Volume 14, Issue 1

A deeper understanding of the underlying biological mechanisms of secondary brain injury induced by traumatic brain injury (TBI) will greatly advance the development of effective treatments for patients with TBI. Hypoxia-inducible factor-1 alpha (HIF-1α) is a central regulator of cellular response to hypoxia. In addition, growing evidence shows that HIF-1α plays the important role in TBI-induced changes in biological processes; however, detailed functional mechanisms are not completely known. The aim of the present work was to further explore HIF-1α-mediated events after TBI. To this end, next-generation sequencing, coupled with cellular and molecular analysis, was adopted to interrogate vulnerable events in a rat controlled cortical impact model of TBI. The results demonstrated that TBI induced accumulation of HIF-1α at the peri-injury site at 24 h post-injury, which was associated with neuronal loss. Moreover, gene set enrichment analysis unveiled that neuroinflammation, especially an innate inflammatory response, was significantly evoked by TBI, which could be attenuated by the inhibition of HIF-1α. Furthermore, the inhibition of HIF-1α could mitigate the activation of microglia and astrocytes. Taken together, all these data implied that HIF-1α might contribute to secondary brain injury through regulating neuroinflammation.

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 The aim of this study was to explore the correlation between non-arteritic anterior ischemic optic neuropathy (NAION) and cerebral infarction (CI). Moreover, the ocular and systemic parameters are also compared between NAION patients with or without CI. Methods Retrospective analysis is performed for NAION patients and the controls. The controls were collected at the eye outpatient with cranial computed tomography (CT), and data of blood triglyceride, cholesterol, low-density lipoprotein, high-density lipoprotein, and apolipoprotein B were drawn. The diagnosed NAION patients with cranial CT are included, and data of clinical history and routine clinical examination were drawn from the medical record. Visual acuity, intraocular pressure (IOP), visual field, and visual evoked potential were also drawn. Results Eighty-two unilateral and 6 bilateral patients, totally 94 eyes for 88 NAION patients and 69 controls are included. NAION and control patients have matched age, gender, and weight. There is no difference in triglyceride, cholesterol, low-density lipoprotein, high-density lipoprotein, and apolipoprotein B between these two groups. NAION patients (43.18%, 38/88) have a higher ratio of CI than the controls (14.49%, 10/69) ( p = 0.000). For NAION, the odds ratio (OR) of CI is 2.691 ( p = 0.011). Body mass index, height, and IOP show no significant difference between NAION patients with or without CI. NAION patients with CI have a significant higher ratio of hypertension than those without CI, and the OR of HBP is 2.623 ( p = 0.008). Conclusions The correlation between NAION and CI is possible as NAION patients have a significant higher ratio with CI. In NAION patients, hypertension is a risk factor for those with CI.

Objective We studied whether enriched environment (EE), a classic epigenetics paradigm, can prevent cellular plasticity damage caused by chronic sleep deprivation (SD). Methods We performed SD in mice by a modified multi-platform method (MMPM). Mice in the SD group were deprived of sleep for 18 h a day. In addition, half of the mice in the chronic SD group were exposed to EE stimuli for 6 h per day. Immunostaining analyzed neurogenesis and neural progenitor cell-differentiated phenotypes in the hippocampal dentate gyrus (DG) region. Result At 13 weeks, compared with the control group, SD severely impaired the proliferation and differentiation of neural stem cells, and EE completely reversed the process. SD can induce gliosis in the mouse hippocampus, and EE can delay the process. Conclusion: Our results suggest that chronic SD may damage the neurogenesis in the DG of the hippocampus. However, enrichment stimulation can reverse the processing by promoting neuronal repair related to neuronal plasticity.

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.

Background Alzheimer’s disease (AD) is characterized by progressive neuronal loss, cognitive disorder, and memory decline. Leptin has been reported to have a neuroprotective effect on neurodegenerative diseases. Objective Our aim was to investigate whether intraperitoneal injection of leptin has a neuroprotective effect and to explore its underlying mechanisms in the AD mouse model. Methods Aβ1-42 was injected into male C57BL/6J mice to construct an AD mouse model, and leptin was injected intraperitoneally to cure AD. The Morris water maze test was used to investigate spatial learning ability. Neuronal loss was tested by tyrosine hydroxylase expression in the hippocampus, and terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling assay was applied to detect neuronal apoptosis. Pro-inflammatory cytokine levels were monitored by RT-PCR and western blotting was selected to explore which signaling pathway leptin acted on. Results Leptin ameliorated spatial learning impairment, restored neuronal loss and apoptosis, and inhibited pro-inflammatory cytokine expression by activating the p-Akt signaling pathway in Aβ1-42-induced AD mice. Conclusion Leptin ameliorates Aβ1-42-induced AD by suppressing inflammation via activating the p-Akt signaling pathway. Graphical abstract

Objective Anesthetic exposure causes learning and memory impairment, the mechanisms of which remain unknown. It has been reported that tumor necrosis factor-α-inducer protein 8-like 2 (TIPE2) is a newly discovered immune negative regulator that is essential for maintaining immune homeostasis. This study aimed to examine the role of TIPE2 in isoflurane-induced postoperative cognitive decline (POCD). Methods An AAV empty vector and AAV shTIPE2 vector for the knockdown of TIPE2 were injected into the dorsal hippocampus of mice. Mice were continuously exposed to 1.5% isoflurane followed by abdominal exploration. Behavioral tests including the open field test and fear conditioning test were performed on the third and fourth day post-operation. Apoptosis was detected by terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling staining. The kits were used to detect the activity of antioxidant enzymes. Inflammatory cytokine levels were detected by enzyme-linked immunosorbent assay. Signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) signaling pathway activities were detected by western blotting. Results TIPE2 expression increased after isoflurane anesthesia and surgery. TIPE2 deficiency aggravated cognitive impairment in mice and further caused apoptosis and oxidative stress in hippocampal neurons. TIPE2 deficiency induced microglial activation and increased secretion of proinflammatory cytokines. In addition, TIPE2 deficiency promoted STAT3 and NF-κB signaling activation induced by isoflurane anesthesia and after surgery. Conclusion TIPE2 may play a neuroprotective role in POCD by regulating STAT3 and NF-κB pathways.

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.

Background Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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.

Objective MiRNAs play a key role in ischemic stroke (IS). Although miR-101-3p can participate in multiple disease processes, its role and mechanism in IS are not clear. The aim of the present study was to observe the effect of miR-101-3p activation on IS in young mice and the role of HDAC9 in this effect. Methods The young mice were first subjected to transient middle cerebral artery occlusion (tMCAO) or sham surgery, and the cerebral infarct area was assessed with 2,3,5-triphenyltetrazolium chloride staining. Meanwhile, the expressions of miR-101-3p and HDAC9 were tested using RT-qPCR or western blot. Besides, neuron morphology and apoptosis were confirmed using Nissl staining and TUNEL staining. Results We first verified that miR-101-3p was downregulated and HDAC9 was upregulated in the brain tissue of tMCAO young mice. Moreover, we proved that overexpression of miR-101-3p could improve cerebral infarction, neuronal morphology, and neuronal apoptosis in tMCAO young mice by lowering the expression of HDAC9. Conclusions Activation of miR-101-3p can protect against IS in young mice, and its mechanism is relevant to the inhibition of HDAC9. Therefore, miR-101-3p and HDAC9 might be the latent targets for IS therapy.

