TREM2 gene induces differentiation of induced pluripotent stem cells into dopaminergic neurons and promotes neuronal repair via TGF-ß activation in 6-OHDA-lesioned mouse model of Parkinson's disease.

OBJECTIVE: Induced pluripotent stem cells (iPSCs) hold a promising potential for rescuing dopaminergic neurons in therapy for Parkinson's disease (PD). This study clarifies a TREM2-dependent mechanism explaining the function of iPSC differentiation in neuronal repair of PD. METHODS: PD-related differentially expressed genes were screened by bioinformatics analyses and their expression was verified using RT-qPCR in nigral tissues of 6-OHDA-lesioned mice. Following ectopic expression and depletion experiments in iPSCs, cell differentiation into dopaminergic neurons as well as the expression of dopaminergic neuronal markers TH and DAT was measured. Stereotaxic injection of 6-OHDA was used to develop a mouse model of PD, which was injected with iPSC suspension overexpressing TREM2 to verify the effect of TREM2 on neuronal repair. RESULTS: TREM2 was poorly expressed in the nigral tissues of 6-OHDA-lesioned mice. In the presence of TREM2 overexpression, the iPSCs showed increased expression of dopaminergic neuronal markers TH and DAT, which facilitated the differentiation of iPSCs into dopaminergic neurons. Mechanistic investigations indicated that TREM2 activated the TGF-ß pathway and induced iPSC differentiation into dopaminergic neurons. In vivo data showed that iPSCs overexpressing TREM2 enhanced neuronal repair in 6-OHDA-lesioned mice. CONCLUSION: This work identifies a mechanistic insight for TREM2-mediated TGF-ß activation in the regulation of neuronal repair in PD and suggests novel strategies for neurodegenerative disorders.

Predictive value of admission red cell distribution width-to-platelet ratio for 30-day death in patients with spontaneous intracerebral hemorrhage: an analysis of the MIMIC database.

Aim: Prognostic assessment plays an important role in the effective management of patients with spontaneous intracerebral hemorrhage (ICH). The study aimed to investigate whether elevated red cell distribution width-to-platelet ratio (RPR) at admission was related to 30-day death in patients with spontaneous intracerebral hemorrhage (ICH). Methods: This retrospective cohort study included 2,823 adult patients with ICH from the Multiparameter Intelligent Monitoring in Intensive Care (MIMIC) III and IV databases between 2001 and 2019. The Cox proportional hazard model was utilized to evaluate the relationship between RPR levels and 30-day death risk. The area under receiver-operating characteristic curve (AUC) was used to assess the predictive ability of RPR for 30-day death in patients with ICH. Results: At the end of the 30-day follow-up, 799 (28.30%) patients died, and the median RPR level was 0.066 (0.053, 0.087). After adjusting for confounders, the tertile 3 of RPR levels [hazard ratio (HR) = 1.37, 95% confidence interval (CI): 1.15-1.64] were associated with a higher risk of 30-day death in patients with ICH compared with tertile 1. In the stratified analyses, elevated RPR levels were found to be associated with an increased risk of 30-day death in patients aged <65 years (HR = 1.77, 95%CI: 1.29-2.43), aged ≥65 years (HR = 1.30, 95%CI: 1.05-1.61), with Glasgow Coma Score (GCS) <14 (HR = 1.65, 95%CI: 1.27-2.14), with Charlson comorbidity index (CCI) ≥4 (HR = 1.45, 95%CI: 1.17-1.80), with (HR = 1.66, 95%CI: 1.13-2.43) or without sepsis (HR = 1.32, 95%CI: 1.08-1.61), and female patients (HR = 1.75, 95%CI: 1.35-2.26) but not in male patients (P = 0.139) and patients with GCS ≥14 (P = 0.058) or CCI <4 (P = 0.188). The AUC for RPR to predict 30-day death in patients with ICH was 0.795 (95%CI: 0.763-0.828) in the testing set, indicating a good predictive ability. Conclusion: Elevated RPR levels were correlated with an increased risk of 30-day death in patients with ICH, and RPP levels showed good predictive ability for 30-day death.

Association between Allium vegetables and the risk of non-digestive tract cancer: A systematic review and meta-analysis of cohort and case-control studies.

PURPOSE: To clarify the role of Allium vegetables in non-digestive tract cancer, we conducted this meta-analysis. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we conducted a meta-analysis of published studies assessing the associations between Allium vegetables and the risk of non-digestive tract cancer. We estimated the pooled odds ratio (OR) of non-digestive tract cancer for the highest and lowest Allium vegetable consumption using random-effects models. A dose-response regression model was used to evaluate the relationship between Allium vegetables and non-digestive tract cancer risk. RESULTS: In a pooled analysis of 25 studies (11 cohort and 14 case-control studies) on Allium vegetables, a total of 18,070 patients with non-digestive tract cancer were finally included. Integrated OR of non-digestive tract cancer was 0.86 [95% confidence interval (CI):0.80-0.93] for the highest versus the lowest Allium vegetable consumption for all studies, 0.78 (95% CI:0.69-0.90) for case-control studies and 0.94 (95%CI: 0.87-1.02) for cohort studies. Sensitivity analysis showed that the pooled effect was stable. No apparent publication bias was identified in this study; however, the cumulative meta-analysis suggested that studies conducted earlier (from 1994 to 1997) might be a source of heterogeneity. Dose-response regression model indicated that Allium vegetable consumption was associated with the risk of non-digestive tract cancer (P = 0.001 for non-linearity; P = 0.032 for linearity). CONCLUSION: Higher Allium vegetable consumption could reduce the risk of non-digestive tract cancers, demonstrating the protective role of Allium vegetables.

