Translational Neuroscience最新文献

Objective: The objective of this study was to investigate the effect of modified Dioscorea pills (MDP) on microcirculatory remodeling in the hippocampus of rats with chronic cerebral hypoperfusion (CCH) through the angiopoietin (Ang)/tyrosine kinase receptor tyrosine kinase with immunoglobulin-like and EGF-like domains (Ang receptor) 2 (Tie-2) signaling pathways, which may underlie the cognitive improvement observed in CCH rats.

Methods: Forty male Sprague-Dawley rats raised under specific pathogen-free conditions were randomly divided into three groups: control group (10 rats), model group (15 rats), and MDP group (15 rats). The rats in the model group and MDP group underwent bilateral common carotid artery occlusion using the 2-vessel occlusion (2-VO) method to induce CCH. Rats in the control group underwent the same surgical procedures as those in the model group, except for ligation and occlusion of the carotid arteries. After 1 week of 2-VO, rats in the MDP group were administered MDP condensed decoction intragastrically at a dose of 1 ml/100 g body weight (prepared by the Preparation Room of Hubei Provincial Hospital of Traditional Chinese Medicine) for 45 days, while rats in the other two groups received normal saline intragastrically with the same dose and duration as the MDP group. After the intervention, all rats were euthanized, and brain perfusion was performed to obtain the hippocampal tissue for analysis. Immunohistochemical staining for CD43 was performed to assess microvessel density (MVD); western blot and the reverse transcription-polymerase chain reaction (RT-PCR) were used to analyze the expression of proteins and genes in angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), Tie-2, and vascular endothelial growth factor (VEGF) proteins and genes in the hippocampal tissue and compute the Ang-1/Ang-2 ratio.

Results: MDP treatment reduced neuronal loss and promoted restoration of the damaged hippocampal structure in CCH rats. The model group showed significantly higher MVD (14.93 ± 1.92) compared to the control group (5.78 ± 1.65) (P < 0.01), whereas MDP treatment further increased MVD (21.19 ± 2.62). Western blot and RT-PCR analysis revealed that CCH significantly increased the expression of Ang-1, Ang-2, Tie-2, and VEGF proteins and genes, while MDP treatment further significantly upregulated the expression of these proteins and genes. In addition, MDP significantly elevated the gene and protein expression of the Ang-1/Ang-2 ratio compared to the control group (P = 0.041, P = 0.029).

Conclusion: CCH induces microvascular neogenesis in the hippocampus, and MDP promotes angiogenesis and microcirculation remodeling in CCH rats via the Ang/Tie signaling pathway, which may be an important mechanism for its restorative effects on hippocampal perfusion and improvement of cognitive function in CCH rats.

Objective: The aim of this study was to ascertain whether dynamic cerebral autoregulation (CA) in the middle cerebral artery (MCA) is disturbed by cerebral infarctions outside the MCA territory.

Methods: We estimated transfer function parameters gain and phase from simultaneous recordings of spontaneous oscillation in blood pressure and MCA cerebral blood flow velocity in 10 consecutive patients with isolated anterior cerebral artery (ACA) infarctions and in 22 consecutive patients with isolated posterior cerebral artery (PCA) infarctions. All ACA infarctions were in the motor, premotor, or supplementary motor cortex areas and presented with pronounced leg hemiparesis. Twenty-eight age- and sex-matched healthy subjects served as controls.

Results: Compared to controls, phase was significantly reduced in the MCA ipsilateral to the lesion site and in the contralateral MCA (unaffected hemisphere) in the very low (0.02-0.07 Hz) and low (0.07-0.15 Hz) frequency ranges in the ACA infarctions but not in the PCA infarctions. Gain was reduced only in the very low frequency range in the MCA contralateral to the ACA lesion site. Systemic factors were unrelated to phase and gain results.

Conclusion: Bilateral impairment of MCA dynamic CA in patients with a unilateral ACA infarction is frequent.

Objective: The main objective of this study is to design a custom-made weight-drop impactor device to produce a consistent spinal cord contusion model in rats in order to examine the efficacy of potential therapies for post-traumatic spinal cord injuries (SCIs).

Methods: Adult female Sprague-Dawley rats (n = 24, 11 weeks old) were randomly divided equally into two groups: sham and injured. The consistent injury pattern was produced by a 10 g stainless steel rod dropped from a height of 30 mm to cause (0.75 mm) intended displacement to the dorsal surface of spinal cord. The neurological functional outcomes were assessed at different time intervals using the following standardized neurobehavioral tests: Basso, Beattie, and Bresnahan (BBB) scores, BBB open-field locomotion test, Louisville Swim Scale (LSS), and CatWalk gait analysis system.

Results: Hind limb functional parameters between the two groups using BBB scores and LSS were significantly different (p < 0.05). There were significant differences (p < 0.05) between the SCI group and the sham group for the hind limb functional parameters using the CatWalk gait analysis.

Conclusion: We developed an inexpensive custom-made SCI device that yields a precise adjustment of the height and displacement of the impact relative to the spinal cord surface.