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.

Objectives Studies have shown that arterial spin labeling (ASL) effectively replaces traditional MRI perfusion imaging for detecting cerebral blood flow (CBF) in patients with Moyamoya angiopathy (MMA). However, there are few reports on the relationship between neovascularization and cerebral perfusion in patients with MMA. The aim of this study is to investigate the effects of neovascularization on cerebral perfusion with MMA after bypass surgery. Methods We selected patients with MMA in the Department of Neurosurgery between September 2019 and August 2021 and enrolled them based on the inclusion and exclusion criteria. ASL imaging was used to monitor the baseline CBF level before surgery and determine the changes in cerebral vessels at postoperative 1 week and 6 months, respectively. The Alberta stroke grade, modified Rankin Scale (mRS), and digital subtraction angiography images were used to evaluate the effect of postoperative CBF status and prognosis. Ninety hemispheres from 51 patients were included in this study. There were no significant differences in the baseline data of the enrolled patients. At 1 week and 6 months post-surgery, the CBF state in the operation area was significantly changed compared with that at baseline ( P < 0.05). The preoperative Alberta score ( t = 2.714, P = 0.013) and preoperative mRS score ( t = 6.678, P < 0.001) correlated with postoperative neovascularization. Conclusion ASL is an effective method for detecting CBF and plays an important role in the long-term follow-up of patients with MMA. Combined cerebral revascularization significantly improves CBF in the operation area both in the short and long terms. Patients with lower preoperative Alberta scores and higher mRS scores were more likely to benefit from combined cerebral revascularization surgery. However, regardless of the type of patient, CBF reconstruction can effectively improve prognosis.

Objective Accumulating evidence has suggested that thyroid hormone levels affect the prognosis of acute ischemic stroke (AIS), but the results have been inconsistent. Methods Basic data, neural scale scores, thyroid hormone levels, and other laboratory examination data of AIS patients were collected. The patients were divided into excellent and poor prognosis group at discharge and 90 days after discharge. Logistic regression models were applied to evaluate the relationship between thyroid hormone levels and prognosis. A subgroup analysis was performed based on stroke severity. Results A number of 441 AIS patients were included in this study. Those in the poor prognosis group were older, with higher blood sugar levels, higher free thyroxine (FT4) levels, and severe stroke (all p < 0.05) at baseline. Free thyroxine (FT4) showed a predictive value (all p < 0.05) for prognosis in the model adjusted for age, gender, systolic pressure, and glucose level. However, after adjustment for types and severity of stroke, FT4 showed insignificant associations. In the severe subgroup at discharge, the change in FT4 was statistically significant ( p = 0.015), odds ratio (95% confidence interval) = 1.394 (1.068–1.820) but not in the other subgroups. Conclusions High-normal FT4 serum levels in patients with severe stroke receiving conservative medical treatment at admission may indicate a worse short-term prognosis.

Context Accumulated evidence indicates that geniposide exhibits neuroprotective effects in ischemic stroke. However, the potential targets of geniposide remain unclear. Objective We explore the potential targets of geniposide in ischemic stroke. Materials and methods Adult male C57BL/6 mice were subjected to the middle cerebral artery occlusion (MCAO) model. Mice were randomly divided into five groups: Sham, MCAO, and geniposide-treated (i.p. twice daily for 3 days before MCAO) at doses of 25, 75, or 150 mg/kg. We first examined the neuroprotective effects of geniposide. Then, we further explored via biological information analysis and verified the underlying mechanism in vivo and in vitro . Results: In the current study, geniposide had no toxicity at concentrations of up to 150 mg/kg. Compared with the MCAO group, the 150 mg/kg group of geniposide significantly ( P < 0.05) improved neurological deficits, brain edema (79.00 ± 0.57% vs 82.28 ± 0.53%), and infarct volume (45.10 ± 0.24% vs 54.73 ± 2.87%) at 24 h after MCAO. Biological information analysis showed that the protective effect was closely related to the inflammatory response. Geniposide suppressed interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) expression in the brain homogenate, as measured by enzyme-linked immunosorbent assay (ELISA). Geniposide upregulated A20 and downregulated TNF receptor-associated factor-6 and nuclear factor kappa-B phosphorylation in the MCAO model and lipopolysaccharide-treated BV2 cells at 100 μM. Conclusions Geniposide exhibited a neuroprotective effect via attenuating inflammatory response, as indicated by biological information analysis, in vivo and in vitro experiments, which may provide a potential direction for the application of geniposide in the treatment of ischemic stroke.

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 Apolipoprotein E (ApoE) is associated with Alzheimer’s disease (AD) and cognitive dysfunction in elderly individuals. There have been extensive studies on behavioral abnormalities in ApoE-deficient (Apoe shl ) mice, which have been described as AD mouse models. Spontaneously hyperlipidemic mice were discovered in 1999 as ApoE-deficient mice due to ApoE gene mutations. However, behavioral abnormalities in commercially available Apoe shl mice remain unclear. Accordingly, we aimed to investigate the behavioral abnormalities of Apoe shl mice. Results Apoe shl mice showed decreased motor skill learning and increased anxiety-like behavior toward heights. Apoe shl mice did not show abnormal behavior in the Y-maze test, open-field test, light/dark transition test, and passive avoidance test. Conclusion Our findings suggest the utility of Apoe shl mice in investigating the function of ApoE in the central nervous system.

Background The role of the willisian collaterals during carotid endarterectomies (CEAs) is a debated issue. The aim of the present work was to test whether an incomplete or non-functional circle of Willis (CoW) is a risk factor for ischemic events during CEA. Patients and methods CEAs were performed under local anesthesia. Patients were considered symptomatic (SY) if neurological signs appeared after the cross-clamping phase. In SY patients shunt insertion was performed. CoW on CT angiograms (CTa) were analyzed offline and categorized as non-functional (missing or hypoplastic collaterals) or functional collaterals by three neuroradiologists. Near-infrared spectroscopy (NIRS) was performed throughout the procedure. Results Based on CTa, 67 incomplete circles were found, 54 were asymptomatic (ASY) and 13 were SY. No complete CoW was found among the SY patients. Significant differences could be detected between incomplete and complete circles between ASY and SY groups (Chi-square: 6.08; p = 0.013). The anterior communicating artery was missing or hypoplastic in 5/13 SY cases. There were no cases of the non-functional anterior communicating arteries in the ASY group (Chi-square: 32.9; p = 10 −8 ). A missing or non-functional bilateral posterior communicating artery was observed in 9/13 SY and in 9/81 ASY patients (Chi-square: 24.4; p = 10 −7 ). NIRS had a sensitivity of 76.9% and a specificity of 74.5% in detecting neurological symptoms. Conclusions Collateral ability of the CoW may be a risk factor for ischemic events during CEAs. Further studies should delineate whether the preoperative assessment of collateral capacity may be useful in decision-making about shunt use during CEA.

