TLR4 Enhances Cerebral Ischemia/Reperfusion Injury via Regulating NLRP3 Inflammasome and Autophagy.

Ischemic stroke is a kind of central nervous disease characterized by high morbidity, high mortality, and high disability. Inflammation and autophagy play important roles in cerebral ischemia/reperfusion (CI/R) injury. The present study characterizes the effects of TLR4 activation on inflammation and autophagy in CI/R injury. An in vivo CI/R rat injury model and an in vitro hypoxia/reoxygenation (H/R) SH-SY5Y cell model were established. Brain infarction size, neurological function, cell apoptosis, inflammatory mediators' levels, and gene expression were measured. Infarction, neurological dysfunction, and neural cell apoptosis were induced in CI/R rats or in H/R-induced cells. The expression levels of NLRP3, TLR4, LC3, TNF-α, interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-18 (IL-18) clearly increased in I/R rats or in H/R-induced cells, while TLR4 knockdown significantly suppressed NLRP3, TLR4, LC3, TNF-α, and interleukin-1/6/18 (IL-1/6/18) in H/R-induced cells, as well as cell apoptosis. These data indicate that TLR4 upregulation induced CI/R injury via stimulating NLRP3 inflammasome and autophagy. Therefore, TLR4, is a potential therapeutic target to improve management of ischemic stroke.

Association between white matter alterations and domain-specific cognitive impairment in cerebral small vessel disease: A meta-analysis of diffusion tensor imaging.

Objective: To investigate the association between diffusion tensor imaging (DTI) findings and domain-specific cognitive impairment in cerebral small vessel disease (CSVD). Methods: Databases such as PubMed, Excerpta Medical Database (EMBASE), Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure Databases (CNKI), Wanfang, Chinese Biomedical Literature Database (SinoMed), and Chongqing Chinese Science and Technology Periodical Database (VIP) were comprehensively retrieved for studies that reported correlation coefficients between cognition and DTI values. Random effects models and meta-regression were applied to account for heterogeneity among study results. Subgroup and publication bias analyses were performed using Stata software. Results: Seventy-seven studies involving 6,558 participants were included in our meta-analysis. The diagnosis classification included CSVD, white matter hyperintensities (WMH), subcortical ischemic vascular disease, cerebral microbleeding, cerebral amyloid angiopathy (CAA), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and Fabry disease. The pooled estimates showed that the fractional anisotropy (FA)-overall exhibited a moderate correlation with general cognition, executive function, attention, construction, and motor performance (r = 0.451, 0.339, 0.410, and 0.319), and the mean diffusitivity/apparent diffusion coefficient (MD/ADC)-overall was moderately associated with general cognition, executive function, and memory (r = -0.388, -0.332, and -0.303, respectively; p s < 0.05). Moreover, FA in cingulate gyrus (CG), cerebral peduncle (CP), corona radiata (CR), external capsule (EC), frontal lobe (FL), fornix (FOR), internal capsule (IC), and thalamic radiation (TR) was strongly correlated with general cognition (r = 0.591, 0.584, 0.543, 0.662, 0.614, 0.543, 0.597, and 0.571), and a strong correlation was found between MD/ADC and CG (r = -0.526), normal-appearing white matter (NAWM; r = -0.546), and whole brain white matter (WBWM; r = -0.505). FA in fronto-occipital fasciculus (FOF) (r = 0.523) and FL (r = 0.509) was strongly associated with executive function. Only MD/ADC of the corpus callosum (CC) was strongly associated with memory (r = -0.730). Besides, FA in CG (r = 0.532), CC (r = 0.538), and FL (r = 0.732) was strongly related to the attention domain. Finally, we found that the sample size, etiology, magnetic resonance imaging (MRI) magnet strength, study type, and study quality contributed to interstudy heterogeneity. Conclusion: Lower FA or higher MD/ADC values were related to more severe cognitive impairment. General cognition and executive function domains attracted the greatest interest. The FL was commonly examined and strongly associated with general cognition, executive function, and attention. The CC was strongly associated with memory and attention. The CG was strongly related to general cognition and attention. The CR, IC, and TR were also strongly related to general cognition. Indeed, these results should be validated in high-quality prospective studies with larger sample sizes. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO, identifier: CRD42021226133.

