Comparison of different rhythmic auditory stimuli on prefrontal cortex cortical activation during upper limb movement in patients with Parkinson's disease: a functional near-infrared spectroscopy study.

Background: A large number of literatures show that rhythmic auditory stimulation (RAS) can effectively improve Parkinson's disease (PD) patients' gait speed, frequency and speed. Its application and curative effect on upper limb motor function is relatively few. Objective: By studying the immediate effect of RAS with different rhythms on the prefrontal cortex (PFC) blood oxygen response during upper limb movement in PD patients, this study discusses the potential neurophysiological mechanism of RAS on upper limb movement in PD patients, which is expected to provide guidance for patients with upper limb dysfunction such as Parkinson's disease. Methods: In this study, 31 PD patients with upper limb static tremors were recruited to complete the nail board task on the healthy upper limb under the baseline rhythm, slow rhythm and fast rhythm provided by the therapist. At the same time, fNIRS was used to observe the blood oxygen response of PFC. Results: There was no significant main effect onsidein all brain regions (p > 0.05), and there was no interaction between rhythm and side (p > 0.05); Except lPFC, the main effect of rhythm in other brain regions was significant (p < 0.05), and ΔHbO increased with the change of rhythm. Paired analysis showed that there were significant differences in ΔHbO between slow rhythm and baseline rhythm, between fast rhythm and baseline rhythm, and between slow rhythm and fast rhythm (p < 0.05); The ΔHbO of rPFC, lDLPFC and rDLPFC were significantly different between slow rhythm and fast rhythm (p < 0.05); there were significant differences in the ΔHbO of BA8 between slow rhythm and baseline rhythm, and between slow rhythm and fast rhythm (p < 0.05). Conclusion: RAS may be a useful upper limb rehabilitation strategy for PD patients with upper limb dysfunction. At the same time, RAS with different rhythms also have different responses to PFC blood oxygen during upper limb movement in PD patients, so that we can design interventions for this kind of cortical mechanism. Identifying the neurophysiological mechanism of RAS on upper limb movement in PD patients may help clinicians customize rehabilitation methods for patients according to clues, so as to highly personalize upper limb training and optimize its effect.

Exploring the application and challenges of fNIRS technology in early detection of Parkinson's disease.

Background: Parkinson's disease (PD) is a prevalent neurodegenerative disorder that significantly benefits from early diagnosis for effective disease management and intervention. Despite advancements in medical technology, there remains a critical gap in the early and non-invasive detection of PD. Current diagnostic methods are often invasive, expensive, or late in identifying the disease, leading to missed opportunities for early intervention. Objective: The goal of this study is to explore the efficiency and accuracy of combining fNIRS technology with machine learning algorithms in diagnosing early-stage PD patients and to evaluate the feasibility of this approach in clinical practice. Methods: Using an ETG-4000 type near-infrared brain function imaging instrument, data was collected from 120 PD patients and 60 healthy controls. This cross-sectional study employed a multi-channel mode to monitor cerebral blood oxygen changes. The collected data were processed using a general linear model and ß values were extracted. Subsequently, four types of machine learning models were developed for analysis: Support vector machine (SVM), K-nearest neighbors (K-NN), random forest (RF), and logistic regression (LR). Additionally, SHapley Additive exPlanations (SHAP) technology was applied to enhance model interpretability. Results: The SVM model demonstrated higher accuracy in differentiating between PD patients and control group (accuracy of 85%, f1 score of 0.85, and an area under the ROC curve of 0.95). SHAP analysis identified the four most contributory channels (CH) as CH01, CH04, CH05, and CH08. Conclusion: The model based on the SVM algorithm exhibited good diagnostic performance in the early detection of PD patients. Future early diagnosis of PD should focus on the Frontopolar Cortex (FPC) region.

Recombination of the right cerebral cortex in patients with left side USN after stroke: fNIRS evidence from resting state.