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.

Sepsis is a potentially fatal organ failure resulting from a dysregulated host response to infection. It can be a substantial financial burden on families and society due to the high cost of medical care. The study aims to investigate the protective roles of Esmolol in mice with sepsis-induced brain injuries against cognitive dysfunction and neuronal inflammation. Male C57BL/6J mice were intraperitoneally injected with LPS (10 mg/kg, L2630, Sigma) to establish a septic encephalopathy model. Esmolol (15 mg/kg/h, HY-B1392, MedChemExpress) was subcutaneously infused using osmotic mini-pumps for 6 h before LPS injection. Morris water maze and novel object recognition tests evaluated LPS-induced cognitive impairment and behavioral phenotypes. Cytokines and protein expression were assessed using ELISA assay and RT-qPCR. Esmolol treatment potentially improved cognitive impairment in septic mice. Esmolol administration markedly diminished the abnormal hippocampal neuronal structure, and the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α was significantly downregulated in the hippocampal tissue. Esmolol treatment significantly reduced apoptotic TUNEL-positive cells and reversed the related gene expression (BAX and BCL-2). The effects of esmolol on the reactive oxidative species and oxidative stress markedly reduce malondialdehyde MDA content and increase superoxide dismutase and catalase in hippocampal tissues. In addition, esmolol significantly reduced the percentage and density of Iba-1 + microglia in septic mice. Our results demonstrated that esmolol potentially improved cognitive impairment and neuronal inflammation in mice with sepsis-induced brain injury.

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.

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.

Background Recent studies have highlighted that circular RNAs regulate cancer-related genes’ expression by functioning as microRNA sponges in cancers. Herein, we investigated the function and molecular mechanism of circYIPF6 in glioma. Methods 5-Ethynyl-2′-deoxyuridine assay, colony formation, and flow cytometry were performed to assess the proliferation and apoptosis of glioma cells. The levels of glycolytic metabolism were evaluated by measuring the glucose uptake and lactate production. The protein levels of Bax, Bcl2, GLUT1, LDHA, and PTBP1 were examined by western blot. The interplay between miR-760 and circYIPF6 or PTBP1 was confirmed by a dual-luciferase reporter. The effect of circYIPF6 silencing on the growth of glioma in vivo was determined by a xenograft experiment. Results circYIPF6 was significantly upregulated in glioma. Knockdown of circYIPF6 suppressed glioma cell proliferation and glycolysis while promoting cell apoptosis. Mechanistic studies revealed that circYIPF6 targeted miR-760 and could abundantly sponge miR-760 to inhibit the expression of its downstream target gene PTBP1. Functional rescue experiments showed that both miR-760 inhibition and PTBP1 overexpression could attenuate the regulatory effect of circYIPF6 silencing on glioma cells. Furthermore, circYIPF6 knocking down effectively impeded glioma growth in vivo . Conclusion These findings suggested that circYIPF6 participated in the proliferation, apoptosis, and glycolysis of glioma through the miR-760/PTBP1 axis.

Objective: This research was conducted to discuss the recent prognosis of patients with acute cerebral infarction (ACI) combined with cerebral-cardiac syndrome (CCS). Method: Eighty-seven patients with ACI were selected, which were divided into the ACI group (52 patients) and the CCS group (35 patients) according to whether the CCS was combined, and another 30 health controls were selected as the control group. Serum hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) levels of subjects in each group at the 1st day, the 3rd day, and the 7th day after admission were measured by enzyme-linked immunosorbent assay. After discharge for 30 days, the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) score were utilized to evaluate the prognosis of patients. The role of serum HIF-1α and VEGF levels in the prognosis of ACI combined with CCS patients was assessed by receiver operating characteristic curve and the binary logistic regression analysis. Results: Higher serum HIF-1α and VEGF levels were observed in the CCS and ACI groups versus the control group, and the levels of which were even higher in the CCS group in comparison to the ACI group. According to the prognosis of the NIHSS score, fasting blood glucose (FBG), Acute Physiology and Chronic Health Evaluation II score, creatine kinase-MB (CK-MB), and HIF-1α and VEGF levels at the 7th day of admission were higher while Glasgow coma scale (GCS) score was lower in the poor prognosis group than those in the good prognosis group, and the area under the curve (AUC) of serum HIF-1α and VEGF levels was 0.895 (95% confident interval [CI], 0.786–1.000), and 0.855 (95% CI, 0.731–0.980). According to the prognosis of the mRS score, FBG, CK-MB, and HIF-1α and VEGF levels at the 7th day of admission were higher while GCS score was lower in the poor prognosis group than those in the good prognosis group, and the AUC of serum HIF-1α and VEGF levels was 0.850 (95% CI, 0.722–0.979) and 0.901 (95% CI, 0.798–1.000). The results of the binary logistic regression analysis revealed that HIF-1α and VEGF levels may be independent risk factors influencing the prognosis of ACI combined with CCS. Conclusion: Serum HIF-1α and VEGF have a good predictive value for assessing the recent prognosis of patients with ACI combined with CCS, which could be independent risk factors influencing the prognosis of disease.

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.

Sleep plays an important role in the learning process and memory consolidation, and sleep deprivation (SD) leads to inadequate memory consolidation and plays an important role in brain development and plasticity. SD increases β-amyloid levels while impairing cognitive function. We explored the effect of enriched environment (EE) on β-amyloid and transporter protein LRP1 and receptor for advanced glycosylation end-products (RAGE) expression in chronic sleep deprived mice. We randomly divided mice into four groups ( n = 10), the standard environment group (Ctrl group), the sleep deprivation group (SD group), the enriched environment intervention group (EE group), and the sleep deprivation plus environmental enrichment intervention group (SD + EE group). A modified multi-platform SD model was used to sleep deprive the mice for 19 h per day. Five hours of EE intervention was performed daily in the EE group and the SD + EE group, respectively. The behavioral measurements of mice were performed by Y-maze method and new object recognition; the expression levels of Aβ1-42, LRP1, and RAGE in prefrontal cortex and hippocampus of mice were measured by immunofluorescence; the expression levels of LRP1 and RAGE in prefrontal cortex and hippocampus were detected by Western blot. The results showed that EE could effectively ameliorate the effects of SD on cognitive impairment, reduce SD induced Aβ deposition, and decrease the expression of RAGE, while increase the expression of LRP1.

Background Baicalin has been shown to promote spatial learning and neural regeneration, which might increase the differentiation of neural stem cells in Alzheimer’s disease (AD) rat models. We aimed to study the role of baicalin on neuronal pentraxin-1 (NPTX-1), neuronal pentraxin-2 (NPTX-2), and C-reactive protein (CRP) in AD model rats. Methods The 30 male Sprague Dawley rats were divided into three groups: the control group, the AD model group, and the AD + baicalin group. Then, the Morris water maze was used to verify the effect of baicalin on the memory and spatial learning of rats. Immunohistochemistry and immunofluorescence were used to observe the expression of NPTX-1, NPTX-2, and CRP in brain tissue. Results Compared with the AD model group, the AD rats treated with baicalin spent significantly less time finding escape latencies ( P = 0.008) and had longer cross-platform times in the target quadrant ( P = 0.015). In addition, the AD + baicalin group had significantly higher numbers of hippocampal neurons compared with the AD model group ( P < 0.05). Baicalin also obviously decreased the apoptosis of neurons. Moreover, compared with the AD model group, the NPTX-1 and CRP expression in the AD + baicalin group was significantly reduced ( P = 0.000) while the expression of NPTX-2 in the brain tissue of AD rats was significantly increased ( P = 0.000). Conclusions Baicalin can play a therapeutic role by downregulating NPTX-1, upregulating NPTX-2, and downregulating CPR in AD model rats.

