A nonhuman primate model of ischemic stroke is considered as an ideal preclinical model to replicate various aspects of human stroke because of their similarity to humans in genetics, neuroanatomy, physiology, and immunology. However, it remains challenging to produce a reliable and reproducible stroke model in nonhuman primates due to high mortality and variable outcomes. Here, we developed a focal cerebral ischemic model induced by topical application of 50% ferric chloride (FeCl3) onto the MCA-M1 segment through a cranial window in the cynomolgus monkeys. We found that FeCl3 rapidly produced a stable intraarterial thrombus that caused complete occlusion of the MCA, leading to the quick decrease of the regional cerebral blood flow in 10 min. A typical cortical infarct was detected 24 hours by magnetic resonance imaging (MRI) and was stable at least for 1 month after surgery. The sensorimotor deficit assessed by nonhuman primate stroke scale was observed at 1 day and up to 3 months after ischemic stroke. No spontaneous revascularization or autolysis of thrombus was observed, and vital signs were not affected. All operated cynomolgus monkeys survived. Our data suggested that FeCl3-induced stroke in nonhuman primates was a replicable and reliable model that is necessary for the correct prediction of the relevance of experimental therapeutic approaches in human beings.

Nonhuman primates are closer to human beings than rodents in genetics, neuroanatomy, physiology and immunology. Nonhuman primates are therefore considered an ideal preclinical model to replicate various aspects of human stroke. Ischemia stroke models in nonhuman primates can better fit the physiological symptoms and changes in humans after cerebral ischemia. Currently, various construction methods and neurological evaluation methods have been developed and applied to stroke models of nonhuman primates, including craniectomy models, endovascular stroke models, autologous thrombus models and intraluminal filament models. Meanwhile, new innovative methods have emerged, such as the endothelin-1 model and photothrombosis model. In the past thirty years, these model studies have explored various mechanisms that are initiated in the first minutes, hours, and days after a stroke. Permanent and temporary middle cerebral artery occlusion models have been trying to simulate the complex situation of human stroke. However, a comprehensive comparison of the above methods, including their advantages and disadvantages, difficulty and application fields, is limited. Here, we introduce various modeling methods that are currently available for nonhuman primate stroke models, compare the differences between these different preparation methods, and analyze the advantages and disadvantages of the various methods and the fields of application. The imaging detection methods of nonhuman primates after cerebral ischemia and the neurological evaluation methods after stroke are also discussed briefly. Methods are sorted and compared so that scholars can choose appropriate modeling methods and evaluation methods to establish nonhuman primate stroke models.

ObjectiveAlthough liver diseases have already been identified as a risk factor for increased recurrence and mortality in patients with chronic subdural hematoma (CSDH), the association between subclinical liver disease, specifically liver fibrosis (LF), and CSDH remains unknown. In the present study, we aimed to investigate the association between the LF scores and CSDH recurrence.MethodsWe retrospectively analyzed consecutive patients with CSDH who underwent burr-hole irrigation in the First Affiliated Hospital of Wenzhou Medical University between January 2015 and December 2018. The clinical data were collected, and the LF scores were calculated including aspartate aminotransferase–platelet ratio index (APRI), fibrosis-4 (FIB-4), and Forns index. Multivariable logistic regression analysis was applied to identify the association between the LF scores and CSDH recurrence, and Cox regression model and Fine–Gray competing risks model were performed to calculate hazard ratios (HRs) for CSDH recurrence based on time-to-event outcomes. The C-statistic, the integrated discrimination improvement (IDI), and the net reclassification improvement (NRI) evaluated the additive value of the LF scores to predict the recurrence of CSDH.ResultsA total of 419 patients with CSDH were included, hematoma recurrence was observed in 62 patients (14.80%) within 1 year after surgery. The LF scores were significantly higher in those who recurred, whereas the standard hepatic assays were mostly normal. The patients were assigned to groups of high and low LF scores based on the validated cut-offs; compared with the subjects with low scores, those with high score levels had significantly higher recurrence rates. After adjusting for potential confounders, the LF scores were independently associated with CSDH recurrence, multivariable-adjusted HRs (95% CI) for those with higher levels of APRI, FIB-4, and Forns score were 4.32 (1.37–13.60), 2.56 (1.20–5.43), and 2.02 (1.07–3.79) for the recurrence of CSDH, respectively. Moreover, adding the APRI to the conventional model improved the C-statistic from 0.731 to 0.763, with an NRI and IDI of 7.50 and 1.35%, respectively. Two further commonly-used LF score indices (FIB-4 score and Forns index) yielded comparable results.ConclusionsThe data from this study first indicated that the high LF scores were significantly associated with the recurrence of CSDH and that careful follow-up in these patients may be needed.

