NRF2 activation suppresses motor neuron ferroptosis induced by the SOD1G93A mutation and exerts neuroprotection in amyotrophic lateral sclerosis.

The progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS) is caused by a decline in motor neuron function, resulting in worsened motor impairments, malnutrition, respiratory failure and mortality, and there is a lack of effective clinical treatments. The exact mechanism of motor neuronal degeneration remains unclear. Previously, we reported that ferroptosis, which is characterized by the accumulation of lipid peroxide and glutathione depletion in an iron-dependent manner, contributed to motor neuronal death in ALS cell models with the hSOD1G93A (human Cu/Zn-superoxide dismutase) gene mutation. In this study, we further explored the role of ferroptosis in motor neurons and its regulation in mutant hSOD1G93A cell and mouse models. Our results showed that ferroptosis was activated in hSOD1G93A NSC-34 cells and mouse models, which was accompanied by decreased nuclear retention of nuclear factor erythroid 2-related factor 2 (NRF2) and downregulation of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) levels. Moreover, RTA-408, an NRF2 activator, inhibited ferroptosis in hSOD1G93A NSC-34 cells by upregulating the protein expression of SLC7A11 and GPX4. Moreover, hSOD1G93A mice treated with RTA-408 showed obvious improvements in body weight and motor function. Our study demonstrated that ferroptosis contributed to the toxicity of motor neurons and that activating NRF2 could alleviate neuronal degeneration in ALS with the hSOD1G93A mutation.

Construction of a novel microRNA-based signature for predicting the prognosis of glioma.

Background and purpose: Glioma is a frequent primary brain tumor. MicroRNAs (miRNA) have been shown to potentially play a crucial part in tumor development. Based on miRNAs and clinical factors, a model was constructed to predict the glioma prognosis. Methods: The miRNA expression profiles of glioma come from The Cancer Genome Atlas (TCGA, training group) and Chinese Glioma Genome Atlas (CGGA, validation group). Regression analyses of Cox and Lasso were applied to identity miRNAs associated with glioma prognosis in the TCGA database. The miRNAs were combined with clinical factors to construct individualized prognostic prediction models, whose performance was validated in the CGGA database. The role of miRNA in glioma development was investigated by in vitro experiments.Results: We identified five key miRNAs associated with glioma prognosis and constructed a prediction model. The area under ROC curve for predicting 3-year survival of glioma patients in the TCGA and CGGA groups was 0.844 and 0.770, respectively. The nomogram constructed using the miRNA risk scores and clinical factors showed high accuracy of prediction in the TCGA group (C-index of 0.820) and the CGGA group (C-index of 0.722). The miR-196b-5p altered the migration, proliferation, invasion, and apoptosis of glioma cells by regulating target genes, according to in vitro experiments.Conclusions: A miRNA-based individualized prognostic prediction model was constructed for glioma and miR-196b-5p was identified as a potential biomarker of glioma development.

Male mice exposed to chronic intermittent ethanol exposure exhibit significant upregulation or downregulation of circular RNAs.

B a ckground: Circular RNAs (circRNAs) have been crucially implicated in various diseases, however, their involvement in chronic intermittent ethanol (CIE) exposure remains unclear.O bjective: The present study was conducted to evaluate the circular RNA expression alteration in brain samples and to identify the molecular mechanisms underlying chronic intermittent ethanol exposure.M ethods: Male C57BL/6J mice (10 for each group) were given 4 weeks of chronic intermittent ethanol exposure. Whole brain samples were collected for high-throughput sequencing and circRNA bioinformatic analysis. Real-time quantitative PCR (RI-qPCR) and agarose electrophoresis were used to validate the differentially expressed circRNAs. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) analysis were performed. A p level < 0.05 was considered statistically significant.R esults: Compared with the control group and baseline values, the CIE group showed a significant increase in ethanol intake. High-throughput sequencing revealed 399 significantly different circRNAs in CIE mice, including 150 up-regulated circRNAs and 249 down-regulated circRNAs. GO analysis showed that the most significantly enriched term for biological process, cellular component, and molecular function were GO:0050885, GO:0016020 and GO:0005515, respectively. The most enriched pathways in KEGG analysis were GABAergic synapse (mmu04727), followed by retrograde endocannabinoid (eCB) signaling (mmu04723) and morphine addiction (mmu05032). Among the circRNAs, RT-qPCR confirmed 14 upregulated and 13 downregulated circRNAs in the brain tissues with 9 upregulated and 10 downregulated circRNAs being observed in blood samples.C onclusions: Our study suggests that chronic ethanol exposure upregulates or downregulates circRNAs in the brain, which, in turn, could alter neurotransmitter release and signal transduction.

