Discovery of a novel lead characterized by a stilbene-extended scaffold against sepsis as soluble epoxide hydrolase inhibitors.

Recently, some inhibitors of soluble epoxide hydrolase (sEH) showed limited potential in treating sepsis by increasing survival time, but they have unfortunately failed to improve survival rates. In this study, we initially identified a new hit 11D, belonging to a natural skeleton known as stilbene and having an IC50 of 644 nM on inhibiting murine sEH. Natural scaffold-based sEH inhibitors are paid less attention. A combination of structure-activity relationships (SARs)-guided structural optimization and computer-aided skeleton growth led to a highly effective lead compound 70P (IC50: 4.0 nM). The dose-response study indicated that 70P (at doses of 0.5-5 mg/kg, ip.) significantly increased survival rates and survival time by reducing the levels of the inflammatory factors TNF-α and IL-6 in the liver. Interestingly, 70P exhibited much higher accumulation in the liver than in plasma (AUC ratio: 175). In addition, 70P exhibits equal IC50 value (1.5 nM) on inhibiting human sEH as EC5026 (1.7 nM). In conclusion, the natural scaffold-extended sEH inhibitor 70P has the potential to become a new promising lead for addressing the unmet medical need in sepsis treatment, which highlighted the importance of natural skeleton in developing sEH inhibitors.

Advances in traditional Chinese medicine as adjuvant therapy for diabetic foot.

Diabetes mellitus (DM) is a complex disease that often causes multiple systemic complications that have become a major international public health problem. Diabetic foot (DF) is one of the severe and frequent chronic complications of DM due to vascular lesions and neuropathy. DF ulcers (DFU) affect approximately 15% of people with DM and are the leading cause of death and disability. The prevalence and recurrence of DF are worrisome, and morbidity and mortality are also on the rise, which poses a substantial socioeconomic burden. Treating DF is difficult for clinicians and requires multidisciplinary cooperation, combining local and systemic therapy to reduce amputation and case-fatality rates. Traditional Chinese Medicine (TCM) has received extensive attention due to noticeable therapeutic effects and few adverse reactions. In recent years, research on DF treatment by TCM has been increasing, and further progress has been made. TCM includes oral medication, injectable preparations, and adjuvant therapy. This article reviews the relevant research on TCM-related adjuvant therapy for DF. We describe current progress in TCM in terms of external application, acupuncture, massage, acupoint injection, foot bath, fumigation, and moxibustion, as well as the mechanisms involved.