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Caffeic acid phenethyl ester (CAPE): scavenger of peroxynitrite in vitro and in sepsis models

Kassim M, Mansor M, Kamalden TA, Shariffuddin II, Hasan MS, Ong G, et al.

Shock, 2014 Aug;42(2):154-60.
PMID: 24667629 DOI: 10.1097/SHK.0000000000000179

Excessive free radical production by immune cells has been linked to cell death and tissue injury during sepsis. Peroxynitrite is a short-lived oxidant and a potent inducer of cell death that has been identified in several pathological conditions. Caffeic acid phenethyl ester (CAPE) is an active component of honeybee products and exhibits antioxidant, anti-inflammatory, and immunomodulatory activities. The present study examined the ability of CAPE to scavenge peroxynitrite in RAW 264.7 murine macrophages stimulated with lipopolysaccharide/interferon-γ that was used as an in vitro model. Conversion of 123-dihydrorhodamine to its oxidation product 123-rhodamine was used to measure peroxynitrite production. Two mouse models of sepsis (endotoxemia and cecal ligation and puncture) were used as in vivo models. The level of serum 3-nitrotyrosine was used as an in vivo marker of peroxynitrite. The results demonstrated that CAPE significantly improved the viability of lipopolysaccharide/interferon-γ-treated RAW 264.7 cells and significantly inhibited nitric oxide production, with effects similar to those observed with an inhibitor of inducible nitric oxide synthase (1400W). In addition, CAPE exclusively inhibited the synthesis of peroxynitrite from the artificial substrate SIN-1 and directly prevented the peroxynitrite-mediated conversion of dihydrorhodamine-123 to its fluorescent oxidation product rhodamine-123. In both sepsis models, CAPE inhibited cellular peroxynitrite synthesis, as evidenced by the absence of serum 3-nitrotyrosine, an in vivo marker of peroxynitrite. Thus, CAPE attenuates the inflammatory responses that lead to cell damage and, potentially, cell death through suppression of the production of cytotoxic molecules such as nitric oxide and peroxynitrite. These observations provide evidence of the therapeutic potential of CAPE treatment for a wide range of inflammatory disorders.
Complete activation of autophagic process attenuates liver injury and improves survival in septic mice

Lin CW, Lo S, Perng DS, Wu DB, Lee PH, Chang YF, et al.

Shock, 2014 Mar;41(3):241-9.
PMID: 24365881 DOI: 10.1097/SHK.0000000000000111

The accumulation of autophagosomes in the terminal step of the autophagic process has recently emerged as a potentially maladaptive process in the septic heart and lung. However, the role of autophagy in the septic liver has not been ascertained. This study was investigated by first examining the entire sequence of the autophagic process in the liver of septic mice. Second, a novel pharmacotherapeutic approach was utilized to treat sepsis with autophagy enhancer/inhibitor. Sepsis was induced by cecal ligation and puncture (CLP). C57BL/6 mice received autophagy enhancer carbamazepine (CBZ), autophagy inhibitor 3-methyladenine (inhibition of autophagosomal formation), or chloroquine (impairment of autophagosomal clearance). We found that the whole autophagic process was activated at 4 h after CLP; however, it did not proceed to completion during the 4- to 24-h time period, as indicated by accumulated autophagosomes and decreased autophagic flux. Carbamazepine, which induced complete activation of the autophagic process, improved CLP survival. This protective effect was also associated with decreased cell death, inflammatory responses, and hepatic injury. However, disruption of autophagosomal clearance with chloroquine abolished the above protective effects in CBZ-treated CLP mice. 3-Methyladenine, which resulted in inhibition of the autophagosomal formation, did not show any above beneficial effects in CLP mice. Impaired autophagosome-lysome fusion resulting in incomplete activation of autophagy may contribute to sepsis-induced liver injury. Treatment with CBZ may serve a protective role in the septic liver, possibly through the effect of complete activation of autophagic process.
Clinical outcomes of patients with cardiogenic shock complicating acute myocardial infarction: The Gulf-Cardiogenic Shock (G-CS) Registry

Daoulah A, Alshehri M, Panduranga P, Aloui HM, Yousif N, Arabi A, et al.

Shock, 2024 Aug 12.
PMID: 39158570 DOI: 10.1097/SHK.0000000000002433

BACKGROUND: There is a paucity of data regarding acute myocardial infarction (MI) complicated by cardiogenic shock (AMI-CS) in the Gulf region. This study addressed this knowledge gap by examining patients experiencing AMI-CS in the Gulf region and analyzing hospital and short-term follow-up mortality.
METHODS: The Gulf-CS registry included 1,513 patients with AMI-CS diagnosed between January 2020 and December 2022.
RESULTS: The incidence of AMI-CS was 4.1% (1513/37379). The median age was 60 years. The most common presentation was ST-elevation MI (73.83%). In-hospital mortality was 45.5%. Majority of patients were in SCAI stage D and E (68.94%). Factors associated with hospital mortality were previous coronary artery bypass graft (OR:2.49; 95%CI: 1.321-4.693), cerebrovascular accident (OR:1.621, 95%CI: 1.032-2.547), chronic kidney disease (OR:1.572; 95%CI1.158-2.136), non-ST-elevation MI (OR:1.744; 95%CI: 1.058-2.873), cardiac arrest (OR:5.702; 95%CI: 3.640-8.933), SCAI stage D and E (OR:19.146; 95CI%: 9.902-37.017), prolonged QRS (OR:10.012; 95%CI: 1.006-1.019), right ventricular dysfunction (OR:1.679; 95%CI: 1.267-2.226) and ventricular septal rupture (OR:6.008; 95%CI: 2.256-15.998). Forty percent had invasive hemodynamic monitoring, 90.02% underwent revascularization, and 45.80% received mechanical circulatory support (41.31% had Intra-Aortic Balloon Pump and 14.21% had Extracorporeal Membrane Oxygenation/Impella devices). Survival at 12 months was 51.49% (95% CI: 46.44- 56.29%).
CONCLUSIONS: The study highlighted the significant burden of AMI-CS in this region, with high in-hospital mortality. The study identified several key risk factors associated with increased hospital mortality. Despite the utilization of invasive hemodynamic monitoring, revascularization, and mechanical circulatory support in a substantial proportion of patients, the 12-month survival rate remained relatively low.

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