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.

CB2R activation ameliorates late adolescent chronic alcohol exposure-induced anxiety-like behaviors during withdrawal by preventing morphological changes and suppressing NLRP3 inflammasome activation in prefrontal cortex microglia in mice.

BACKGROUND: Chronic alcohol exposure (CAE) during late adolescence increases the risk of anxiety development. Alcohol-induced prefrontal cortex (PFC) microglial activation, characterized by morphological changes and increased associations with neurons, plays a critical role in the pathogenesis of anxiety. Alcohol exposure increases NLRP3 inflammasome expression, increasing cytokine secretion by activated microglia. Cannabinoid type 2 receptor (CB2R), an essential receptor of the endocannabinoid system, regulates microglial activation and neuroinflammatory reactions. We aimed to investigate the role of CB2R activation in ameliorating late adolescent CAE-induced anxiety-like behaviors and microglial activation in C57BL/6J mice. METHODS: Six-week-old C57BL/6J mice were acclimated for 7 days and then were administered alcohol by gavage (4 g/kg, 25 % w/v) for 28 days. The mice were intraperitoneally injected with the specific CB2R agonist AM1241 1 h before alcohol treatment. Anxiety-like behaviors during withdrawal were assessed by open field test and elevated plus maze test 24 h after the last alcohol administration. Microglial activation, microglia-neuron interactions, and CB2R and NLRP3 inflammasome-related molecule expression in the PFC were measured using immunofluorescence, immunohistochemical, qPCR, and Western blotting assays. Microglial morphology was evaluated by Sholl analysis and the cell body-to-total cell size index. Additionally, N9 microglia were activated by LPS in vitro, and the effects of AM1241 on NLRP3 and N9 microglial activation were investigated. RESULTS: After CAE, mice exhibited severe anxiety-like behaviors during withdrawal. CAE induced obvious microglia-neuron associations, and increased expression of microglial activation markers, CB2R, and NLRP3 inflammasome-related molecules in the PFC. Microglia also showed marked filament retraction and reduction and cell body enlargement after CAE. AM1241 treatment ameliorated anxiety-like behaviors in CAE model mice, and it prevented microglial morphological changes, reduced microglial activation marker expression, and suppressed the microglial NLRP3 inflammasome activation and proinflammatory cytokine secretion induced by CAE. AM1241 suppressed the LPS-induced increase in NLRP3 inflammasome-related molecules, IL-1ß release, and M1 phenotype markers (iNOS and CD86) in N9 cell, which was reversed by CB2R antagonist treatment. CONCLUSIONS: CAE caused anxiety-like behaviors in late adolescent mice at least partly by inducing microglial activation and increasing microglia-neuron associations in the PFC. CB2R activation ameliorated these effects by preventing morphological changes and suppressing NLRP3 inflammasome activation in PFC microglia.

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.

Morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by NLRX1.

BACKGROUND: Chronic morphine exposure induces immunosuppression in the peripheral and central nervous system, resulting in susceptibility of patients to invading pathogens. Mitophagy is a crucial regulator of inflammation, and dysregulated mitophagy may cause immunosuppression, but whether mitophagy is linked with morphine-induced immunosuppression in the brain remains unknown. NLRX1 is the only mitochondrially localized NOD family receptor protein which serves as a critical regulator in immunity and mitophagy activation, but it remains an enigma how NLRX1 functions in the crosstalk between microglial inflammatory defense and mitophagy in the presence of morphine. METHODS: Primary microglia and astrocytes, BV2 and MA cell lines were utilized. Mice were stimulated with repeated morphine treatment to mimic chronic morphine exposure, and activation of mitophagy, lysosomal functions, and inflammation were assayed in specific brain regions and immune organs with or without NLRX1-silencing. RESULTS: Morphine induced microglial mitophagy in a LC3 (microtubule-associated proteins light chain 3)-dependent manner, which was mediated by NLRX1. Contrastingly, morphine impaired lysosomal functions, including generation, acidification and mitophagosome-lysosome fusion, thus leading to insufficient mitophagy activation in microglia. NLRX1-silencing inhibited mitophagy activity and rescued lysosomal functions including generation and acidification in microglia. The NLRX1-mediated incomplete mitophagy in microglial cells contributed to immunosuppression and vulnerability towards pathogenic challenge after morphine treatment. In vivo, NLRX1-mediated microglial mitophagy activation by morphine was mainly located in the murine brain cortex, striatum, and cerebellum, where NLRX1 functioned as a negative immune regulator and facilitated septic shock. Collectively, microglial immune responses to septic shock were amenable to NLRX1 silencing in the brain with morphine treatment. CONCLUSION: Morphine activated insufficient mitophagy in microglia which was regulated by NLRX1, ultimately leading to host immunosuppression and susceptible conditions in the brain.

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.

Toxicity of Ag+ on microstructure, biochemical activities and genic material of Trifolium pratense L. seedlings with special reference to phytoremediation.

