brief notes - doxycycline, TGF-beta, microgravity

The topic of low dose doxycycline (DOX) for Parkinson's came up on a forum. Rationale for its use in PD is typically based inhibition of a-syn aggregation, however DOX is a matrix metalloproteinase inhibitor (2 and 9). Matrix metalloproteinases are a group of enzymes that break down collagen and some other extracellular matrix proteins. White tea is supposed to be good for preventing skin aging since it contains a substance that inhibits one or two matrix metalloproteinases (can't remember which ones). The extracellular matrix is the stuff in between cells and it is mostly collagen. A lot of TGF-beta, a signalling molecule involved in the immune system, is localized in the ECM and engages in 'solid state' signalling - it is not dissolved in fluid, it stays put and interacts with cells as they come in contact when the tissue is deformed by mechanical pressure or cells migrate . People with connective tissue disorders often have immune system problems because their collagen does not work properly and that leads to problems with TGF-beta signalling; this is also probably is at least partly why microgravity (weightlessness) that astronauts experience is so bad for so many aspects of health.

Could DOX or losartan (see below) mitigate some of the effects of  microgravity?

Some have said there should not be trials of low dose DOX for PD because of antibiotic resistance concerns. Another issue is that doxycycline (and other antibiotics) can inhibit mitochondrial function, but on the other hand it can also reduce production of reactive oxygen species (ROS). 

References -

Marfan and DOX - https://www.ahajournals.org/doi/full/10.1161/circresaha.108.174367

Connective tissue disorders, TGF-beta and allergy - News article: https://www.genengnews.com/news/shared-genetic-aberration-links-connective-tissue-disorders-to-common-allergies/ suggests repurposing losartan, an  angiotensin II receptor type 1 antagonist, to improve TGF-beta function. Original research paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905327/

TGF-beta in the ECM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875828/

https://pubmed.ncbi.nlm.nih.gov/1378310/  [1992, paywalled]

DOX and mitochondrial toxicity - https://www.jbc.org/article/S0021-9258(21)00935-2/fulltext

DOX reduces ROS  - https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175195

~

"... spaceflight may affect the onset and progression of immunological conditions such as allergy and autoimmunity. Some astronauts experience allergy-like symptoms during spaceflight73. Moreover, skin rashes and hypersensitivity frequently occur in astronauts74. These reports suggest dysregulation of immune and inflammatory responses by spaceflight environments. The mechanisms underlying this dysregulation remain unclear. Various stressors can be risk factors for such symptoms75, thus it is possible that psychological stress during spaceflight indirectly contributes to their onset and/or progression. To date there is no clear evidence that spaceflight is associated risk of developing autoimmunity."

https://www.nature.com/articles/s41526-020-0104-1

We don't know what's causing it therefore it must be something psychological. The TGF-beta-allergy connection (see ref under connective tissue disorders) seems worth looking into and guess what - it generates testable hypotheses.

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