Presently, traumatic brain injury (TBI) is a leading contributor to disability and mortality that places a considerable financial burden on countries all over the world. Docosahexaenoic acid and eicosapentaenoic acid are two kinds of omega-3 polyunsaturated fatty acids (ω-3 PUFA), both of which have been shown to have beneficial biologically active anti-inflammatory and antioxidant effects. However, the neuroprotective effect of ω-3 PUFA in TBI has not been proven, and its probable mechanism remains obscure. We suppose that ω-3 PUFA can alleviate early brain injury (EBI) via regulating necroptosis and neuroinflammation after TBI. This research intended to examine the neuroprotective effect of ω-3 and its possible molecular pathways in a C57BL/6 mice model of EBI caused by TBI. Cognitive function was assessed by measuring the neuronal necroptosis, neuroinflammatory cytokine levels, brain water content, and neurological score. The findings demonstrate that administration of ω-3 remarkably elevated neurological scores, alleviated cerebral edema, and reduced inflammatory cytokine levels of NF-κB, interleukin-1β (IL-1β), IL-6, and TNF-α, illustrating that ω-3 PUFA attenuated neuroinflammation, necroptosis, and neuronal cell death following TBI. The PPARγ/NF-κB signaling pathway is partially responsible for the neuroprotective activity of ω-3. Collectively, our findings illustrate that ω-3 can alleviate EBI after TBI against neuroinflammation and necroptosis.

Background: Ca²⁺ channels are abnormally expressed in various tumor cells and are involved in the progression of human glioma. Here, we explored the role of a calcium channel, voltage-dependent, T-type, alpha 1H subunit (CACNA1H), which encodes T-type Ca²⁺ channel Cav3.2 in glioma cells.

Methods: Cell viability and apoptosis were detected using cell-counting kit-8 and flow cytometry, respectively. The expression of target protein was determined using western blot analysis.

Results: Cell viability of U251 cells was inhibited significantly after the knockdown of CACNA1H. The apoptosis of U251 cells was enhanced significantly after the knockdown of CACNA1H. Importantly, knockdown of CACNA1H decreased the levels of p-PERK, GRP78, CHOP, and ATF6, indicating that CACNA1H knockdown activated endoplasmic reticulum stress (ERS) in U251 cells. In addition, T-type Ca²⁺ channel inhibitor NNC55-0396 also induced apoptosis through the activation of ERS in U251 cells. ERS inhibitor UR906 could block CACNA1H inhibitor ABT-639-induced apoptosis.

Conclusion: Suppression of CACNA1H activated the ERS and thus induced apoptosis in glioma cells. T-type Ca²⁺ channel inhibitors ABT-639 and NNC55-0396 also induced apoptosis through ERS in glioma cells. Our data highlighted the effect of CACNA1H as an oncogenic gene in human glioma.

This study aimed to explore the clinical characteristics of acute cerebral infarction (ACI) patients with thalassemia through the analysis of clinical data. Adult patients with ACI who were admitted to the First Affiliated Hospital of Hainan Medical College, the Second Affiliated Hospital of Hainan Medical College, Hainan Provincial People's Hospital, and the Department of Neurology of Haikou People's Hospital from January 2008 to December 2018 were enrolled. According to the eligibility criteria, 183 ACI patients were examined, of whom there were 33 cases with thalassemia, 50 cases with iron-deficiency anemia (IDA), and 100 non-anemic cases. Laboratory data, including platelet count, homocysteine count, and hemoglobin level, were collected. Besides, the results of auxiliary examinations, such as brain magnetic resonance imaging or computed tomography, carotid ultrasound, electrocardiogram, and cardiac color ultrasound, were collected. Baseline clinical data (e.g., history of smoking and drinking) were acquired. The clinical characteristics were compared and analyzed among the three groups. There were more female ACI patients with thalassemia than male ones. Furthermore, lesions in the thalassemia and IDA groups were mainly located in the region from the corona radiata and the centrum semiovale, in which multiple small infarcts were dominant. In the non-anemia group, patients' lesions were mainly found in the basal ganglia area, and single small infarcts had the highest proportion.

Background: The effect of circular RNA in many human cancers is widely studied. Nevertheless, their specific biological functions and mechanisms in glioma remain unclear.

Methods: CircEXOC6, miR-433-3p, and frizzled class receptor 6 (FZD6) mRNA expression levels were measured by quantitative reverse transcription polymerase chain reaction assay. Cell proliferation, migration, invasion, apoptosis, and angiogenesis were tested by colony formation, cell-light 5-ethynyl-2'-deoxyuridine, transwell, and tube formation assays, respectively. Moreover, glucose consumption and lactate production were calculated to evaluate the glycolytic metabolism using the respective kits. Western blot assay was carried out to measure the protein levels of apoptotic markers (Bcl-2 and Bax), glycolytic markers (HK2 and GLUT1), and FZD6. The targeted relationship of miR-433-3p and circEXOC6 or FZD6 was verified by dual-luciferase reporter or RNA immunoprecipitation assays. In vivo, xenograft and immunohistochemistry assay was conducted to discriminate the effect of circEXOC6.

