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Background and purposeDiabetic nephropathy is a common complications related to high morbidity and mortality in type 2 diabetes. We investigated the action of the dual modulator, PTUPB, a soluble epoxide hydrolase and cyclooxygenase-2 inhibitor against diabetic nephropathy.Experimental approachSixteen-week-old type 2 diabetic and proteinuric obese ZSF1 rats were treated with vehicle, PTUPB or enalapril for 8 weeks. Measurements were made of epoxyeicosatrienoic acids, thromboxane B2 (TBX2 ) and prostaglandin E2 (PGE2 ) in the kidney of these and lean ZSF1 rats along with their blood pressure.Key resultObese ZSF1 rats were diabetic with fivefold higher fasting blood glucose levels and markedly higher HbA1c levels compared with lean ZSF1 rats. PTUPB nor enalapril reduced fasting blood glucose or HbA1c but alleviated the development of diabetic nephropathy. In PTUPB-treated obese ZSF1 rats, glomerular nephrin expression was preserved. Enalapril also alleviated diabetic nephropathy. Diabetic renal injury in obese ZSF1 rats was accompanied by renal inflammation with six to sevenfold higher urinary MCP-1 (CCR2) level and renal infiltration of CD-68 positive cells. PTUPB and enalapril significantly reduced urinary MCP-1 levels and renal mRNA expression of cytokines. Both PTUPB and enalapril lowered blood pressure. PTUPB but not enalapril decreased hyperlipidaemia and liver injury in obese ZSF1 rats.Conclusion and implicationsOverall, the dual modulator PTUPB does not treat hyperglycaemia but can effectively alleviate hypertension, diabetic nephropathy, hyperlipidaemia and liver injury in type 2 diabetic rats. Our data further demonstrate that the renal actions of PTUPB are comparable with a current standard diabetic nephropathy treatment.

Kidney injury from antiangiogenic chemotherapy is a significant clinical challenge, and we currently lack the ability to effectively treat it with pharmacological agents. Thus, we set out to investigate whether simultaneous soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) inhibition using a dual sEH/COX-2 inhibitor PTUPB could be an effective strategy for treating antiangiogenic therapy-induced kidney damage. We used a multikinase inhibitor, sorafenib, which is known to cause serious renal side effects. The drug was administered to male Sprague-Dawley rats that were on a high-salt diet. Sorafenib was administered over the course of 56 days. The study included three experimental groups; 1) control group (naïve rats), 2) sorafenib group [rats treated with sorafenib only (20 mg/kg/day p.o.)], and 3) sorafenib + PTUPB group (rats treated with sorafenib only for the initial 28 days and subsequently coadministered PTUPB (10 mg/kg/day i.p.) from days 28 through 56). Blood pressure was measured every 2 weeks. After 28 days, sorafenib-treated rats developed hypertension (161 ± 4 mmHg). Over the remainder of the study, sorafenib treatment resulted in a further elevation in blood pressure through day 56 (200 ± 7 mmHg). PTUPB treatment attenuated the sorafenib-induced blood pressure elevation and by day 56, blood pressure was 159 ± 4 mmHg. Urine was collected every 2 weeks for biochemical analysis. After 28 days, sorafenib rats developed pronounced proteinuria (9.7 ± 0.2 P/C), which intensified significantly (35.8 ± 3.5 P/C) by the end of day 56 compared with control (2.6 ± 0.4 P/C). PTUPB mitigated sorafenib-induced proteinuria, and by day 56, it reduced proteinuria by 73%. Plasma and kidney tissues were collected on day 56. Kidney histopathology revealed intratubular cast formation, interstitial fibrosis, glomerular injury, and glomerular nephrin loss at day 56 in sorafenib-treated rats. PTUPB treatment reduced histological features by 30%-70% compared with the sorafenib-treated group and restored glomerular nephrin levels. Furthermore, PTUPB also acted on the glomerular permeability barrier by decreasing angiotensin-II-induced glomerular permeability to albumin. Finally, PTUPB improved in vitro the viability of human mesangial cells. Collectively, our data demonstrate the potential of using PTUPB or dual sEH/COX-2 inhibition as a therapeutic strategy against sorafenib-induced glomerular nephrotoxicity.