SOS1-IT1 silencing alleviates MPP+-induced neuronal cell injury through regulating the miR-124-3p/PTEN/AKT/mTOR pathway.

Long non-coding RNA (lncRNA) has been found to be involved in the regulation of a variety of disease progression, including Parkinson's disease (PD). However, the role and underlying mechanism of SOS1 intronic transcript 1 (SOS1-IT1) in the progression of PD is still unclear. 1-methyl-4-phenyl pyridine (MPP+) induced SK-N-SH cells were used to construct PD cell models in vitro. The expression levels of SOS1-IT1, microRNA (miR)-124-3p and phosphatase and tensin homolog (PTEN) were determined using quantitative real-time PCR. Cell counting kit 8 assay and flow cytometry were used to measure cell viability and apoptosis. Western blot analysis was performed to detect protein expression. The levels of inflammation cytokines and oxidative stress markers were examined to assess cell inflammation and oxidative stress. In addition, dual-luciferase reporter assay, RIP assay and RNA pull-down assay were used to confirm RNA interaction. Our results showed that SOS1-IT1 was upregulated in MPP+-induced SK-N-SH cells, and its silencing reversed the inhibition effect of MPP+ on the viability and the promotion effect on the apoptosis, inflammation and oxidative stress of SK-N-SH cells. MiR-124-3p was targeted by SOS1-IT1, and its inhibitor reversed the suppressive effect of SOS1-IT1 knockdown on MPP+-induced SK-N-SH cell injury. Furthermore, PTEN was a target of miR-124-3p, and the reduction effect of miR-124-3p on MPP+-induced SK-N-SH cell injury was reversed by PTEN overexpression. Additionally, the activity of AKT/mTOR pathway was regulated by the SOS1-IT1/miR-124-3p/PTEN axis. In conclusion, SOS1-IT1 regulated the miR-124-3p/PTEN/AKT/mTOR pathway to participate in the regulation of MPP+-induced neuronal cell injury, indicating the SOS1-IT1 might be an effective therapeutic target for PD.

Decreased spasticity of Baishaoluoshi Decoction through the BDNF/TrKB-KCC2 pathway on poststroke spasticity rats.

OBJECTIVE: K+-Cl- cotransporter-2 (KCC2), which primarily extrudes chloride in mature neurons, triggers hemiplegia limb spasticity after ischemic stroke by affecting neuronal excitability. Our previous study revealed that the Chinese herb Baishaoluoshi Decoction decreases hemiplegia limb spasticity in poststroke spasticity (PSS) patients. This study aimed at elucidating on the effects of Baishaoluoshi Decoction on the BDNF/TrKB-KCC2 pathway in PSS rat models. METHODS: Middle cerebral artery occlusion (MCAO) was adopted for the establishment of PSS rat models. Muscle tension was evaluated by Modified Ashworth Scale. Nissl staining and transmission electron microscopy were used to measure the protective effects of Baishaoluoshi Decoction on ischemic injury-induced neuronal damage due to MCAO. Expression levels of BDNF, TrKB, and KCC2 in brain tissues around the infarct and brainstem were detected by immunohistochemical staining. RESULTS: It was found that Baishaoluoshi Decoction suppressed hemiplegia limb spasticity and alleviated the damage in neurons and synapses in PSS rat models. Importantly, the expression of BDNF, TrKB, and KCC2 in brain tissues around the infarct and brainstem were significantly upregulated after treatment with low-dose and high-dose Baishaoluoshi Decoction. CONCLUSION: Suppression of spasticity by Baishaoluoshi Decoction in PSS rat models may be correlated with upregulated BDNF/TrKB-KCC2 pathway, which may be a complementary therapeutic strategy for PSS.