Circular RNA expression alteration identifies a novel circulating biomarker in serum exosomal for detection of alcohol dependence.

Alcohol dependence (AD) is one of the most common and detrimental neuropsychological disorders. Recently, more and more studies have focused on circular RNA as markers for central nervous system (CNS) diseases. The present study was conducted to evaluate the circular RNA expression alteration in serum exosomal and to identify a novel circulating biomarker for the detection of AD. We first isolated exosomes from serum and then investigated the circRNA expression alterations by high throughput whole transcriptome sequencing. The data were then analyzed using bioinformatics methods. Moreover, we verified the circRNA-seq by qRT-PCR. Furthermore, we analyzed the correlations between the levels of hsa_circ_0004771 and both Severity of Alcohol Dependence Questionnaire (SADQ) and Alcohol Dependence Scale (ADS). The diagnostic value of hsa_circ_0004771 in AD patients was evaluated by receiver operating characteristic (ROC). In this study, 254 differentially expressed circRNAs were identified, with 149 upregulated and 105 downregulated. GO analysis showed that these differentially expressed circRNAs from exosomes might be associated with the regulation of neuron projection and axon regeneration. KEGG analysis revealed that T cell receptor signaling and antigen processing and presentation pathway had a regulating effect on upstream levels. We found that hsa_circ_0004771 was related to the severity of AD. The AUC for the diagnostic value of hsa_circ_0004771 in AD patients was 0.874. These findings indicated that circRNA in serum exosomes provide novel targets for further research on molecular mechanisms of AD. Among these, hsa_circ_0004771 may be a sensitive biomarker that was related to the severity of AD.

Cerebral Hemorrhage and Alcohol Exposure: A Review.

AIMS: To investigate the dose-response relationships between alcohol and intracerebral hemorrhage (ICH), the impact of alcohol on the outcome of ICH and possible mechanisms underlying hypertensive ICH (HICH) caused by heavy drinking. METHODS: Literature search from 1985 to August 2019 in the PubMed database. RESULTS: The relationship between low-middle alcohol consumption and ICH remains controversial for various reasons, whereas chronic heavy drinking increases the incidence of ICH and exerts worse outcome. More attention is needed to clarify the characteristics of chronic alcohol intake and binge drinking. Chronic alcohol abuse tends to elevates blood pressure, resulting in increased occurrence of HICH and exaggerated HICH-contributed brain injury. CONCLUSION: It is important to develop strategies to promote reasonable intake categories, prevent alcoholism and thus reduce the risk of ICH.

Effect of alteplase versus aspirin plus clopidogrel in acute minor stroke.

Background and purpose: The optimal treatment for acute ischemic stroke with mild neurologic deficits is unclear. We aimed to compare the efficacy and safety of alteplase versus dual-antiplatelet therapy in acute minor stroke.Methods: We performed a retrospective cohort study of patients with minor ischemic stroke and National Institutes of Health Stroke Scale scores ≤5 presenting within 24 h from last seen normal. Patients were divided into intravenous alteplase or dual-antiplatelet therapy group. The primary outcome was a modified Rankin Scale (mRS) score of 0 or 1 at 90 days. Secondary outcomes included mRS score at 7 days, and composite outcome of vascular events within 90 days. The safety outcome was any intracranial hemorrhage (ICH) according to the ECASS II criteria. Clinical outcomes were compared using a multivariable logistic regression after adjusting for confounding factors. We then performed the propensity score matching as a sensitivity analysis.Results: Two hundred twenty-eight patients met the eligibility criteria were included for analysis between January 2015 and September 2018. In the aspirin-clopidogrel group, 109 patients (91.6%) achieved a favorable functional outcome at 3-month versus 85(78.0%) in the alteplase group (OR 4.463, 95%CI 1.708-11.662, p = .002). The difference of the composite outcome of vascular events were not statistical significance between the two groups (p > .05). Asymptomatic ICH occurred in 0.8% patients who received aspirin-clopidogrel, as compared with 3.7% patients in alteplase group (p = .030).Conclusions: Patients treated with dual-antiplatelet therapy with acute minor ischemic stroke had greater functional outcome at 3 months compared with patients who received alteplase therapy.Classification of evidence: This study provides Class IV evidence that dual-antiplatelet therapy is superior to alteplase for achieving a better functional outcome and does not increase the risk of hemorrhage in acute minor ischemic stroke.

