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Background Overactivated microglia are a key contributor to Parkinson’s disease (PD) by inducing neuroinflammation. CD200R1, a membrane glycoprotein mainly found on microglia, is crucial for maintaining quiescence with its dysregulation linked to microglia’s abnormal activation. We and other groups have reported a decline in CD200R1 levels in several neurological disorders including PD. However, the mechanism regulating CD200R1 expression and the specific reasons for its reduction in PD remain largely unexplored. Given the pivotal role of transcription factors in gene expression, this study aimed to elucidate the transcriptional regulation of CD200R1 and its implications in PD. Methods The CD200R1 promoter core region was identified via luciferase assays. Potential transcription factors were predicted using the UCSC ChIP-seq database and JASPAR. NFKB1 binding to the CD200R1 core promoter was substantiated through electrophoretic mobility shift and chromatin immunoprecipitation assays. Knocking-down or overexpressing NFKB1 validated its regulatory effect on CD200R1. Correlation between decreased CD200R1 and deficient NFKB1 was studied using Genotype-Tissue Expression database. The clinical samples of the peripheral blood mononuclear cells were acquired from 44 PD patients (mean age 64.13 ± 9.78, 43.2% male, median Hoehn-Yahr stage 1.77) and 45 controls (mean age 64.70 ± 9.41, 52.1% male). NFKB1 knockout mice were utilized to study the impact of NFKB1 on CD200R1 expression and to assess their roles in PD pathophysiology. Results The study identified the CD200R1 core promoter region, located 482 to 146 bp upstream of its translation initiation site, was directly regulated by NFKB1. Significant correlation between NFKB1 and CD200R1 expression was observed in human PMBCs. Both NFKB1 and CD200R1 were significantly decreased in PD patient samples. Furthermore, NFKB1-/- mice exhibited exacerbated microglia activation and dopaminergic neuron loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Conclusion Our study identified that NFKB1 served as a direct regulator of CD200R1. Reduced NFKB1 played a critical role in CD200R1 dysregulation and subsequent microglia overactivation in PD. These findings provide evidence that targeting the NFKB1-CD200R1 axis would be a novel therapeutic strategy for PD.

Background Epidemiological studies have revealed increased Parkinson’s disease (PD) risk among individuals exposed to pesticides like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP is frequently used to induce PD-like symptoms in research models by disrupting mitochondrial complex I (CI) function and causing dopaminergic neuronal loss in the nigrostriatal region. However, the pathway(s) through which MPTP impairs mitochondrial CI function remain to be elucidated. In this study, we aim to identify the molecular mechanisms through which MPTP modulates CI function and define the specific subunits of mitochondrial CI affected by MPTP. Methods Male mice encompassing either wild-type Sirt3 or Sirt3 K223R de-SUMOylation mutation, were intraperitoneally injected with either MPTP or saline. In vitro experiments were conducted using the SH-SY5Y cell line with or without the Sirt3 de-SUMOylation mutation. Movement performance, mitochondrial function, and protein acetylation were evaluated. Results MPTP exposure, both in vitro and in vivo, disrupted the AMPK–SENP1–Sirt3 axis, leading to impairment of mitochondrial function. Specifically, MPTP suppressed activation of AMPK, impeding the entry of SENP1 into the mitochondria. The lack of mitochondrial SENP1 resulted in increased levels of SUMOylated Sirt3, which inhibited its deacetylase activity. This led to a significant increase in the acetylation of CI subunits NDUFS3 and NDUFA5, which resulted in reduced CI activity and inhibition of mitochondrial function, and eventually dopaminergic neuronal death. In this pathway, sustained deSUMOylation mutation of Sirt3 (K223R in mice, K288R in humans) mitigated the impact of MPTP on mitochondrial dysregulation, as well as dopaminergic neuronal death and behavioral deficits. Conclusion The disordered AMPK-SENP1-Sirt3 pathway plays a crucial role in the MPTP-induced CI dysfunction and PD-like phenotype, which provide valuable insights into the mechanisms of PD pathogenesis.

Background: Cognitive impairment has become an important problem in ischemic cerebrovascular disorder survivors as disease related deaths have been significantly reduced. Aerobic exercise, the most prevalent mode of physical activity, positively contributes to cognition in both healthy population and people with cognitive impairment. However, studies on its associations with cognitive gains in patients with ischemic cerebrovascular disease showed mixed findings. Objective: To explore the cognitive effects of aerobic exercise on ischemic cerebrovascular disorder survivors and investigate the possible moderators on exercise benefits. Method: Randomized controlled trials investigating the effects of sole aerobic exercise on cognitive function in population with ischemic intracranial vascular disorder compared to any control group who did not receive the intervention were enrolled in this systematic review and meta-analysis. Four online database (Pubmed, Cochrane Library, Embase, and Web of Science) were searched. Results: The initial search returned 1,522 citations and ultimately 11 studies were included in the systematic review. Analysis of seven studies showed the beneficial but not statistically significant impact of aerobic exercise on global cognitive function (0.13; 95% Cl −0.09 to 0.35; p = 0.25). Participants already with cognitive impairment benefited more from this intervention (0.31; 95% Cl 0.07–0.55; p = 0.01) and moderate intensity might be the optimal choice (0.34; 95% Cl −0.01 to 0.69; p = 0.06). The program duration and initiation time after stroke occurrence did not predict better cognitive outcome. Aerobic exercise was not associated with improvement of processing speed and executive function, the two subdomains of cognitive function. Conclusions: Aerobic exercise may contribute to cognitive gains in survivors of ischemic cerebrovascular disorder, especially for population already with cognitive decline. Our findings suggest that the adoption of moderate intensity aerobic exercise might improve cognition in such population.

