Nrf2 pathway activation promotes the expression of genes related to glutathione metabolism in alcohol-exposed astrocytes.

Introduction: Oxidative and antioxidant pathways play essential roles in the development of alcohol-induced brain injury. The Nrf2 pathway is an endogenous antioxidant response pathway, but there has been little research on the role of Nrf2 in alcohol-related diseases. Thus, we examined the effects of alcohol and an Nrf2 agonist (TBHQ) on astrocyte function, mRNA expression, and metabolite content to further explore the protective mechanisms of Nrf2 agonists in astrocytes following alcohol exposure. Methods: CTX TNA2 astrocytes were cultured with alcohol and TBHQ and then subjected to transcriptome sequencing, LC-MS/MS analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and malondialdehyde (MDA) and superoxide dismutase (SOD) activity assays. Results: Alcohol exposure significantly increased malondialdehyde (MDA) levels while decreasing superoxide dismutase (SOD) levels in astrocytes. Treatment with TBHQ effectively reversed these effects, demonstrating its protective role against oxidative stress induced by alcohol. Transcriptome sequencing and qRT-PCR analysis revealed that TBHQ specifically upregulates genes involved in glutathione metabolism, including a notable increase in the expression of the glutathione S-transferase A5 (GSTA5) gene, which was suppressed by alcohol exposure. Additionally, metabolomic analysis showed that TBHQ regulates key components of ether lipid metabolism in alcohol-exposed astrocytes, with significant reductions in the levels of lysophosphatidylcholine (18:0) (LysoPC (18:0)) and 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine, both of which are critical markers in the ether lipid metabolic pathway. Discussion: The findings underscore the role of TBHQ as an Nrf2 agonist in mitigating alcohol-induced oxidative damage in astrocytes by modulating glutathione metabolism and ether lipid metabolism. The regulation of GSTA5 gene expression emerges as a key mechanism through which Nrf2 agonists confer neuroprotection against oxidative stress and lipid oxidation. These insights pave the way for potential therapeutic strategies targeting the Nrf2 pathway to protect astrocytes from alcohol-induced damage.

Fasudil may alleviate alcohol-induced astrocyte damage by modifying lipid metabolism, as determined by metabonomics analysis.

Alcohol dependence is a chronic, relapsing encephalopathy characterized by compulsive craving for alcohol, loss of control over alcohol use, and the presence of negative emotions and physical discomfort when alcohol is unavailable. Harmful use of alcohol is one of the greatest risk factors for death, illness, and disability. Rho kinase inhibitors have neuroprotective effects. This study used metabonomics analysis to assess untreated astrocytes, astrocytes exposed to 75 mmol/L of alcohol, and astrocytes exposed to 75 mmol/L of alcohol and treated with 15 µg/mL fasudil for 24 h. One of the clearest differences between the alcohol-exposed and fasudil-treated alcohol-exposed groups was the abundance of lipids and lipid-like molecules, although glycerophospholipid metabolism was comparable in both groups. Our findings show that fasudil may alleviate alcohol-induced astrocyte damage by modifying lipid metabolism, providing a new approach for preventing and treating alcohol dependence.

[Effectiveness of new Pilon plate in treatment of type C Pilon fracture].

