The Curcumin Analog EF24 Inhibits Proliferation and Invasion of Triple-Negative Breast Cancer Cells by Targeting the Long Noncoding RNA HCG11/Sp1 Axis.

EF24, a curcumin analog, exerts a potent antitumor effect on various cancers. However, whether EF24 retards the progression of triple-negative breast cancer (TNBC) remains unclear. In this study, we explored the role of EF24 in TNBC and clarified the underlying mechanism. In a mouse model of TNBC xenograft, EF24 administration reduced the tumor volume, suppressed cell proliferation, promoted cell apoptosis, and downregulated long noncoding RNA human leukocyte antigen complex group 11 (HCG11) expression. In TNBC cell lines, EF24 administration reduced cell viability, suppressed cell invasion, and downregulated HCG11 expression. HCG11 overexpression reenhanced the proliferation and invasion of TNBC cell lines suppressed by EF24. The following mechanism research revealed that HCG11 overexpression elevated Sp1 transcription factor (Sp1) expression by reducing its ubiquitination, thereby enhanced Sp1-mediated cell survival and invasion in the TNBC cell line. Finally, the in vivo study showed that HCG11-overexpressed TNBC xenografts exhibited lower responsiveness in response to EF24 treatment. In conclusion, EF24 treatment reduced HCG11 expression, resulting in the degradation of Sp1 expression, thereby inhibiting the proliferation and invasion of TNBC cells.

Exogenous BDNF Increases Mitochondrial pCREB and Alleviates Neuronal Metabolic Defects Following Mechanical Injury in a MPTP-Dependent Way.

Metabolic defects are common pathological phenomena following traumatic brain injury (TBI) which contribute to poor prognosis. Brain-derived neurotrophic factor (BDNF) is an important regulator of neuronal survival, development, function, and plasticity. This study was designed to investigate the potential effects of BDNF on TBI-induced metabolic defects and their underlying molecular mechanisms. BDNF was added into cultured neurons to a concentration of 25, 50, and 100 ng/ml, respectively, right after mechanical injury and metabolite levels were analyzed 4 h post injury. The mitochondrial phosphorylated cAMP response element-binding protein (pCREB) distribution and complex V synthesis, as well as their roles in metabolic defects, were evaluated. We found that exogenous BDNF improved metabolic defects, especially the uncoupling of oxidative phosphorylation. BDNF increased pCREB in mitochondrial inner membrane and matrix and promoted mitochondrial complex V synthesis. We also found that these results were negatively regulated by the mitochondrial permeability transition pore (MPTP) antagonist CsA and positively regulated by the MPTP agonist atractyloside. BDNF's protectional effects on metabolic defects were abolished by CREB knockout. When administrated in a dominant interfering CREB mutant (A-CREB) model, mitochondrial pCREB accumulation could still be observed, but the synthesis of complex V and alleviation of metabolic defects were repressed. Our data demonstrate that exogenous BDNF mitigates neuronal metabolic defects following mechanical injury by promoting the pCREB accumulation in mitochondrial inner membrane and matrix, which is regulated by MPTP opening, thus facilitating the synthesis of mitochondrial complex V.

Acute upregulation of neuronal mitochondrial type-1 cannabinoid receptor and it's role in metabolic defects and neuronal apoptosis after TBI.

Metabolic defects and neuronal apoptosis initiated by traumatic brain injury (TBI) contribute to subsequent neurodegeneration. They are all regulated by mechanisms centered around mitochondrion. Type-1 cannabinoid receptor (CB1) is a G-protein coupled receptor (GPCR) enriched on neuronal plasma membrane. Recent evidences point to the substantial presence of CB1 receptors on neuronal mitochondrial outer membranes (mtCB1) and the activation of mtCB1 influences aerobic respiration via inhibiting mitochondrial cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/complex I pathway. The expression and role of neuronal mtCB1 under TBI are unknown. Using TBI models of cultured neurons, wild type and CB1 knockout mice, we found mtCB1 quickly upregulated after TBI. Activation of mtCB1 promoted metabolic defects accompanied with ATP shortage but protected neurons from apoptosis. Selective activation of plasma membrane CB1 showed no effects on neuronal metabolism and apoptosis. Activation of mtCB1 receptors inhibited mitochondrial cAMP/PKA/complex I and resulted in exacerbated metabolic defects accompanied with a higher ratio of ATP reduction to oxygen consumption decrease as well as neuronal apoptosis. Further research found the remarkable accumulation of protein kinase B (AKT) on neuronal mitochondria following TBI and the activation of mtCB1 upregulated mitochondrial AKT/complex V activity. Upregulation of mitochondrial AKT/complex V activity showed anti-apoptosis effects and alleviated ATP shortage in metabolic defects. Taken together, we have identified mtCB1 quickly upregulate after TBI and a dual role the mtCB1 might play in metabolic defects and neuronal apoptosis initiated by TBI: the inhibition of mitochondrial cAMP/PKA/complex I aggravates metabolic defects, energy insufficiency as well as neuronal apoptosis, but the coactivation of mitochondrial AKT/complex V mitigates energy insufficiency and neuronal apoptosis.

Predictive value of early decreased plasma ghrelin level for three-month cognitive deterioration in patients with mild traumatic brain injury.

The orexigenic hormone, ghrelin, is tightly linked to cognition impairment in neurodegenerative disorders. No previous studies have investigated the early ghrelin concentration change in patients with mild traumatic brain injury (mTBI) and it's relationship to cognitive deterioration. This study was performed to investigate the early plasma ghrelin concentrations in patients with mTBI and to explore the relationship between ghrelin and cognitive deterioration. Plasma ghrelin concentrations of 118 adults after acute mTBI were determined by enzyme-linked immunosorbent assay. Forty patients (33.9%) had cognitive deterioration three months after mTBI. Plasma ghrelin levels were significantly lower in mTBI patients with cognitive deterioration than patients without cognitive deterioration (38.8±4.5 pg/mL vs 50.8±7.7 pg/mL, P<0.001). Decreased Plasma ghrelin level was identified as an independent predictor for three-month cognitive deterioration after mTBI (odds ratio, 0.746; 95% confidence interval, 0.651-0.856; P<0.001). Plasma ghrelin level was negatively associated with serum adrenocorticotrophin hormone level (t=-6.854, P<0.001) and age (t=-6.112, P<0.001). A plasma ghrelin level of 41.6 pg/mL predicted three-month cognitive deterioration after mTBI with the optimal sensitivity (85.9%) and specificity (80.0%) values (area under curve, 0.904; 95% confidence interval, 0.852-0.957; P<0.001). The predictive value of ghrelin was bigger than that of serum adrenocorticotrophin hormone level (area under curve, 0.638; 95% confidence interval, 0.536-0.741; P=0.014) and age (area under curve, 0.638; 95% confidence interval, 0.536-0.741; P=0.014) for three-month cognitive deterioration after mTBI.