shogaol and Reperfusion-Injury

Intestinal ischemia-reperfusion (II/R) injury is a common pathological process with high morbidity and mortality. Effective prevention and treatment therapies for II/R are clinically necessary. 6-Shogaol (6-SG), the main active ingredient in dried ginger, behaviors multiple biological activities, including anti-inflammation, antioxidation, and anti-apoptosis. This study aims to elucidate the protective effects and mechanism of 6-SG against II/R-induced injury.. Sprague-Dawley rats are pre-treated orally with 6-SG and subjected to II/R injury by clamping superior mesenteric artery for 1 h and reperfusion for 2 h. Caco-2 cells are challenged by hypoxia/reoxygenation to mimic II/R in vitro. 6-SG pre-treatment protects against II/R injury by reducing intestinal morphological damage and intestinal barrier injury via inhibiting cell apoptosis. Network pharmacology and molecular docking analyses reveal that 6-SG has a high affinity with brain-derived neurotrophic factor (BDNF) formed homodimer or heterodimer with NT4 instead of the monomer, and thus the dimer configuration is stabilized, activating BDNF/TrkB/PI3K/AKT signaling pathway and inhibiting II/R-induced cell apoptosis. The outcome is further validated both in vivo and in vitro.. 6-Shogaol protects against II/R injury by inhibiting cell apoptosis through the BDNF/TrkB/PI3K/AKT pathway. This study offers a new understanding of the protection mechanism of 6-SG against II/R-induced injury.

Topics: Animals; Brain-Derived Neurotrophic Factor; Caco-2 Cells; Humans; Intestinal Diseases; Ischemia; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Zingiber officinale

Acute kidney injury (AKI) due to renal ischemia-reperfusion (I/R) is a major clinical problem without effective therapy. Ginger is one of the most widely consumed spices in the world, and 6-shogaol, a major ginger metabolite, has anti-inflammatory effects in neuronal and epithelial cells. Here, we demonstrate our novel findings that 6-shogaol treatment protected against renal I/R injury with decreased plasma creatinine, blood urea nitrogen, and kidney neutrophil gelatinase-associated lipocalin mRNA synthesis compared with vehicle-treated mice subjected to renal I/R. Additionally, 6-shogaol treatment reduced kidney inflammation (decreased proinflammatory cytokine and chemokine synthesis as well as neutrophil infiltration) and apoptosis (decreased TUNEL-positive renal tubular cells) compared with vehicle-treated mice subjected to renal I/R. In cultured human and mouse kidney proximal tubule cells, 6-shogaol significantly attenuated TNF-α-induced inflammatory cytokine and chemokine mRNA synthesis. Mechanistically, 6-shogaol significantly attenuated TNF-α-induced NF-κB activation in human renal proximal tubule cells by reducing IKKαβ/IκBα phosphorylation. Furthermore, 6-shogaol induced a cytoprotective chaperone heme oxygenase (HO)-1 via p38 MAPK activation in vitro and in vivo. Consistent with these findings, pretreatment with the HO-1 inhibitor zinc protoporphyrin IX completely prevented 6-shogaol-mediated protection against ischemic AKI in mice. Taken together, our study showed that 6-shogaol protects against ischemic AKI by attenuating NF-κB activation and inducing HO-1 expression. 6-Shogaol may provide a potential therapy for ischemic AKI during the perioperative period.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Apoptosis; Catechols; Cell Line; Cytokines; Disease Models, Animal; Heme Oxygenase-1; Humans; Inflammation Mediators; Kidney; Male; Membrane Proteins; Mice, Inbred C57BL; Neutrophil Infiltration; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Reperfusion Injury; Signal Transduction