Objective: Unilateral spatial neglect (USN) is an impaired contralesional stimulus detection, response, or action, causing functional disability. After a stroke, the right hemisphere experiences USN more noticeably, severely, and persistently than the left. However, few studies using fNIRS have been reported in cases of USN. This study aimed to confirm weaker RSFC in USN and investigate the potential inherent features in hemodynamic fluctuations that may be associated with USN. Furthermore, these features were combined into a mathematical model for more accurate classification. Methods: A total of 33 stroke patients with right-sided brain damage were chosen, of whom 12 had non-USN after stroke, and 21 had USN after stroke (the USN group). Graph theory was used to evaluate the hemodynamic signals of the brain's right cerebral cortex during rest. Furthermore, a support vector machine model was built to categorize the subjects into two groups based on the chosen network properties. Results: First, mean functional connectivity was lower in the USN group (0.745 ± 0.239) than in the non-USN group (0.843 ± 0.254) (t = -4.300, p < 0.001). Second, compared with the non-USN group, USN patients had a larger clustering coefficient (C) (t = 3.145, p < 0.001), local efficiency (LE) (t = 3.189, p < 0.001), and smaller global efficiency (GE) (t = 3.047, p < 0.001). Notably, there were differences in characteristic path length (L) and small worldness (σ) values between the two groups at certain thresholds, mainly as higher L (t = 3.074, p < 0.001) and lower small worldness (σ) values (t = 2.998, p < 0.001) in USN patients compared with non-USN patients. Finally, the classification accuracy of the SVM model based on AUC aC (t = -2.259, p = 0.031) and AUC aLE (t = -2.063, p = 0.048) was 85%, the sensitivity was 75%, and the specificity was 89%. Conclusion: The functional network architecture of the right cerebral cortex exhibits significant topological alterations in individuals with USN following stroke, and the sensitivity index based on the small-world property AUC may be utilized to identify these patients accurately.

Effects of Rehabilitation Therapy at Different Intervention Times on Daily Living Activity and Motor Function in Patients with Traumatic Spinal Cord Injury.

Objectives: We investigated the impact of traumatic spinal cord injury (TSCI) on daily living activities and motor function of TSCI patients. Methods: A total of 88 TSCI patients were randomly divided into Group A (N=44) and Group B (N=44). Group A received rehabilitation treatment 7 days after the stabilization of vital signs, and Group B received rehabilitation treatment 30 days after hospitalization. Results: The compliance rate of Group A (93.18%) was higher than that of Group B (72.73%) (χ 2 =6.510, p<.05); The scores of American Spinal Injury Association (ASIA) and Activities of Daily Living (ADL) in Group A were higher than those in Group B. The self-rating score of anxiety and depression was lower than that of Group B (p<.05). Conclusion: For the rehabilitation treatment of TSCI patients, it is better to choose the intervention after the vital signs are stable to improve patients' ability for daily living activities and motor function.

Association between heavy metals exposure (cadmium, lead, arsenic, mercury) and child autistic disorder: a systematic review and meta-analysis.

Background: Studies have found that toxic heavy metals exposure could induce the generation of reactive oxygen species (ROS), and is of epigenetic effect, which might be associated with the occurrence of Autistic Disorder (ASD). This systematic review and meta-analysis aims to elucidate the association between exposure to 4 heavy metals, cadmium (Cd), lead (Pb), arsenic(As), and mercury (Hg), and the occurrence of ASD in children. Methods: We searched PubMed, Web of Science, Embase, and Cochrane Library, from their inception to October 2022, for epidemiological investigations that explore the association between exposure to Cd, Pb, As, or Hg and the occurrence of child ASD. Results: A total of 53 studies were included, involving 5,054 individuals aged less than 18 (2,533 ASD patients and 2,521 healthy controls). Compared with the healthy controls, in hair and blood tests, concentrations of the 4 heavy metals were significantly higher in the ASD group than in the healthy control group, and the differences in Pb, arsenic and Hg were statistically significant (P < 0.05). In the urine test, concentrations of arsenic and Hg were significantly higher in the ASD group than in the healthy control group (P < 0.05), while the results of Cd and Pb were opposite to those of arsenic and Hg (P > 0.05). Subgroup analysis for geographic regions showed that ASD patients in Asia and Europe had higher concentrations of the 4 heavy metals, compared with the healthy controls, in which the differences in Pb, arsenic, and Hg were statistically significant (P < 0.05), while in North America, the healthy controls had higher Cd, arsenic, and Hg concentrations (P > 0.05). Conclusion: Compared with the healthy control group, the ASD group had higher concentrations of Cd, Pb, arsenic, and Hg. These 4 heavy metals play different roles in the occurrence and progression of ASD. Moreover, there is significant heterogeneity among the included studies due to controversies about the study results among different countries and regions and different sources of detection materials. The results of this study firmly support the policies to limit heavy metals exposure, especially among pregnant women and young children, so as to help reduce the incidence of ASD.