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 Thoracic surgery is easy to cause various perioperative complications, especially in elderly patients, due to their physical weakness and physiological function degeneration. Postoperative cognitive dysfunction is a common complication in elderly patients undergoing thoracic surgery. This study focuses on exploring the effects of thoracic paravertebral block (TPVB) combined with general anesthesia on postoperative functional recovery in elderly patients undergoing thoracoscopic radical resection for lung cancer based on enhanced recovery after surgery (ERAS) pathway. Methods A total of 104 patients aged 60 years or older undergoing thoracoscopic radical resection of lung cancer were randomized into the combination group ( n = 52) and the control group ( n = 52). Patients in the control group were given general anesthesia alone, while patients in the combination group were given TPVB combined with general anesthesia. All patients applied the ERAS model for the perioperative intervention. Hemodynamic indices (heart rate [HR] and mean arterial pressure [MAP]) before anesthesia (T0), 5 min after thoracoscopic trocar placement (T1), at extubation (T2), 30 min after extubation (T3), and 6 h after the surgery (T4), postoperative analgesia, preoperative and postoperative serum pain stress factors (5-hydroxytryptamine [5-HT], prostaglandin E2 [PGE2], cortisol [Cor], substance P [SP], and norepinephrine [NE]), tumor markers (CYFRA21-1, CEA, and CA50), inflammatory factors (IL-6, TNF-α, and c-reactive protein (CRP)), lung function indicators (forced vital capacity [FVC] and forced expiratory volume in the first second [FEV1]), 6 min walking distance (6MWD), clinical recovery indicators, hospitalization status, and postoperative complications in patients between both groups were compared. Results Compared with the control group, patients in the combination group had lower HR and MAP at T1–T4 time points, less intraoperative doses of remifentanil and propofol, less patient-controlled interscalene analgesia compression number 24 h after the surgery, lower visual analogue scale scores 24 h after the surgery, shorter hospitalization time, postoperative off-bed time, postoperative chest tube removal time, postoperative first feeding time and gastrointestinal function recovery time, reduced postoperative serum levels of 5-HT, PGE2, Cor, SP, NE, CYFRA21-1, CEA, CA50, IL-6, TNF-α, and CRP, decreased complications, and higher FVC, FEV1, and 6MWD. Conclusion Based on the ERAS pathway, TPVB combined with general anesthesia in thoracoscopic surgery for lung cancer in elderly patients can effectively reduce the patients’ hemodynamic fluctuations, alleviate postoperative pain, accelerate the recovery process, and reduce complications.

Objective This study aims to investigate the impact of vagus nerve stimulation (VNS) on the connectivity and small-world metrics of brain functional networks during seizure periods. Methods Ten refractory epilepsy patients underwent video encephalographic monitoring before and after VNS treatment. The 2-min electroencephalogram segment containing the ictal was selected for each participant, resulting in a total of 20 min of seizure data. The weighted phase lag index (wPLI) and small-world metrics were calculated for the whole frequency band and different frequency bands (delta, theta, alpha, beta, and gamma). Finally, the relevant metrics were statistically analyzed, and the false discovery rate was used to correct for differences after multiple comparisons. Results In the whole band, the wPLI was notably enhanced, and the network metrics, including degree (D), clustering coefficient (CC), and global efficiency (GE), increased, while characteristic path length (CPL) decreased ( P < 0.01). In different frequency bands, the wPLI between the parieto-occipital and frontal regions was significantly strengthened in the delta and beta bands, while the wPLI within the frontal region and between the frontal and parieto-occipital regions were significantly reduced in the beta and gamma bands ( P < 0.01). In the low-frequency band (<13 Hz), the small-world metrics demonstrated significantly increased CC, D, and GE, with a significantly decreased CPL, indicating a more efficient network organization. In contrast, in the gamma band, the GE decreased, and the CPL increased, suggesting a shift toward less efficient network organization. Conclusion VNS treatment can significantly change the wPLI and small-world metrics. These findings contribute to a deeper understanding of the impact of VNS therapy on brain networks and provide objective indicators for evaluating the efficacy of VNS.

Background Idiopathic intracranial hypertension (IIH) is a condition of increased intracranial pressure of unknown aetiology. Principal symptoms are headache, visual disturbances, and obesity, together with elevated intracranial pressure. Unspecified MRI, despite normal ventricle size, suggests alterations in the water flux cellular mediated by the brain water channel aquaporin-4 (AQP4). The association among IIH, cerebral spinal fluid malfunction, reabsorption, and functional or regulatory modifications of AQP4 is a hypothesis not confirmed. Methods Blood samples were collected from 72 Spanish Caucasian patients with IIH. A genetic association study was performed with bi-allelic SNPs rs1049305 and rs10244884 in AQ1 and rs2075575, rs3763043, and rs3763040 in AQ4. Genetic data were compared with 94 healthy Caucasian control. Statistics studies were assessed by Pearson’s χ 2 tests for 2 × 2 (alleles) or 3 × 2 (genotypes) contingency tables. A P value < 0.05 was considered to be statistically significant. Results Statistically significant differences were found when comparing the results of the rs3763040 polymorphism of the AQ4 locus of IIH patients with controls, in genotypic frequencies ( P = 0.0442) and allele frequencies ( P = 0.0171). Furthermore, a statistically significant difference ( P = 0.0207) was found in individuals carrying and not carrying the minor allele (GG + GA individuals vs GG homozygotes). No statistically significant differences were found when comparing allele and genotypic frequencies for SNPs rs1049305 and rs10244884 of AQ1 and rs2075575 and rs3763043 of AQ4. Conclusions The association of AQP4 and specifically of its polymorphic variant rs3763040 with IIH should be validated in other ethnic groups in order to assess more precisely the role of AQP4 in the etiopathogenesis of IIH.