Autophagy alleviates ethanol-induced memory impairment in association with anti-apoptotic and anti-inflammatory pathways.

Chronic excessive drinking leads to a wide spectrum of neurological disorders, including cognitive deficits, such as learning and memory impairment. However, the neurobiological mechanisms underlying these deleterious changes are still poorly understood. We conducted a comprehensive study to investigate the role and mechanism of autophagy in alcohol-induced memory impairment. To establish an ethanol-induced memory impairment mouse model, we allowed C57BL/6J mice intermittent access to 20% ethanol (four-bottle choice) to escalate ethanol drinking levels. Memory impairment was confirmed by a Morris water maze test. We found that mice exposed to EtOH (ethanol) and EtOH combined with the autophagy inhibitor 3-methyladenine (3-MA) showed high alcohol intake and blood alcohol concentration. We confirmed that the EtOH group exhibited notable memory impairment. Inhibition of autophagy by 3-MA worsened ethanol-induced memory impairment. Ethanol induced autophagy in the hippocampus of mice as indicated by western blotting, electron microscopy, RT-qPCR, and fluorescence confocal microscopy. We determined that the mTOR/BECN1 (S14) pathway is involved in ethanol-induced autophagy in vivo. Further, ethanol-induced autophagy suppressed the NLRP3 inflammatory and apoptosis pathways in the hippocampus in mice and in vitro. These findings suggest that autophagy activation in hippocampal cells alleviates ethanol-induced memory impairment in association with anti-apoptotic and anti-inflammatory pathways.

Hyponatremia is a potential predictor of progression in radiation-induced brain necrosis: a retrospective study.

BACKGROUND: To investigate the prognostic value of hyponatremia, defined as serum sodium level < 135 mEq/L, in radiation-induced brain necrosis (RN) patients. METHODS: We performed a retrospective analysis of the RN patients (The patients included in our study had a history of primary cancers including nasopharyngeal carcinoma/glioma/oral cancer and received radiotherapy previously and then were diagnosed with RN) treated in Sun yat-sen Memorial Hospital from January 2013 to August 2015. Patients without cranial magnetic resonance imaging (MRI) scan and serum sodium data were excluded. Progression was identified when the increase of edema area ≥ 25% on the MRI taken in six months comparing with those taken at the baseline. Factors that might associate with prognosis of RN were collected. Multivariable logistic regression analyses were used to identify potential predictors. RESULTS: We total included 135 patients, 32 (23.7%) of them with hyponatremia and 36 (26.7%) with RN progression. Percentage of progression was roughly three fold in hyponatremia patients compared with nonhyponatremia patients (53.1% versus 18.4%), translating into a 5-fold increased odds ratio (P <  0.001). Multivariable analyses identified hyponatremia as a potential predictor of progression (OR, 4.82; 95% CI [1.94-11.94]; P = 0.001). CONCLUSIONS: Hyponatremia was identified as a potential predictor for the progression of patients with RN. Hyponatremia management in patients with RN should be paid much more concern in clinical practice.

Intravenous Thrombolysis for Stroke Patients with G6PD Deficiency.