The objective of this research was to evaluate Ag+ toxicity in Trifolium pratense L. seedlings subjected to increasing doses of Ag+ by determining photosynthetic pigment and malondialdehyde (MDA) contents, microstructure and hereditary substance alterations, changes in activities of antioxidase-superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) as well as the content of total Ag absorbed in vivo with evaluation of root growth. Doses of approximately 80 mg L-1 Ag+ severely affected photosynthetic efficiency in Trifolium pratense L. seedlings promoted by damages in photosynthetic apparatus evidenced by downward trend in photosynthetic pigment contents and obvious chlorosis. Alterations in enzymatic activity, lipid peroxidation, genic material damage and the presence of Ag+in vivo had impacted on photosynthetic machinery as well. A hormesis effect was observed at 60 mg L-1 Ag+ for the photosynthetic pigments and antioxidase for Trifolium pratense L. seedlings. Tissue changes (i.e., roots, stems and leaves) observed in fluorescence microscope with obvious chlorosis, roots blackening and formation of agglomerated black particles, were related to the lesion promoted by excessive ROS in vivo. Asynchronous change of antioxidase activity corresponded to the alteration in the MDA content, indicating the synchronization in the elimination of ROS. The changes occurred in RAPD profiles of treated samples following Ag+ toxicity containing loss of normal bands, appearance of new bands and variation in band intensity compared to the normal plants with a dose-dependent effect. On average, the roots of Trifolium pratense L. immobilized 92.20% of the total Ag absorbed as a metal exclusion response. Root growth was significantly sensitive to Ag+ stress with obvious hormesis, which corresponded to the changes in Ag uptake, demonstrating the functional alterations in plants. To sum up, we suggest that modulating the genotype of Trifolium pratense L. seedlings to bear higher proportion of pollutants is conducive to contamination site treatment.

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.

[Thoracoscopic repair of congenital diaphragmatic hernia in neonates: a report of 47 cases].

OBJECTIVE: To review the application of thoracoscopic repair for treatment of congenital diaphragmatic hernia in neonates, so as to improve the cure rate. METHODS: Clinical data of 47 neonates with congenital diaphragmatic hernia receiving thoracoscopic repair from June 2012 to June 2017 were reviewed. The admission age, gestational age, birth weight, timing of diagnosis, hernia location, clinical manifestation, surgical timing, surgical method, operation time, postoperative mechanical ventilation time of patients were analyzed. RESULTS: There were 42 cases of left diaphragmatic hernia and 5 cases of right diaphragmatic hernia. Thirteen cases were diagnosed prenatally. Primary diaphragmatic repair was successfully accomplished under thoracoscope in 45 neonates without perioperative complications, while 2 patients were converted to open surgery. The average operation time was (63±13) min (42-150 min), the average blood loss was (3.0±1.7) mL (1.0-9.0 mL), and the average postoperative mechanical ventilation time was (3.9±1.4) d (2.0-11.0 d). Two patients died and the treatment was withdrawn in 3 patients with an overall cure rate of 89.4% (42/47). CONCLUSIONS: Thoracoscopic repair is effective and can be used as first-choice treatment of diaphragmatic hernia in neonates.

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.

Temporal pattern of Toll-like receptor 9 upregulation in neurons and glial cells following cerebral ischemia reperfusion in mice.

PURPOSE: The family of Toll-like receptors (TLRs) has recently been reported to play a role in ischemic injury, but the time course and cell types of the post-stroke TLR9 upregulation remain unclear. In this study, we investigated the dynamic changes of TLR9 expression and the expression of TLR9 in neurons and glial cells after cerebral ischemia reperfusion in mice. METHODS: Focal cerebral ischemia was induced by middle cerebral artery occlusion for 90 min in male C57BL/6 mice. The TLR9 expression levels in the tissue surrounding the infarct were detected by Western Blot at 6 h, 3 d, 7 d, 14 d, 21 d, and 28 d after reperfusion. The expression of TLR9 in neurons and glial cells was observed by immunofluorescence staining. RESULTS: The expression of TLR9 protein first increased and then decreased, with the peak observed at 14 d-21 d. Only small punctate intracellular TLR9 was occasionally observed in the neurons at each time point, and the TLR9-positive rate showed no difference at different time points. By contrast, the activated microglia gathered at the margin of the infarct, and the intracellular TLR9 changed from scattered small punctate to coarse and lumpy. The TLR9-positive rate of microglia was first increased and then decreased with time, with the peak observed at 3 d. No positive TLR9 staining was found in the astrocytes and oligodendrocytes. CONCLUSIONS: TLR9 expression showed dynamic changes for a long period of time and microglias were the main brain cells to express TLR9 after cerebral ischemia and reperfusion.

Techno-functional properties of active film based on guar gum-propolis and its application for "Nanguo" pears preservation.

