A dual COX-2/sEH inhibitor improves the metabolic profile and reduces kidney injury in Zucker diabetic fatty rat

Abstract

Cyclooxygenase (COX) and soluble epoxide hydrolase (sEH) inhibitors have therapeutic potential. The present study investigated efficacy of a novel dual acting COX-2/sEH inhibitor, PTUPB in type 2 diabetic Zucker Diabetic Fatty (ZDF) rats. Male ZDF rats were treated with vehicle or PTUPB (10 mg/kg/d, i.p.) for 8 weeks. At the end of the 8-week experimental period, ZDF rats were diabetic (fasting blood glucose, 287±45 mg/dL) compared to Zucker Diabetic Lean rats (ZDL, 99±6 mg/dL), and PTUPB treatment improved glycemic status in ZDF rats (146±6 mg/dL). Kidney injury was evident in ZDF compared to ZDL rats with elevated albuminurea (44±4 vs 4±2 mg/d) and nephrinurea (496±127 vs 16±4 μg/d). Marked renal fibrosis, tubular cast formation and glomerular injury were also present in ZDF compared to ZDL rats. In ZDF rats, PTUPB treatment reduced kidney injury parameters by 30–80% compared to vehicle. The ZDF rats also demonstrated increased inflammation and oxidative stress with elevated levels of urinary monocyte chemoattractant protein-1 excretion (862±300 vs 319±75 ng/d), renal macrophage infiltration (53±2 vs 37±4 /mm2) and kidney malondialdehyde/protein ratio (10±1 vs 5±1 μmol/mg). PTUPB treatment decreased these inflammatory and oxidative stress markers in the kidney of ZDF rats by 25–57%. These data demonstrate protective actions of a novel dual acting COX-2/sEH inhibitor on the metabolic abnormalities and kidney function in ZDF rat model of type 2 diabetes.

COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

“…Our previous studies developed a novel COX‐2 and sEH dual inhibitor, PTUPB. It has been reported to potentiate the antitumor efficacy of cisplatin, reduce kidney injury, and suppress the chemotherapy‐induced cytokine/lipid mediator surge and ovarian cancer . Inhibition of COX‐2/sEH by PTUPB blocks and even reverses the adverse toxicities caused by NSAIDs .…”

“…The mice were randomly divided into four groups: (a) the control group: intratracheal injection of saline plus subcutaneous injection of PEG 400 (vehicle for PTUPB); (b) the PTUPB group: intratracheal injection of saline plus subcutaneous injection of PTUPB (5 mg·kg −1 ·day −1 , PTUPB was synthesized according to our previous report ); (c) the BLM group: intratracheal injection of BLM plus subcutaneous injection of PEG 400; and (d) the BLM + PTUPB group: intratracheal injection of BLM plus subcutaneous injection of PTUPB (5 mg·kg −1 ·day −1 ). Mice were intratracheally instilled with saline or BLM (1.5 mg·kg −1 , in 50 μL saline; Nippon Kayaku, Tokyo, Japan) on day 0.…”

“…So, we developed a novel cyclooxygenase‐2 (COX‐2)/sEH dual inhibitor, PTUPB, which prevents the release of PGs and increases the blood levels of EETs . We found that PTUPB reduces kidney injury, suppresses the growth of glioblastoma, and reduces liver fibrosis . However, it remains unknown whether the dual inhibition has a protective effect against PF.…”

Carcinogenesis: Failure of resolution of inflammation?

“…Cancer progression is stimulated by inflammation, fibrosis, and oxidative stress. Dual COX-2/sEH inhibition via PTUPB inhibits allergic airway inflammation, pulmonary fibrosis, kidney injury and sepsis via anti-oxidative stress ( Dileepan et al, 2019 ; Hye Khan et al, 2016 ; Zhang et al, 2020 ; Zhang et al, 2019 ) . Dual COX-2/sEH inhibition inhibits primary tumor growth including glioblastoma growth, metastasis and potentiates the antitumor efficacy of chemotherapeutic agents such as cisplatin ( Li et al, 2017 ; Wang et al, 2018 ; Zhang, Panigrahy, et al, 2014 ).…”

<p>The Human Genetic Variants CYP2J2 rs2280275 and EPHX2 rs751141 and Risk of Diabetic Nephropathy in Egyptian Type 2 Diabetic Patients</p>

“…The main EETs producers are CYP2C and CYP2J subfamilies 7 which show higher expression in the proximal tubules of the kidney. 8 CYP2J subfamily contains only one member termed CYP2J2. 9 Experimentally, over expression of CYP2J2 has been considered a safeguarding factor against kidney damage.…”