BACKGROUND AND PURPOSE: No reports regarding the safety of thrombolysis in acute stroke patients with a G6PD deficiency have been published to date. Here we aimed to evaluate the safety of intravenous thrombolysis for G6PD-deficient stroke patients. METHODS: We enrolled each patient with acute ischemic stroke who arrived in our stroke unit within the therapeutic window and received systemic thrombolysis using recombinant tissue plasminogen activator (rt-PA), between January 2015 and March 2016. The primary clinical outcome was measured 3 months after treatment, and defined as a "good" outcome by a modified Rankin Scale (mRS) score of 0-2. Major safety outcomes were incidences of intracranial hemorrhage (ICH) or mortality at 90 days. RESULTS: A total of 96 individuals were analyzed, of which 20 patients were G6PD deficient. The rates of ICH after rt-PA treatment were 12% the in G6PD-deficient group versus 15% in G6PD non-deficient group, and the incidences of symptomatic intracranial hemorrhage were also similar between the G6PD-deficient and non-deficient cohorts. No hemolysis crisis occurred, and no significant difference in mortality rate was found between the 2 groups. The overall rate of a good outcome at 3 months after stroke in the whole cohort was 60%, whereas 50% of patients achieved an excellent outcome (mRS 0-1) in the G6PD-deficient cohort, and 42% in the G6PD non-deficient group. CONCLUSIONS: Thrombolytic therapy for patients with G6PD deficiency seems to pose a similar risk of ICH and clinical outcome to those with G6PD non-deficiency.

Statin treatment may lower the risk of postradiation epilepsy in patients with nasopharyngeal carcinoma.

OBJECTIVE: This study aimed to clarify the effect of statins on preventing the risk of postradiation epilepsy. METHODS: We performed a retrospective analysis of neurological nasopharyngeal carcinoma patients with a history of radiotherapy. Patients with a history of epilepsy before radiation and those who received prophylactically antiepileptic treatment were excluded. The demographic and clinical data of these patients were collected through chart review. We used Kaplan-Meier analysis (log-rank test) to examine the effect of statins on epilepsy-free survival. Cox regression analysis was utilized to identify independent predictive variables. RESULTS: Our study included 532 patients (405 males and 127 females) with a mean follow-up of 28.1 months. During follow-up, 471 (88.5%) patients developed radiation-induced brain necrosis (RN). Within a mean latency of 24.1 months, 88 (16.5%) patients experienced epilepsy, of whom 27 (27 of 88, 30.7%) patients suffered from epilepsy before the diagnosis of RN. Thirty-six (36 of 88, 40.9%) cases of epilepsy occurred after RN onset, and in 22 cases (22 of 88, 25.0%) epilepsy was the first presentation of RN. Three patients suffered from epilepsy but did not have RN. Eighty-eight patients in our cohort were treated with statins because of hyperlipidemia or prevention of cardiocerebrovascular diseases, of whom six (6.8%) developed epilepsy, whereas in those without statin, the epileptic rate was 18.5%. Log-rank test found that there was a significant difference in epilepsy-free survival between patients who used statins and those who did not (p = 0.016). After adjusting for confounding variables, multivariate Cox regression analysis revealed that statin use could still significantly reduce the risk of epilepsy after radiation (hazard ratio = 0.36, 95% confidence interval = 0.15-0.82, p = 0.015). However, for the patients who already suffered from RN, statin treatment did not lower the risk of post-RN epilepsy. SIGNIFICANCE: Early statin use may reduce the risk of postradiotherapy epilepsy in patients with nasopharyngeal carcinoma.

Neuroprotective effect of Dl-3-n-butylphthalide on patients with radiation-induced brain injury: a clinical retrospective cohort study.

PURPOSE: To evaluate the neuroprotective effects of Dl-3-n-butylphthalide (NBP) on patients with radiation-induced brain injury, a hospital-based, clinical retrospective cohort study was conducted. PATIENTS AND METHODS: Data were collected on patients diagnosed with radiation-induced brain injury from January 2009 to January 2015 in Department of Neurology, Sun Yat-Sen Memorial Hospital. All patients enrolled have received cranial radiotherapy and were diagnosed with radiation-induced brain injury. Patients fulfilling certain eligibility criteria were recruited for analysis. The clinical therapeutic effects were observed and evaluated by LENT/SOMA scores before and one month after treatment in these two groups, respectively. RESULTS: The therapeutic effects of headache (total efficiency 75.76%), eurologic deficit (total efficiency 81.58%), cognitive functions (total efficiency 77.78%) and MRI results (total efficiency 74.29%) were better in the experimental group than those in the control group (p < 0.05). Nevertheless, there was no significant difference in mood and personality changes between these two groups. CONCLUSIONS: Administration of Dl-3-n-butylphthalide, in adjunct to corticosteroid therapy, might provide a better outcome in patients with radiation-induced brain injury.