A diagnostic model of nerve root compression localization in lower lumbar disc herniation based on random forest algorithm and surface electromyography.

Objective: This study aimed to investigate the muscle activation of patients with lumbar disc herniation (LDH) during walking by surface electromyography (SEMG) and establish a diagnostic model based on SEMG parameters using random forest (RF) algorithm for localization diagnosis of compressed nerve root in LDH patients. Methods: Fifty-eight patients with LDH and thirty healthy subjects were recruited. The SEMG of tibialis anterior (TA) and lateral gastrocnemius (LG) were collected bilaterally during walking. The peak root mean square (RMS-peak), RMS-peak time, mean power frequency (MPF), and median frequency (MF) were analyzed. A diagnostic model based on SEMG parameters using RF algorithm was established to locate compressed nerve root, and repeated reservation experiments were conducted for verification. The study evaluated the diagnostic efficiency of the model using accuracy, precision, recall rate, F1-score, Kappa value, and area under the receiver operating characteristic (ROC) curve. Results: The results showed that delayed activation of TA and decreased activation of LG were observed in the L5 group, while decreased activation of LG and earlier activation of LG were observed in the S1 group. The RF model based on eight SEMG parameters showed an average accuracy of 84%, with an area under the ROC curve of 0.93. The RMS peak time of TA was identified as the most important SEMG parameter. Conclusion: These findings suggest that the RF model can assist in the localization diagnosis of compressed nerve roots in LDH patients, and the SEMG parameters can provide further references for optimizing the diagnosis model in the future.

Added forearm weights for gait pattern normalization in patients with Parkinson's disease.

Patients with Parkinson's Disease presented gait impairment. Applying additional weights to enhancing sensory input may improve gait impairment. We assumed that gait impairment could be improved when patients walked with additional forearm weights, and the gait improvement was associated with clinical characteristic of Parkinson's Disease. Thirty patients with Parkinson's Disease and 30 age-sex matched controls were recruited. Spatiotemporal and joint kinematics parameters were evaluated by a three-dimensional motion capture system in normal walking and walking with sandbags, respectively. The comparisons of spatiotemporal parameters were analyzed using t-test or nonparametric tests. The comparison of joint kinematic data was analyzed using statistical parametric mapping. The correlation between motor symptom and gait parameters changes was analyzed using Pearson's correlation analysis. During normal walking, patients showed deteriorated gait compared with controls. After applying weights to forearms patients increased cadence (p = 0.004), speed (p < 0.001) and step length (p = 0.048), and decreased stride time (p = 0.003). The hip angles significantly increased during 5%-23% and 87%-100% of gait cycle, while knee angles during 9%-25% and 88%-98% of the gait cycle, and ankle angles in 92%-100% of gait cycle. The gait parameters of patients with forearm-loading showed no significant difference compared with healthy subjects walking normally. The change of gait parameters correlated positively with the axial and tremor severity while correlated negatively with the rigidity sub-score. Patients with tremor dominant subtype also showed greater improvement of speed and step time compared with patients with postural instability/gait difficulty subtype. Applying added weights bilaterally to the forearms of patients can normalize gait patterns. Notably, patients with higher scores on axial and tremor and lower rigidity scores gained more benefits.

Meta-analysis of repetitive transcranial magnetic stimulation combined with task-oriented training on upper limb function in stroke patients with hemiplegia.

