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The preventive effect of the first-generation "magic drug" aspirin in cancer has been verified in many studies, among which colorectal cancer (CRC) has the most significant effect.
Recommended drugs for CRC prevention in people at cardiovascular risk
.
However, at present, the mechanism by which aspirin regulates immunity is not very clear
.
A recent study in the journal Science Advances [1] just revealed the answer
.
The researchers found that aspirin can act in multiple ways to limit the progression of inflammatory CRC
.
It reduces proto-oncogene expression, increases levels of specific pro-inflammatory mediators (SPMs) including lipoxin A4 and resolvin D1, etc.
, reprograms macrophages to a protective phenotype, reduces macrophage Expression of the immunosuppressive receptor PD-1 in cells and colonic mucosal CD8+ T cells
.
Previous studies have shown that aspirin, as a cyclooxygenase (COX) inhibitor, can be acetylated and modified to inhibit the production of prostaglandins and thromboxane, and prostaglandin E2 can inhibit host immunity and promote tumor growth [2], And thromboxane A2 can promote tumor metastasis in a platelet-dependent way [3]
.
However, increasing evidence suggests that these mechanisms alone are not sufficient to explain the immunomodulatory effects of aspirin in CRC
.
The enzymatic activity is inhibited upon acetylation of COX-1, whereas the enzymatic activity is retained upon acetylation of COX-2, and its catalytic activity is transferred to promote the production of a protective molecule, aspirin-induced SPM (AT-SPM).
[4,5]
.
Moreover, studies have shown that people with high COX-2 expression levels regularly take aspirin to reduce the risk of CRC more significantly than those with low COX-2 levels [6]
.
Therefore, the researchers focused this study on SPM
.
They selected the AOM/DSS-induced inflammatory bowel cancer mouse model, and first determined the appropriate aspirin dose.
The experiment showed that the moderate dose of 43mg/kg (equivalent to the human dose of 325mg/day) had the greatest degree of protection.
It can effectively inhibit inflammation, prevent the shortening of the colon caused by inflammation, and reduce the area of intestinal polyps
.
Comparison of colon length and polyp area between aspirin group (ASA) and control group At the same time, compared with placebo, the proto-oncogene c-myc and trefoil factor 3 involved in cellular glycolysis in the colorectal tissue of aspirin mice (Tff3) and triose phosphate isomerase 1 (Tpi1) expression decreased, and the number of ki67-positive cells was significantly reduced
.
Correspondingly, the expression of the tumor suppressor gene Pten increased
.
At this dose, there were significant reductions in the levels of all intermediates in the glycolytic pathway in colon tissue, most of which were statistically significant, such as dihydroxyacetone phosphate and lactate
.
Increased glycolysis is a typical metabolic change in CRC and is thought to be responsible for part of the immunosuppressive pathway
.
There were also significant changes in immune cells
.
First, the number of lamina propria macrophages is reduced and the cellular phenotype changes, and this phenotypic change is associated with increased expression of the chemokine receptor CX3CR1, which is also associated with improved prognosis in inflammatory CRC [7]
.
Multivariate analysis of the lipid mediator profiles of macrophages revealed increased levels of several SPMs, including lipoxin A4 and resolvin D1, suggesting that aspirin directly modulates macrophage phenotype and function, converting them Reprogrammed to a protective phenotype
.
Expression analysis of macrophage phenotypic markers in aspirin group mice (ASA) and control group showed significant separation.
At the same time, the expression of the immunosuppressive receptor PD-1 in macrophages was also significantly reduced, which improved macrophage response to Phagocytosis rate and number of apoptotic cells
.
In addition to macrophages, aspirin also affected the phenotype and function of different types of T cells
.
As the core force of identifying and killing cancer cells, CD8+ T cells are also the main target of cancer cells.
Aspirin reduces the expression level of PD-1 on each CD8+ T cell, and also reduces the CD8+ T cells expressing PD-1.