Objective: By comparing with traditional L-shaped plate, to explore the effectiveness of new Pilon plate in the treatment of type C Pilon fracture. Methods: A clinical data of 57 patients with type C Pilon fractures who met the selection criteria between May 2018 and January 2020 was analyzed retrospectively. Thirty-two patients were treated with new Pilon plate (trial group) and 25 patients with traditional L-shaped plate (control group). There was no significant difference in gender, age, cause of injury, fracture side and type, the interval between injury and operation between the two groups (P>0.05). The operation time and complications of the two groups were recorded. X-ray films were taken after operation to assess the quality of fracture reduction according to the Burwell-Charnley classification and fracture healing. Ankle function was evaluated according to Johner-Wruhs scoring standard and American Orthopaedic Foot and Ankle Society (AOFAS) score. Results: The operations of the two groups were completed successfully, and the operation time of the trial group was significantly shorter than that of the control group (t=-3.025, P=0.005). After operation, the incision necrosis occurred in 2 cases of the control group, and the incisions of other patients in both groups healed by first intention. All patients were followed up 8-16 months, with an average of 10.1 months. There was no significant difference in follow-up time between the two groups (t=0.433, P=0.667). X-ray films showed that the ankle reduction of the trial group was rated as excellent in 28 cases and good in 4 cases, with an excellent and good rate of 100%, while in the control group, the ankle reduction was rated as excellent in 15 cases, good in 5 cases, and fair in 5 cases, with an excellent and good rate of 80.0%. There was a significant difference in the excellent and good rate of fracture reduction between the two groups (Z=-2.565，P=0.010). The fracture healed in both groups, and the healing time was (16.59±3.78) weeks in the trial group and (17.80±3.81) weeks in the control group, and there was no significant difference between the two groups (t=-1.191, P=0.239). At last follow-up, according to Johner-Wruhs scoring standard, the ankle joint function in the trial group was evaluated as excellent in 25 cases and good in 7 cases, with an excellent and good rate of 100%; the AOFAS score was 90.9±4.5. In the control group, 16 cases were excellent, 5 cases were good, and 4 cases were fair, and the excellent and good rate was 84.0%; the AOFAS score was 85.2±10.0. The ankle function scores of the trial group was superior to that of the control group (P<0.05). During follow-up, except for 1 case of ankle traumatic arthritis in the control group, there was no complication such as ankle malunion, plate loosening and fracture, or fracture reduction loss in both groups. Conclusion: Compared with the traditional L-shaped plate, the new Pilon plate in the treatment of type C Pilon fracture has the advantages of high reduction quality, reliable fixation, less irritation to soft tissue, high fracture healing rate, and satisfactory functional recovery of ankle joint.

High Mobility Group Box 1/Toll-like Receptor 4 Signaling Increases GABRB3 Expression in Alcohol Exposure.

INTRODUCTION: Prefrontal cortex (PFC) and striatal neurotransmitter homeostasis is affected by alcohol dependence. In this study, the microarray dataset from the Gene Expression Omnibus (GEO) database were downloaded. The prefrontal and striatum data were cross-analyzed to reveal the co-effects of alcohol dependence on the two brain regions of mice. METHODS: The GSE123114 microarray profile was downloaded from the GEO database, and differentially expressed genes (DEGs) between the two groups were acquired by GEO2R. KEGG analyses were performed to identify the pivotal pathways of these DEGs. Key differential gene expressions and their mechanism associated with alcohol exposure were investigated by an intraperitoneal alcohol model. RESULTS: A total of 13 overlapping DEGs from the PFC and striatal datasets of the GSE123114 microarray profile were identified, and they were significantly enriched in the morphine addiction pathway. The transcript levels and protein expression of Gabrb3 were consistent with the microarray data both in the PFC and striatum. The transcript levels of HMGB1, TLR4, TNFα and IL-1ß were upregulated in the PFC and striatum of mice in the alcohol group. The HMGB1 inhibitor decreased Gabrb3 transcript and protein levels as well as TNFα and IL-1ß transcript levels both in the PFC and striatum in the intraperitoneal alcohol model mice. DISCUSSION: Through the reanalysis of GSE123114 microarray profile, we found that Gabrb3 is a key gene associated with alcohol exposure. In further experiments, our findings suggest that alcohol exposure modulates Gabrb3 expression through the HMGB1/TLR4 pathway. Moreover, inflammation-associated factors, such as IL-1ß and TNFα, may be related to the HMGB1/TLR4-mediated regulation of GABRB3 expression in alcohol exposure.

