Interesting diagram and agree that cumulative affect of both treatments extremely unlikely particularly as you say the mechanism of action is so similar.
However, let’s not forget Rapamycin is extremely cost effective and we have options for Senolytics management - expect greater criticism of Rapamycin et al as the $ signs start to ride high
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Cohen
#45
You might achieve the same effect with ruxolitinib, but no one has investigated whether it extends the lifespan of C. elegans.
CAFs, an important element in tumor microenvironment, have been demonstrated to secret various cytokines to participate in the tumor growth and metastasis [32]. However, the mechanisms of the CAFs induced tumor progressions are still remained to be unclear. Our studies firstly demonstrated that CAFs could facilitate the gastric cancer drug resistance development through the secretion of IL-11. A recent study showed that activation phosphoinositide 3-kinase signal is associated with the IL-11 induced the tumor growth enhancement [33]. And recent studies proved that IL-11 also serves as tumor-promoting cytokines in colon cancer through the activation of GP130 receptor [34]. Here, we revealed that the Bcl2 up-regulation in gastric cancer results in the drug resistance, which is induced by the activation of JAK/STAT3 signaling pathway. Furthermore, Ruxolitinib, a JAK signaling inhibitor, could serve as a potential agent to block the IL-11/IL-11R paracrine pathway induced by CAFs and be combined with multiple chemotherapeutic agents to effectively reverse the drug resistance and inhibit gastric cancer progression.
In conclusion, our results described a novel role of CAFs and IL-11 in drug resistance of gastric cancer. Our findings validated that CAFs could regulate the drug resistance in a paracrine manner through IL-11/JAK/STAT3/BCL2 signaling pathway. And the combination of IL-11R inhibitor and chemotherapeutic agents might be explored as a potential strategy to gastric cancer therapy.
Hutchinson–Gilford progeria syndrome (HGPS) is caused by an LMNA mutation that results in the production of the abnormal progerin protein. Children with HGPS display phenotypes of premature aging and have an average lifespan of 13 years. We found earlier that the targeting of the transmembrane protein PLA2R1 overcomes senescence and improves phenotypes in a mouse model of progeria. PLA2R1 is regulating the JAK/STAT signaling, but we do not yet know whether targeting this pathway directly would influence cellular and in vivo progeria phenotypes. Here, we show that JAK1/2 inhibition with ruxolitinib rescues progerin‐induced cell cycle arrest, cellular senescence, and misshapen nuclei in human normal fibroblasts expressing progerin. Moreover, ruxolitinib administration reduces several premature aging phenotypes: bone fractures, bone mineral content, grip strength, and a trend to increase survival in a mouse model of progeria. Thus, we propose that ruxolitinib, an FDA‐approved drug, should be further evaluated as a drug candidate in HGPS therapy.
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So should that be Trametinib in the diagram rather than ‘tramedinib’ - cannot find any reference to tramedinib?
Interesting that I use Dasatinib as a Senolytics (Dr Green) - perhaps those with greater knowledge could tell me if the use of Dasatinib is analogous to Trametinib in this diagram or is it wholly associated with the senolytic action described at the bottom of this diagram and as I have always assumed?
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ng0rge
#47
Yes, just a misspelling. Here’s what I found on Dasatinib and Trametinib (often syngestic for cancer):
“Pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease that is expected to become the second cause of cancer fatalities during the next decade.
Dasatinib-induced ERK activation was completely abolished by exposure to the FDA-approved MEK inhibitor trametinib. A combination of dasatinib and trametinib potently and synergistically inhibited colony formation by PDAC cells. The results provide rationale for considering a combination(s) of FDA-approved SFK (dasatinib) and MEK (e.g., trametinib) inhibitors in prospective clinical trials for the treatment of PDAC.”
https://pubmed.ncbi.nlm.nih.gov/35999654/
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Are there no natural il-11 inhibitors that are strong enough? I know some il-6 inhibitors have been identified, but there appears to be less data on il-11.
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How would this be dosed? I see most of the sources are 0.05-0.1 mg, but would that even be adequate for human dosing?
Good question, I have no idea on dosing. And the traditional translation metrics for small molecules going from rodents to humans would not seem to apply for antibodies.
1 Like
Neo
#51
The best way is probably to measure IL-6 itself?
At least in the US, IL-6 tests are widely available and can be done at a Quest diagnostic and one can order it online via Ulta Labs if one wants to get it without a doctors prescription for the test.
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Yes:
The test on the Ultra Lab site:
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AnUser
#53
Either way this isn’t IL-11.
ng0rge
#54
We heard you the first time…Anyway, since there aren’t blood tests for IL-11, your suggestion of Hs-CRP may serve as a rough measure of IL-11 levels since both IL-6 and IL-11 are inflammatory.
https://www.ukri.org/news/turning-off-inflammatory-protein-extends-healthy-lifespan-in-mice/
" Assistant Professor Anissa Widjaja, who was co-corresponding author, from Duke-NUS Medical School, Singapore, said:
This project started back in 2017 when a collaborator of ours sent us some tissue samples for another project. Out of curiosity, I ran some experiments to check for IL-11 levels. From the readings, we could clearly see that the levels of IL-11 increased with age and that’s when we got really excited!