BACKGROUND: To evaluate the effect of repetitive transcranial magnetic stimulation (rTMS) combined with task-oriented training (TOT) on upper limb function in stroke patients with hemiplegia. METHODS: A systematic review and meta-analysis was performed using PRISMA guidelines. Computer searches of PubMed, Cochrane Library, Embase, Web of science, China Knowledge Network, Wanfang, and Wipu databases were conducted from the time of database creation to October 27, 2022. Clinical trials meeting the inclusion criteria were screened, with rTMS combined with TOT in the test group and other therapies in the control group. Literature screening and data extraction were performed independently by 2 investigators, and meta-analysis was performed using Stata software after quality evaluation of the literature. RESULTS: Meta-analysis results showed that repeated transcranial magnetic stimulation combined with TOT was more effective in box and block test (I2 = 0%, P = .820, 95% confidence interval [CI] [-0.20, 0.88]), Fugl-Meyer Assessment (I2 = 0%, P = .569, 95% CI [0.88, 1.26]), and modified Barthel Index (I2 = 39.9%, P = .189, 95% CI [0.45, 1.03]) were not significantly different from controls, and the efficacy was significantly better in motor evoked potentials (I2 = 86.5%, P < .001, 95% CI [-1.38, -0.83]). CONCLUSIONS: Data analysis clarified the efficacy of rTMS) combined with TOT on upper extremity motor function disorders after stroke, but there was no significant difference between the efficacy in box and block test, Fugl-Meyer Assessment, and modified Barthel Index and the efficacy in motor evoked potentials between rTMS and the control group, suggesting that the neuro plasticizing effect of rTMS may translate into functional improvement by promoting neuro electrical signaling.

Surface electromyography characteristics of patients with anterior cruciate ligament injury in different rehabilitation phases.

Background: Anterior cruciate ligament reconstruction (ACLR) is a common treatment for anterior cruciate ligament (ACL) injury. However, after ACLR, a significant proportion of patients do not return to pre-injury levels. Research on muscle function during movement has important implications in rehabilitation. Methods: Sixty patients with unilateral ACL injury were recruited for this study and assigned into three groups: group A, individuals with an ACL injury before 6 months; group B, individuals with ACLR from 6 months to 1 year; and group C, individuals with ACLR 1 year later. Surface electromyography (SEMG) signals were collected from the bilateral rectus femoris (RF), vastus medialis (VM), vastus lateralis (VL), biceps femoris (BF), and semitendinosus (ST). The tasks performed during the experiment included straight leg raising (SLR) training at 30°, SLR training at 60°, ankle dorsiflexion, walking, and fast walking. Results: In the maximum muscle strength test, the affected side of the BF in group A (199.4 ± 177.12) was significantly larger than in group B (53.91 ± 36.61, p = 0.02) and group C (75.08 ± 59.7, p = 0.023). In the walking test, the contralateral side of the RF in group B (347.53 ± 518.88) was significantly greater than that in group C (139.28 ± 173.78, p = 0.029). In the SLR training (60°) test, the contralateral side of the RF in group C (165.37 ± 183.06) was significantly larger than that in group A (115.09 ± 62.47, p = 0.023) and smaller than that in group B (226.21 ± 237.17, p = 0.046); In the ankle dorsiflexion training test, the contralateral side of the RF in group B (80.37 ± 87.9) was significantly larger than that in group C (45.61 ± 37.93, p = 0.046). Conclusion: This study showed the EMG characteristics of patients with ACL injury helped to determine which muscle requires more training and which exercise model would be best suited for intervention.

The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery.

Stroke causes varying degrees of neurological deficits, leading to corresponding dysfunctions. There are different therapeutic principles for each stage of pathological development. Neuroprotection is the main treatment in the acute phase, and functional recovery becomes primary in the subacute and chronic phases. Neuroplasticity is considered the basis of functional restoration and neurological rehabilitation after stroke, including the remodeling of dendrites and dendritic spines, axonal sprouting, myelin regeneration, synapse shaping, and neurogenesis. Spatiotemporal development affects the spontaneous rewiring of neural circuits and brain networks. Microglia are resident immune cells in the brain that contribute to homeostasis under physiological conditions. Microglia are activated immediately after stroke, and phenotypic polarization changes and phagocytic function are crucial for regulating focal and global brain inflammation and neurological recovery. We have previously shown that the development of neuroplasticity is spatiotemporally consistent with microglial activation, suggesting that microglia may have a profound impact on neuroplasticity after stroke and may be a key therapeutic target for post-stroke rehabilitation. In this review, we explore the impact of neuroplasticity on post-stroke restoration as well as the functions and mechanisms of microglial activation, polarization, and phagocytosis. This is followed by a summary of microglia-targeted rehabilitative interventions that influence neuroplasticity and promote stroke recovery.

