Stem Cell-Based Therapy for Experimental Ischemic Stroke: A Preclinical Systematic Review.

Stem cell transplantation offers promise in the treatment of ischemic stroke. Here we utilized systematic review, meta-analysis, and meta-regression to study the biological effect of stem cell treatments in animal models of ischemic stroke. A total of 98 eligible publications were included by searching PubMed, EMBASE, and Web of Science from inception to August 1, 2020. There are about 141 comparisons, involving 5,200 animals, that examined the effect of stem cell transplantation on neurological function and infarct volume as primary outcome measures in animal models for stroke. Stem cell-based therapy can improve both neurological function (effect size, -3.37; 95% confidence interval, -3.83 to -2.90) and infarct volume (effect size, -11.37; 95% confidence interval, -12.89 to -9.85) compared with controls. These results suggest that stem cell therapy could improve neurological function deficits and infarct volume, exerting potential neuroprotective effect for experimental ischemic stroke, but further clinical studies are still needed.

Neuroprotective Effect of Astragaloside IV on Cerebral Ischemia/Reperfusion Injury Rats Through Sirt1/Mapt Pathway.

Background: Ischemic stroke is a common disease with poor prognosis, which has become one of the leading causes of morbidity and mortality worldwide. Astragaloside IV (AS-IV) is the main bioactive ingredient of Astragali Radix (which has been used for ischemic stroke for thousands of years) and has been found to have multiple bioactivities in the nervous system. In the present study, we aimed to explore the neuroprotective effects of AS-IV in rats with cerebral ischemia/reperfusion (CIR) injury targeting the Sirt1/Mapt pathway. Methods: Sprague-Dawley rats (male, 250-280 g) were randomly divided into the Sham group, middle cerebral artery occlusion/reperfusion (MCAO/R) group, AS-IV group, MCAO/R + EX527 (SIRT1-specific inhibitor) group, and AS-IV + EX527 group. Each group was further assigned into several subgroups according to ischemic time (6 h, 1 d, 3 d, and 7 days). The CIR injury was induced in MCAO/R group, AS-IV group, MCAO/R + EX527 group, and AS-IV + EX527 group by MCAO surgery in accordance with the modified Zea Longa criteria. Modified Neurological Severity Scores (mNSS) were used to evaluate the neurological deficits; TTC (2,3,5-triphenyltetrazolium chloride) staining was used to detect cerebral infarction area; Western Blot was used to assess the protein levels of SIRT1, acetylated MAPT (ac-MAPT), phosphorylated MAPT (p-MAPT), and total MAPT (t-MAPT); Real-time Quantitative Polymerase Chain Reaction (qRT-PCR) was used in the detection of Sirt1 and Mapt transcriptions. Results: Compared with the MCAO/R group, AS-IV can significantly improve the neurological dysfunction (p < 0.05), reduce the infarction area (p < 0.05), raise the expression of SIRT1 (p < 0.05), and alleviate the abnormal hyperacetylation and hyperphosphorylation of MAPT (p < 0.05). While compared with the AS-IV group, AS-IV + EX527 group showed higher mNSS scores (p < 0.05), more severe cerebral infarction (p < 0.05), lower SIRT1 expression (p < 0.01), and higher ac-MAPT and p-MAPT levels (p < 0.05). Conclusion: AS-IV can improve the neurological deficit after CIR injury in rats and reduce the cerebral infarction area, which exerts neuroprotective effects probably through the Sirt1/Mapt pathway.

Preclinical systematic review of ginsenoside Rg1 for cognitive impairment in Alzheimer's disease.

Ginseng has been used for the treatment of aging and memory impairment for thousands of years. Several studies have found that ginsenoside Rg1, as one of the main active components of ginseng, could potentially improve cognitive function in several different animal models. A preclinical systematic review to evaluate the efficacy and mechanisms of ginsenoside Rg1 for ameliorating cognitive impairments in Alzheimer's disease is reported here. We searched six databases from their inceptions to January 2019. Thirty-two studies were selected, which included a total of 1,643 animals. According to various cognitive behavioral tests, the results of the meta-analyses showed that ginsenoside Rg1 significantly improved cognitive behavioral impairments in most Alzheimer's disease models (P < 0.05), but there were no significant effects in animals with neuronal degeneration induced by chronic stress or in SAMP8 transgenic mice. The potential mechanisms included antioxidant and anti-inflammatory effects, amelioration of Alzheimer's disease-related pathology, synapse protection, and up-regulation of nerve cells via multiple signaling pathways.

Extracts or Active Components from Acorus gramineus Aiton for Cognitive Function Impairment: Preclinical Evidence and Possible Mechanisms.

Extracts or active components from Acorus gramineus Aiton (EAAGA) have been clinically used for cognition impairment more than hundreds of years and are still used in modern times in China and elsewhere worldwide. Previous studies reported that EAAGA improves cognition impairment in animal models. Here, we conducted a preclinical systematic review to assess the current evidence of EAAGA for cognition impairment. We searched 7 databases up until June 2019. Methodological quality for each included studies was accessed according to the CAMARADES 10-item checklist. The primary outcome measures were neurobehavioral function scores evaluated by the Morris water maze test, electrical Y-maze test, step-down test, radial eight-arm maze test, and step-through test. The secondary outcome measures were mechanisms of EAAGA for cognition function. Finally, 34 studies involving 1431 animals were identified. The quality score of studies range from 1 to 6, and the median was 3.32. Compared with controls, the results of the meta-analysis indicated EAAGA exerted a significant effect in decreasing the escape latency and error times and in increasing the length of time spent in the platform quadrant and the number of platform crossings representing learning ability and memory function (all P < 0.01). The possible mechanisms of EAAGA are largely through anti-inflammatory, antioxidant, antiapoptosis activities, inhibition of neurotoxicity, regulating synaptic plasticity, protecting cerebrovascular, stimulating cholinergic system, and suppressing astrocyte activation. In conclusion, EAAGA exert potential neuroprotective effects in experimental cognition impairment, and EAAGA could be a candidate for cognition impairment treatment and further clinical trials.

