Honglu Chao

Melatonin attenuates traumatic brain injury-induced inflammation: a possible role for mitophagy.

Melatonin functions as a crucial mediator of sterile neuroinflammation; however, the underlying mechanisms remain poorly understood. Dysfunctional mitochondria, a main source of reactive oxygen species, are impacted in inflammation activation. This study aimed to examine the effect of melatonin on inflammation via elimination of damaged mitochondria after controlled cortical impact, an in vivo model of traumatic brain injury (TBI). Here, we demonstrated that inhibition of mitophagy, the selective degradation of damaged mitochondria by autophagy, markedly enhanced inflammation induced by TBI. Melatonin treatment activated mitophagy through the mTOR pathway, then to attenuate TBI‐induced inflammation. Furthermore, treatment with melatonin significantly ameliorated neuronal death and behavioral deficits after TBI, while 3‐methyladenine reversed this effect by inhibiting mitophagy. Taken together, these results highlight a role for melatonin in protecting against TBI‐triggered immunopathology, which is accomplished by negatively regulating inflammation activation and IL‐1β secretion via the autophagy of damaged mitochondria.

Omega-3 fatty acids regulate NLRP3 inflammasome activation and prevent behavior deficits after traumatic brain injury

&NA; Omega‐3 fatty acids (&ohgr; − 3 FAs) attenuate inflammation and improve neurological outcome in response to traumatic brain injury (TBI), but the specific anti‐inflammatory mechanisms remain to be elucidated. Here we found that NLRP3 inflammasome and subsequent pro‐inflammatory cytokines were activated in human brains after TBI. Rats treated with &ohgr; − 3 FAs had significantly less TBI‐induced caspase‐1 cleavage and IL‐1&bgr; secretion than those with vehicle. G protein‐coupled receptor 40 (GPR40) was observed to be involved in this anti‐inflammation. GW1100, a GPR40 inhibitor, eliminated the anti‐inflammatory effect of &ohgr; − 3 FAs after TBI. &bgr;‐Arrestin‐2 (ARRB2), a downstream scaffold protein of GPR40, was activated to inhibit inflammation via directly binding with NLRP3 in the &ohgr; − 3 FAs treatment group. Interestingly, we also observed that &ohgr; − 3 FAs prevented NLRP3 mitochondrial localization, which was reversed by GW1100. Furthermore, &ohgr; − 3 FAs markedly ameliorated neuronal death and behavioral deficits after TBI, while GW1100 significantly suppressed this effect. Collectively, these data indicate that the GPR40‐mediated pathway is involved in the inhibitory effects of &ohgr; − 3 FAs on TBI‐induced inflammation and ARRB2 is activated to interact with NLRP3. HighlightsInflammation was readily observed in human brains after TBI in comparison to control.&ohgr;‐3 FAs ameliorate TBI‐induced inflammation and behavior deficits in part by inhibiting NLRP3 inflammasome activation.ARRB2 functions as a key regulator to directly bind with NLRP3 in the &ohgr;‐3 FA‐mediated inflammation.

Efficacy of progesterone for moderate to severe traumatic brain injury: a meta-analysis of randomized clinical trials

Progesterone has been shown to have neuroprotective effects in multiple animal models of brain injury, whereas the efficacy and safety in patients with traumatic brain injury (TBI) remains contentious. Here, a total of seven randomized controlled trials (RCTs) with 2492 participants were included to perform this meta-analysis. Compared with placebo, there was no significant decrease to be found in the rate of death or vegetative state for patients with acute TBI (RR = 0.88, 95%CI = 0.70, 1.09, p = 0.24). Furthermore, progesterone was not associated with good recovery in comparison with placebo (RR = 1.00, 95%CI = 0.88, 1.14, p = 0.95). Together, our study suggested that progesterone did not improve outcomes over placebo in the treatment of acute TBI.

Extracellular Signal-Regulated Kinase/Nuclear Factor-Erythroid2-like2/Heme Oxygenase-1 Pathway-Mediated Mitophagy Alleviates Traumatic Brain Injury-Induced Intestinal Mucosa Damage and Epithelial Barrier Dysfunction.

Gastrointestinal dysfunction is one of several physiologic complications in patients with traumatic brain injury (TBI). TBI can result in increased intestinal permeability resulting from apoptosis of intestinal epithelial cells, which contain a large number of mitochondria for persisting barrier function. Autophagy of damaged mitochondria (mitophagy) controls the quality of the mitochondria and regulates cellular homeostasis. However, the exact mechanism of mitophagy that underlies the pathological changes induced by TBI is unknown. Here, we report that mitophagy decreases the intestinal epithelial cell damage and apoptosis that are activated in a rat model of controlled cortical impact (CCI). CCI-induced mitophagy is associated with an increase in 3-nitrotyrosine and 4-hydroxynonenal, indicating that oxidative stress may increase in response to mitochondrial disturbance. CCI also results in the expression of the tight junction proteins zonula occludens-1 (ZO-1) and occludin, which may regulate the in vivo intestinal hyperpermeability induced by CCI. Additionally, CCI-induced mitophagy was shown to be mediated by the oxidative stress-related extracellular signal-regulated kinase (ERK)/nuclear factor-erythroid2-like2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway, which may serve to reduce the apoptosis induced by oxidative stress. These results suggest that CCI-induced mitophagy serves to diminish apoptosis-mediated intestinal epithelial cell damage and to improve intestinal permeability, via ERK/Nrf2/HO-1 signaling. These findings may be useful in the design of rational approaches for the prevention and treatment of symptoms associated with TBI.