Objective Spinal cord injury (SCI) is caused by disease or trauma and results in a partial or complete loss of motor or sensory function below the injury level. Most patients with SCI are young, and long-term disability imposes both psychological and financial burdens. Rice is the most abundant source of γ-oryzanol, which exhibits both antioxidant and anti-inflammatory properties. γ-Oryzanol has been shown to cross the blood–brain barrier in an intact form and have beneficial effects on brain function. To the best of our knowledge, this is the first study to report the effect of γ-oryzanol on motor function recovery in mice after SCI. Methods Mice were randomly divided into three groups: the sham group, the injury group, and the γ-oryzanol-treated group that received an intraperitoneal γ-oryzanol (100 mg/kg) injection every 2 days for 42 days after SCI. The effect of γ-oryzanol was assessed through various approaches. Behavioral tests were performed using Basso mouse scale scores and gait analysis. Hematoxylin and eosin staining, Luxol fast blue staining, magnetic resonance imaging ,and immunofluorescence staining were used to observe the lesion area changes, demyelination, axonal regeneration, and scar tissue formation. The levels of inflammatory cytokines in the peripheral blood of mice were assessed by enzyme-linked immunosorbent assay. Results Behavioral tests showed that γ-oryzanol treatment improved gait following SCI. Pathological examination revealed that demyelination at the site of injury improved with γ-oryzanol treatment and was accompanied by the retention of axons associated with motor function and reduced scarring. Additionally, γ-oryzanol treatment decreased the serum levels of pro-inflammatory factors. Conclusions Studies have shown that γ-oryzanol promotes motor function recovery in mice after SCI. Therefore, γ-oryzanol might be the latent target for SCI therapy.

Background The high-mobility group box 1 (HMGB1)/receptor for advanced glycation end products (RAGE) signaling pathway holds promise as a potential therapeutic target for ischemic brain injury. The effects of FPS-ZM1 and electroacupuncture (EA) on activation of the HMGB1/RAGE signaling pathway after cerebral ischemia remain uncertain. Methods Middle cerebral artery occlusion (MCAO) model was established. Neurological function was assessed using Longa scores. Nissl staining was used to observe the morphology of neurons. The expression levels of HMGB1 and RAGE were assayed with immunofluorescence staining and western blot. Results The results showed that EA and FPS-ZM1 could reduce the neural function score and neurons cell injury in cerebral ischemia rats by inhibiting the expression of HMGB1 and RAGE in primary motor cortex (M1) region. In addition, EA combined with FPS-ZM1 had a better therapeutic effect. Conclusions The HMGB1/RAGE pathway could be activated after cerebral ischemia. Both EA and FPS-ZM1 improved neurological deficits and attenuated neuronal damage in rats. They had synergistic effects. These interventions were observed to mitigate brain damage by suppressing the activation of HMGB1/RAGE.

The goal of this study is to evaluate and analyze the effects of edaravone (EDV) dexborneol on neurological function and serum inflammatory factor levels among patients with acute anterior circulation big artery blockage stroke. A total of 142 patients with acute anterior circulation large vessel occlusion (LVO) were randomly allocated to the study group (69 patients) or the control group (73 patients). In the study group, patients were treated with 37.5 mg EDV dexborneol twice a day for 10–14 days, based on the control group. The primary efficacy outcome was the National Institutes of Health Stroke Scale score change from baseline to 90 days and the proportion of modified Rankin Scale (mRS)score ≤1 at 90 days after randomization. The secondary outcome included the decrease in inflammatory factors at 14 days. The primary safety outcome was the incidence of hemorrhagic transformation assessed according to Heidelberg bleeding classification within 7 days. A higher percentage of patients with HIHSS score ≤5 at 90 days in the EDV dexcamphorol group was observed than in the control group (75.36% vs 64.38%; P = 0.015). A higher percentage of patients with mRS score ≤1 at 90 days in the EDV dexcamphorol group was observed than in the control group (63.77% vs 50.68%; P = 0.012). After treatment, the levels of IL-6 and hs-CRP were significantly lower following treatment and compared to the control group ( P < 0.05). In patients receiving the EDV dexborneol group, a significantly decreased risk of radiographic intracranial hemorrhage was found compared with the control group (20.29% vs 39.73%; P = 0.0006). In conclusion, EDV dexborneol can improve the clinical outcomes of patients with acute anterior circulation LVO stroke, which can be used as an effective supplement to thrombectomy therapy.

High concentrations of unconjugated bilirubin (UCB) have toxic effects. The aim of our study was to find a way to elevate UCB tolerance or inhibit its toxicity in neurocytes. It has been reported that cystatin C (CST3) concentrations have a significant positive correlation with total bilirubin (TB) levels and a negative correlation with albumin levels. In addition, CST3 can directly bind UCB, decrease human umbilical vein endothelial cells’ permeability, improve blood–brain barrier integrity after ischemic brain injury in mice, and induce autophagy. We hypothesized that CST3 could increase the solubility of UCB, decrease permeability of neurocytes, induce autophagy of neurocytes, and alleviate bilirubin-induced damage. To verify our hypothesis, we measured TB and conjugated bilirubin levels, and the permeability and autophagy of neurocytes treated with UCB and CST3. Our findings suggest that CST3 can protect against UCB-induced damage in neurocytes and that autophagy played an important role in this process.

Increased B cell activating factor (BAFF) expression in patients with neuromyelitis optica spectrum disorder (NMOSD) is associated with B cell overstimulation, but the underlying mechanism remains unclear. This study aimed to reveal the emerging mechanisms that regulate BAFF expression in the inflammatory process of NMOSD. The results showed that the expression of miR-30b-5p was significantly decreased in NMOSD CD14 + monocytes compared with the normal control. Furthermore, we confirmed that metastasis-associated lung adenocarcinoma transcription 1 (MALAT1) is an upstream target of miR-30b-5p, and it could act as a ceRNA and absorb miR-30b-5p with reduced expression of miR-30b-5p. The low expression of miR-30b-5p could not bind to BAFF messenger RNA (mRNA), which resulted in the overexpression of both BAFF mRNA and protein expression. Overexpression of BAFF could bind to the corresponding receptors on B cells, which may initiate activation and proliferation of B cells and increase their production of autoantibodies. Therefore, these findings interpreted that excessive MALAT1 expression in NMOSD mononuclear macrophages led to increased BAFF expression by targeting miR-30b-5p, which caused B cell autoimmune reaction and autoantibodies production, aggravated the disease progression of NMOSD. Graphical abstract

Background Spontaneous subarachnoid hemorrhage (SAH) is the most severe form of hemorrhagic stroke and accounts for 5–7% of all strokes. Several chemical enzymes and cytokines are thought to cause reactions that may affect the mortality and morbidity of SAH patients. This study aimed to examine the possible relationships between these parameters and the occurrence of SAH and the clinical–radiological parameters in patients with acute SAH. Methods This study evaluated 44 patients, including 20 with SAH and 24 controls. We obtained blood from the patients and control groups, which was stored in heparinized tubes and used in determining tumor necrosis factor alpha (TNF-α), brain-derived neurotrophic factor (BDNF), acetylcholinesterase (AChE), caspase-3, and butyrylcholinesterase (BChE) enzymes. Results TNF-α, BDNF, AChE, and BChE enzyme levels were not related to the Glasgow Coma scale (GCS) score in the patient group ( p > 0.05), whereas higher enzyme levels of caspase-3 were associated with lower GCS scores ( p < 0.05). The difference between the control and patient groups in terms of mean TNF-α levels was statistically significant ( p < 0.01). The BDNF levels were statistically insignificant in the patient groups ( p > 0.05). Caspase-3, AChE, and BChE levels were significantly different between the control and patient groups ( p < 0.01). Conclusions Our results may be valuable for predicting the prognosis, diagnosis, and follow-up of patients with SAH. However, further studies are required to elucidate the relationship between the clinical and radiological results in patients with SAH and certain enzymes, cytokines, and growth factors.

