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Background: Low-dose aspirin's mechanism of action for preventing colorectal cancer (CRC) is still debated, and the optimal dose remains uncertain. We aimed to optimize the aspirin dose for cancer prevention in CRC patients through deep phenotyping using innovative biomarkers for aspirin's action. Methods: We conducted a Phase II, open-label clinical trial in 34 CRC patients of both sexes randomized to receive enteric-coated aspirin 100 mg/d, 100 mg/BID, or 300 mg/d for 3 ± 1 weeks. Biomarkers were evaluated in blood, urine, and colorectal biopsies at baseline and after dosing with aspirin. Novel biomarkers of aspirin action were assessed in platelets and colorectal tissues using liquid chromatography-mass spectrometry to quantify the extent of cyclooxygenase (COX)-1 and COX-2 acetylation at Serine 529 and Serine 516, respectively. Results: All aspirin doses caused comparable % acetylation of platelet COX-1 at Serine 529 associated with similar profound inhibition of platelet-dependent thromboxane (TX)A2 generation ex vivo (serum TXB2) and in vivo (urinary TXM). TXB2 was significantly reduced in CRC tissue by aspirin 300 mg/d and 100 mg/BID, associated with comparable % acetylation of COX-1. Differently, 100 mg/day showed a lower % acetylation of COX-1 in CRC tissue and no significant reduction of TXB2. Prostaglandin (PG)E2 biosynthesis in colorectal tumors and in vivo (urinary PGEM) remained unaffected by any dose of aspirin associated with the variable and low extent of COX-2 acetylation at Serine 516 in tumor tissue. Increased expression of tumor-promoting genes like VIM (vimentin) and TWIST1 (Twist Family BHLH Transcription Factor 1) vs. baseline was detected with 100 mg/d of aspirin but not with the other two higher doses. Conclusion: In CRC patients, aspirin 300 mg/d or 100 mg/BID had comparable antiplatelet effects to aspirin 100 mg/d, indicating similar inhibition of the platelet's contribution to cancer. However, aspirin 300 mg/d and 100 mg/BID can have additional anticancer effects by inhibiting cancerous tissue's TXA2 biosynthesis associated with a restraining impact on tumor-promoting gene expression. EUDRACT number: 2018-002101-65. [ABSTRACT FROM AUTHOR]

Many drugs can act on multiple targets or disease pathways, regardless of their original purpose. Drug repurposing involves reevaluating existing compounds for new medical uses. This can include repositioning approved drugs, redeveloping unapproved drugs, or repurposing any chemical, nutraceutical, or biotherapeutic product for new applications. Traditional drug development is slow, expensive, and has high failure rates. Drug repurposing can speed up the process, costing less and saving time. This approach can save 6–7 years of early-stage research time. Drug repurposing benefits from existing compounds with optimized structures and approved for clinical use with associated structure-activity relationship publications, supporting the development of new effective compounds. Drug repurposes can now utilize advanced in silico screening enabled by artificial intelligence (AI) and sophisticated tissue and organ-level in vitro models. These models more accurately replicate human physiology and improve the selection of existing drugs for further pre-clinical testing and, eventually, clinical trials for new indications. This mini-review discusses some examples of drug repurposing and novel strategies for further development of compounds for targets of the arachidonic acid cascade. In particular, we will delve into the prospect of repurposing antiplatelet agents for cancer prevention and addressing the emerging noncanonical functionalities of 5-lipoxygenase, potentially for leukemia therapy. [ABSTRACT FROM AUTHOR]

It has been hypothesized that cellular damage caused by oxidative stress is associated with late-life depression but epidemiological evidence is limited. In the present study we evaluated the association between urinary 8-iso-prostaglandin F2α (8-iso-PGF2α), a biomarker of lipid peroxidation, and depressed mood in a large sample of community-dwelling older adults. Participants were selected from the Health, Aging and Body Composition study, a community-based longitudinal study of older persons (aged 70-79 years). The present analyses was based on a subsample of 1027 men and 948 women free of mobility disability. Urinary concentration of 8-iso-PGF2α was measured by radioimmunoassay methods and adjusted for urinary creatinine. Depressed mood was defined as a score greater than 5 on the 15-item Geriatric Depression Scale and/or use of antidepressant medications. Depressed mood was present in 3.0% of men and 5.5% of women. Depressed men presented higher urinary concentrations of 8-iso-PGF2α than non-depressed men even after adjustment for multiple sociodemographic, lifestyle and health factors (p = 0.03, Cohens d = 0.30). This association was not present in women (depressed status-by-sex interaction p = 0.04). Our study showed that oxidative damage may be linked to depression in older men from a large sample of the general population. Further studies are needed to explore whether the modulation of oxidative stress may break down the link between late-life depression and its deleterious health consequences.

It has been hypothesized that cellular damage caused by oxidative stress is associated with late-life depression but epidemiological evidence is limited. In the present study we evaluated the association between urinary 8-iso-prostaglandin F2α (8-iso-PGF2α), a biomarker of lipid peroxidation, and depressed mood in a large sample of community-dwelling older adults. Participants were selected from the Health, Aging and Body Composition study, a community-based longitudinal study of older persons (aged 70-79 years). The present analyses was based on a subsample of 1027 men and 948 women free of mobility disability. Urinary concentration of 8-iso-PGF2α was measured by radioimmunoassay methods and adjusted for urinary creatinine. Depressed mood was defined as a score greater than 5 on the 15-item Geriatric Depression Scale and/or use of antidepressant medications. Depressed mood was present in 3.0% of men and 5.5% of women. Depressed men presented higher urinary concentrations of 8-iso-PGF2α than non-depressed men even after adjustment for multiple sociodemographic, lifestyle and health factors (p = 0.03, Cohen's d = 0.30). This association was not present in women (depressed status-by-sex interaction p = 0.04). Our study showed that oxidative damage may be linked to depression in older men from a large sample of the general population. Further studies are needed to explore whether the modulation of oxidative stress may break down the link between late-life depression and its deleterious health consequences.

Diabetes mellitus is associated with platelet hyperactivity, which leads to increased morbidity and mortality from cardiovascular disease. This is coupled with enhanced levels of thromboxane (TX), an eicosanoid that facilitates [...]