Antioxidants with high efficacy and low toxicity have the potential to treat cerebral ischemia reperfusion injury (CIRI). Dienone monocarbonyl curcumin analogs (DMCA) capable of overcoming the instability and pharmacokinetic defects of curcumin possess notable antioxidant activity but are found to be significantly toxic. In this study, a novel skeleton of the monoenone monocarbonyl curcumin analogue sAc possessing reduced toxicity and improved stability was designed on the basis of the DMCA skeleton. Moreover, 32 sAc analogs were obtained by applying a green, simple, and economical synthetic method. Multiple sAc analogs with an antioxidant protective effect in PC12 cells were screened using an H2O2-induced oxidative stress damage model, and quantitative evaluation of structure-activity relationship (QSAR) model with regression coefficient of R2 = 0.918921 was built through random forest algorithm (RF). Among these compounds, the optimally active compound sAc15 elicited a potent protective effect on cell growth of PC12 cells by effectively eliminating ROS generation in response to oxidative stress injury by activating the Nrf2/HO-1 antioxidant signaling pathway. In addition, sAc15 exhibited good protection against CIRI in the mice middle cerebral artery occlusion (MCAO) model. In this paper, we provide a novel class of antioxidants and a potential compound for stroke treatment.

Bone marrow mesenchymal stem cells (BMMSCs)-based therapy has emerged as a promising novel therapy for Traumatic Brain Injury (TBI). However, the therapeutic quantity of viable implanted BMMSCs necessary to initiate efficacy is still undetermined. Increased oxidative stress following TBI, which leads to the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase signaling pathway, has been implicated in accounting for the diminished graft survival and therapeutic effect. To prove this assertion, we silenced the expression of NADPH subunits (p22-phox, p47-phox, and p67-phox) and small GTPase Rac1 in BMMSCs using shRNA. Our results showed that silencing these proteins significantly reduced oxidative stress and cell death/apoptosis, and promoted implanted BMMSCs proliferation after TBI. The most significant result was however seen with Rac1 silencing, which demonstrated decreased expression of apoptotic proteins, enhanced in vitro survival ratio, reduction in TBI lesional volume and significant improvement in neurological function post shRac1-BMMSCs transplantation. Additionally, two RNA-seq hub genes (VEGFA and MMP-2) were identified to play critical roles in shRac1-mediated cell survival. In summary, we propose that knockdown of Rac1 gene could significantly boost cell survival and promote the recovery of neurological functions after BMMSCs transplantation in TBI mice.

The tumor microenvironment (TME) plays an important role in the growth and invasion of glioma. This study aimed to analyze the composition of the immune microenvironment in glioma samples and analyze the important differentially expressed genes to identify novel immune-targeted therapy for glioma. We downloaded transcriptomic data of 669 glioma samples from The Cancer Genome Atlas database. CIBERSORT and ESTIMATE methods were used to calculate the proportion of tumor-infiltrating immune cells and ratio of immune and stromal components in the TME. The differentially expressed genes (DEGs) were screened by comparing the genes expressed by both stromal and immune cells. Annexin A1 (ANXA1) was determined to be an important prognostic indicator through the common overlap of univariate Cox regression analysis and protein–protein interaction network analysis. The proportion of tumor-infiltrating immune cells, calculated by CIBERSORT algorithm, had a significant difference in distribution among the high and low ANXA1 expression groups, indicating that ANXA1 could be an important immune marker of TME. Furthermore, ANXA1 level was positively correlated with the histopathological factors and negatively related to the survival of glioma patients based on the analysis of multiple databases. Finally, in vitro experiments verified that antagonizing ANXA1 expression promoted cell apoptosis and inhibited the invasion and migration capacities of glioma cells. Therefore, ANXA1 due to its immune-related functions, can be an important prognostic indicator and immune microenvironmental marker for gliomas. Further studies are warranted to confirm ANXA1 as a potential immunotherapeutic target for gliomas.