Background Early neurological deterioration after endovascular thrombectomy (EVT) is associated with poor prognosis. National Institutes of Health Stroke Scale (NIHSS) score measured at 24 h after EVT may be a better outcome predictor than other methods that focus on changes in NIHSS. Nevertheless, clinical fluctuations in ischemic stroke patients during the immediate phase after symptoms onset are well recognized. Therefore, a delayed NIHSS evaluation may improve prognostic accuracy. We evaluate the 7-day NIHSS in predicting long-term patient outcomes after EVT. Methods This was a multi-center retrospective cohort study of 300 consecutive ischemic stroke patients with large vessel occlusion who underwent EVT at three-stroke centers in China from August 2018 to March 2022. NIHSS was recorded on admission, pre-EVT, 24 h, and 7 days after EVT. Results A total of 236 eligible patients were subdivided into two groups: 7-day NIHSS ≤6 and NIHSS >6 post-EVT. 88.29% achieved a favorable outcome (modified Rankin Scale 0–2) in the NIHSS ≤6 group compared to 15.20% in the NIHSS >6 group at 90 days, and an improved favorable outcome in the former group was observed after adjusting for potential confounding factors (adjusted odds ratio 39.7, 95% confidence interval, 17.5–89.7, p < 0.001). Conclusion The 7-day NIHSS score may be a reliable predictor of 90-day stroke patient outcome after EVT.

Objectives Cyclin-dependent kinase 5 (Cdk5) activity is specifically active in neurogenesis, and Cdk5 and neocortical neurons migration related biomarker are expressed in Cos-7 cells. However, the function of Cdk5 on the transformation of immortalized Cos-7 cells into neuronal-like cells is not clear. Methods Cdk5 kinase activity was measured by [γ- 32 P] ATP and p81 phosphocellulose pads based method. The expression of neuron liker markers was evaluated by immunofluorescence, real-time PCR, Western blot, and Elisa. Results P35 overexpression upregulated Cdk5 kinase activity in Cos-7 cells. p35 mediated Cdk5 expression promoted the generation of nerite-like outgrowth. Compared with the empty vector, p35-induced Cdk5 activation resulted in time-dependent increase in neuron-like marker, including Tau, NF-H, NF-H&M, and TuJ1. Tau-5 and NF-M exhibited increased expression at 48 h while TuJ1 was only detectable after 96 h in p35 expressed Cos-7 cells. Additionally, the neural cell biomarkers exhibited well colocation with p35 proteins. Next-generation RNA sequence showed that p35 overexpression significantly upregulated the level of nerve growth factor (NGF). Gene set enrichment analysis showed significant enrichment of multiple neuron development pathways and increased NGF expression after p35 overexpression. Conclusion p35-mediated Cdk5 activation promotes the transformation of immortalized Cos-7 cells into neuronal-like cells by upregulating NGF level.

Background Due to high rates of incidence and disability, postoperative cognitive dysfunction (POCD) currently receives a lot of clinical attention. Disturbance of fatty acid oxidation is a potential pathophysiological manifestation underlying POCD. Peroxisome proliferator-activated receptor α (PPARα) is a significant transcription factor of fatty acid oxidation that facilitates the transfer of fatty acids into the mitochondria for oxidation. The potential role of PPARα intervention in POCD warrants consideration. Objective The present study is aimed to investigate whether PPARα agonist fenofibrate (FF) could protect long-term isoflurane anesthesia-induced POCD model and to explore the potential underlying function of fatty acid oxidation in the process. Methods We established the POCD model via 6 h long-term isoflurane anesthesia in vivo with C57BL/6J mice and in vitro with N2a cells. Cells and mice were pretreated with PPARα agonist FF before anesthesia, after which fatty acid oxidation and cognitive function were assessed. The level of fatty acid oxidation-related proteins was determined using western blotting. The contextual fear conditioning test was utilized to evaluate mice’s learning and memory. Results Our results showed that 6 h long-term isoflurane anesthesia induced contextual memory damage in mice, accompanied by decreases of fatty acid oxidation-related proteins (peroxisome proliferator-activated receptor γ coactivator 1α, carnitine palmitoyltransferase 1A, and PPARα) both in the hippocampus of POCD mice and in N2a cells. In the N2a cell model, pretreatment of PPARα agonist FF led to the upregulation of fatty acid oxidation-related proteins. In vivo results showed that preconditioned FF reached similar effects. More crucially, FF has been shown to reduce cognitive damage in mice after long-term isoflurane anesthesia. Additionally, our data showed that after blocking fatty acid oxidation by Etomoxir, FF failed to protect cognitive function from long-term isoflurane anesthesia. Conclusions Pretreatment of PPARα agonist FF can protect against long-term isoflurane anesthesia-induced POCD by enhancing fatty acid oxidation. Graphical abstract

Background Endovascular therapy (EVT) was the standard treatment for acute ischemic stroke with large vessel occlusion. Prognosis after EVT is always a major concern. Here, we aimed to explore a predictive model for patients after EVT. Method A total of 156 patients were retrospectively enrolled. The primary outcome was functional dependence (defined as a 90-day modified Rankin Scale score ≤ 2). Least absolute shrinkage and selection operator and univariate logistic regression were used to select predictive factors. Various machine learning algorithms, including multivariate logistic regression, linear discriminant analysis, support vector machine, k -nearest neighbors, and decision tree algorithms, were applied to construct prognostic models. Result Six predictive factors were selected, namely, age, baseline National Institute of Health Stroke Scale (NIHSS) score, Alberta Stroke Program Early CT (ASPECT) score, modified thrombolysis in cerebral infarction score, symptomatic intracerebral hemorrhage (sICH), and complications (pulmonary infection, gastrointestinal bleeding, and cardiovascular events). Based on these variables, various models were constructed and showed good discrimination. Finally, a nomogram was constructed by multivariate logistic regression and showed a good performance. Conclusion Our nomogram, which was composed of age, baseline NIHSS score, ASPECT score, recanalization status, sICH, and complications, showed a very good performance in predicting outcome after EVT.

Dorsal root injury usually leads to irreversible sensory function loss and lacks effective treatments. (−)-epigallocatechin-3-gallate (EGCG) is reported to exert neuroprotective roles in the nervous systems. However, the function of EGCG in treating dorsal root injury remains unclear. Hence, we built the dorsal root crush injury (DRCI) rat model to be treated with EGCG, followed by the western blot, Enzyme-linked immunosorbent assay, and sensory behavior tests. We observed that EGCG can upregulate the Lysine acetyltransferase 6A (KAT6A) level and inhibit the pyroptosis, indicated by downregulated gasdermin-D, caspase-1, and interleukin 18 protein levels, and alleviate the neuropathic pain, indicated by the decreased paw withdraw threshold in Plantar test and decreased paw withdraw latency in von Frey test, and downregulated calcitonin gene-related peptide, nerve growth factor, and c-Fos protein levels. But EGCG cannot alleviate the neuropathic pain when the KAT6A was inhibited by CTX-0124143 and pyroptosis was activated by Miltirone. These combined results indicated that EGCG can promote the sensory function recovery in rats after DRCI via upregulating KAT6A and inhibiting pyroptosis, laying the foundation for EGCG to be a novel candidate for the treatment of dorsal root injury.