Background: There is a limited evidence‐base describing clinical features of delirium in youth. What is known is largely extrapolated from studies of adults or samples with heterogeneous etiologies. It is unclear if the symptoms experienced by adolescents differ from those experienced by adults, or the degree to which delirium impacts the ability of adolescents to return to school or work. Objective: To describe delirium symptomatology among adolescents following a severe traumatic brain injury (TBI). Symptoms were compared by adolescent delirium status and across age groups. Delirium and its relationship with adolescent employability 1 year post‐injury was also examined. Design: Exploratory secondary analysis of prospectively collected data. Setting: Free‐standing rehabilitation hospital. Patients: Severely injured TBI Model Systems neurorehabilitation admissions (n = 243; median Glasgow Coma Scale = 7). The sample was divided into three age groups (adolescents, 16–21 years, n = 63; adults 22–49 years, n = 133; older adults ≥50 years, n = 47). Interventions: Not applicable. Measures: We assessed patients using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV) diagnostic criteria and the Delirium Rating Scale‐Revised 98 (DRS‐R‐98). The employability item from the Disability Rating Scale was the primary 1‐year outcome. Results: Most items on the DRS‐R‐98 differentiated delirious from non‐delirious adolescents. Only "delusions" differed among age groups. Among adolescents, delirium status 1 month post‐TBI provided acceptable classification of employability prediction 1 year later (area under the curve [AUC]: 0.80, 95% confidence interval [CI]: 0.69–0.91, p <.001). Delirium symptom severity (AUC: 0.86, 95% CI: 0.68–1.03, SE: 0.09; p <.001) and days of post‐traumatic amnesia (AUC: 0.85, 95% CI: 0.68–1.01, SE: 0.08; p <.001) provided excellent prediction of outcomes for TBI patients in delirium. Conclusions: Delirium symptomatology was similar among age groups and useful in differentiating the delirium status within the adolescent TBI group. Delirium and symptom severity at 1 month post‐TBI were highly predictive of poor outcomes. Findings from this study support the utility of DRS‐R‐98 at 1 month post‐injury to inform treatment and planning. [ABSTRACT FROM AUTHOR]

Approximately 10% of US births deliver preterm before 37 weeks of completed gestation. Premature infants are at risk for life‐long debilitating morbidities and death, and spontaneous preterm labour explains 50% of preterm births. In all cases existing treatments are ineffective, and none are FDA approved. The mechanisms that initiate preterm labour are not well understood but may result from dysfunctional regulation of quiescence mechanisms. Human pregnancy is accompanied by large increases in blood flow, and the uterus must enlarge by orders of magnitude to accommodate the growing fetus. This mechanical strain suggests that stretch‐activated channels may constitute a mechanism to explain gestational quiescence. Here we identify for the first time that Piezo1, a mechanosensitive cation channel, is present in the uterine smooth muscle and microvascular endothelium of pregnant myometrium. Piezo is downregulated during preterm labour, and stimulation of myometrial Piezo1 in an organ bath with the agonist Yoda1 relaxes the tissue in a dose‐dependent fashion. Further, stimulation of Piezo1 while inhibiting protein kinase A, AKT, or endothelial nitric oxide synthase mutes the negative inotropic effects of Piezo1 activation, intimating that actions on the myocyte and endothelial nitric oxide signalling contribute to Piezo1‐mediated contractile dynamics. Taken together, these data highlight the importance of stretch‐activated channels in pregnancy maintenance and parturition, and identify Piezo1 as a tocolytic target of interest. Key points: Spontaneous preterm labour is a serious obstetric dilemma without a known cause or effective treatments.Piezo1 is a stretch‐activated channel important to muscle contractile dynamics.Piezo1 is present in the myometrium and is dysregulated in women who experience preterm labour.Activation of Piezo1 by the agonist Yoda1 relaxes the myometrium in a dose‐dependent fashion, indicating that Piezo1 modulation may have therapeutic benefits to treat preterm labour. [ABSTRACT FROM AUTHOR]