Gifu Pharmaceutical University

Endothelial glycocalyx (eGCX) is shed into the bloodstream during reperfusion injury and ischemia, and its core proteins, syndecan-1 and glypican-1, can be measured in the blood. However, no studies have measured cardiac serum syndecan-1 concentrations in blood from the coronary sinus. Therefore, we aimed to examine the relationship between the degree and changes in eGCX damage and postoperative clinical outcomes using blood drawn from the coronary sinus.

Serum eGCX concentrations in the coronary sinus of 56 patients who underwent cardiac and thoracic aortic surgery with combined ante- and retrograde cardioplegia were analyzed. The association between maximum postoperative troponin T (TnT) level, as a myocardial damage marker, and eGCX injury markers, including syndecan-1 and glypican-1, measured in coronary sinus blood drawn immediately after reperfusion, was assessed. The association between eGCX injury markers and duration of cardioplegic arrest was also investigated.

An association between degree of change in coronary sinus serum syndecan-1 concentration during reperfusion and postoperative maximum serum TnT levels was observed. No such association was found between the degree of change in coronary sinus serum glypican-1 concentration during reperfusion and postoperative serum TnT levels. Similar results were obtained for somatic circulation. Moreover, an association between maximum change in serum syndecan-1 concentration in the coronary sinus during reperfusion and cardioplegic arrest duration was observed. No such association was found for glypican-1 concentration.

The degree of endothelial damage to the coronary sinuses during reperfusion may predict myocardial injury following cardiac surgery.

Macrophages play a pivotal role in both the initiation and resolution of intestinal inflammation, positioning them as potential therapeutic target in inflammatory bowel disease. Intracellular ion such as Ca²⁺ are increasingly recognized as key regulators of macrophage function and inflammatory responses. The Na⁺/Ca²⁺ exchanger is a membrane protein predominantly expressed in excitable cells, where it regulates intracellular Na⁺ and Ca²⁺ concentrations. This study aims to elucidate the role of Na⁺/Ca²⁺ exchanger in macrophages and its potential implications for inflammatory bowel disease therapy.

We investigated macrophage function using Na⁺/Ca²⁺ exchanger inhibitor and evaluated the effects of Na⁺/Ca²⁺ exchanger inhibition in a dextran sodium sulfate-induced mouse model of colitis.

Na⁺/Ca²⁺ exchanger-1 expression was elevated inflammatory macrophages and colonic tissues from mice with dextran sodium sulfate-induce colitis. Treatment with the Na⁺/Ca²⁺ exchanger inhibitor SN-6 ameliorated dextran sodium sulfate-induce colitis symptoms and suppressed the release of pro-inflammatory cytokines from murine and canine macrophage. Inhibition of Na⁺/Ca²⁺ exchanger increased Ca²⁺ influx and promoted phosphorylated of nuclear factor of activated T-cells in mouse macrophages. Furthermore, Na⁺/Ca²⁺ exchanger-1 mRNA expression was upregulated in colonic tissues from both human and canine inflammatory bowel disease patients.

These findings suggest that Na⁺/Ca²⁺ exchanger-1 plays a critical role in inflammatory responses in macrophages. Inhibition of Na⁺/Ca²⁺ exchanger exerts anti-inflammatory effects and attenuates colonic inflammation across multiple species, including humans and dogs, highlighting its potential as a therapeutic target for inflammatory bowel disease.

The barrier function of granular layer in the skin is mainly sustained by claudin-1 (CLDN1) and CLDN4, tight junctional components. We recently found that the activity of sirtuin-2 (SIRT2), an anti-aging molecule, is decreased with aging in keratinocytes, leading to the attenuation of CLDN4 expression and paracellular barrier function. SIRT2 may be a novel target for enhancing skin barrier function in elderly people. In vitro SIRT2 activity assay showed that epigallocatechin gallate (EGCG) and green tea extract (GT) have a potent ability to activate SIRT2. Tenovin-1 (Ten-1), a sirtuin-1/2 inhibitor, decreased the SIRT2 activity in human keratinocyte-derived HaCaT cells, which was rescued by EGCG and GT. Ten-1 decreased the protein level of CLDN4, which was rescued by EGCG, whereas CLDN1 expression was changed by neither Ten-1 nor EGCG. Ten-1 decreased the tight junctional localization of CLDN4, transepithelial electrical resistance, and paracellular permeability to FD4, a fluorescence paracellular flux marker, which were rescued by EGCG. Ten-1 increased the acetylation level of CLDN4, which was inhibited by EGCG without affecting NAD⁺ content, a substrate for SIRT2. The protein levels of wild-type and K191A mutant were decreased by Ten-1, whereas that of K196A was not. Furthermore, Ten-1 increased the acetylation levels of WT and K191A mutant. We suggest that Ten-1 decreases CLDN4 expression mediated by the acetylation of K196 of CLDN4 and EGCG is useful to protect from aging-induced dysfunction of paracellular barrier in the keratinocytes.