responses.

Berberine (from Goldenseal and other plants):

Exhibits anti-inflammatory, antimicrobial, and immune-modulating properties.

Berberine has been studied for its effects on various signaling pathways, including those related to inflammation and immune responses.

Quercetin (from Onions, Apples, and other plants):

Known for its anti-inflammatory, antioxidant, and immune-modulating effects.

Quercetin has been shown to affect various molecular targets and signaling pathways involved in immune responses.

These compounds have demonstrated a range of bioactive properties that could make them interesting candidates for further investigation as potential STING inhibitors. The next steps would involve screening these compounds for activity against the STING pathway, followed by structural optimization to enhance their potency, selectivity, and pharmacokinetic properties. Additionally, conducting computational modeling and in vitro assays could help in understanding their interactions with the STING protein and guide the development of more effective derivatives.”

All of our favourites!