The efficacy of transcranial magnetic stimulation on migraine: a meta-analysis of randomized controlled trails.

OBJECTIVES: As a non-invasive therapy, whether transcranial magnetic stimulation (TMS) is effective on migraine. This article was aimed to assess the efficacy of TMS on migraine based on randomized controlled trails (RCTs). METHODS: We searched PubMed, Embase and Cochrane Library electronic databases for published studies which compared TMS group with sham group, conducted a meta-analysis of all RCTs. RESULTS: Five studies, consisting of 313 migraine patients, were identified. Single-pulse transcranial magnetic stimulation is effective for the acute treatment of migraine with aura after the first attack (p = 0.02). And, the efficacy of TMS on chronic migraine was not significant (OR 2.93; 95% CI 0.71-12.15; p = 0.14). CONCLUSIONS: TMS is effective for migraine based on the studies included in the article.

Influence of insurance status on survival of adults with glioblastoma multiforme: A population-based study.

BACKGROUND: To the authors' knowledge, the impact of insurance status on the survival time of patients with glioblastoma multiforme (GBM) has not been fully understood. The objective of the current study was to clarify the association between insurance status and survival of patients with GBM by analyzing population-based data. METHODS: The authors performed a cohort study using data from the Surveillance, Epidemiology, and End Results program. They included adult patients (aged ≥18 years) with GBM as their primary diagnosis from the years 2007 to 2012. Patients without information regarding insurance status were excluded. A survival analysis between insurance status and GBM-related death was performed using an accelerated failure time model. Demographic and clinical variables were included to adjust for confounding effects. RESULTS: Among the 13,665 adult patients in the study cohort, 558 (4.1%) were uninsured, 1516 (11.1%) had Medicaid coverage, and 11,591 (84.8%) had non-Medicaid insurance. Compared with patients who were uninsured, insured patients were more likely to be older, female, white, married, and with a smaller tumor size at diagnosis. Accelerated failure time analysis demonstrated that older age (hazard ratio [HR], 1.04; P<.001), male sex (HR, 1.08; P<.001), large tumor size at the time of diagnosis (HR, 1.26; P<.001), uninsured status (HR, 1.14; P =.018), and Medicaid insurance (HR, 1.10; P =.006) were independent risk factors for shorter survival among patients with GBM, whereas radiotherapy (HR, 0.40; P<.001) and married status (HR, 0.86; P<.001) indicated a better outcome. The authors discovered an overall yearly progressive improvement in survival in patients with non-Medicaid insurance who were diagnosed from 2007 through 2011 (P =.015), but not in uninsured or Medicaid-insured patients. CONCLUSIONS: Variations existed in insurance status within the GBM population. Uninsured status and Medicaid insurance suggested shorter survival compared with non-Medicaid insurance among a population of patients with GBM. Cancer 2016;122:3157-65. © 2016 American Cancer Society.

Sertraline plus deanxit to treat patients with depression and anxiety in chronic somatic diseases: a randomized controlled trial.

