Syringaresinol inhibits cardiorenal fibrosis through HSP90 in a cardiorenal syndrome type 2.

BACKGROUND: Syringaresinol processes anti-inflammatory and antioxidative activity. However, the effects of syringaresinol on cardiorenal fibrosis caused by cardiorenal syndrome type 2 (CRS2) are unclear. METHODS: Molecular docking predicted binding activity of syringaresinol to heat shock protein 90 (HSP90). The toxicity of a 4-weeks treatment with 20 mg/kg of syringaresinol was observed by measuring serum pro-inflammatory cytokines levels and by cardiorenal pathology. A CRS2 rad model was established by myocardial infarction using ligation over an 8 week-period. Rats were divided into five groups, including sham, CRS2, pimitespib, syringaresinol, and HSP90 + syringaresinol. Rats were received a 4-weeks daily treatment with 10 mg/kg pimitespib (a HSP90 inhibitor) or 20 mg/kg syringaresinol. Recombinant adeno-associated virus (rAAV) carrying a periostin (PE) promoter driving the expression of wild-type HSP90 (rAAV9-PE-HSP90, 1 × 1011 µg) was treated intravenously once in CRS2 model rats. Cardiorenal function and pathology were assessed. Expressions of HSP90 and TGF-ß1 in the myocardium and kidney were measured by immunohistochemistry and western blotting. RESULTS: Syringaresinol showed good binding activity with HSP90, and no signs of toxicity in rats following treatment. Pimitespib or syringaresinol significantly improved the cardiorenal function and fibrosis in rats with CRS2. Meanwhile, the rAAV9-PE-HSP90 injection obviously blocked the effects of syringaresinol. CONCLUSIONS: Syringaresinol targets HSP90 to suppress CRS2-induced cardiorenal fibrosis, providing a promising therapeutic drug for CRS2.

Reduced Intellectual Ability in Offspring Born from Preeclamptic Mothers: A Prospective Cohort Study.

BACKGROUND: Severe preeclampsia may affect placental development, and high homocysteine (Hcy) levels are linked to intellectual disability. However, the correlation between perinatal Hcy levels and intellectual ability remains unknown in severe preeclampsia-affected offspring. OBJECTIVE: We aimed to investigate the intellectual ability in offspring born from preeclamptic mothers and examine the role of prenatal Hcy in the prediction of intellectual disability in preschool-aged offspring. METHODS: The IQ scores were compared between 101 children born to mothers with severe preeclampsia and 202 offsprings born to normotensive mothers. Maternal Hcy levels within 7 days prior to delivery and postnatal cord blood Hcy were measured. The associations of Hcy with IQ scores were evaluated, and the optimal cut-off values for predicting intellectual disability in the offspring were estimated. RESULTS: The children born to mothers with severe preeclampsia had a greater postnatal cord blood Hcy than those born from normotensive mothers (P < 0.001), and the mothers with severe preeclampsia presented a higher prenatal Hcy (P < 0.001). The children born to mothers with severe preeclampsia had significantly lower IQ scores than those born from normotensive mothers, and a higher Hcy was associated with a lower IQ in preeclampsia-affected offspring. The prevalence of intellectual disability was 2.86 times higher in severe preeclampsia-affected offspring than in children born from normotensive mothers, and the prevalence of low IQ was greater in children born to mothers with severe preeclampsia than in those from normotensive mothers. ROC curve analysis showed that both maternal and cord blood Hcy were predictors of intellectual disability, and the optimal cut-off for predicting intellectual disability was 17.7 and 9.75 µmol/L for maternal and cord blood Hcy. CONCLUSION: Perinatal exposure to severe preeclampsia has an adverse effect on postnatal intellectual development, and high maternal and cord blood Hcy may contribute to this association.