Translational Neuroscience最新文献

Objective: This research was designed to ascertain the function of euchromatic histone lysine methyltransferase 2 (EHMT2) in ischemic stroke-induced neuronal damage and inflammatory response and its regulatory mechanism.

Methods: Mouse microglia (BV-2 cells) were induced by oxygen glucose deprivation/reoxygenation (OGD/R) to establish a cellular model, and then co-cultured with HT22 hippocampal neurons. After that, HT22 cell viability and apoptosis were evaluated, followed by the measurement of apoptosis-related factors (B-cell lymphoma-2, Bcl-2 associated X, and cleaved-Caspase 3). Meanwhile, the expression of inducible nitric oxide synthase (M1 microglia polarization marker) and arginase 1 (M2 microglia polarization marker) in BV-2 cells was detected, as well as the levels of inflammatory factors (tumor necrosis factor-α, interleukin [IL]-6, IL-10, IL-1β, and IL-4). Additionally, the expression of EHMT2 and heme oxygenase 1 (HMOX1) in BV-2 cells was assessed by quantitative reverse transcription polymerase chain reaction and western blot, and the binding between EHMT2 and HMOX1 was predicted and verified.

Results: OGD/R treatment led to decreased cell viability and increased cell apoptosis in HT22 cells, and aggravated inflammatory response in BV-2 cells. In OGD/R-induced BV-2 cells, EHMT2 and HMOX1 were increasingly expressed, and knockdown of EHMT2 or HMOX1 in BV-2 cells could inhibit neuronal damage and inflammatory response. Moreover, EHMT2 promoted HMOX1 transcription level by histone methylation.

Conclusion: Collected evidence showed that down-regulation of EHMT2 relieved neuronal damage and inflammatory response by inhibiting HMOX1 expression.

Objective: The internal capsule of the basal ganglia is vulnerable to direct pressure from the hematoma and to secondary damage from toxic products of hemorrhage. Our study evaluated the risk and benefits of active strategies including ultra-early surgery and hematoma evacuation through a transsylvian-transinsular approach for moderate basal ganglia hemorrhage.

Methods: We retrospectively collected patients with moderate basal ganglia hemorrhage in two hospitals. The conservative group contained 51 patients who had the best medical treatment, and the surgery group contained 36 patients who were treated with hematoma evacuation through a transsylvian-transinsular approach within 6 h from ictus. Motor function of upper and lower limbs recorded with the motor sub-score of NIHSS (m-NIHSS) at the baseline, 7 days, 30 days, and 90 days, the modified Rankin Scale (mRS), and Barthel Index (BI) scores at 30 and 90 days were compared between the two groups. Good recovery was defined as an m-NIHSS of 0-2 and poor recovery as 3-4. Favorable prognosis was defined as an mRS of 0-3 and unfavorable prognosis as 4-5.

Results: The mean time from ictus to surgery was 250.3 ± 57.3 min. The good recovery proportions of upper and lower limbs in the surgery group were significantly higher than that in the conservative group (p < 0.05) at 7 days after hemorrhage. The good recovery proportion of upper limbs was significantly higher in the surgery group than in the conservative group (p < 0.05) at 3 months after hemorrhage. Living ability using BI scores was significantly higher in the surgery group than the conservative group (p < 0.05) at 3 months after hemorrhage. The favorable prognosis proportion had no statistically significant difference between the two groups at 3 months after hemorrhage.

Conclusions: Ultra-early hematoma evacuation through a transsylvian-transinsular approach are active strategies for moderate basal ganglia hemorrhage and have potential advantages in improving motor function recovery and daily living. The postoperative rebleeding rate does not increase simultaneously.

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.