Aspirin has a long history and is a common nonsteroidal anti-inflammatory drug. Its predecessor, acetylsalicylic acid, was derived from the chemical found in willow bark.
As early as 2,000 years ago, willow bark was used to treat diseases. Legend has it that Hippocrates used it to treat headaches and fever. Li Shizhen's "Compendium of Materia Medica" also mentions that the use of willow bark to boil water can relieve the pain of patients with arthropathy.
After the willow bark is treated, there will be some yellowish or white powder - salicylic acid, which people used at that time to relieve pain.
In 1874, Scottish physician McClagan lowered the body temperature of rheumatism patients with willow bark extract and relieved the patients' pain and puffiness. Two years later, his experimental report was published in the medical journal The Lancet.
In 1897, Felix Hoffmann, a chemist at Bayer Pharmaceuticals in Germany, synthesized acetylsalicylic acid on the basis of salicylic acid, improving the shortcomings of salicylic acid and retaining the efficacy. In 1899, Bayer sold the drug worldwide under the trademark Aspirin.
Aspirin, as the world's most widely used antipyretic analgesic, has been used for a hundred years and is one of the three classic drugs in the history of medicine. In addition to understanding heat analgesia, aspirin also has anti-platelet coagulation effects, and has been later used in the treatment of acute myocardial infarction, diabetes, stroke, heart disease and other diseases.
The first generation of "magic medicine" can always bring new surprises.
In 1995, American researchers discovered that aspirin protects against bowel cancer. An Ascensiin activates resolution pathways to reprogram T cell and macrophage responses in colitis-associated colorectal was recently published on Science Advances Cancer (aspirin reprograms T cells and macrophages in inflammatory bowel cancer to activate the immune response), and the paper reveals why aspirin can prevent bowel cancer.
Prior to this, we explained that most of the efficacy of aspirin is derived from the inhibition of cyclooxygenase (COX). Inflammation leads to an increase in COX-2, and COX-2 induces the synthesis of prostaglandin E2; COX-1 is expressed in most tissues such as blood vessels, stomach, kidneys and platelets, and is involved in platelet aggregation, vasomotor and blood flow regulation.
The production of prostaglandin E2 in patients with bowel cancer increases and is associated with the occurrence of cancer, because prostaglandin E2 can inhibit host immunity and promote tumor growth. Thromboxane A2, on the other hand, promotes tumor metastasis in a platelet-dependent pathway. Previous studies have shown that aspirin can indeed reduce the incidence of bowel cancer, but it does not fully explain its role in being involved in regulating the immune regulation of bowel cancer.
Enzyme activity is inhibited after COX-1 acetylation, while enzyme activity is retained after COX-2 acetylation and its catalytic activity is transferred to the production of SPM (AT-SPM), a specialized regulatory mechanism initiated by aspirin. An Ascendin-triggered proresolving mediators stimulate resolution in cancer published in PNAS (Proceedings of the National Academy of Sciences) in 2019 mentioned that treating mice with SPM can inhibit the growth of primary tumors by enhancing the phagocytosis of macrophages on tumor cell debris and counter-regulating pro-inflammatory cytokines secreted by macrophages. This is used as an explanation for the anti-cancer effects of aspirin.
The researchers focused their research on SPM this time, choosing a mouse model of AOM/DSS-induced inflammatory bowel cancer. Experiments have shown that the metering of 43mg/kg has the greatest protective effect, which can effectively inhibit inflammation, prevent the shortening of the colon caused by inflammation, and reduce the area of intestinal polyps. Compared with the placebo group, the expression of the oncogene c-myc, trilobite factor (Tff3), and propylose phosphate isomerase 1 (Tpi1) in the colorectal tissue of mice in this group decreased, and the expression of the tumor suppressor gene Pten increased.
Comparison of colon length and polyp area in mice in the aspirin group and control group
The immune cells of the experimental group mice at this dose also had significant changes, the number of macrophages decreased, and the cell phenotype changed. This phenomenon is associated with an increase in the expression of the chemokine receptor CX3CR1, and an increase in CX3CR1 is also associated with an improvement in the prognosis of inflammatory bowel cancer. Multivariate analysis of lipid media profiles of macrophages showed increased SPM levels, suggesting that aspirin directly regulates the phenotype and function of macrophages, reprogramming them into protective phenotypes.
In addition, PD-1 expression in macrophages is reduced. Observing this phenomenon, the researchers then prepared human macrophages and cultured them with human bowel cancer cells and found a significant increase in the expression of PD-1. Recent studies have shown that increased expression of PD-1 in macrophages is associated with dysfunction of their function. When the supernatant of human bowel cancer cells is treated with aspirin, the expression of PD-1 in macrophages decreases, and the act of exocytosis increases.
Macrophage phenotypic marker expression analysis of mice in the aspirin group and control group showed significant isolation
Aspirin-affected immune cells are not only macrophages, aspirin reduces the expression level of PD-1 on each CD8+ T cell, but also reduces the number of CD8+ T cells expressing PD-1, and the decrease in PD-1 is significantly associated with an increase in the level of effector cytokine interferon γ; in CD4+ T cells with immunosuppressive function, the level of the pro-inflammatory cytokine interleukin-17 is significantly reduced.
To determine the mechanism by which aspirin exerts its immunoprotective effect, the researchers evaluated the level of SPM synthesis in mice, and the data showed that aspirin administration was able to rapidly increase the biosynthesis of various SPM substances in mouse colon tissues and reach a maximum value one week after administration.
Levels of desregulatins D1, D3 and lipoxinS A4 and B4 in mice and control groups in the aspirin group over time
The researchers detected acetylated COX-2 in the colorectal tissues of mice administered aspirin, and the levels of lipoxins A4, B4, and prosthetins D1, D3 also increased with the duration of treatment, which, in conjunction with a decrease in the immunosuppressive mediators prostaglandins E2, D2, and thromboxane A2, mediating the protective effect of aspirin in inflammatory bowel cancer.
The researchers believe that this study identifies a previously underappreciated mechanism for aspirin to prevent bowel cancer that could be used to develop immune reprogramming therapies to treat bowel cancer. In future studies, SPM may serve as a potential biomarker to assess the effectiveness of aspirin in preventing inflammatory bowel cancer.
Resources:
1.Aspirin activates resolution pathways to reprogram T cell and macrophage responses in colitis-associated colorectal cancer
2.Aspirin-triggered proresolving mediators stimulate resolution in cancer
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Edit: Ge Ge Wu