Results: CircEXOC6 and FZD6 were highly expressed, while miR-433-3p was significantly lowly expressed in glioma tissues or cells. Deficiency of circEXOC6 inhibited cell proliferation, migration, invasion, angiogenesis, and glycolysis, and triggered cell apoptosis ratio in glioma; simultaneously, it could block the growth of tumor in vivo. In addition, miR-433-3p was a target of circEXOC6, and downregulated miR-433-3p could partly weaken the inhibitory effect of circEXOC6 deficiency. Besides, miR-433-3p enrichment inhibited cell progression and glycolysis in glioma, and the effect was reversed by overexpression of FZD6.

Conclusion: Deletion of circEXOC6 restrained cell progression and glycolysis by sponging miR-433-3p and interacting with FZD6, which might provide an underlying target for glioma treatment.

Mitochondria play a key role in the cerebral ischemia-reperfusion injury. Although the extracellular signal-regulated kinase 1/2 inhibitor PD98059 (PD) is a selective and reversible flavonoid that can protect the mitochondria in a rat model of cardiac arrest/cardiopulmonary resuscitation, its role requires further confirmation. In this study, we investigated whether PD could maintain mitochondrial homeostasis and decrease reactive oxygen species (ROS) production in neuroblastoma (SH-SY5Y) cells exposed to oxygen-glucose deprivation/reperfusion (OGD/R). PD improved the mitochondrial morphology and function, reversed the increase in ROS production and cell apoptosis, and reduced total-superoxide dismutase and Mn-superoxide dismutase activities induced by OGD/R. PD decreases ROS production and improves mitochondrial morphology and function, protecting SH-SY5Y cells against OGD/R-induced injury.

Objective: Parkinson's disease (PD) is the second most common neurodegenerative disease with complex pathogenesis. Although HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is upregulated in PD, its exact role in HOTAIRM1 is seldom reported. The purpose of this study is to research the effect of HOTAIRM1 on 1-methyl-4-phenylpyridonium (MPP⁺)-induced cytotoxicity and oxidative stress in SH-SY5Y cells.

Methods: SH-SY5Y cells were treated with MPP⁺ at various concentrations or time points to induce SH-SY5Y cytotoxicity, so as to determine the optimal MPP⁺ concentration and time point. HOTAIRM1 expression upon MPP⁺ treatment was analyzed through qRT-PCR. Next, HOTAIRM1 was downregulated to observe the variance of SH-SY5Y cell viability, apoptosis, oxidative stress-related indexes, and protein levels of the Nrf2/HO-1 pathway. In addition, rescue experiments were carried out to assess the role of Nrf2 silencing in HOTAIRM1 knockdown on MPP⁺-induced oxidative stress in SH-SY5Y cells.

Results: MPP⁺ treatment-induced cytotoxicity and upregulated HOTAIRM1 expression in SH-SY5Y cells in a dose- and time-dependent manner. Mechanically, HOTAIRM1 knockdown enhanced cell viability, limited apoptosis, and oxidative stress, therefore protecting SH-SY5Y cells from MPP⁺-induced SH-SY5Y cytotoxicity. On the other hand, HOTAIRM1 knockdown activated the protein levels of Nrf2 and HO-1. Nrf2 silencing could counteract the neuroprotective effect of HOTAIRM1 knockdown on in vitro PD model.

Conclusion: Our data demonstrated that HOTAIRM1 knockdown could inhibit apoptosis and oxidative stress and activated the Nrf2/HO-1 pathway, therefore exerting neuroprotective effect on the PD cell model.

Background: Stroke patients often show postural instability. The patellar tendon reflex is a basic physical examination for stroke patients. This study aimed to explore the correlation between patellar tendon reflex grade and postural stability among stroke patients.

Methods: A total of 37 elderly stroke patients, each with the same quadriceps muscle strength but different patellar tendon reflex levels, were tested on a force platform under eyes-open (EO) and eyes-closed (EC) conditions. Parametric analysis, detrended fluctuation analysis (DFA), and power spectral density (PSD) analysis were used in centre of pressure (COP) signal processing. The correlation between the results of measured data processing and the level of patellar tendon reflex was analysed.

Results: All three parameters of COP (the length of the sway trajectory, the mean range of the sway trajectory in the mediolateral [ML] direction [R _x ], and the mean range of the sway trajectory in the anterior-posterior [AP] directions [R _y ]) were negatively correlated with the patient's patellar tendon reflex grade under the EC condition. The DFA results showed that a higher grade of patellar tendon reflex was associated with a smaller value of the crossover point in the AP direction. Only the PSD values of each frequency band in the AP direction were negatively correlated with patellar tendon reflex grade with EO and became negatively correlated in both AP and ML directions with EC. Overall, the results showed a strong correlation between patellar tendon reflex and postural stability in stroke patients when vision was blocked.

Significance: The strong correlation with EC may provide insights into clinic evaluation and treatment for rehabilitation or fall risks of stroke patients.