Background and purpose Headache attributed to craniotomy is an underestimated and under-treated condition. Previous studies confirmed the efficacy of preemptive analgesia with non-steroidal anti-inflammatory agents. The aim of the present work was to test the hypothesis of whether a single preoperatively administered dose of dexketoprofen (DEX) has the potency to decrease postcraniotomy headache (PCH) as compared to placebo (PL). Patients and methods This is a single-centre, randomized, PL-controlled trial comparing the effect of a single oral dose of 25 mg DEX to PL on the intensity of PCH. Patients undergoing craniotomy were randomly allocated to DEX and PL groups. Patients rated their actual and worst daily pain using visual analogue scale (VAS) scores during intrahospital treatment (0–5 days) and 30 and 90 days postoperatively. Results Two hundred patients were included. DEX decreased the worst daily pain intensity in the first 24 h only; the 5-days cumulative score of actual pain was 9.7 ± 7.9 cm for the DEX group and 12.6 ± 10.5 cm for the PL group, respectively ( p = 0.03). This difference disappeared in the late, 30-, and 90-day follow-up period. No differences in VAS scores could be detected in supra- and infratentorial cases among the DEX and PL groups. Conclusions A single preoperative dose of 25 mg of DEX slightly decreases the intensity of PCH in the first 5 days after craniotomy but it does not have an effect on chronic headaches and postoperative analgesic requirements.

C. and O. Vogt had set up a research program with the aim of establishing a detailed cartography of the medullary fiber distribution of the human brain. As part of this program, around 200 cortical fields were differentiated based on their myeloarchitectural characteristics and mapped with regard to their exact location in the isocortex. The typical features were graphically documented and classified by a sophisticated linguistic coding. Their results have only recently received adequate attention and applications. The reasons for the revival of this spectrum of their research include interest in the myeloarchitecture of the cortex as a differentiating feature of the cortex architecture and function, as well as the importance for advanced imaging methodologies, particularly tractography and molecular imaging. Here, we describe our approach to exploit the original work of the Vogts and their co-workers to construct a myeloarchitectonic map that is referenced to the Atlas of the Human Brain (AHB) in standard space. We developed a semi-automatic pipeline for processing and integrating the various original maps into a single coherent map. To optimize the precision of the registration between the published maps and the AHB, we augmented the maps with topographic landmarks of the brains that were originally analyzed. Registration of all maps into the AHB opened several possibilities. First, for the majority of the fields, multiple maps from different authors are available, which allows for sophisticated statistical integration, for example, unification with a label-fusion technique. Second, each field in the myeloarchitectonic surface map can be visualized on the myelin-stained cross-section of the AHB at the best possible correspondence. The features of each field can be correlated with the fiber-stained cross-sections in the AHB and with the extensive published materials from the Vogt school and, if necessary, corrected. Third, mapping to the AHB allows the relationship between fiber characteristics of the cortex and the subcortex to be examined. Fourth, the cytoarchitectonic maps from Brodmann and von Economo and Koskinas, which are also registered to the AHB, can be compared. This option allows the study of the correspondence between cyto- and myeloarchitecture in each field. Finally, by using our “stripe” technology – where any other feature registered to the same space can be directly compared owing to the linear and parallel representation of the correlated cortex segments – this map becomes part of a multidimensional co-registration platform.

Brain vascular inflammation is characterized by endothelial activation and immune cell recruitment to the blood vessel wall, potentially causing a breach in the blood – brain barrier, brain parenchyma inflammation, and a decline of cognitive function. The clinical-stage small molecule, apabetalone, reduces circulating vascular endothelial inflammation markers and improves cognitive scores in elderly patients by targeting epigenetic regulators of gene transcription, bromodomain and extraterminal proteins. However, the effect of apabetalone on cytokine-activated brain vascular endothelial cells (BMVECs) is unknown. Here, we show that apabetalone treatment of BMVECs reduces hallmarks of in vitro endothelial activation, including monocyte chemoattractant protein-1 (MCP-1) and RANTES chemokine secretion, cell surface expression of endothelial cell adhesion molecule VCAM-1, as well as endothelial capture of THP-1 monocytes in static and shear stress conditions. Apabetalone pretreatment of THP-1 downregulates cell surface expression of chemokine receptors CCR1, CCR2, and CCR5, and of the VCAM-1 cognate receptor, integrin α4. Consequently, apabetalone reduces THP-1 chemoattraction towards soluble CCR ligands MCP-1 and RANTES, and THP-1 adhesion to activated BMVECs. In a mouse model of brain inflammation, apabetalone counters lipopolysaccharide-induced transcription of endothelial and myeloid cell markers, consistent with decreased neuroendothelial inflammation. In conclusion, apabetalone decreases proinflammatory activation of brain endothelial cells and monocytes in vitro and in the mouse brain during systemic inflammation.

Hypoxic–ischemic encephalopathy (HIE) is a common neurological disorder characterized by ischemia and hypoxia in the perinatal period, which seriously affects the growth and development of newborns. To date, there is no specific drug for the treatment of HIE. Previous studies have shown that ferroptosis plays an important role in the pathogenesis of HIE. Carthamin yellow (CY) is believed to have antioxidant and anti-inflammatory effects. However, no studies have reported the role of CY in ferroptosis in HIE in vivo until now. The aim of this study was to investigate the effect and mechanism of CY on HIE in vivo and to provide an experimental basis for the clinical treatment of HIE. The results demonstrated that CY increased the expression of NeuN in the neonatal rat hypoxic-ischemic brain damage (HIBD) model. Further exploration revealed that CY increased the expression of glutathione peroxidase 4 and ferritin heavy chain 1 while it decreased the expression of PTGS2 and ACSL2. Moreover, CY decreased malondialdehyde expression and increased superoxide dismutase and glutathione expression in vivo . The findings also indicated that CY downregulated the expression of Nrf2 and Keap-1. In conclusion, this study demonstrated that CY attenuated brain injury in an experimental HIBD model, potentially by alleviating hippocampal neuronal ferroptosis through inhibition of the Nrf2/Keap-1 signaling pathway. These findings provide a novel therapeutic strategy for the clinical treatment of HIE.

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders diagnosed in childhood. Two common features of ADHD are impaired behavioural inhibition and sustained attention. The Go/No-Go experimental paradigm with concurrent functional magnetic resonance imaging (fMRI) scanning has previously revealed important neurobiological correlates of ADHD such as the supplementary motor area and the prefrontal cortex. The coordinate-based meta-analysis combined with quantitative techniques, such as activation likelihood estimate (ALE) generation, provides an unbiased and objective method of summarising these data to understand the brain network architecture and connectivity in ADHD children. Go/No-Go task-based fMRI studies involving children and adolescent subjects were selected. Coordinates indicating foci of activation were collected to generate ALEs using threshold values (voxel-level: p < 0.001; cluster-level: p < 0.05). ALEs were matched to one of seven canonical brain networks based on the cortical parcellation scheme derived from the Human Connectome Project. Fourteen studies involving 457 children met the eligibility criteria. No significant convergence of Go/No-Go related brain activation was found for ADHD groups. Three significant ALE clusters were detected for brain activation relating to controls or ADHD < controls. Significant clusters were related to specific areas of the default mode network (DMN). Network-based analysis revealed less extensive DMN, dorsal attention network, and limbic network activation in ADHD children compared to controls. The presence of significant ALE clusters may be due to reduced homogeneity in the selected sample demographic and experimental paradigm. Further investigations regarding hemispheric asymmetry in ADHD subjects would be beneficial.