BACKGROUND: Patients in chronic somatic diseases are often accompanied with depression and anxiety, remission of which may be observed in the third or fourth week after applying common antidepressant medications. We investigate the efficacy and safety of sertraline plus deanxit on patients with depression and anxiety in chronic somatic diseases. METHODS: 75 Patients who met the criteria were randomly assigned to deanxit group or placebo group: sertraline (75 mg/day) plus deanxit (one piece/day) (N = 38), or sertraline (75 mg/day) plus placebo (one piece/day) (N = 37) for 2 weeks, both groups received sertraline (75 mg/day) in the following 2 weeks. Changes from baseline to day 4, day 8, day 15, and day 29 in Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) total scores were the efficacy measures. Adverse events were monitored and registered systematically during the trial. RESULTS: Response rates for HAM-D scores in deanxit group and placebo group were significantly different on day 8(55.26% ± 2.56% VS 24.32% ± 2.19%, p = 0.006) and day 15(78.95% ± 3.89% VS 40.54% ± 4.18%, p = 0.001), while no statistical differences were observed on day 4 and day 29. Respectively, response rates for HAM-A scores on day 4 (34.21% ± 2.21% VS 8.11% ± 1.37%, p = 0.006), day 8 (57.89% ± 3.56% VS 18.92% ± 2.68%, p = 0.001) and day 15 (78.95% ± 4.37% VS 43.24% ± 4.68%, p = 0.002), favoring the deanxit group. However, HAM-A scores were not remarkably different at the end point. The overall safety profile of both groups was favorable with no distinct differences. CONCLUSIONS: The efficacy was exhibited in the deanxit group, with evidence for similar safety. The rapid onset of sertraline plus short-term deanxit indicated that it might be an inspiring strategy to manage depression and anxiety within the first two weeks in chronic somatic diseases.

Long-term toxicity study of rAd5-hTERTC27 in SD rats and Cynomolgus monkeys by intravenous injection.

rAd5-hTERTC27, a replication-defective adenovirus vector carrying hTERTC27, has been proposed for possible use against hepatocellular carcinoma (HCC). In this study, we investigated the long-term toxicity of rAd5-hTERTC27 in SD rats and Cynomolgus monkeys. rAd5-hTERTC27 was administered intravenously once a week for 13 weeks followed by a one-month recovery period. As of 4 months, all animals displayed overall good health. Anti-adenoviral antibodies emerged in a dose-independent manner. The levels of complement components, C3 and C4, in the rAd5-hTERTC27 middle-dose and high-dose groups and C4 in the rAd5-EGFP group increased significantly after the 2nd treatment in monkeys. Slight-mild pathological changes of the liver occurred only in the rAd5-hTERTC27 high-dose group (2/16) in rats and not in any other group in either rats or monkeys. With the increase of the dose, the incidence of lymphocyte depletion in the spleen of rats and reactive hyperplasia of the splenic corpuscle in monkeys increased. However, the changes in the liver and spleen were reversible. Given the above data, intravenous administration of rAd5-hTERTC27 (up to 4×10(10)VP/kg in rats and 0.9×10(10)VP/kg in monkeys) appears to be well-tolerated, providing support for its potentially safe use in clinical trials for the treatment of HCC.

Effect of edaravone on radiation-induced brain necrosis in patients with nasopharyngeal carcinoma after radiotherapy: a randomized controlled trial.

Excessive generation of free radicals plays a critical role in the pathogenesis of radiation-induced brain injury. This study was designed to evaluate the protective effect of edaravone, a free radical scavenger, on radiation-induced brain necrosis in patients with nasopharyngeal carcinoma. Eligible patients were randomized 1:1 to the control group and the edaravone group (intravenous 30 mg twice per day for 2 weeks). Both groups received intravenous conventional steroid therapy and were monitored by brain MRI and LENT/SOMA scales prior to the entry of the trial and at 3-months after completing the trial. The primary end point was a 3-month response rate of the proportional changes determined by MRI. The trial is registered at Clinicaltrials.gov Identifier: NCT01865201. Between 2009 and 2012, we enrolled 154 patients. Of whom 137 were eligible for analysis. The volumes of necrosis estimated on T(2)-weighted image showed that 55.6 % edaravone-treated patients (40 out of 72) showed edema decreases ≥25 %, which was significantly higher than that in the control group (35.4 %, 23 out of 65, p = 0.025). Forty-four patients treated with edaravone (61.1 %) reported improvement in neurologic symptoms and signs evaluated by LENT/SOMA scales, while the rate was 38.5 % in the control group (p = 0.006). MRI of the edaravone group showed a significant decrease in area of T(1)-weighted contrast enhancement (1.67 ± 4.69 cm(2), p = 0.004) and the T(2)-weighted edema (5.08 ± 10.32 cm(2), p = 0.000). Moreover, compared with those in control group, patients with edaravone exhibited significantly better radiological improvement measured by T(2)-weighted image (p = 0.042). Administration of edaravone, in adjunct to steroid regimen, might provide a better outcome in patients with radiation-induced brain necrosis.