Human nuclear receptors (NRs) genes have prognostic significance in hepatocellular carcinoma patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality in the world. METHOD: We downloaded the mRNA profiles and clinical information of 371 HCC patients from The Cancer Genome Atlas (TCGA) database. The consensus clustering analysis with the mRNA levels of 48 nuclear receptors (NRs) was performed by the "ConsensusClusterPlus." The univariate Cox regression analysis was performed to predict the prognostic significance of NRs on HCC. The risk score was calculated by the prognostic model constructed based on eight optimal NRs. Then multivariate Cox regression analysis was performed to determine whether the risk score is an independent prognostic signature. Finally, the nomogram based on multiple independent prognostic factors was used to predict the long-term survival of HCC patients. RESULTS: The prognostic model constructed based on the eight optimal NRs (NR1H3, ESR1, NR1I2, NR2C1, NR6A1, PPARD, PPARG, and VDR) could effectively predict the prognosis of HCC patients as an independent prognostic signature. Moreover, the nomogram was constructed based on multiple independent prognostic factors including risk score and tumor node metastasis (TNM) stage and could better predict the long-term survival for 3- and 5-year of HCC patients. CONCLUSION: Our results provided novel evidences that NRs could act as the potential prognostic signatures for HCC patients.

A protocol of systematic review and meta-analysis of Mozart's Music for drug-resistant epilepsy.

BACKGROUND: This study will aim to assess the effectiveness of Mozart's Music (MM) for the management of patients with drug-resistant epilepsy (DRE). METHODS: In this study, we will search MEDLINE, EMBASE, Cochrane Library, Web of Science, CINAHL, Chinese Scientific Journal Database Information, WANGFANG, and China National Knowledge Infrastructure from their inauguration to March 1, 2020 without language and publication time restrictions. We will also identify other literature resources, such as reference lists of any related reviews. Trial quality will be examined by Cochrane risk of bias tool; reporting bias will be identified by a funnel plot and Egger test; and statistical analysis will be undertaken by RevMan 5.3 software. RESULTS: This study will summarize high quality randomized controlled trials to appraise the effectiveness and safety of MM for the treatment of patients with DRE. CONCLUSIONS: The findings of this study will supply evidence to judge whether MM is effective on DRE at evidence-based medicine level. STUDY REGISTRATION NUMBER: CRD42020170512.

Effectiveness of rehabilitation training combined with acupuncture on aphasia after cerebral hemorrhage: A systematic review protocol of randomized controlled trial.

BACKGROUND: This study aims to systematically evaluate the effectiveness of rehabilitation training (RT) combined with acupuncture on aphasia after cerebral hemorrhage (CH). METHODS: PUBMED, Cochrane Central Register of Controlled Trials, EMBASE, Web of Science, Ovid, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure will be searched to identify any potential studies from inception to March 1, 2019, without language restrictions. All randomized controlled trials and case-controlled studies assessing the effectiveness of RT combined with acupuncture for the treatment of aphasia following CH will be included in this study. Cochrane risk of bias tool will be used to determine the methodological quality for included studies. RevMan 5.3 software (Cochrane Community, London, UK) will be utilized to perform statistical analysis. RESULTS: This study will systematically evaluate the effectiveness of RT and acupuncture for aphasia post CH. Primary outcome includes aphasia, which can be measured by Aachener Aphasia Test or Communicative Activity Log or other related scales. Secondary outcomes consist of speech performance, as assessed by Western Aphasia Battery-Revised; measure of skill in Supported Conversation scales; measure of Participation in Conversation scales; types of strategies used in conversation; occurrence and repair of conversation breakdowns; as well as any adverse events. CONCLUSION: The results of this study will provide present evidence on assessing effectiveness of RT and acupuncture after CH. DISSEMINATION AND ETHICS: The findings of this study are expected to be published in peer-reviewed journals. It does not require ethical approval, because no individual data will be utilized in this study. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019131587.