Prion diseases and the prion protein are only partially understood so far in many aspects. This explains the continued research on this topic, calling for an overview on the current state of knowledge. The main objective of the present review article is to provide a comprehensive up-to-date presentation of all major features of human prion diseases bridging the gap between basic research and clinical aspects. Starting with the prion protein, current insights concerning its physiological functions and the process of pathological conversion will be highlighted. Diagnostic, molecular, and clinical aspects of all human prion diseases will be discussed, including information concerning rare diseases like prion-associated amyloidoses and Huntington disease-like 1, as well as the question about a potential human threat due to the transmission of prions from prion diseases of other species such as chronic wasting disease. Finally, recent attempts to develop future therapeutic strategies will be addressed.

Neuroinflammation, a complex process involving the activation of microglia, astrocytes, and other immune cells in the brain, plays a role in neurodegeneration and psychiatric disorders. Current therapeutic strategies for neuroinflammation are limited, necessitating the development of improved approaches. Nanopharmacology offers unprecedented opportunities to access and treat neuroinflammatory disorders at the brain level. Nanoscaffolds can target specific cells or tissues and protect drugs from degradation or elimination, making them ideal candidates for treating neurodegenerative and psychiatric diseases. Recent advancements in nanoparticle development have enabled the targeting of microglia, astrocytes, and other immune cells in the brain, reducing neuroinflammation and protecting neurons from injury. Nanoparticles targeting specific neurons have also been developed. Clinical trials are in progress to evaluate the safety and efficacy of nano drugs for treating neuroinflammatory, neurodegenerative, and psychiatric diseases. The successful development of these nanodrugs holds immense promise for treating these devastating and increasingly prevalent conditions. On the other hand, several limitations and unanswered questions remain. First, the long-term effects of nanoparticles on the brain need to be thoroughly investigated to ensure their safety. Second, optimizing the targeting and delivery of nanoparticles to specific brain regions remains a challenge. Understanding the complex interplay between nanoparticles and the brain’s immune system is crucial for developing effective nanotherapies. Despite these limitations, nanopharmacology presents a transformative approach to treating neuroinflammatory disorders. Future research should address the aforementioned limitations and further elucidate the mechanisms of nanoparticle-mediated therapy. The successful development of safe and effective nanodrugs can revolutionize the treatment of neuroinflammatory disorders, alleviating the suffering of millions.

Background Cohen syndrome (OMIM No. # 216550) is a rare autosomal recessive disorder caused by homozygous mutation in the vacuolar protein sorting 13 homolog B ( VPS13B ) gene on chromosome 8q22.2. Clinical manifestations include hypermobile joints, microcephaly, intellectual disabilities, craniofacial and limb anomalies, and neutropenia. To date, more than 200 mutations of VPS13B have been reported in over 1,000 Cohen syndrome patients. This article reviews the clinical data of two cases of Cohen syndrome diagnosed by whole exome sequencing. Results Both children visited for psychomotor retardation. Gene detection showed a mutation in 8q22.2, NM_017890.4 Intron38 c.6940+1G > T and heterozygotic deletion of exon 3-19 of the VPS13B gene (Case 1), and a mutation in 8q22.2, NM_017890.4 Intron38 c.6940+1G > T and 8q22, NM_017890.4 Exon56 c10334_10335del in the VPS13B gene (Case 2). The variation was predicted to be pathogenic by related software, and they have not been reported. Conclusion Cohen syndrome should be considered in the differential diagnosis of any child with developmental retardation and neutropenia. The present study increases the mutation spectrum of the VPS13B gene and could be helpful in genetic diagnosis and genetic counseling in Cohen syndrome patients.

Advanced sensors/electrodes and signal processing techniques provide powerful tools to analyze surface electromyographic signals (sEMG) and their features, to decompose sEMG into the constituent motor unit action potential trains, and to identify synergies, neural muscle drive, and EEG–sEMG coherence. However, despite thousands of articles, dozens of textbooks, tutorials, consensus papers, and European and International efforts, the translation of this knowledge into clinical activities and assessment procedures has been very slow, likely because of lack of clinical studies and competent operators in the field. Understanding and using sEMG-based hardware and software tools requires a level of knowledge of signal processing and interpretation concepts that is multidisciplinary and is not provided by most academic curricula in physiotherapy, movement sciences, neurophysiology, rehabilitation, sport, and occupational medicine. The chasm existing between the available knowledge and its clinical applications in this field is discussed as well as the need for new clinical figures. The need for updating the training of physiotherapists, neurophysiology technicians, and clinical technologists is discussed as well as the required competences of trainers and trainees. Indications and examples are suggested and provide a basis for addressing the problem. Two teaching examples are provided in the Supplementary Material.

David M. Holtzman and his team at the University of Washington School of Medicine have made breakthroughs in their research on neurodegenerative diseases. They discovered that the infiltration of T cells into the brain, instigated by activated microglia, is a critical factor in the progression of tauopathy. The groundbreaking findings were published in Nature on March 8, 2023. This research delineates a pivotal immune hub linked to tauopathy and neurodegeneration; a complex interplay involving activated microglia and T cell responses. This discovery could potentially become a target for developing therapeutic interventions for Alzheimer’s disease and primary neurodegeneration.

Spinal cord injury (SCI) is a serious disabling injury, and the main factors causing SCI in patients include car accidents, falls from heights, as well as heavy blows and falls. These factors can all cause spinal cord compression or even complete rupture. After SCI, problems with the movement, balance, and walking ability of the lower limbs are most common, and SCI can cause abnormalities in patient’s movement, sensation, and other aspects. Therefore, in the treatment of SCI, it is necessary to strengthen the rehabilitation training (RT) of patients based on data science to improve their motor ability and play a positive role in the recovery of their walking ability. This article used lower limb rehabilitation robot (LLRR) to improve the walking ability of SCI patients and applied them to SCI rehabilitation. The purpose is to improve the limb movement function of patients by imitating and assisting their limb movements, thereby achieving pain relief and muscle strength enhancement and promoting rehabilitation. The experimental results showed that the functional ambulation category (FAC) scale scores of Group A and Group B were 0.79 and 0.81, respectively, in the first 10 weeks of the experiment. After 10 weeks of the experiment, the FAC scores of Group A and Group B were 2.42 and 4.36, respectively. After the experiment, the FAC score of Group B was much higher than that of Group A, indicating that Group B was more effective in improving patients’ walking ability compared to Group A. This also indicated that LLRR rehabilitation training can enhance the walking ability of SCI patients.