Quantitatively, reductions in PD-1 were significantly associated with increased levels of the effector cytokine interferon gamma
.
Levels of the proinflammatory cytokine interleukin-17 were significantly reduced in immunosuppressive CD4+ T cells
.
In human CD8+ T cells, the researchers found the same changes
.
These changes in tissue metabolism and immune cell phenotype and function are based on changes in SPM levels.
In the colon tissue of aspirin-treated mice, the researchers detected acetylated COX-2, lipoxins A4, B4 and Levels of resolvin D1 and D3 also increased with treatment time, reaching a peak after one week, and this increase cooperated with a decrease in the immunosuppressive mediators prostaglandins E2, D2, and thromboxane A2, mediating the effect of aspirin in inflammatory conditions.
Protection in CRC
.
Changes in the levels of resolvin D1, D3 and lipoxin A4, B4 with time (starting from AOM/DSS induction) in aspirin group mice (ASA) and control group Lipoxin A4 and resolvin D1, D3 have Homologous receptor Alx/Fpr2 receptor, polyp size, macrophage phenotype and PD-1 expression, CD8+ T cell PD-1 expression, and disease in mice deficient in Alx/Fpr2 receptor, even on aspirin Severity was indistinguishable from placebo treatment
.
Likewise, pharmacological inhibition of SPM synthesis would also negate the protective effect of aspirin
.
Direct treatment of mice with a 15 ng dose of the SPM mixture resulted in protection similar to aspirin treatment
.
This suggests that aspirin indeed modifies the phenotype, function and/or PD-1 expression levels of macrophages, CD8+ T cells and CD4+ T cells by acetylating COX-2, increasing SPM levels, binding to Alx/Fpr2 receptors , plays a protective role in inflammatory bowel cancer
.
The researchers believe that this study identifies a previously underappreciated mechanism of aspirin's prevention of CRC, which could be used to develop immune reprogramming therapies for CRC, and that, in future studies, SPM could be used to assess the efficacy of aspirin in preventing inflammatory CRC.
a potential biomarker [8]
.
Reference: [1] De Matteis R, Flak MB, Gonzalez-Nunez M, et al.
Aspirin activates resolution pathways to reprogram T cell and macrophage responses in colitis-associated colorectal cancer [J].
Science Advances, 2022, 8(5 ): eabl5420.
[2] Zelenay S, Van Der Veen AG, Böttcher JP, et al.
Cyclooxygenase-dependent tumor growth through evasion of immunity[J].
Cell, 2015, 162(6): 1257-1270.
[3] Lucotti S, Cerutti C, Soyer M, et al.
Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A 2[J].
The Journal of clinical investigation, 2019, 129(5): 1845- 1862.
[4] Serhan CN, Hong S, Gronert K, et al.
Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals[J].
The Journal of experimental medicine, 2002, 196(8):1025-1037.
[5] Claria J, Serhan C N.
Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions[J].
Proceedings of the National Academy of Sciences, 1995, 92(21): 9475-9479.
[6] Chan AT, Ogino S, Fuchs C S.
Aspirin use and survival after diagnosis of colorectal cancer[J].
Jama, 2009, 302(6): 649-658.
[7] Marelli G, Erreni M, Anselmo A , et al.
Heme-oxygenase-1 production by intestinal CX3CR1+ macrophages helps to resolve inflammation and prevents carcinogenesis[J].
Cancer research, 2017, 77(16): 4472-4485.
[8] https:// ac.
uk/whri/news-and-events/2022/items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlBy Ying YuyanAspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions[J].
Proceedings of the National Academy of Sciences, 1995, 92(21): 9475-9479.
[6] Chan AT, Ogino S, Fuchs C S.
Aspirin use and survival after diagnosis of colorectal cancer[J].
Jama, 2009, 302(6): 649-658.
[7] Marelli G, Erreni M, Anselmo A, et al.