The NRF2 activator RTA-408 ameliorates chronic alcohol exposure-induced cognitive impairment and NLRP3 inflammasome activation by modulating impaired mitophagy initiation.

BACKGROUND: Chronic alcohol exposure induces cognitive impairment and NLRP3 inflammasome activation in the mPFC (medial prefrontal cortex). Mitophagy plays a crucial role in neuroinflammation, and dysregulated mitophagy is associated with behavioral deficits. However, the potential relationships among mitophagy, inflammation, and cognitive impairment in the context of alcohol exposure have not yet been studied. NRF2 promotes the process of mitophagy, while alcohol inhibits NRF2 expression. Whether NRF2 activation can ameliorate defective mitophagy and neuroinflammation in the presence of alcohol remains unknown. METHODS: BV2 cells and primary microglia were treated with alcohol. C57BL/6J mice were repeatedly administered alcohol intragastrically. BNIP3-siRNA, PINK1-siRNA, CCCP and bafilomycin A1 were used to regulate mitophagy in BV2 cells. RTA-408 acted as an NRF2 activator. Mitochondrial dysfunction, mitophagy and NLRP3 inflammasome activation were assayed. Behavioral tests were used to assess cognition. RESULTS: Chronic alcohol exposure impaired the initiation of both receptor-mediated mitophagy and PINK1-mediated mitophagy in the mPFC and in vitro microglial cells. Silencing BNIP3 or PINK1 induced mitochondrial dysfunction and aggravated alcohol-induced NLRP3 inflammasome activation in BV2 cells. In addition, alcohol exposure inhibited the NRF2 expression both in vivo and in vitro. NRF2 activation by RTA-408 ameliorated NLRP3 inflammasome activation and mitophagy downregulation in microglia, ultimately improving cognitive impairment in the presence of alcohol. CONCLUSION: Chronic alcohol exposure-induced impaired mitophagy initiation contributed to NLRP3 inflammasome activation and cognitive deficits, which could be alleviated by NRF2 activation via RTA-408.

Activation of STING signaling aggravates chronic alcohol exposure-induced cognitive impairment by increasing neuroinflammation and mitochondrial apoptosis.

AIMS: Chronic alcohol exposure leads to persistent neurological disorders, which are mainly attributed to neuroinflammation and apoptosis. Stimulator of IFN genes (STING) is essential in the cytosolic DNA sensing pathway and is involved in inflammation and cellular death processes. This study was to examine the expression pattern and biological functions of STING signaling in alcohol use disorder (AUD). METHODS: Cell-free DNA was extracted from human and mouse plasma. C57BL/6J mice were given alcohol by gavage for 28 days, and behavior tests were used to determine their mood and cognition. Cultured cells were treated with ethanol for 24 hours. The STING agonist DMXAA, STING inhibitor C-176, and STING-siRNA were used to intervene the STING. qPCR, western blot, and immunofluorescence staining were used to assess STING signaling, inflammation, and apoptosis. RESULTS: Circulating cell-free mitochondrial DNA (mtDNA) was increased in individuals with AUD and mice chronically exposed to alcohol. Upregulation of STING signaling under alcohol exposure led to inflammatory responses in BV2 cells and mitochondrial apoptosis in PC12 cells. DMXAA exacerbated alcohol-induced cognitive impairment and increased the activation of microglia, neuroinflammation, and apoptosis in the medial prefrontal cortex (mPFC), while C-176 exerted neuroprotection. CONCLUSION: Activation of STING signaling played an essential role in alcohol-induced inflammation and mitochondrial apoptosis in the mPFC. This study identifies STING as a promising therapeutic target for AUD.

Radiation-induced chronic pain plagues head and neck cancer survivors: A cross-sectional analysis from the Cohort in Radiotherapy-related Nervous System Complications.

