Septic cardiomyopathy is characterized by impaired contractive function with mitochondrial dysregulation. Songorine is a typical active C 20 -diterpene alkaloid from the lateral root of Aconitum carmichaelii , which has been used for the treatment of heart failure. This study investigated the protective role of songorine in septic heart injury from the aspect of mitochondrial biogenesis. Songorine (10, 50 mg/kg) protected cardiac contractive function against endotoxin insult in mice with Nrf2 induction. In cardiomyocytes, lipopolysaccharide (LPS) evoked mitochondrial reactive oxygen species (ROS) production and redistributed STIM1 to interact with Orai1 for the formation of calcium release-activated calcium (CRAC) channels, mediating calcium influx, which were prevented by songorine, likely due to ROS suppression. Songorine activated Nrf2 by promoting Keap1 degradation, having a contribution to enhancing antioxidant defenses. When LPS shifted metabolism away from mitochondrial oxidative phosphorylation (OXPHOS) in cardiomyocytes, songorine upregulated mitochondrial genes involved in fatty acid β-oxidation, tricarboxylic acid (TCA) cycle and electron transport chain in a manner dependent on Nrf2, resultantly protecting the capability of OXPHOS. Songorine increased luciferase report gene activities of nuclear respiratory factor-1 ( Nrf1 ) and mitochondrial transcription factor A ( Tfam ) dependently on Nrf2, indicative of the regulation of Nrf2/ARE and NRF1 signaling cascades. Songorine promoted PGC-1α binding to Nrf2, and the cooperation was required for songorine to activate Nrf2/ARE and NRF1 for the control of mitochondrial quality and quantity. In support, the beneficial effects of songorine on cardioprotection and mitochondrial biogenesis were diminished by cardiac Nrf2 deficiency in mice subjected to challenge. Taken together, these results showed that Nrf2 transcriptionally promoted mitochondrial biogenesis in cooperation with PGC-1α. Songorine activated Nrf2/ARE and NRF1 signaling cascades to rescue cardiomyocytes from endotoxin insult, suggesting that protection of mitochondrial biogenesis was a way for pharmacological intervention to prevent septic heart injury.

BackgroundFormaldehyde can induce misfolding and aggregation of Tau protein and β amyloid protein, which are characteristic pathological features of Alzheimer’s disease (AD). An increase in endogenous formaldehyde concentration in the brain is closely related to dementia in aging people. Therefore, the discovery of effective drugs to counteract the adverse impact of formaldehyde on neuronal cells is beneficial for the development of appropriate treatments for age-associated cognitive decline.MethodsIn this study, we assessed the neuroprotective properties of TongLuoJiuNao (TLJN), a traditional Chinese medicine preparation, against formaldehyde stress in human neuroblastoma cells (SH-SY5Y cell line). The effect of TLJN and its main ingredients (geniposide and ginsenoside Rg1) on cell viability, apoptosis, intracellular antioxidant activity and the expression of apoptotic-related genes in the presence of formaldehyde were monitored.ResultsCell counting studies showed that in the presence of TLJN, the viability of formaldehyde-treated SH-SY5Y cells significantly recovered. Laser scanning confocal microscopy revealed that the morphology of formaldehyde-injured cells was rescued by TLJN and geniposide, an effective ingredient of TLJN. Moreover, the inhibitory effect of geniposide on formaldehyde-induced apoptosis was dose-dependent. The activity of intracellular antioxidants (superoxide dismutase and glutathione peroxidase) increased, as did mRNA and protein levels of the antiapoptotic gene Bcl-2 after the addition of geniposide. In contrast, the expression of the apoptotic-related gene - P53, apoptotic executer - caspase 3 and apoptotic initiator - caspase 9 were downregulated after geniposide treatment.ConclusionsOur results indicate that geniposide can protect SH-SY5Y cells against formaldehyde stress through modulating the expression of Bcl-2, P53, caspase 3 and caspase 9, and by increasing the activity of intracellular superoxide dismutase and glutathione peroxidase.

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The authors aimed to explore the association between visit‐to‐visit blood pressure variability (BPV) in pregnant women and adverse neonatal outcomes. The study included 52 891 pregnant women. BPV was calculated as standard deviation (SD) and coefficient of variation (CV) of systolic blood pressure (SBP) or diastolic blood pressure (DBP). All participants were divided into four groups by the quartiles of BPV. When comparing the highest quartiles to the lowest quartiles of DBP SD in all participants, the fully adjusted ORs were 1.19 (95% CI 1.11–1.27, p for trend < .001) for fetal distress, 1.32 (95% CI 1.14–1.54, p for trend < .001) for small for gestational age, 1.32 (95% CI 1.06–1.63, p for trend = .003) for 1‐min Apgar score ≤ 7. When comparing the highest quartiles to the lowest quartiles of DBP CV, ORs were 1.22 (95% CI 1.14–1.30, p for trend < .001) for fetal distress, 1.38 (95% CI 1.17–1.61, p for trend < .001) for small for gestational age, 1.43 (95% CI 1.14–1.79, p for trend < .001) for 1‐min Apgar score ≤ 7. ORs for preterm birth and 5‐min Apgar score ≤ 7 were not statistically significant. However, in participants with gestational hypertension or preeclampsia, ORs for preterm birth were 2.80 (95% CI 1.99–3.94, p for trend < .001) in DBP SD and 3.25 (95% CI 2.24–4.72, p for trend < .001) in DBP CV when extreme quartiles were compared. In conclusion, higher visit‐to‐visit BPV was associated with adverse neonatal outcomes.