CBX7 negatively regulates migration and invasion in glioma via Wnt/β-catenin pathway inactivation

CBX7, a member of the Polycomb-group proteins, plays a significant role in normal and cancerous tissues and has been defined as a tumor suppressor in thyroid, breast and pancreatic cancers. However, its function in glioma remains undefined. CBX7 expression is decreased in glioma, especially in higher grade cases, according to data in the CGGA, GSE16001 and TCGA databases. Further experimental evidence has shown that exogenous CBX7 overexpression induced apoptosis and inhibited cell proliferation, colony formation and migration of glioma cells. In this study, we show that the invasive ability of glioma cells was decreased following CBX7 overexpression and CBX7 overexpression was associated with Wnt/β-catenin pathway inhibition, which also decreased downstream expression of ZEB1, a core epithelial-to-mesenchymal transition factor. This reduction in Wnt signaling is controlled by DKK1, a specific Wnt/β-catenin inhibitor. CBX7 enhances DKK1 expression by binding the DKK1 promoter, as shown in Luciferase reporter assays. Our data confirm that CBX7 inhibits EMT and invasion in glioma, which is manifested by influencing the expression of MMP2, MMP9, E-cadherin, N-cadherin and Vimentin in LN229, T98G cells and primary glioma cells (PGC). Furthermore, as a tumor suppressor, CBX7 expression is pivotal to reduce tumor invasion and evaluate prognosis.

Genetic association between IL-27 rs153109 polymorphism and cancer risk in Chinese population: a meta-analysis.

Abstract IL-27 plays an important role in anti-cancer activity. The -964A/G polymorphism in IL-27 gene has been implicated in susceptibility to cancer, but the results were conflicting. The aim of this study was to assess the association between this polymorphism and cancer risk. Pubmed and Wanfang database were searched for all publications concerning IL-27 -964A/G polymorphism and cancer risk. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of association. Statistical analysis was performed using Stata 11.0 software. A total of eight case–control studies including 2044 cancer cases and 2197 controls were identified. Overall, significant association between IL-27 -964A/G polymorphism and cancer risk was observed (GG versus AA: OR = 1.26, 95% CI = 1.03–1.52; GG versus AG + AA: OR = 1.20, 95% CI = 1.00–1.44). In subgroup analysis based on cancer type, significant association was found in colorectal cancer (GG versus AA: OR = 1.55, 95% CI = 1.07–2.27; AG versus AA: OR = 1.31, 95% CI = 1.02–1.67). The current meta-analysis suggests that IL-27 -964A/G polymorphism might enhance cancer risk. However, large-scale and well-designed studies are still needed to confirm the result of our meta-analysis. The association of IL-27 polymorphism with colorectal cancer may provide insight for future therapies.

ERK1/2/mTOR/Stat3 pathway-mediated autophagy alleviates traumatic brain injury-induced acute lung injury

Acute lung injury (ALI) is one of several complications in patients with traumatic brain injury (TBI). Autophagy is a primary homeostatic process that promotes cell survival under stress. Accumulating evidence implicates autophagy in the pathogenesis of ALI under various conditions. However, the role of autophagy in TBI-induced ALI remains unknown. The aim of this study was to adjust autophagy with pharmacological agents to determine its functional significance in TBI-induced ALI. Rats were preconditioned with autophagy promoter rapamycin or inhibitor 3-methyladenine before they were challenged with TBI. Extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor U0126, mechanistic target of rapamycin (mTOR) inhibitor rapamycin, and signal transducer and activator of transcription 3 (Stat3) inhibitor S31-201 were used to test the role of ERK1/2/mTOR/Stat3 signaling pathway in regulating autophagy. Autophagy is activated in lung tissues after TBI. Enhancement of autophagy suppressed apoptosis, inflammation and oxidative stress in lung tissues, which were activated after TBI, whereas inhibition of autophagy aggravated these critical pathological changes. Autophagy also improved TBI-induced impairment in pulmonary barrier function, oxygenation function and static compliance. Furthermore, TBI-induced autophagy was mediated by ERK1/2/mTOR/Stat3 pathway, which may serve to reduce ALI and improve pulmonary barrier function, oxygenation function and static compliance. These findings are important for the prevention and treatment of TBI-induced ALI.