Background The cardiotoxicity of isoniazid on zebrafish embryos and its underlying mechanism is unclear. Methods Here, we exposed zebrafish embryos at 4 h post-fertilization to different levels of isoniazid and recorded the morphology and number of malformed and dead embryos under the microscope. Results The high concentration of isoniazid group showed more malformed and dead embryos than the low concentration of isoniazid group and control group. The morphology of the heart and its alteration were visualized using transgenic zebrafish ( cmlc2 : GFP) and confirmed by in situ hybridization. The negative effects of isoniazid on the developing heart were characterized by lower heart rate and more heart looping disorders. Mechanistically, PCR showed decreased expression of heart-specific transcription factors when exposed to isoniazid. Oxidative stress was induced by isoniazid in cardiomyocytes, mediated by decreased activities of catalase and superoxide dismutase, which were rescued by scavengers of reactive oxygen species. Conclusion In conclusion, this study demonstrated that isoniazid led to heart looping disturbance by the downregulation of cardiac-specific transcription factors and induction of cardiomyocyte apoptosis.

Objective: This study determined whether the effect of combination therapy for hepatic carcinoma (HCC) is comparable to surgical resection (SR). According to the guidelines of the American Association for the Study of Liver Disease, radiofrequency ablation (RFA) and SR are recommended for early HCC. However, patients treated with RFA had worse long-term survival than those who received SR. Many studies utilizing the combination therapy with RFA and transarterial chemoembolization (TACE) have reported better prognosis as compared to RFA alone. Materials and Methods: A comprehensive search in databases was conducted. Six retrospective studies and one cohort were enrolled in this meta-analysis. The overall survival (OS), disease-free survival (DFS), and major complications were compared between RFA plus TACE and SR. The pooled hazard ratio and 95% confidence interval (CI) were calculated and analyzed. Results: After comparison, no significant difference in the OS and DFS at 1 and 3 years between the combination therapy and SR was observed (OS1: pooled relative risk [RR]: 0.82, 95% CI [0.56, 1.21]; OS3: pooled RR: 1.07, 95% CI [0.82, 1.39]; DFS1: pooled RR: 0.92, 95% CI [0.58, 1.45]; DFS3: pooled RR: 1.18, 95% CI [1.00, 1.40]). SR had better clinical outcomes than combination therapy with respect to long-term survival and disease progression (OS5: pooled RR: 1.12, 95% CI [1.03, 1.23]; DFS5: pooled RR: 1.15, 95% CI [1.03, 1.28]). Major complications were reduced with combination therapy (pooled RR: 0.46, 95% CI [0.25, 0.85]). Conclusion: SR should remain as the first-line therapy for early HCC.

Objective: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate hepatocellular carcinoma. Drug-eluting beads (DEB)-TACE is a promising approach expected to improve the efficiency and safety of conventional (c) TACE. However, controversy remains whether DEB-TACE performs better than cTACE. This meta-analysis aimed to compare cTACE and DEB-TACE in terms of overall survival (OS), adverse events, and response rate. Literature search was performed in PubMed, Cochrane, Embase, and Web of Science. Complete response (CR), partial response (PR), disease control (DC), stable disease (SD), OS, and major complications were compared between these two modalities. The pooled relative risk and 95% confidence interval were calculated for assessment. Six randomized controlled trials were included for further analysis after a comprehensive search. No significant difference was found in overall response at 3, 6, 9, and 12 months, CR, PR, DC (SD), OS and complications between cTACE and DEB-TACE. Conclusion: DEB-TACE had similar therapeutic effects to those of cTACE. Furthermore, major complications in both therapies were similar. The superiority of DEB-TACE over cTACE remains unclear, and further research with high-quality evidence is needed.