Heme-oxygenase-1 production by intestinal CX3CR1+ macrophages helps to resolve inflammation and prevents carcinogenesis[J].
Cancer research, 2017, 77(16): 4472-4485.
[8] https:// items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlThe author of this articleYing YuyanAspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions[J].
Proceedings of the National Academy of Sciences, 1995, 92(21): 9475-9479.
[6] Chan AT, Ogino S, Fuchs C S.
Aspirin use and survival after diagnosis of colorectal cancer[J].
Jama, 2009, 302(6): 649-658.
[7] Marelli G, Erreni M, Anselmo A, et al.
Heme-oxygenase-1 production by intestinal CX3CR1+ macrophages helps to resolve inflammation and prevents carcinogenesis[J].
Cancer research, 2017, 77(16): 4472-4485.
[8] https:// items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlThe author of this articleYing YuyanFuchs C S.
Aspirin use and survival after diagnosis of colorectal cancer[J].
Jama, 2009, 302(6): 649-658.
[7] Marelli G, Erreni M, Anselmo A, et al.
Heme-oxygenase-1 production by intestinal CX3CR1+ macrophages helps to resolve inflammation and prevent carcinogenesis[J].
Cancer research, 2017, 77(16): 4472-4485.
[8] https:// -events/2022/items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlThe author of this articleYing YuyanFuchs C S.
Aspirin use and survival after diagnosis of colorectal cancer[J].
Jama, 2009, 302(6): 649-658.
[7] Marelli G, Erreni M, Anselmo A, et al.
Heme-oxygenase-1 production by intestinal CX3CR1+ macrophages helps to resolve inflammation and prevent carcinogenesis[J].
Cancer research, 2017, 77(16): 4472-4485.
[8] https:// -events/2022/items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlThe author of this articleYing Yuyanuk/whri/news-and-events/2022/items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlBy Ying Yuyanuk/whri/news-and-events/2022/items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlBy Ying Yuyan
Recommended drugs for CRC prevention in people at cardiovascular risk
.
However, at present, the mechanism by which aspirin regulates immunity is not very clear
.
A recent study in the journal Science Advances [1] just revealed the answer
.
The researchers found that aspirin can act in multiple ways to limit the progression of inflammatory CRC
.
It reduces proto-oncogene expression, increases levels of specific pro-inflammatory mediators (SPMs) including lipoxin A4 and resolvin D1, etc.
, reprograms macrophages to a protective phenotype, reduces macrophage Expression of the immunosuppressive receptor PD-1 in cells and colonic mucosal CD8+ T cells
.
Previous studies have shown that aspirin, as a cyclooxygenase (COX) inhibitor, can be acetylated and modified to inhibit the production of prostaglandins and thromboxane, and prostaglandin E2 can inhibit host immunity and promote tumor growth [2], And thromboxane A2 can promote tumor metastasis in a platelet-dependent way [3]
.
However, increasing evidence suggests that these mechanisms alone are not sufficient to explain the immunomodulatory effects of aspirin in CRC
.
The enzymatic activity is inhibited upon acetylation of COX-1, whereas the enzymatic activity is retained upon acetylation of COX-2, and its catalytic activity is transferred to promote the production of a protective molecule, aspirin-induced SPM (AT-SPM).
[4,5]
.
Moreover, studies have shown that people with high COX-2 expression levels regularly take aspirin to reduce the risk of CRC more significantly than those with low COX-2 levels [6]
.
Therefore, the researchers focused this study on SPM
.
They selected the AOM/DSS-induced inflammatory bowel cancer mouse model, and first determined the appropriate aspirin dose.
The experiment showed that the moderate dose of 43mg/kg (equivalent to the human dose of 325mg/day) had the greatest degree of protection.
It can effectively inhibit inflammation, prevent the shortening of the colon caused by inflammation, and reduce the area of intestinal polyps
.