The epidemiology and prognosis of radiation-induced chronic pain, especially chronic neuropathic pain (CNP), are the understudied domain among head and neck cancer (HNC) survivors after radiotherapy (RT). This study aimed to estimate the prevalence of such chronic pain, and explore their correlations with mental health, sleep disorders, cognitive function, and quality of life (QOL) within these patients. This research encompassed HNC survivors post-RT. The determination of radiation-induced chronic pain and CNP adhered to the guidelines outlined by the International Association for the Study of Pain (IASP). Multivariable regression analyses were employed to explore the relationship between pain and anxiety, depression, sleep disturbances, cognitive function, and QOL. A total of 1071 HNC survivors post-RT were included in this study. The prevalence of radiation-induced chronic pain was 67.1%, and the prevalence of RT-associated CNP was 38.3%,. Compared with those reporting no pain, patients with radiation-induced chronic pain had a significantly increased risk of anxiety, depression and sleep disorders (all p < 0.001). And there was a significantly negative association between chronic pain and QOL across physiological (p < 0.001), psychological (p < 0.001), social relationships (p = 0.001) and environmental (p = 0.009) domains. Compared with non-CNP, patients with RT-related CNP had a higher risk of anxiety (p= 0.027) and sleep disorders (p= 0.013). The significantly negative associations were found between CNP and the physiological (p = 0.001), psychological (p = 0.012) and social score (p = 0.035) in WHOQOL-BREF. This study underscores the substantial prevalence of chronic pain, particularly CNP, and their potential impact on the mental health, sleep, and QOL among HNC survivors post-RT. PERSPECTIVE: This study highlights the high prevalence of radiation-induced chronic pain and CNP, and their potential impacts on anxiety, depression, sleep and QOL among the HNC survivors. Clinically, these findings have important implications for improving the care and outcomes of HNC survivors.

Efficacy and safety of short-term edaravone or nerve growth factor add-on therapy for alcohol-related brain damage: A multi-centre randomised control trial.

AIMS: To measure the therapeutic effect of an anti-oxidant, edaravone (EDV), or neurotrophic treatment with nerve growth factor (NGF) as an add-on treatment for alcohol-related brain damage (ARBD). DESIGN: Multi-centre, randomised, single-blinded, comparative clinical trial. SETTING AND PARTICIPANTS: One hundred and twenty-two inpatients recruited from seven hospitals in different regions of China, all diagnosed with ARBD and aged 18 to 65 years old; among them, only two were female. INTERVENTION AND COMPARATOR: Patients were randomly assigned to receive one of three treatments for 2 weeks: 40 patients, treatment as usual (TAU: a combination of intramuscular injections of thiamine, intravenous infusions of other B vitamins with vitamin C and oral medication with vitamin E per day); 40, EDV add-on treatment to TAU (intravenous infusion with 30 mg of EDV twice per day); and 42, NGF add-on treatment to TAU (intramuscular injection of 20 µg of NGF per day). The patients underwent follow-up for 24 weeks. MEASUREMENTS: The primary outcome was the composite score of executive cognitive function in the 2nd week after treatment, which was measured as the mean of the Z scores of the assessments, including the digit symbol substitute test (DSST), digit span memory test-forward (DST-F), digit span memory test-reverse (DST-R) and space span memory test (SSMT). The secondary outcomes were the composite scores at later follow-ups, the score for each component of cognitive function, global cognitive function measured by the Montreal Cognitive Assessment (MoCA), craving for alcohol and the safety of the therapies. FINDINGS: EDV add-on treatment improved the composite score of executive cognitive function better than TAU in the 2nd week (adjusted mean difference: 0.24, 95% confidence interval 0.06 to 0.41; P = 0.008), but NGF add-on treatment did not (adjusted mean difference: 0.07, 95% confidence interval -0.09 to 0.24; P = 0.502). During the follow-up to 24 weeks, EDV add-on treatment improved the composite score of executive cognitive function and DST-R score better than TAU (both P < 0.01). Craving for alcohol was relieved in all three groups. No severe adverse events were observed. CONCLUSION: The short-term addition of edaravone to supplementary therapy treatment for alcohol-related brain damage (ARBD) improved executive cognitive function in patients with ARBD.