Soluble epoxide hydrolase inhibitors(University of California)

Cancer is a multifactorial disease involving multiple interrelated molecular targets and signaling pathways. Some epidemiological studies have suggested that nonsteroidal anti-inflammatory drugs could reduce the incidence of certain types of cancer, indicating the interplay between inflammation and cancer. Designing compounds that inhibit an enzyme of the arachidonic acid inflammatory cascade while exhibiting anticancer effects has emerged as a promising strategy.

A descriptive review and analysis of recently published studies on the synthesis of compounds that target two enzymes of the arachidonic acid cascade and simultaneously exhibit anticancer activity was performed.

Numerous cyclooxygenase-2 (COX-2) inhibitors with anticancer activity are known. Fewer examples exist for 5-lipoxygenase (5-LOX) inhibitors, while many dual COX-2/5-LOX inhibitors also display anticancer effects. Some examples of dual inhibitors with anticancer potential include 5-LOX/microsomal prostaglandin E2 synthase (mPGES), and COX-2/soluble epoxide hydrolase inhibitors. There are also compounds designed to inhibit three targets: COX-2, 15-LOX, and carbonic anhydrase.

Given the complex interplay between inflammation and cancer, the term "anticancer effects" encompasses various therapeutic opportunities, ranging from adjuvant therapy and chemoprevention to angiogenic and cytotoxic activity.

This multitarget approach highlights the broad therapeutic possibilities of targeting inflammatory pathways, establishing a direction for the development of innovative anticancer therapies with improved safety profiles.

Cornea alkali injuries are difficult to treat and potentially blinding, and there are still no specific treatments. The cytochrome P450 arachidonic acid metabolism pathway generates epoxy fatty acids (EpFAs) which have analgesic, anti‐inflammatory, and anti‐fibrotic activities. EpFAs have anti‐fibrotic effects in several tissues including kidney, heart, liver, and lungs, while the cornea has never been examined. Soluble epoxide hydrolase (sEH) metabolizes EpFAs to biologically less active diols, and its inhibitors (sEHi) can alleviate or prevent fibrosis. The current studies were designed to examine the role of sEHi in NaOH and ammonia wounded corneas and develop new in vitro and in vivo cornea ammonia wound models. Haziness was reduced or eliminated in NaOH wounded mouse corneas treated with sEHi by day 17 post‐injury. Ammonia wounded corneas treated with sEHi did not vascularize and most of the haze resolved. αSMA, collagen III, and fibronectin were significantly decreased in NaOH and ammonia wounded corneas treated with sEHi. Fewer CD45 + and F4/80 + cells were observed in NaOH wounded sEH KO mouse corneas compared to WT by day 31 post‐injury. Collagen I and CD45 + cells persisted within WT corneas at 31 days post‐injury, suggesting more matrix remodeling and inflammation in WT compared to sEH KO corneas. TGFβ1‐stimulated αSMA and sEH expression was reduced in human corneal fibroblasts cultured with sEHi. The results demonstrate that sEHi can play a critical role in NaOH and ammonia injury responses and indicate that topical sEHi administration works to effectively treat these wounds.