Exploring the relationship between intestinal flora and the pathological mechanism of myopia in adolescents from the perspective of Chinese and Western medicine: A review.

The etiology of adolescent myopia involves genetic and environmental factors. The pathological mechanism of modern medicine includes blood perfusion, changes in blood molecules, neurotransmitters, and sclera remodeling. Chinese medicine believes that myopia is mainly related to the deficiency of liver blood and spleen and stomach disorders. The prevention and treatment of myopia in adolescents are very important, but in terms of the current incidence of myopia in adolescents and the level of clinical diagnosis and treatment, its prevention and treatment are insufficient. Modern medicine and traditional Chinese medicine both pay attention to integrity, so adolescent myopia should not only pay attention to eye changes but also pay attention to other body systems and other aspects of change. Intestinal flora has become a research hotspot in recent years, and it has been found that it is closely associated with multi-system and multi-type diseases. No studies have directly investigated the link between Intestinal flora and myopia in adolescents. Therefore, by summarizing the pathological mechanism of adolescent myopia and the connection between intestinal flora and the pathological mechanism of adolescent myopia, this paper analyzes the possible pathological mechanism of the influence of intestinal flora on adolescent myopia, providing a theoretical basis for future studies on the correlation between changes of intestinal flora and its metabolites and the incidence of adolescent myopia, which is of great significance for the study on the risk prediction of adolescent myopia.

Effects of different types of visual music on the prefrontal hemodynamics of children with autism spectrum disorder based on functional near-infrared spectroscopy.

Background: Music therapy has been shown to improve communication in children with autism spectrum disorders (ASD), but little is known about how different types of music and images affect hemodynamic changes in the frontal lobe of the brain in children with ASD. This study aims to use functional near infrared spectroscopy (fNIRS) to explore the effects of different types of visual music on different brain regions of oxyhemoglobin (HbO) in the prefrontal lobe of children with ASD and children with typical development (TD), so as to provide evidence for better application of different types of visual music in the treatment of children with ASD. Methods: Seven children with ASD and nine matched children with TD were selected. Changes in HbO in their prefrontal lobes were determined by fNIRS after resting states and 12 different types of visual music tasks. Results: (I) Intra-group comparison: the influence of different types of light and music on ∆HbO in ROI (zone F) of ASD children is different, the activation degree shows that red light & positive music is less than green light & neutral music, red light & positive music is less than blue light & negative music, and there is no difference between green light & neutral music and blue light & negative music. (II) Comparison between groups: Visual musical tasks 1, 2, 3, 4, and 8 positively activated HbO in the prefrontal B and E regions of the brain in children with ASD and negatively activated HbO in TD children. Visual musical tasks 5, 9, 10, and 12 negatively activated HbO in the prefrontal F regions of the brain in children with ASD and positively activated HbO in TD children. Conclusions: When the two groups of children received the same visual music task, the changes of HbO in different regions of the prefrontal lobe were different; The effects of different types of visual music on the frontal lobe of the brain in children with ASD are inconsistent.

The Validity and Reliability of a New Intelligent Three-Dimensional Gait Analysis System in Healthy Subjects and Patients with Post-Stroke.

Odonate is a new, intelligent three-dimensional gait analysis system based on binocular depth cameras and neural networks, but its accuracy has not been validated. Twenty-six healthy subjects and sixteen patients with post-stroke were recruited to investigate the validity and reliability of Odonate for gait analysis and examine its ability to discriminate abnormal gait patterns. The repeatability tests of different raters and different days showed great consistency. Compared with the results measured by Vicon, gait velocity, cadence, step length, cycle time, and sagittal hip and knee joint angles measured by Odonate showed high consistency, while the consistency of the gait phase division and the sagittal ankle joint angle was slightly lower. In addition, the stages with statistical differences between healthy subjects and patients during a gait cycle measured by the two systems were consistent. In conclusion, Odonate has excellent inter/intra-rater reliability, and has strong validity in measuring some spatiotemporal parameters and the sagittal joint angles, except the gait phase division and the ankle joint angle. Odonate is comparable to Vicon in its ability to identify abnormal gait patterns in patients with post-stroke. Therefore, Odonate has the potential to provide accessible and objective measurements for clinical gait assessment.