ERK/Nrf2/HO-1 Pathway-Mediated Mitophagy Alleviates Traumatic Brain Injury-Induced Intestinal Mucosa Damage and Epithelial Barrier Dysfunction.

Gastrointestinal dysfunction is one of several physiologic complications in patients with traumatic brain injury (TBI). TBI can result in increased intestinal permeability resulting from apoptosis of intestinal epithelial cells, which contain a large number of mitochondria for persisting barrier function. Autophagy of damaged mitochondria (mitophagy) controls the quality of the mitochondria and regulates cellular homeostasis. However, the exact mechanism of mitophagy that underlies the pathological changes induced by TBI is unknown. Here, we report that mitophagy decreases the intestinal epithelial cell damage and apoptosis that are activated in a rat model of controlled cortical impact (CCI). CCI-induced mitophagy is associated with an increase in 3-nitrotyrosine and 4-hydroxynonenal, indicating that oxidative stress may increase in response to mitochondrial disturbance. CCI also results in the expression of the tight junction proteins zonula occludens-1 (ZO-1) and occludin, which may regulate the in vivo intestinal hyperpermeability induced by CCI. Additionally, CCI-induced mitophagy was shown to be mediated by the oxidative stress-related extracellular signal-regulated kinase (ERK)/nuclear factor-erythroid2-like2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway, which may serve to reduce the apoptosis induced by oxidative stress. These results suggest that CCI-induced mitophagy serves to diminish apoptosis-mediated intestinal epithelial cell damage and to improve intestinal permeability, via ERK/Nrf2/HO-1 signaling. These findings may be useful in the design of rational approaches for the prevention and treatment of symptoms associated with TBI.

Sex-related differences in striatal dopaminergic system after traumatic brain injury.

Several studies have demonstrated alterations in the dopamine (DA) system after traumatic brain injury (TBI). Additionally, the existence of significant sex-related differences in the dopaminergic system has long been recognized. Accordingly, the purpose of the present study was to investigate whether TBI would differentially alter, in female and male mice, the expression and the function of the striatal vesicular monoamine transporter-2 (VMAT-2), an important DA transporter. After controlled cortical impact (CCI) injury, female mice showed significantly lower striatal DA concentrations and K(+)-evoked DA output. By contrast, no significant sex-related differences were observed in the mRNA and protein levels of striatal dopamine transporter (DAT) and VMAT-2 and the methamphetamine (MA)-evoked DA output. These results demonstrated clear sex-related differences in striatal VMAT-2 function in response to TBI and suggested that female mice may be more sensitive to the TBI-induced inhibition of the VMAT-2 function, as indicated by the greater degree of deficits observed when the VMAT-2 DA-storage function was inhibited by TBI. Moreover, the TBI-induced suppression of locomotion was more pronounced than female mice. Such findings highlight the need for sex-specific considerations when examining differences among brain injury conditions.

Lowered iPLA 2 γ activity causes increased mitochondrial lipid peroxidation and mitochondrial dysfunction in a rotenone-induced model of Parkinson's disease

ABSTRACT iPLA2&ggr;, calcium‐independent phospholipase A2&ggr;, discerningly hydrolyses glycerophospholipids to liberate free fatty acids. iPLA2&ggr;‐deficiency has been associated with abnormal mitochondrial function. More importantly, the iPLA2 family is causative proteins in mitochondrial neurodegenerative disorders such as parkinsonian disorders. However, the mechanisms by which iPLA2&ggr; affects Parkinsons disease (PD) remain unknown. Mitochondrion stress has a key part in rotenone‐induced dopaminergic neuronal degeneration. The present evaluation revealed that lowered iPLA2&ggr; function provokes the parkinsonian phenotype and leads to the reduction of dopamine and its metabolites, lowered survival, locomotor deficiencies, and organismal hypersensitivity to rotenone‐induced oxidative stress. In addition, lowered iPLA2&ggr; function escalated the amount of mitochondrial irregularities, including mitochondrial reactive oxygen species (ROS) regeneration, reduced ATP synthesis, reduced glutathione levels, and abnormal mitochondrial morphology. Further, lowered iPLA2&ggr; function was tightly linked with strengthened lipid peroxidation and mitochondrial membrane flaws following rotenone treatment, which can cause cytochrome c release and eventually apoptosis. These results confirmed the important role of iPLA2&ggr;, whereby decreasing iPLA2&ggr; activity aggravates mitochondrial degeneration to induce neurodegenerative disorders in a rotenone rat model of Parkinsons disease. These findings may be useful in the design of rational approaches for the prevention and treatment of PD‐associated symptoms. HighlightsDecreasing iPLA2&ggr; activity deteriorated the outcome of rats and worsened PDsymptoms after rotenone treatment.Decreasing iPLA2&ggr; activity increased oxidative stress, which was accompanied by mitochondria disorders and apoptosis.iPLA2&ggr; functions as a protective enzyme in the midbrain during oxidative stress.