Our Love Life Needs You © Nina Otulakowski August 2022
RxISK regularly gets enquiries about what can be done to find an answer to the sexual dysfunctions following SSRIs, Finasteride and Isotretinoin – PSSD, PFS and PRSD.
RxISK and Sharks outlined the likely Endgame. This outcome would be terrible – especially as its highly likely there is someone out there who has the answer we need but doesn’t know we have the problem they have the answer to. At least four things can be done to help avoid this outcome.
First: We need someone to build a Wiki into which everyone can load leads. See below.
Second: We need you and others to load targets like the ones below and other targets that look suitable into the Wiki, along with the emails of the researchers listed in the articles.
Third: We need you to start emailing these researchers mentioning the RxISK Prize which you (yes you) can play a part in getting for them. Doesn’t matter if a researcher gets emails from 20 different people.
You should not think of the RxISK Prize as being owned byRxISK – the criteria for the Prize means that we in RxISK have to decide if a breakthrough merits the Prize but the Prize belongs to everyone with PSSD, PFS, PRSD or anyone linked to them or just interested in the issues.
Everyone one of you can bring it to the attention of anyone out there who might have the winning formula – we have no favorites or favorite answers, so if the person you find comes up with the breakthrough s/he wins.
You can also ask everyone you email if they know anyone working for instance on prokineticin, VEGF, p53, p63 or p73 or whatever other targets you or others identify. It would be great if you can then feed these back to the Wiki, along with the names of researchers who are willing to engage and their emails.
Fourth: We need links to epigeneticists who can locate other epigeneticists. Someone needs to be able to tell all of us what the Baylor Finasteride Epigenetics study means, what an earlier Citalopram Epigenetics study means and what isotretinoin studies reveal.
This needs epigeneticists who are not blinkered by being told to look for leads linked to the serotonin or dopamine or depression markers that PSSD folk have been focused on or the neurosteroids that those with PFS have felt certain must be involved.
We need to know where the biggest effects are seen (it will likely not be on serotonin or neurosteroids).
We need to know whether an epigeneticist can spot an effect that could be conceivably linked to a switch mechanism – some protein that might turn processes on or off, as the key to PSSD, PFS and PRSD is not just an effect on sexual function but on some on/off-switch.
All the targets below have come from people like you, usually with no background in research or healthcare – not from any high-powered (but blinkered) researchers or from anyone in RxISK. You out there are almost certainly better placed than you think to find the missing link.
What these targets have in common is that they are proteins or enzymes that come in genetic isoforms which might predispose some of us to have a semi-permanent knock-out effect where others of us can tolerate taking SSRIs or finasteride or isotretinoin just fine.
There are almost certainly lots of other researchers working on this. Finding them will involve looking up articles on Prokineticin or PROKR-1 or PROKR-2 and tracking
This looks such a promising protein – it mediates the emotional aspect of touch that seems missing in PSSD, PFS and PRSD.
Can you add more prokineticin articles and researchers?
Angiotensin Converting Enzyme 2 – ACE-2 – was also mentioned in Holy Grail. This is also fascinating because it looks like one of those things that ties thalidomide, SSRIs and at least isotretinoin together, along with cancer, Covid and sexual dysfunction.
There is far more interaction between ACE systems and serotonin, even in the brain, than there is with dopamine or other systems. The same applies to isotretinoin. And we differ in the types of ACE-2 receptors we have.
ACE-2 might explain the sexual dysfunction all three can cause along with the birth defects all three can cause. And it links to regulatory proteins like p63 below.
Although p53 has long been known as the “guardian of the genome” with a role in tumor suppression in many tissues, the discovery of two p53 ancestral genes, p63 and p73, more than a decade ago has triggered a considerable amount of research into the role of these genes in skin development and diseases. In this review, we primarily focus on mechanisms of action of p53 and p63, which are the best-studied p53 family members in the skin. The existence of multiple isoforms and their roles as transcriptional activators and repressors are key to their function in multiple biological processes including the control of skin morphogenesis, regeneration, tumorigenesis, and response to chemotherapy. Last, we provide directions for further research on this family of genes in skin biology and pathology.
The genome is constantly harmed by spontaneous damage caused by endogenous factors produced by normal cellular physiological conditions such as bases alteration, aberrant DNA enzyme function or oxidation, and by a large variety of exogenous genotoxic factors . Cells have evolved a complex network of hundreds of proteins, named the DNA damage response (DDR), to ensure genome integrity and the expression of dedicated proteins to each cell type.
