Mitochondrial aldehyde dehydrogenase (ALDH2) rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer's disease via inhibition of ACSL4-dependent ferroptosis.

Alzheimer's disease (AD) is associated with high incidence of cardiovascular events but the mechanism remains elusive. Our previous study reveals a tight correlation between cardiac dysfunction and low mitochondrial aldehyde dehydrogenase (ALDH2) activity in elderly AD patients. In the present study we investigated the effect of ALDH2 overexpression on cardiac function in APP/PS1 mouse model of AD. Global ALDH2 transgenic mice were crossed with APP/PS1 mutant mice to generate the ALDH2-APP/PS1 mutant mice. Cognitive function, cardiac contractile, and morphological properties were assessed. We showed that APP/PS1 mice displayed significant cognitive deficit in Morris water maze test, myocardial ultrastructural, geometric (cardiac atrophy, interstitial fibrosis) and functional (reduced fractional shortening and cardiomyocyte contraction) anomalies along with oxidative stress, apoptosis, and inflammation in myocardium. ALDH2 transgene significantly attenuated or mitigated these anomalies. We also noted the markedly elevated levels of lipid peroxidation, the essential lipid peroxidation enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4), the transcriptional regulator for ACLS4 special protein 1 (SP1) and ferroptosis, evidenced by elevated NCOA4, decreased GPx4, and SLC7A11 in myocardium of APP/PS1 mutant mice; these effects were nullified by ALDH2 transgene. In cardiomyocytes isolated from WT mice and in H9C2 myoblasts in vitro, application of Aß (20 µM) decreased cell survival, compromised cardiomyocyte contractile function, and induced lipid peroxidation; ALDH2 transgene or activator Alda-1 rescued Aß-induced deteriorating effects. ALDH2-induced protection against Aß-induced lipid peroxidation was mimicked by the SP1 inhibitor tolfenamic acid (TA) or the ACSL4 inhibitor triacsin C (TC), and mitigated by the lipid peroxidation inducer 5-hydroxyeicosatetraenoic acid (5-HETE) or the ferroptosis inducer erastin. These results demonstrate an essential role for ALDH2 in AD-induced cardiac anomalies through regulation of lipid peroxidation and ferroptosis.

IGF-1 alleviates serum IgG-induced neuronal cytolysis through PI3K signaling in children with opsoclonus-myoclonus syndrome and neuroblastoma.

BACKGROUND: Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disorder, usually accompanied by neuroblastoma (NB). There is no targeted treatment and animal model of OMS. We aimed to investigate whether insulin-like growth factor 1 (IGF-1)/phosphoinositide 3-kinase (PI3K) signaling alleviates neuronal cytolysis in pediatric OMS. METHODS: Cultured rat cerebral cortical neurons and cerebellar neurons were incubated with sera or IgG isolated from sera of children with OMS and NB. Cytolysis and PI3K expression were measured by the lactate dehydrogenase assay and enzyme-linked immunosorbent assay, respectively. Using inhibitors and activators, the effects of IGF-1 and PI3K on cytolysis were investigated. RESULTS: The incubation of sera or IgG from children with OMS and NB increased cytolysis in not only cerebellar neurons, but also cerebral cortical neurons. Furthermore, the IGF-1 receptor antagonist NVP-AEW541 exaggerated cytolysis in children with OMS and NB. IGF-1 alleviated cytolysis, which was blocked by the PI3K inhibitor LY294002. Additionally, sera or IgG from children with OMS and NB compensatively elevated PI3K expression. LY294002 exacerbated cytolysis; whereas, the PI3K activator 740 Y-P suppressed cytolysis. CONCLUSION: IGF-1/PI3K signaling alleviates the cytolysis of cultured neurons induced by serum IgG from children with OMS and NB, which may be innovation therapy targets.

[The use of sodium bicarbonate in stages in treating hypoperfusion induced lactic acidemia in septic shock].

OBJECTIVE: To explore the use of sodium bicarbonate in stages in treating hypoperfusion induced lactic acidemia due to septic shock. METHODS: In this prospective randomized, double-blind, controlled clinical trial, a total of 65 patients of hypoperfusion induced lactic acidemia due to septic shock admitted between April 2006 and April 2010 were assigned to two groups. Thirty-five patients of "stage" group sodium bicarbonate was used in two stages: in first stage sodium bicarbonate was given by venous drip until pH≥7.15, and in second stage sodium bicarbonate was given by intravenous drip till pH≥7.25 after 6 hours. Thirty patients in control group intravenous drip of sodium bicarbonate was used till pH≥7.15. Early goal-directed therapy(EGDT) was used in the first 6 hours of fluid resuscitation. The number of dysfunction organ, time of mechanical ventilation, maximum sequential organ failure assessment (SOFA) score, delta SOFA score, durations of stay in intensive care unit (ICU) and in hospital, and mortality were recorded in two groups. Blood gas analysis and index of hemodynamics were monitored at 0 hour and 8 hours in both groups. RESULTS: Compared with control group, "stage" group was associated with a lower number of dysfunction organ, time of mechanical ventilation, maximum SOFA score, delta SOFA score, durations of stay in ICU and in hospital, and mortality (number of dysfunction organ: 2.68±0.79 vs. 3.28±0.80, time of mechanical ventilation: 10.32±2.26 days vs. 13.80±2.56 days, maximum SOFA score: 11.01±2.26 vs. 13.11±2.26, delta SOFA score: 1.71±1.25 vs. 3.43±1.27, duration of stay in ICU: 14.0±3.6 days vs. 20.0±3.7 days, duration of stay in hospital: 28.3±12.9 days vs. 41.9±13.2 days, mortality: 34.28% vs. 60.00%, P<0.05 or P<0.01). There were no significant differences in blood gas analysis and index of hemodynamics at 0 hour, and they were improved at 8 hours. Compared with control group, in "stage" group, lactic acid (Lac) was significantly lowered (1.50±1.08 mmol/L vs. 2.93±1.09 mmol/L), and pH, mixed venous oxygen saturation (SvO2), oxygen extraction ratio (O2ER), cardiac index (CI), oxygen delivery (DO2) were significantly increased (pH:7.29±0.05 vs. 7.20±0.05, SvO2: 0.75±0.18 vs. 0.66±0.17, O2ER: 0.32±0.06 vs. 0.25±0.06, CI: 113.36±13.34 ml×s(-1)×m(-2) vs. 83.35±13.34 ml×s(-1)×m(-2), DO2: 840±170 ml×min(-1)×m(-2) vs. 630±171 ml×min(-1)×m(-2), all P<0.01). CONCLUSION: The use of sodium bicarbonate in stages in treating hypoperfusion induced lactic acidemia as a result of septic shock can lower the occurrence rate of multiple organ dysfunction syndrome, time of mechanical ventilation, durations of stay in ICU and in hospital, and mortality.