Immune checkpoint inhibitors (ICIs) have emerged as one of the most promising therapeutic options for patients with advanced cancer. The aim of the present study was to investigate the prognostic value of somatic mutations in mismatch repair (MMR) genes in metastatic cancers after ICI treatment, as well as their association with tumor mutational burden (TMB). Information regarding gene mutations in mismatch repair and the survival time of patients with advanced cancer following ICI treatment was collected from the cBioPortal database. The prognostic value of somatic mutations in MMR genes and the association between the mutation status and TMB score were analyzed among multiple types of cancer. Somatic mutation frequency in the MMR genes was identified to be 7% among all patients, which varied across different types of cancer. Somatic mutations in the MMR genes were associated with improved overall survival time in all tested patients (P=0.004). Following stratification by type of ICI treatment, a significant association was observed between somatic mutations in the MMR genes and overall survival time in patients treated with cytotoxic T-lymphocyte-associated protein 4 inhibitors (P=0.01). In addition, marked but non-significant association between somatic mutations in the MMR genes and overall survival time was revealed in patients administered with programmed death-1/programmed death-ligand-1 inhibitors (P=0.09). Multivariate Cox proportional hazards regression analysis demonstrated that somatic mutations in MMR genes were significantly associated with overall survival time (hazard ratio, 0.683; 95% confidence interval, 0.497-0.938; P=0.01). Patients with somatic mutations in the MMR genes demonstrated higher TMB compared with those not harboring mutations (P<0.01). The results of the present study suggested that somatic mutations in the MMR genes may be used as a prognostic marker of a positive outcome in patients with metastatic cancer receiving ICI treatment, since somatic mutations in the MMR genes may be one of the main factors affecting the tumor mutation load.

Objective: To investigate the effect of curcumin on endogenous neuron regeneration in rats after traumatic brain injury (TBI) in rats. Methods: TBI model was prepared with controlled cortical impact model. SD rats were divided into 3 groups: control group, TBI+vehicle group and TBI+curcumin group. Serum SOD and MDA levels were detected by ELISA. The cognitive function of the rats was observed by Morris water maze (MWM). Then the TUNEL method was used to detect the apoptosis of the injured area. NeuN/BrdU immunofluorescence double labeling was used to detect the newly matured neurons in the injured area. Western blot was used to detect DCX protein in the hippocampus. Results: Curcumin decresed the serum MDA level and increased the serum SOD level in rats with TBI. MWM test showed curcumin decreased the escape latency and increased the number of platform crossover of rats with TBI. The apoptotic cells in the injured area of the rats in the TBI+curcumin group were significantly less than those in other TBI rats. More NeuN+/BrdU+ double-label positive neonatal mature neurons were observed in the cortex of the TBI+curcumin group, which was more significant than those in other TBI rats. The expression of DCX protein in the hippocampus of the rats in the TBI+curcumin group was dramatically more than that in other TBI rats. Conclusion: Curcumin can reduce the level of oxidative stress in TBI rats, protect neurons from apoptosis, and promote the development of neurons in the injured cortex and hippocampus, thus improving the learning and memory functions of TBI rats.

To analyse the dynamic changes of the microbial community and biodiversity in potato liquor, this experiment uses potato and corn as raw materials and uses solid fermentation method to obtain potato liquor to brew liquor. The fermentation of the 1st, 3rd, 5th, 7th, 9th, 11th, 13th and 15th days of wine samples and sent for inspection. The results show that potato liquor brews wine in the fermentation process, the bacterial community is more than fungi, and in the end of fermentation is mainly played by bacteria. Lactobacillus and Weissella accounted for the largest proportion of lactobacillus and Weissella, and found that the number of Lactobacillus (Lactobacillus) increased as fermentation progressed, but the number of Weissella continued to decrease. In the fungal community, the abnormal Wickerham yeast and the false silk yeast genus (Candida) account edged the largest proportion of the entire fermentation process. Aspergillus, on the other hand, plays a role in the early fermentation phase.

Deficiency of the essential trace element selenium (Se) can lead to cell apoptosis, and various microRNAs (miRNAs) are known to participate in the regulation of apoptosis by regulating their target genes. In this study, we explore the effect of Se deficiency on porcine cerebellar cell apoptosis and the role of miRNA in this process. After constructing a low-Se pig model, we observed the porcine cerebellum through an electron microscope and observed obvious characteristics of apoptosis. Moreover, it was found that the expression of miR-294 in Se-deficient pigs was significantly lower than that in the control group. Through bioinformatics, qRT-PCR, western blot analysis, and other experimental techniques, we further confirmed that inducible nitric oxide synthase (iNOS) is one of the target genes of miR-294. Our experimental results show that Se deficiency can reduce the expression of miR-294 and increase both the expression of iNOS and the nitric oxide (NO) content (P < 0.01). The expression of heat shock proteins (HSPs, such as HSP70, HSP90, HSP60, HSP40, and HSP27) and mitochondrial pathway-related indicators, such as Bcl2-associated X protein (Bax), cytochrome C (Cyt-C), and cysteinyl aspartate–specific proteinases (caspase 3, caspase 7, and caspase 8), was upregulated (P < 0.05), and the expression of B cell lymphoma-2 (Bcl-2) was downregulated (P < 0.05). In summary, we believe that Se deficiency can lead to abnormal expression of miR-294 and HSPs; moreover, the mitochondrial apoptosis pathway is activated, which significantly enhances apoptosis of cerebellar cells in Se-deficient pigs. These results enrich the biological effects of Se deficiency.