– in the last decade as part of anti-cancer therapy have been designed inhibitors of proteins that play a role as DDRs: DNA damage response inhibitors
– among these proteins, P53 plays a central role in managing cell proliferation, inducing cells with damaged DNA to apoptosis (death) and autophagy (eating parts of itself)
The p53 protein plays a passive and an active role in stem cells. The transcriptional activities of p53 for cell-cycle arrest and DNA repair are largely turned off in stem cells, but there is some indication that long-term stem-cell viabilitymay require other p53-regulated functions. When p53 is activated in stem cells, it stops cell division and promotes the commitment to a differentiation pathway and the formation of progenitor cells. In the absence of any p53 activity, stem-cell replication continues and mistakes in the normal epigenetic pathway occur at a higher probability. In the presence of a functionally active p53 protein, epigenetic stability is enforced and stem-cell replication is regulated by commitment to differentiation.
This review based on translational research predicts that the transcription factor p53 is the key effector of all anti-acne therapies. All-trans retinoic acid (ATRA) and isotretinoin (13-cis retinoic acid) enhance p53 expression. Tetracyclines and macrolides via inhibiting p450 enzymes attenuate ATRA degradation, thereby increase p53. Benzoyl peroxide and hydrogen peroxide elicit oxidative stress, which upregulates p53. Azelaic acid leads to mitochondrial damage associated with increased release of reactive oxygen species inducing p53. p53 inhibits the expression of androgen receptor and IGF-1 receptor, and induces the expression of IGF binding protein 3. p53 induces FoxO1, FoxO3, p21 and sestrin 1, sestrin 2, and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the key inducer of isotretinoin-mediated sebocyte apoptosis explaining isotretinoin’s sebum-suppressive effect. Anti-androgens attenuate the expression of miRNA-125b, a key negative regulator of p53. It can thus be concluded that all anti-acne therapies have a common mode of action, i.e., upregulation of the guardian of the genome p53. Immortalized p53-inactivated sebocyte cultures are unfortunate models for studying acne pathogenesis and treatment.
– isotretinoin via increased p53 signalling apparently depletes the number and survival of p63-regulated sebocyte progenitor cells.
Biopsies from back skin of patients taken before and after isotretinoin treatment show that the treatment significantly increased the nuclear expression of p53 in sebaceous glands, the p53 protein and gene expression significantly increased in the skin after isotretinoin treatment
– isotretinoin induces both p53-mediated autophagy as well as p53-induced apoptosis, depending on the dose and duration of isotretinoin exposure and the resulting magnitude of p53 expression.
– isotretinoin-induced expression of p53 not only promotes sebocyte apoptosis in human sebaceous glands as the predominant sebum-suppressive effect bit is also responsible for isotretinoin´s adverse effects [such as..]
These researchers believe they have obtained a valid model of PGAD on rats.
“Microvascular injury can significantly appeared in the model, and the VEGF-ERK signaling pathway is a possible mechanism involved”
Maybe this VEGF (Vascular endothelial growth factor, a signalling protein that promotes the growth of new blood vessels) is one of those things that would have something to do with anything
– is expressed and released by endothelial cells (the tissue that lines the inner surface of blood vessels)
– treatment target in cases of erectile dysfunction with vascular causes
– potential target for therapeutic intervention in depression
– overexpression of VEGF has been associated with tumor progression
– critical player in the neurovascular stem cell niche of the hippocampus
– SSRIs and SNRIs increase VEGF expression in the hippocampus
– Finasteride inhibits angiogenesis and expression of VEGF in human
– Retinoids are potent inhibitors of VEGF/VPF production by normal human Keratinocytes
– Thalidomide is a potent inhibitor of angiogenesis due to direct inhibitory action on VEGF secretion
– the two major isoforms of the p63 gene exert opposite effects on the VEGF gene expression
This seems to be a process to get to the bottom of what causes the persistence of an iatrogenic effect to the point of targeting a specific protein.
“The analysis of data from 3 studies describing serum leptin levels in PE patients before and after treatment with SSRIs showed that there was a significant decrease with leptin levels in PE patients after treatment”
There must be at least ten more plausible target proteins or enzymes like these out there.
We need someone to build a Wiki or maybe an APP that can help make all this happen. The gadget doesn’t need to be much more than a glorified spreadsheet with a user-friendly interface.
Something that makes it easy for anyone to find researchers to harass, places to upload articles, perhaps a place to comment back on responses from researchers or others, and a place to follow up researchers who have shown some interest – did they do anything, did it lead anywhere.
It would have sections for PSSD, PGAD, PFS and PRSD.
We need to be able to host articles on prokineticin or whatever. Ideally, this would be done in a way that has a high SEO so that people looking for prokineticin or leptin or p53 find us.
A place where researchers might also start coming off their own bat looking for evidence of links between things like p73, VEGF and serotonin or isotretinoin not easily found elsewhere.
The Wiki/APP would host a template message/letter giving details about PSSD, PFS and PRSD and the Prize that can be downloaded, modified and sent to researchers.
Please get in touch if you can build one of these.