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Ischemic stroke results in disruption of the blood-brain barrier (BBB), edema formation and neuronal cell loss. Some neuroprotective factors such as vascular endothelial growth factor (VEGF) favor edema formation, while others such as erythropoietin (Epo) can mitigate it. Both factors are controlled by hypoxia inducible transcription factors (HIF) and the activity of prolyl hydroxylase domain proteins (PHD). We hypothesize that activation of the adaptive hypoxic response by inhibition of PHD results in neuroprotection and prevention of vascular leakage. Mice, subjected to cerebral ischemia, were pre- or post-treated with the novel PHD inhibitor FG-4497. Inhibition of PHD activity resulted in HIF-1α stabilization, increased expression of VEGF and Epo, improved outcome from ischemic stroke and reduced edema formation by maintaining BBB integrity. Additional in vitro studies using brain endothelial cells and primary astrocytes confirmed that FG-4497 induces the HIF signaling pathway, leading to increased VEGF and Epo expression. In an in vitro ischemia model, using combined oxygen and glucose deprivation, FG-4497 promoted the survival of neurons. Furthermore, FG-4497 prevented the ischemia-induced rearrangement and gap formation of the tight junction proteins zonula occludens 1 and occludin, both in cultured endothelial cells and in infarcted brain tissue in vivo. These results indicate that FG-4497 has the potential to prevent cerebral ischemic damage by neuroprotection and prevention of vascular leakage.

Background Although in most patients with inflammatory bowel diseases, conservative therapy is successful, a significant proportion of patients still require surgery once in their lifetime. Development of a safe perioperative treatment to dampen colitis activity without disturbance of anastomotic healing is an urgent and unmet medical need. Annexin A1 (ANXA1) has been shown to be effective in reducing colitis activity. Herein, a nanoparticle-based perioperative treatment approach was used for analysis of the effects of ANXA1 on the resolution of inflammation after surgery for colitis. Methods Anxa1-knockout mice were used to delineate the effects of ANXA1 on anastomotic healing. A murine model of preoperative dextran sodium sulfate colitis was performed. Collagen-IV-targeted polymeric nanoparticles, loaded with the ANXA1 biomimetic peptide Ac2-26 (Ac2-26-NPs), were synthesized and administered perioperatively during colitis induction. The effects of the Ac2-26-NPs on postoperative recovery and anastomotic healing were evaluated using the disease activity index, histological healing scores, and weight monitoring. Ultimately, whole-genome RNA sequencing of the anastomotic tissue was performed to unravel underlying molecular mechanisms. Results Anxa1-knockout exacerbated the inflammatory response in the healing anastomosis. Treatment with Ac2-26-NPs improved preoperative colitis activity (P < 0.045), postoperative healing scores (P < 0.018), and weight recovery (P < 0.015). Whole-genome RNA sequencing revealed that the suppression of proinflammatory cytokine and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was associated with the treatment effects and a phenotypic switch toward anti-inflammatory M2 macrophages. Conclusions Proresolving therapy with Ac2-26-NPs promises to be a potent perioperative therapy because it improves colitis activity and even intestinal anastomotic healing by the suppression of proinflammatory signaling.

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Purpose Despite primary conservative therapy for Crohn’s disease, a considerable proportion of patients ultimately needs to undergo surgery. Presumably, due to the increased use of biologics, the number of surgeries might have decreased. This study aimed to delineate current case numbers and trends in surgery in the era of biological therapy for Crohn’s disease. Methods Nationwide standardized hospital discharge data (diagnosis-related groups statistics) from 2010 to 2017 were used. All patients who were admitted as inpatient Crohn’s disease cases in Germany were included. Time-related development of admission numbers, rate of surgery, morbidity, and mortality of inpatient Crohn’s disease cases were analyzed. Results A total number of 201,165 Crohn’s disease cases were included. Within the analyzed time period, the total number of hospital admissions increased by 10.6% (n = 23,301 vs. 26,069). While gender and age distribution remained comparable, patients with comorbidities such as stenosis formation (2010: 10.1%, 2017: 13.4%) or malnutrition (2010: 0.8%, 2017: 3.2%) were increasingly admitted. The total number of all analyzed operations for Crohn’s disease increased by 7.5% (2010: n = 1567; 2017: n = 1694). On average, 6.8 ± 0.2% of all inpatient patients received ileocolonic resections. Procedures have increasingly been performed minimally invasive (2010: n = 353; 2017: n = 687). The number of postoperative complications remained low. Conclusion Despite the development of novel immunotherapeutics, the number of patients requiring surgery for Crohn’s disease remains stable. Interestingly, patients have been increasingly hospitalized with stenosis and malnutrition. The trend towards more minimally invasive operations has not relevantly changed the rate of overall complications.