Intersegmental Coordination in Patients With Total Knee Arthroplasty During Walking.

Precise identification of deficient intersegmental coordination patterns and functional limitations is conducive to the evaluation of surgical outcomes after total knee arthroplasty (TKA) and the design of optimal personalized rehabilitation protocols. However, it is still not clear how and when intersegmental coordination patterns change during walking, and what functional limitations are in patients with TKA. This study was designed to investigate lower limb intersegmental coordination patterns in patients with knee osteoarthritis before and after TKA and identify how intersegmental coordination of patients is altered during walking before and after TKA. It was hypothesized that 6-month after TKA, intersegmental coordination patterns of patients are improved compared with that before TKA, but still do not recover to the level of healthy subjects. Gait analysis was performed on 36 patients before and 6-month after TKA and on 34 healthy subjects. Continuous relative phase (CRP) derived from the angle-velocity phase portrait was used to measure the coordination between interacting segments throughout the gait cycle. Thigh-shank CRP and shank-foot CRP were calculated for each subject. Statistical parametric mapping (SPM), a one-dimensional analysis of the entire gait cycle curve, was performed directly to determine which periods of the gait cycle were different in patients and healthy subjects. Six-month after TKA, thigh-shank CRP was significantly higher during 5-12% of the gait cycle (p = 0.041) and lower during 44-95% of the gait cycle (p < 0.001) compared with healthy subjects, and was significantly higher during 62-91% of the gait cycle (p = 0.002) compared with pre-operation. Shank-foot CRP was significantly lower during 0-28% of the gait cycle (p < 0.001) and higher during 58-94% of the gait cycle (p < 0.001) compared with healthy subjects, and was significantly lower during 3-18% of the gait cycle (p = 0.005) compared with pre-operation. This study found that patients exhibited altered intersegmental coordination during the loading response and swing phase both before and after TKA. Six-month after TKA, the thigh-shank coordination was partially improved compared with pre-operation, but still did not recover to the level of healthy subjects, while there was no improvement in the shank-foot coordination pattern after TKA compared with pre-operation. CRP combined with SPM methods can provide insights into the evaluation of surgical outcomes and the design of rehabilitation strategy.

The efficacy of 5 rehabilitation treatments after anterior cruciate ligament reconstruction: A network meta-analysis.

BACKGROUND: The efficacy of traditional rehabilitation, proprioceptive training, and neuromuscular training after anterior cruciate ligament (ACL) reconstruction is also controversial. In order to help medical staff better choose the rehabilitation treatment plan after ACL reconstruction, we conducted this network meta-analysis. METHODS: Chinese and English databases such as Wanfang, Weipu, China Zhiwang, and PubMed, Cochrane Library, Embase were retrieved. We collected clinical controlled trial papers on traditional rehabilitation therapy, proprioceptive training and neuromuscular training after ACL reconstruction for meta-analysis. RESULTS: In this meta-analysis, 12 studies were included, including 486 patients who received rehabilitation treatment after ACL reconstruction. Based on network meta-analysis, it was found that 4 groups of direct comparison and 6 groups of indirect comparison were formed for 5 rehabilitation treatment schemes after ACL reconstruction. The curative effect of traditional rehabilitation training combined with proprioception training is better than that of traditional rehabilitation training (mean difference value of traditional rehabilitation training combined with proprioception training vs traditional rehabilitation training was 8.00, 95% confidence interval: 2.61,13.39). The efficacy of proprioceptive training is better than that of traditional rehabilitation training (mean difference value of proprioceptive training vs traditional rehabilitation training is 11.01, 95% confidence interval: 0.62,21.39). There was no statistical significance between the other rehabilitation trainings. According to the surface under cumulative ranking curve, the therapeutic effects of the 5 rehabilitation treatment programs after ACL reconstruction were ranked as follows: proprioceptive training (72%) > traditional rehabilitation training combined with neuromuscular training (70.8%) > traditional rehabilitation training combined with proprioception training (57.1%) > neuromuscular training (45.5%) > traditional rehabilitation training (4.6%). No publication bias was found in the funnel plot. CONCLUSION: Combined with the results of meta-analysis and surface under cumulative ranking efficacy sequence diagram, it can be seen that traditional rehabilitation training combined with proprioceptive training and traditional rehabilitation training combined with neuromuscular training have significant efficacy. Due to the limitations of this study, the conclusions of this network meta-analysis still need to be further confirmed by a large sample size and well-designed randomized controlled trials.