Chrysin Ameliorates Influenza Virus Infection in the Upper Airways by Repressing Virus-Induced Cell Cycle Arrest and Mitochondria-Dependent Apoptosis.

Chrysin has been proven to possess antiviral properties, but the precise underlying anti-influenza mechanism and its anti-influenza efficacy in vivo are largely unclear. In this study, we investigated the involvement of chrysin in the blockade of cell cycle and apoptosis in distinct cell lines subjected to two H1N1 influenza A virus (IAV) strains, as well as its anti-IAV activity in vivo. Here, we found an early unidentified finding that chrysin strongly impeded IAV replication through a mechanism that was autonomous of innate antiviral immune activation and viral protein interaction. Surprisingly, chrysin can suppress IAV-induced cell cycle arrest in the G0/G1 phase by downregulating the expression levels of P53 and P21 while promoting Cyclin D1/CDK4 and Cyclin E1/CDK2 activation. Furthermore, chrysin dramatically inhibited the IAV-triggered mitochondrial apoptotic pathway by altering the balance of Bax/Bcl-xl and reducing caspase-9 and caspase-3 activation. Accumulated reactive oxygen species (ROS) reduction may contribute to the inhibitory role of chrysin in cell cycle arrest and apoptosis following IAV infection. Notably, chrysin preferably inhibited IAV replication in the upper respiratory tract, indicating that it might be a promising drug for restraining the spread of respiratory viruses.

The neuroprotective and neurorescue effects of carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson's disease.

Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons. Thus the development of therapeutic neuroprotection and neurorescue strategies to mitigate disease progression is important. In this study we evaluated the neuroprotective/rescue effects of erythropoietin Fc fusion protein (EPO-Fc) and carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson's disease. Adult female Sprague-Dawley rats received intraperitoneal injection of EPO-Fc, CEPO-Fc or PBS. Behavioral evaluations consisted of rota-rod, cylinder and amphetamine-induced rotation tests. In the neuroprotection experiment, the CEPO-Fc group demonstrated significant improvement compared with the EPO-Fc group on the amphetamine-induced rotation test throughout the four-week follow-up period. Histologically, significantly more tyrosine hydroxylase (TH)-positive neurons were recognized in the substantia nigra (SN) pars compacta in the CEPO-Fc group than in the PBS and EPO-Fc groups. In the neurorescue experiment, rats receiving CEPO-Fc showed significantly better behavioural scores than those receiving PBS. The histological data concerning striatum also showed that the CEPO-Fc group had significantly better preservation of TH-positive fibers compared to the PBS and EPO-Fc groups. Importantly, there were no increases in hematocrit or hemoglobin levels in the CEPO-Fc group in either the neuroprotection or the neurorescue experiments. In conclusion, the newly developed CEPO-Fc might confer neuroprotective and neurorescue benefits in a rat model of Parkinson's disease without the side effects associated with polycythemia. CEPO-Fc might be a therapeutic tool for patients with Parkinson's disease.

Urinary 8-OHdG elevations in a partial lesion rat model of Parkinson's disease correlate with behavioral symptoms and nigrostriatal dopaminergic depletion.

Increased oxidative stress contributes to pathogenesis of Parkinson's disease (PD). 8-hydroxy-2'-deoxyguanosine (8-OHdG) is the oxidation product most frequently measured as an indicator of oxidative DNA damage. Several studies have shown increased 8-OHdG in PD patients. There are few basic laboratory data examining 8-OHdG levels in animal models of PD. In this study, we utilized hemiparkinsonian model of rats induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA). The urinary 8-OHdG level was measured in relation to behavioral and pathological deficits arising from 6-OHDA-induced neurotoxic effects on the nigrostriatal dopaminergic pathway. All rats were subjected to a series of behavioral tests for 42 days after 6-OHDA injection. We collected urine samples with subsequent measurement of 8-OHdG level using ELISA kits. For immunohistochemical evaluation, tyrosine hydroxylase (TH) staining was performed. Significant increments in urinary 8-OHdG level were observed continuously from day 7 until day 35 compared to control group, which showed a trend of elevation as early as day 3. Such elevated urinary 8-OHdG level significantly correlated with all of the behavioral deficits measured here, suggesting that urinary 8-OHdG level provides a good index of severity of parkinsonism. Urinary 8-OHdG level also had a significant positive correlation with the survival rate of dopaminergic fibers or neurons, advancing the concept that oxidative stress during the early phase of 6-OHDA neurotoxicity may correspond to disease progression closely approximating neuronal degeneration in the nigrostriatal dopaminergic system. The present results demonstrate that alterations in urinary 8-OHdG level closely approximate onset and disease progression in PD.