AbstractMillions of individuals worldwide, across all age groups, suffer from the widespread health issue of gastric ulcers. In many experiments, cilostazol (Cls), a phosphodiesterase-3 inhibitor, was recently shown to have anti-ulcer activity. Notably, Cls increases the expression and transcriptional activity of PPAR-γ in vitro and in vivo. This study aimed to evaluate the protective effect of Cls against ethanol-induced gastric ulcers and clarify the possible underlying mechanisms with an emphasis on the role of PPAR-γ. Male albino rats were treated with ethanol to induce gastric ulcers, or they were pretreated with Cls, omeprazole (Omp), GW9662, or Cls + GW9662 for 14 consecutive days before receiving ethanol. Cls protects against ethanol-induced gastric ulcers. Cls treatment significantly reduced ethanol-induced upregulation of the pro-inflammatory markers (IL-1β, IL-6, TNF-α, and NF-κB), MDA (a marker of lipid peroxidation), and caspase-3 and cleaved caspase-3 (apoptotic markers). On the other hand, Cls treatment counteracted ethanol-induced downregulation of PPAR-γ, pErk-1, HO-1 and GSH (antioxidant markers), PECAM-1 and NO (healing markers), and Bcl-2 (antiapoptotic marker). However, when combined with GW9662, a potent antagonist of PPAR-γ, Cls loses its effects. In conclusion, these results suggest that PPAR-γ and pErk-1 are essential for Cls’s protective effects against ethanol-induced gastric ulcers.Graphical abstract

01 Oct 2024·Journal of Critical Care

Phosphodiesterase 3 inhibitors do not influence lactate kinetics and clinical outcomes in patients with septic shock: A multicentre cohort study

Article

Author: Slegers, Claire A D ; Goedegebuur, Jamilla ; van der Elsen, Fieke ; Koopmans, Matty ; van Lookeren Campagne, Michiel ; Pickkers, Peter ; Kiers, Dorien ; Waalders, Nicole ; van den Beuken, Wisse M F ; Schroten, Nicolas ; Tai-Passmann, Sharon ; Kuindersma, Marnix ; van den Bogaard, Bas ; Grady, Bart P X ; Hemelaar, Pleun ; van den Oever, Huub L A

PURPOSEWe investigated the association between the administration of phosphodiesterase 3 inhibitors (PDE3i) and lactate kinetics, resolution of organ failure, ICU and hospital length of stay (LOS) and hospital mortality in a retrospective cohort of patients with septic shock and persistently elevated lactate concentrations.MATERIAL AND METHODSPatients with septic shock and two arterial lactate concentrations ≥4 mmol/L with at least 4 h between measurements were eligible. Clinical data of the first four days of admission were collected in an online database. For each patient, the area between the actual lactate concentrations and 2.2 mmol/L (AUC_lact2.2), was calculated for three days.RESULTSData on 229 patients from 10 hospitals were collected, of whom 123 received PDE3i (54%). First, a linear multivariate model was developed to predict AUC_lact2.2 (R² = 0.57). Adding PDE3i as a cofactor did not affect R². Second, 60 patients receiving PDE3i at any time between days 0 and 2 were compared to 60 propensity matched no-PDE3i patients. Third, 30 patients who received PDE3i from ICU admission to day 3 were compared to 30 propensity-matched no-PDE3i patients. These analyses showed no differences in AUC_lact2.2, SOFA scores, ICU or hospital LOS or hospital mortality between treatment groups.CONCLUSIONSNo association was found between the administration of PDE3i and lactate kinetics, resolution of organ failure, ICU or hospital LOS or hospital mortality.

01 Aug 2024·Vascular

The effect of cilostazol on the platelet-derived growth factor-beta/beta isoform reduction on venous hyperplasia in an experimental balloon-induced injury model

Article

Author: Manzo-Merino, Joaquin ; Ortega-Gómez, Alette ; Antuñano-Blanco, Maria del Carmen ; Lozano-Corona, Rodrigo ; Vergara-Ascencio, Carlos Acxel ; Zentella-Dehesa, Alejandro ; Laparra-Escareño, Hugo ; Anaya-Ayala, Javier E. ; Hinojosa, Carlos A. ; Lopez-Santacruz, Jose Roberto ; Montalvo-Jave, Eduardo Esteban

Background Intimal hyperplasia is the response to endothelial injury. Platelet-derived growth factor is released early and favors the formation of intimal hyperplasia. Although multiple treatments, from open surgery to endovascular techniques, have been used they remain controversial. There is currently interest in developing pharmacological strategies to address this pathology. Local vascular inflammation induced by vessel barotrauma generates intimal hyperplasia due to mechanical stress over the venous endothelium. Cilostazol is a selective phosphodiesterase type 3 (PDE3) selective inhibitor with a regulatory effect over intimal hyperplasia. The objective was to investigate cilostazol’s role in inhibiting smooth muscle cell proliferation due to changes in the expression and release of PDGF-BB isoform and the effect on developing IH using an experimental model of vascular barotrauma (balloon-induced injury model). Methods We included 12 New Zealand rabbits. The balloon-induced injury model (BIIM) and experimental group cilostazol (20 mg/kg/day) included 6 rabbits each. Contralateral veins from 6 rabbits used in BIIM model has been taken as control group. We measured and compared the expression of PDGF-BB and the development of IH. A pathologist board chooses a PDGFRα antibody to localized its expression by immunohistochemistry analysis. Subsequently, using an automated immunohistochemical staining machine, the PDGFR expression was evaluated using a Zeiss Primo Star 4 light microscope. Results The measurement obtained in the intimal layer was: 126.12 μm2 in the CG, 232 μm2 in the BIIM group, and 178 μm2 in the EG. A statistically significant difference was observed. Baseline serum concentrations of PDGF-BB in the BIIM group were 0.22 pg/mL. At 12 h 0.42 pg/mL, and 0.17 pg/mL at seven days. In the experimental group, the basal levels were 0.33 pg/mL. With the use of cilostazol, a lower peak was obtained at 12 h (0.08 pg/mL). This difference was statistically significant. Conclusions Cilostazol induced a significant reduction of IH caused by barotrauma in the venous endothelium, which correlates with decrease in the PDGF-BB in serum. This could be attributed to the pharmacologic effect on PDGFR expression.

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