Guar gum (GG) composite films, incorporating the ethanolic extract of propolis (EEP), were prepared and subjected to a comprehensive investigation of their functional characteristics. The addition of EEP resulted in a discernible enhancement in the opacity, moisture barrier capacity, and elongation at break. Incorporating EEP led to a noteworthy increase in the total phenolic and total flavonoid content of the films, resulting in superior antioxidant capacity upon GG-EEP films. Remarkably, the addition of 5 % EEP yielded noteworthy outcomes, manifesting in a DPPH radical scavenging rate of 47.60 % and the ABTS radical scavenging rate of 94.87 %, as well as FRAP and cupric reducing power of 331.98 mmol FeSO4-7H2O kg-1 and 56.95 µg TE mg-1, respectively. In addition, GG-EEP films demonstrated antifungal effect against Penicillium expansum and Aspergillus niger, along with a sustained antibacterial effect against Escherichia coli and Staphylococcus aureus. GG-EEP films had superior inhibitory ability against Gram-positive bacteria than Gram-negative bacteria. Crucially, GG-EEP composite films played a pivotal role in reducing both lesion diameter and depth, concurrently mitigating weight loss and firmness decline during the storage period of "Nanguo" pears. Therefore, GG-EEP composite films have the considerable potential to serve as advanced and effective active packaging materials for food preservation.

MRI-based radiomics feature combined with tumor markers to predict TN staging of rectal cancer.

The aim of this study is to evaluate the predictive ability of MRI-based radiomics combined with tumor markers for TN staging in patients with rectal cancer and to develop a prediction model for TN staging. A total of 190 patients with rectal adenocarcinoma who underwent total mesorectal excision at the First Affiliated Hospital of the Air Force Medical University between January 2016 and December 2020 were included in the study. An additional 54 patients from a prospective validation cohort were included between August 2022 and August 2023. Preoperative tumor markers and MRI imaging data were collected from all enrolled patients. The 190 patients were divided into a training cohort (n = 133) and a validation cohort (n = 57). Radiomics features were extracted by outlining the region of interest (ROI) on T2WI sequence images. Feature selection and radiomics score (Rad-score) construction were performed using least absolute shrinkage and selection operator regression analysis (LASSO). The postoperative pathology TNM stage was used to differentiate locally advanced rectal cancer (T3/4 or N1/2) from locally early rectal cancer (T1/2, N0). Logistic regression was used to construct separate prediction models for T stage and N stage. The models' predictive performance was evaluated using DCA curves and calibration curves. The T staging model showed that Rad-score, based on 8 radiomics features, was an independent predictor of T staging. When combined with CEA, tumor diameter, mesoretal fascia (MRF), and extramural venous invasion (EMVI), it effectively differentiated between T1/2 and T3/4 stage rectal cancers in the training cohort (AUC 0.87 [95% CI: 0.81-0.93]). The N-staging model found that Rad-score, based on 10 radiomics features, was an independent predictor of N-staging. When combined with CA19.9, degree of differentiation, and EMVI, it effectively differentiated between N0 and N1/2 stage rectal cancers. The training cohort had an AUC of 0.84 (95% CI: 0.77-0.91). The calibration curves demonstrated good precision between the predicted and actual results. The DCA curves indicated that both sets of predictive models could provide net clinical benefits for diagnosis. MRI-based radiomics features are independent predictors of T staging and N staging. When combined with tumor markers, they have good predictive efficacy for TN staging of rectal cancer.

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.

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.

Clipping versus coiling for ruptured intracranial aneurysms: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Endovascular treatment has increasingly been used for aneurismal subarachnoid aneurismal hemorrhage. The aim of this analysis is to assess the current evidence regarding safety and efficiency of clipping compared with coiling. METHODS: We conducted a meta-analysis of studies that compared clipping with coiling between January 1999 and July 2012. Comparison of binary outcomes between treatment groups was described using odds ratios (OR; clip versus coil). RESULTS: Four randomized controlled trials and 23 observational studies were included. Randomized controlled trials showed that coiling reduced the 1-year unfavorable outcome rate (OR, 1.48; 95% confidence interval [CI], 1.24-1.76). However, there was no statistical deference in nonrandomized controlled trials (OR, 1.11; 95% CI, 0.96-1.28). Subgroup analysis revealed coiling yielded better outcomes for patients with good preoperative grade (OR, 1.51; 95% CI, 1.24-1.84) than for poor preoperative patients (OR, 0.88; 95% CI 0.56-1.38). Additionally, the incidence of rebleeding is higher after coiling (OR, 0.43; 95% CI, 0.28-0.66), corresponding to a better complete occlusion rate of clipping (OR, 2.43; 95% CI, 1.88-3.13). The 1-year mortality showed no significant difference (OR, 1.07; 95% CI, 0.88-1.30). Vasospasm was more common after clipping (OR, 1.43; 95% CI, 1.07-1.91), whereas the ischemic infarct (OR, 0.74; 95% CI, 0.52-1.06), shunt-dependent hydrocephalus (OR, 0.84; 95% CI, 0.66-1.07), and procedural complication rates (OR, 1.19; 95% CI, 0.67-2.11) did not differ significantly between techniques. CONCLUSIONS: Coiling yields a better clinical outcome, the benefit being greater in those with a good preoperative grade than those with a poor preoperative grade. However, coiling leads to a greater risk of rebleeding. Well-designed randomized trials with special considerations to the aspect are needed.