Gossypol stimulates opening of a Ca2+‐ and Na+‐permeable but Ni2+‐ and Co2+‐impermeable pore in bEND.3 endothelial cells

Gossypol, a polyphenolic dialdehyde toxin isolated from cotton seed, has anti‐cancer properties and has recently shown some success in the treatment of glioma. Its effects on brain neurons and blood vessels are poorly understood. In this work we examined the effects of gossypol on cytosolic Ca²⁺ concentration ([Ca²⁺]_i) of mouse brain bEND.3 endothelial cells. Cell viability tests revealed that after 3 hour and 18 hour exposures, 10 µmol/L gossypol caused 23% and 65% cell death, respectively; 3 µmol/L gossypol caused no and 21% cell death, respectively. [Ca²⁺]_i was raised concentration‐dependently by 1‐10 µmol/L gossypol. We then explored the Ca²⁺ signalling triggered by 3 µmol/L gossypol, which inflicted minimal toxicity: the Ca²⁺ signal was composed largely of Ca²⁺ influx and to a small extent, intracellular Ca²⁺ release. Such Ca²⁺ influx was much larger than store‐operated Ca²⁺ influx triggered by maximal Ca²⁺ pool depletion. The Ca²⁺ influx triggered by 3 and 10 µmol/L gossypol caused NO release and cell death, respectively. Gossypol also triggered influx of Mn²⁺ and Na⁺, but not Ni²⁺ and Co²⁺. Gossypol‐triggered Ca²⁺ signal was inhibited only by 14% and 37% by 100 µmol/L La³⁺ and 10 µmol/L nimodipine, respectively; and not suppressed at all by 5 mmol/L Ni²⁺. Gossypol‐triggered Ca²⁺ signal was suppressed by 78% by 30 µmol/L ruthenium red, suggesting gossypol may act on TRPV channels. Our results suggest gossypol triggered opening of a non‐selective cation pore, possibly a member of the TRPV family.     

Prenatal immune activation potentiates endocannabinoid-related plasticity of inhibitory synapses in the hippocampus of adolescent rat offspring

There is strong evidence that immune activation from prenatal infection increases the risk for offspring to develop schizophrenia. The endocannabinoid (eCB) system has been implicated in the pathophysiology of schizophrenia while models of cortical dysfunction postulate an imbalance between neuronal excitation and inhibition in the disorder. The current study examined the impact of prenatal immune activation on eCB-mediated inhibitory mechanisms. We compared two forms of eCB-related plasticity of evoked inhibitory postsynaptic currents, namely depolarization-induced suppression of inhibition (DSI) and metabotropic glutamate receptor-induced long term depression (mGluR-iLTD), in both the dorsal and ventral hippocampus between adolescent offspring from rat dams that received either saline or bacterial lipopolysaccharide (LPS) during pregnancy. Compared to prenatal saline offspring, prenatal LPS offspring displayed prolonged DSI and stronger mGluR-iLTD in the dorsal and ventral hippocampus, respectively. The sensitivity of mGluR-iLTD to the CB1 receptor antagonist AM251 was also lower in the dorsal hippocampus of prenatal LPS compared to prenatal saline offspring. Testing whether changes in eCB receptor signaling or levels could contribute to these changes in inhibitory transmission, we found region specific increases in 2-arachidonoylglycerol-stimulated signaling and in basal and mGluR-induced levels of anandamide in prenatal LPS offspring when compared to prenatal saline offspring. Our findings indicate that prenatal immune activation can lead to long-term changes in eCB-related plasticity of hippocampal inhibitory synaptic transmission in adolescent rat offspring. Perturbation of the eCB system resulting from prenatal immune activation could represent a mechanism linking early life immune events to the development of psychopathology in adolescence.     

Frailty and Clinical Outcomes in Advanced Heart Failure Patients Undergoing Left Ventricular Assist Device Implantation: A Systematic Review and Meta-analysis

Background

Frailty has been identified as a risk factor for adverse clinical outcomes after cardiac intervention or surgery. However, whether it increases the risk of adverse outcomes in patients undergoing left ventricular assist device (LVAD) therapy has been controversial. Therefore, we conducted a systematic review and meta-analysis of the frailty measures and clinical outcomes of length of stay and mortality in this setting.