Comparison of colon length and polyp area between aspirin group (ASA) and control group At the same time, compared with placebo, the proto-oncogene c-myc and trefoil factor 3 involved in cellular glycolysis in the colorectal tissue of aspirin mice (Tff3) and triose phosphate isomerase 1 (Tpi1) expression decreased, and the number of ki67-positive cells was significantly reduced
.
Correspondingly, the expression of the tumor suppressor gene Pten increased
.
At this dose, there were significant reductions in the levels of all intermediates in the glycolytic pathway in colon tissue, most of which were statistically significant, such as dihydroxyacetone phosphate and lactate
.
Increased glycolysis is a typical metabolic change in CRC and is thought to be responsible for part of the immunosuppressive pathway
.
There were also significant changes in immune cells
.
First, the number of lamina propria macrophages is reduced and the cellular phenotype changes, and this phenotypic change is associated with increased expression of the chemokine receptor CX3CR1, which is also associated with improved prognosis in inflammatory CRC [7]
.
Multivariate analysis of the lipid mediator profiles of macrophages revealed increased levels of several SPMs, including lipoxin A4 and resolvin D1, suggesting that aspirin directly modulates macrophage phenotype and function, converting them Reprogrammed to a protective phenotype
.
Expression analysis of macrophage phenotypic markers in aspirin group mice (ASA) and control group showed significant separation.
At the same time, the expression of the immunosuppressive receptor PD-1 in macrophages was also significantly reduced, which improved macrophage response to Phagocytosis rate and number of apoptotic cells
.
In addition to macrophages, aspirin also affected the phenotype and function of different types of T cells
.
As the core force of identifying and killing cancer cells, CD8+ T cells are also the main target of cancer cells.
Aspirin reduces the expression level of PD-1 on each CD8+ T cell, and also reduces the CD8+ T cells expressing PD-1.
Quantitatively, reductions in PD-1 were significantly associated with increased levels of the effector cytokine interferon gamma
.
Levels of the proinflammatory cytokine interleukin-17 were significantly reduced in immunosuppressive CD4+ T cells
.
In human CD8+ T cells, the researchers found the same changes
.
These changes in tissue metabolism and immune cell phenotype and function are based on changes in SPM levels.
In the colon tissue of aspirin-treated mice, the researchers detected acetylated COX-2, lipoxins A4, B4 and Levels of resolvin D1 and D3 also increased with treatment time, reaching a peak after one week, and this increase cooperated with a decrease in the immunosuppressive mediators prostaglandins E2, D2, and thromboxane A2, mediating the effect of aspirin in inflammatory conditions.
Protection in CRC
.
Changes in the levels of resolvin D1, D3 and lipoxin A4, B4 with time (starting from AOM/DSS induction) in aspirin group mice (ASA) and control group Lipoxin A4 and resolvin D1, D3 have Homologous receptor Alx/Fpr2 receptor, polyp size, macrophage phenotype and PD-1 expression, CD8+ T cell PD-1 expression, and disease in mice deficient in Alx/Fpr2 receptor, even on aspirin Severity was indistinguishable from placebo treatment
.
Likewise, pharmacological inhibition of SPM synthesis would also negate the protective effect of aspirin
.
Direct treatment of mice with a 15 ng dose of the SPM mixture resulted in protection similar to aspirin treatment
.
This suggests that aspirin indeed modifies the phenotype, function and/or PD-1 expression levels of macrophages, CD8+ T cells and CD4+ T cells by acetylating COX-2, increasing SPM levels, binding to Alx/Fpr2 receptors , plays a protective role in inflammatory bowel cancer
.
The researchers believe that this study identifies a previously underappreciated mechanism of aspirin's prevention of CRC, which could be used to develop immune reprogramming therapies for CRC, and that, in future studies, SPM could be used to assess the efficacy of aspirin in preventing inflammatory CRC.
a potential biomarker [8]
.