We found these rising levels contribute to negative effects in the body, such as inflammation and preventing organs from healing and regenerating after injury. Although our work was done in mice, we hope that these findings will be highly relevant to human health, given that we have seen similar effects in studies of human cells and tissues."
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Danny
#55
Omega 3 fatty acids seem to inhibit IL-11 expression in some cells.
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Has anyone found any research that suggests that IL-6 and IL-11 (and CRP) trend upwards or downwards together?
Perhaps @desertshores can check his medical AI bot he uses for its take on this issue.
ChatGPT suggests:
IL-6 (Interleukin-6) and IL-11 (Interleukin-11) are both cytokines involved in inflammatory responses and various physiological processes in humans. While they belong to the same family of cytokines (the IL-6 cytokine family), their specific roles and regulation can vary.
In general, IL-6 and IL-11 can be regulated similarly in certain contexts because they share some signaling pathways and regulatory mechanisms. For example, both cytokines can be induced by similar stimuli such as inflammation, infections, or tissue injury. Therefore, in situations where these stimuli are present, both IL-6 and IL-11 levels may increase simultaneously.
However, there are also instances where IL-6 and IL-11 may not trend in the same direction. They can have distinct functions and may respond differently to specific stimuli or conditions. Their expression can be regulated independently in certain tissues or under specific pathological conditions.
Overall, while IL-6 and IL-11 can exhibit coordinated regulation in some situations due to their shared signaling pathways and responses to similar stimuli, their expression and roles can also diverge depending on the context.
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AnUser
#57
Waiting for people to stop speculating you say?
ng0rge
#58
Oh, go back to your cave and quit trolling!
From the study that @Danny posted above, but the full-text version:
https://www.spandidos-publications.com/ijmm/48/4/190#
IL-11 belongs to the IL-6 family and shares the same gp130 homodimer receptor complex with IL-6. Specificity is gained through an individual IL-6/IL-11 α-receptor (31). Previous studies have demonstrated that IL-6 and IL-11 exert the opposite effect on immune regulation. It has been reported that IL-6 promotes type 2 T helper (Th2) cell response in an asthma model, while IL-11 inhibits Th2 type inflammation (32). IL-6 and IL-11 exhibit similar biological outcomes in the induction of the acute-phase response (33). In a previous study, both IL-11 and IL-6 increased the level of phosphorylated STAT3 in hepatocytes, however, only IL-6, but not IL-11, could induce STAT3 phosphorylation in Kupffer cells, which indicates that hepatocytes may be the target of IL-11.
IL-11 is a pleiotropic cytokine with biological functions in different cell types (2). It is mainly produced by hepatocytes in response to ROS during acute liver injury in mice (3). In a previous study, livers of mice receiving IL-11 exhibited damage, with elevated markers of fibrosis, hepatocyte cell death and inflammation (34). Notably, inhibiting IL-11 signaling by neutralizing antibodies could reduce hepatocyte death, inflammation and hyperglycemia in mouse models of diet-induced steatohepatitis (34). A previous study reported the pathological function of IL-11 in hepatocytes during the early stages of metabolic liver disease (2). MAPK/ERK activation is crucial for the oxidative stress-induced production of IL-11 (3). Treatment with ERK inhibitors can efficiently suppress TNF-α-induced IL-11 induction in murine embryonic fibroblasts.
And to answer the question (which you, @AnUser should take as Scientific Gospel) is yes, I think Omega 3 fatty acids would inhibit IL-11 and inflammation.
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AnUser
#59
Which didn’t answer his question…
Work with us here please.
Its a start… this isn’t something we are going to determine in 30 seconds of Pubmed research, I think it will take a little more time.
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Danny
#62
Reading about them briefly, they are generally expressed in different cell types. The paper I cited above notes that Omega 3 fatty acids suppress both IL-6 and IL-11 in specific types of cells at least. Also this paper indicates that excess Iron stimulates their over production in some cells. Until 2018 IL-11 was thought to be anti-inflammatory and beneficial from what I read.
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ng0rge
#63
Yes, but again, in the paper you cited:
In summary, the present results revealed that n-3 PUFAs inhibit IL-11 production and downstream STAT3 phosphorylation in hepatocytes, thereby aggravating acetaminophen (APAP)‑induced liver damage. The present study demonstrated that the ERK1/2-Fra-1 axis is important for the regulatory function of n-3 PUFAs on IL-11 expression.
So, in this case, inhibiting IL-11 aggravated the liver damage.
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But I wonder… is that only a concern if taking acetaminophen, or is it more generalizable?
“aggravating acetaminophen (APAP)‑induced liver damage.”
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