The incidence of myocardial dysfunction caused by sepsis is high, and the mortality of patients with sepsis can be significantly increased. During sepsis, oxidative stress and inflammation can lead to severe organ dysfunction. Flavone chrysin is one of the indispensable biological active ingredients for different fruits and vegetables and has antioxidant and anti-inflammatory properties. However, it is not clear whether chrysin is an effective treatment for heart dysfunction caused by sepsis. We found that it had protective effects against the harmful effects caused by LPS, manifested in improved survival, normalized cardiac function, improved partial pathological scores of myocardial tissue, and remission of apoptosis, as well as reduced oxidative stress and inflammation. Mechanism studies have found that chrysin is an important antioxidant protein, a key regulator of heme oxygenase 1 (HO-1). We found that HO-1 levels were increased after LPS intervention, and chrysin further increased HO-1 levels, along with the addition of Nrf2, a regulator of antioxidant proteins. Pretreatment with PD98059, an extracellular signal-regulated kinase-specific inhibitor, blocked chrysin-mediated phosphorylation of Nrf2 and the nuclear translocation of Nrf2. The protective effect of chrysin on sepsis-induced cardiac dysfunction was blocked by ZnPP, which is a HO-1 blocker. Chrysin increased antioxidant activity and reduced markers of oxidative stress (SOD and MDA) and inflammation (MPO and IL-1β), all of which were blocked by ZnPP. This indicates that HO-1 is the upstream molecule regulating the protective effect of chrysin. Thus, by upregulation of HO-1, chrysin protects against LPS-induced cardiac dysfunction and inflammation by inhibiting oxidative stress.

Background Renal ischemia-reperfusion (I/R) injury causes renal tubular necrosis, apoptosis, and inflammation leading to acute renal dysfunction. Recent studies have revealed that deletion of Gα12 mitigates the renal damage due to I/R injury. Our previous study showed that activation of dopamine D₃ receptor (D₃R) increased its linkage with Gα12, and hampered Gα12-mediated stimulation of renal sodium transport. In the present study, we used an in-vivo rat model and an in vitro study of the renal epithelial cell line (NRK52E) to investigate whether or not an increased linkage between D₃R and Gα12 contributes to the protective effect of D₃R on renal I/R injury. Methods For in vivo studies, I/R injury was induced in a rat renal unilateral clamping model. For in vitro studies, hypoxia/reoxygenation and cold storage/rewarming injuries were performed in NRK52E cells. PD128907, a D₃R agonist, or vehicle, was administered 15 minutes before clamping (or hypoxia) in both the in vivo or in vitro studies. Results In the rat renal unilateral clamping model, pretreatment with PD128907 (0.2 mg/kg, intravenous) protected against renal I/R injury and increased survival rate during a long-term follow-up after 7 days. A decrease in the generation of reactive oxygen species, apoptosis, and inflammation may be involved in the D₃R-mediated protection because pretreatment with PD128907 increased renal glutathione and superoxide dismutase levels and decreased malondialdehyde levels in the I/R group. The increase in cytokines (TNF-α, IL-1β, and IL-10) and myeloperoxidase in I/R injured kidney was also prevented with a simultaneous decrease in the apoptosis of the epithelial cells and expression of apoptosis biomarkers in kidney harvested 1 day after I/R injury. The increase in the coimmunoprecipitation between D₃R and Gα12 with D₃R stimulation paralleled the observed renal protection from I/R injury. Moreover, in vitro studies showed that transient overexpression of Gα12 in the NRK52E cells attenuated the protective effect of PD128907 on hypoxia/reoxygenation injury. The protective effect of PD128907 might be of significance to renal transplantation because cold storage/rewarming induced injury increased lactate dehydrogenase release and decreased cell viability in NRK52E cells. Conversely, in the presence of PD128907, the increased lactate dehydrogenase release and decreased cell viability were reversed. Conclusions These results suggest that activation of D₃R, by decreasing Gα12-induced renal damage, may exert a protective effect from I/R injury.

Obesity plays an important role in the pathogenesis of hypertension. Renal dopamine D1-like receptor-mediated diuresis and natriuresis are impaired in the obese Zucker rat, an obesity-related hypertensive rat model. The role of arterial D1 receptors in the hypertension of obese Zucker rats is not clear.