Sanhua Decoction, a Classic Herbal Prescription, Exerts Neuroprotection Through Regulating Phosphorylated Tau Level and Promoting Adult Endogenous Neurogenesis After Cerebral Ischemia/Reperfusion Injury.

Background: Ischemia stroke is the leading cause of death and long-term disability. Sanhua Decoction (SHD), a classic Chinese herbal prescription, has been used for ischemic stroke for about thousands of years. Here, we aim to investigate the neuroprotective effects of SHD on cerebral ischemia/reperfusion (CIR) injury rat models. Methods: The male Sprague-Dawley rats (body weight, 250-280 g; age, 7-8 weeks) were randomly divided into sham group, CIR group, and SHD group and were further divided into subgroups according to different time points at 6 h, 1, 3, 7, 14, 21, and 28 d, respectively. The SHD group received intragastric administration of SHD at 10 g kg-1 d-1. The focal CIR models were induced by middle cerebral artery occlusion according to Longa's method, while sham group had the same operation without suture insertion. Neurological deficit score (NDS) was evaluated using the Longa's scale. BrdU, doublecortin (DCX), and glial fibrillary acidic protein (GFAP) were used to label proliferation, migration, and differentiation of nerve cells before being observed by immunofluorescence. The expression of reelin, total tau (t-tau), and phosphorylated tau (p-tau) were evaluated by western blot and RT-qPCR. Results: SHD can significantly improve NDS at 1, 3, 7, and 14 d (p < 0.05), increase the number of BrdU positive and BrdU/DCX positive cells in subventricular zone at 3, 7, and 14 d (p < 0.05), upregulate BrdU/GFAP positive cells in the ischemic penumbra at 28 d after CIR (p < 0.05), and reduce p-tau level at 1, 3, 7, and 14 d (p < 0.05). There was no significant difference on reelin and t-tau level between three groups at each time points after CIR. Conclusions: SHD exerts neuroprotection probably by regulating p-tau level and promoting the proliferation, migration, and differentiation of endogenous neural stem cells, accompanying with neurobehavioral recovery.

Kaixinsan, a Well-Known Chinese Herbal Prescription, for Alzheimer's Disease and Depression: A Preclinical Systematic Review.

Alzheimer's disease (AD), the most common cause of dementia, is highly prevalent worldwide with no modifying therapy. Behavioral and psychological symptoms of dementia (BPSD) occur in most patients with AD, and depression is one of the most common AD-related BPSD. Kaixinsan (KXS) is an ancient Chinese herbal prescription widely used to treat dementia and forgetfulness. In this systematic review, we conducted a meta-analysis to assess preclinical evidence for the effects of KXS on cognitive impairment and depression. Thirty-eight articles involving 1,050 animals were included after searching from six databases from the inception up to June 2019. The primary outcome measures were behavioral outcome. Indicators of cognitive function in AD included escape latency, time spent on the target quadrant, and the number of target platform crossings in the Morris water maze (MWM) test. Indicators of depression included number of rearing events and total distance in the open-field test, duration of immobility in the forced swim test, and sucrose consumption or sucrose preference index in the sucrose preference test. The secondary outcomes were mechanisms of KXS for treatment of AD and depression. The results showed that KXS significantly reduced escape latency (P < 0.01), increased time spent in the target quadrant (P < 0.01), and increased the number of target platform crossings (P < 0.01) in the MWM test in AD models compared with control. The possible mechanisms for KXS-mediated improvements in cognitive function were antioxidant activity, anti-inflammatory activity, antiapoptotic activity, neuroprotection, and synapse protection. In addition, the results demonstrated that KXS significantly increased the number of rearing instances (P < 0.01) in the open-field test, decreased the duration of immobility (P < 0.01) in forced swim test, and increased sucrose consumption or sucrose preference index (P < 0.01) in the sucrose preference test in depression models compared with control. The mechanisms of KXS-mediated anti-depressive effects were HPA axis regulation, antioxidant activity, anti-inflammatory activity, synapse protection, and neuroprotection. The results of this study suggested that KXS can be used to effectively treat AD and depression through multiple mechanisms, extrapolating the therapeutic potential of KXS for treating AD-related BPSD.

[Three-dimensional low-dose CT volume reconstruction based on non-local weights optimization and GPU acceleration].

OBJECTIVE: Concerns have been raised over x-ray radiation dose associated with repeated computed tomography (CT) scans for tumor surveillance and radiotherapy planning. In this paper, we present a low-dose CT image reconstruction method for improving low-dose CT image quality. The method proposed exploited rich redundancy information from previous normal-dose scan image for optimizing the non-local weights construction in the original non-local means (NLM)-based low-dose image reconstruction. The objective 3D low-dose volume and the previous 3D normal-dose volume were first registered to reduce the anatomic structural dissimilarity between the two datasets, and the optimized non-local weights were constructed based on the registered normal-dose volume. To increase the efficiency of this method, GPU was utilized to accelerate the implementation. The experimental results showed that this method obviously improved the image quality, as compared with the original NLM method, by suppressing the noise-induced artifacts and preserving the edge information.