Browsing by Subject "PPAR delta"

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    Pseudomonas Aeruginosa Theft Biofilm Require Host Lipids of Cutaneous Wound
    (Wolters Kluwer, 2023) Sinha, Mithun; Ghosh, Nandini; Wijesinghe, Dayanjan S.; Mathew-Steiner, Shomita S.; Das, Amitava; Singh, Kanhaiya; El Masry, Mohamed; Khanna, Savita; Inoue, Hiroyuki; Yamazaki, Katsuhisa; Kawada, Manabu; Gordillo, Gayle M.; Roy, Sashwati; Sen, Chandan K.; Surgery, School of Medicine
    Objective: This work addressing complexities in wound infection, seeks to test the reliance of bacterial pathogen Pseudomonas aeruginosa (PA) on host skin lipids to form biofilm with pathological consequences. Background: PA biofilm causes wound chronicity. Both CDC as well as NIH recognizes biofilm infection as a threat leading to wound chronicity. Chronic wounds on lower extremities often lead to surgical limb amputation. Methods: An established preclinical porcine chronic wound biofilm model, infected with PA or Pseudomonas aeruginosa ceramidase mutant (PA ∆Cer ), was used. Results: We observed that bacteria drew resource from host lipids to induce PA ceramidase expression by three orders of magnitude. PA utilized product of host ceramide catabolism to augment transcription of PA ceramidase. Biofilm formation was more robust in PA compared to PA ∆Cer . Downstream products of such metabolism such as sphingosine and sphingosine-1-phosphate were both directly implicated in the induction of ceramidase and inhibition of peroxisome proliferator-activated receptor (PPAR)δ, respectively. PA biofilm, in a ceram-idastin-sensitive manner, also silenced PPARδ via induction of miR-106b. Low PPARδ limited ABCA12 expression resulting in disruption of skin lipid homeostasis. Barrier function of the wound-site was thus compromised. Conclusions: This work demonstrates that microbial pathogens must co-opt host skin lipids to unleash biofilm pathogenicity. Anti-biofilm strategies must not necessarily always target the microbe and targeting host lipids at risk of infection could be productive. This work may be viewed as a first step, laying fundamental mechanistic groundwork, toward a paradigm change in biofilm management.
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    The Effects of Peroxisome Proliferator-Activated Receptor-Delta Modulator ASP1128 in Patients at Risk for Acute Kidney Injury Following Cardiac Surgery
    (Elsevier, 2023-04-08) van Till, J. W. Olivier; Nojima, Hiroyuki; Kameoka, Chisato; Hayashi, Chieri; Sakatani, Taishi; Washburn, T. Benton; Molitoris, Bruce A.; Shaw, Andrew D.; Engelman, Daniel T.; Kellum, John A.; Medicine, School of Medicine
    Introduction: Peroxisome proliferator-activated receptor δ (PPARδ) plays a central role in modulating mitochondrial function in ischemia-reperfusion injury. The novel PPARδ modulator, ASP1128, was evaluated. Methods: A randomized, double-blind, placebo-controlled, biomarker assignment-driven, multicenter study was performed in adult patients at risk for acute kidney injury (AKI) following cardiac surgery, examining efficacy and safety of a 3-day, once-daily intravenous dose of 100 mg ASP1128 versus placebo (1:1). AKI risk was based on clinical characteristics and postoperative urinary biomarker (TIMP2)•(IGFBP7). The primary end point was the proportion of patients with AKI based on serum creatinine within 72 hours postsurgery (AKI-SCr72h). Secondary endpoints included the composite end point of major adverse kidney events (MAKE: death, renal replacement therapy, and/or ≥25% reduction of estimated glomerular filtration rate [eGFR]) at days 30 and 90). Results: A total of 150 patients were randomized and received study medication (81 placebo, 69 ASP1128). Rates of AKI-SCr72h were 21.0% and 24.6% in the placebo and ASP1128 arms, respectively (P = 0.595). Rates of moderate/severe AKI (stage 2/3 AKI-SCr and/or stage 3 AKI-urinary output criteria) within 72 hours postsurgery were 19.8% and 23.2%, respectively (P = 0.609). MAKE occurred within 30 days in 11.1% and 13.0% in the placebo and ASP1128 arms (P = 0.717), respectively; and within 90 days in 9.9% and 15.9% in the placebo and ASP1128 arms (P = 0.266), respectively. No safety issues were identified with ASP1128 treatment, but rates of postoperative atrial fibrillation were lower (11.6%) than in the placebo group (29.6%). Conclusion: ASP1128 was safe and well-tolerated in patients at risk for AKI following cardiac surgery, but it did not show efficacy in renal endpoints.