Reference: [1] De Matteis R, Flak MB, Gonzalez-Nunez M, et al.
Aspirin activates resolution pathways to reprogram T cell and macrophage responses in colitis-associated colorectal cancer [J].
Science Advances, 2022, 8(5 ): eabl5420.
[2] Zelenay S, Van Der Veen AG, Böttcher JP, et al.
Cyclooxygenase-dependent tumor growth through evasion of immunity[J].
Cell, 2015, 162(6): 1257-1270.
[3] Lucotti S, Cerutti C, Soyer M, et al.
Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A 2[J].
The Journal of clinical investigation, 2019, 129(5): 1845- 1862.
[4] Serhan CN, Hong S, Gronert K, et al.
Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals[J].
The Journal of experimental medicine, 2002, 196(8):1025-1037.
[5] Claria J, Serhan C N.
Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions[J].
Proceedings of the National Academy of Sciences, 1995, 92(21): 9475-9479.
[6] Chan AT, Ogino S, Fuchs C S.
Aspirin use and survival after diagnosis of colorectal cancer[J].
Jama, 2009, 302(6): 649-658.
[7] Marelli G, Erreni M, Anselmo A , et al.
Heme-oxygenase-1 production by intestinal CX3CR1+ macrophages helps to resolve inflammation and prevents carcinogenesis[J].
Cancer research, 2017, 77(16): 4472-4485.
[8] https:// ac.
uk/whri/news-and-events/2022/items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlBy Ying YuyanAspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions[J].
Proceedings of the National Academy of Sciences, 1995, 92(21): 9475-9479.
[6] Chan AT, Ogino S, Fuchs C S.
Aspirin use and survival after diagnosis of colorectal cancer[J].
Jama, 2009, 302(6): 649-658.
[7] Marelli G, Erreni M, Anselmo A, et al.
Heme-oxygenase-1 production by intestinal CX3CR1+ macrophages helps to resolve inflammation and prevents carcinogenesis[J].
Cancer research, 2017, 77(16): 4472-4485.
[8] https:// items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlThe author of this articleYing YuyanAspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions[J].
Proceedings of the National Academy of Sciences, 1995, 92(21): 9475-9479.
[6] Chan AT, Ogino S, Fuchs C S.
Aspirin use and survival after diagnosis of colorectal cancer[J].
Jama, 2009, 302(6): 649-658.
[7] Marelli G, Erreni M, Anselmo A, et al.
Heme-oxygenase-1 production by intestinal CX3CR1+ macrophages helps to resolve inflammation and prevents carcinogenesis[J].
Cancer research, 2017, 77(16): 4472-4485.
[8] https:// items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlThe author of this articleYing YuyanFuchs C S.
Aspirin use and survival after diagnosis of colorectal cancer[J].
Jama, 2009, 302(6): 649-658.
[7] Marelli G, Erreni M, Anselmo A, et al.
Heme-oxygenase-1 production by intestinal CX3CR1+ macrophages helps to resolve inflammation and prevent carcinogenesis[J].
Cancer research, 2017, 77(16): 4472-4485.
[8] https:// -events/2022/items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlThe author of this articleYing YuyanFuchs C S.
Aspirin use and survival after diagnosis of colorectal cancer[J].
Jama, 2009, 302(6): 649-658.
[7] Marelli G, Erreni M, Anselmo A, et al.
Heme-oxygenase-1 production by intestinal CX3CR1+ macrophages helps to resolve inflammation and prevent carcinogenesis[J].
Cancer research, 2017, 77(16): 4472-4485.
[8] https:// -events/2022/items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlThe author of this articleYing Yuyanuk/whri/news-and-events/2022/items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlBy Ying Yuyanuk/whri/news-and-events/2022/items/researchers-investigate-previously-unappreciated-mechanisms-in-the-cancer-protective-actions-of-aspirin.
htmlBy Ying Yuyan