Baicalein ameliorates ischemic brain damage through suppressing proinflammatory microglia polarization via inhibiting the TLR4/NF-κB and STAT1 pathway.

Microglial polarization mediated neuroinflammation plays an important role in the pathological process of stroke. The aim of this study is to determine whether baicalein indirectly ameliorates neuronal injury through modulating microglial polarization after stroke and if so, then by what mechanism. The effects of baicalein on microglial polarization were revealed through the middle cerebral artery occlusion mouse model (MCAO, n = 6), the lipopolysaccharide (LPS) + interferon-γ (IFN-γ) and oxygen-glucose deprivation (OGD) induced neuroinflammatory microglia model (BV2, n = 3), respectively. Mice were treated with baicalein (100 mg/kg, i.g.) after reperfusion, and followed by daily administrations for 3 days. Results showed that the infarct volumes at 3 d in vehicle and baicalein-treated MCAO mice were 91.18 ± 4.02% and 55.36 ± 4.10%. Baicalein improved sensorimotor functions (p < 0.01) after MCAO. Real-time PCR revealed that baicalein decreased proinflammatory markers expression (p < 0.05), while elevated the anti-inflammatory markers (p < 0.05) in vivo and in vitro. Both western blot and immunofluorescent staining further confirmed that baicalein reduced proinflammatory marker CD16 levels (p < 0.01) and enhanced anti-inflammatory marker CD206 or Arg-1 levels (p < 0.05). Notably, baicalein suppressed the release of proinflammatory cytokines (p < 0.05) and nitric oxide (NO, p < 0.001). Mechanistically, baicalein prevented increases in TLR4 protein levels (p < 0.001), the phosphorylation of IKBα and p65 (p < 0.01), and the nuclear translocation of NF-κB p65 (p < 0.05). The NF-κB inhibitor, BAY 11-7085, enhanced the inhibitory effect of baicalein on the proinflammatory microglial polarization. Baicalein also inhibited the phosphorylation of signal transducer and activator of transcription 1 (STAT1, p < 0.001). A microglia-neuron co-culture system revealed that baicalein driven neuroprotection against OGD induced neuronal damage through modulating microglial polarization (p < 0.05). Baicalein indirectly ameliorates neuronal injury after stroke by polarizing microglia toward the anti-inflammatory phenotype via inhibition of the TLR4/NF-κB pathway and down-regulation of phosphorylated STAT1, suggesting that baicalein might serve a potential therapy for stroke.

sDR5-Fc inhibits macrophage M1 polarization by blocking the glycolysis.

BACKGROUND: M1 polarization of macrophages is an important pathological process in myocardial ischemia reperfusion injury, which is the major obstacle for the treatment of acute myocardial infarction. Currently, the strategies and mechanisms of inhibiting M1 polarization are poorly explored. This study aims to investigate the role of soluble death receptor 5-Fc (sDR5-Fc) in regulating M1 polarization of macrophages under extreme conditions and explore the mechanisms from the aspect of glycolysis. METHODS: Extreme conditions were induced in RAW264.7 cells. Real-time quantitative polymerase chain reaction and western blot were used to detect the expression of mRNA and proteins, respectively. Cell counting kit-8 was used to investigate the proliferation activity of cells. Expression levels of inflammatory cytokines were determined by enzyme-linked immunosorbent assay. RESULTS: We found that sDR5-Fc rescues the proliferation of macrophages under extreme conditions, including nutrition deficiency, excessive peroxide, and ultraviolet irradiation. In addition, administration of sDR5-Fc inhibits the M1 polarization of macrophages induced by lipopolysaccharide (LPS) and interferon-gamma (IFN-γ), as the expression of M1 polarization markers CD86, CXC motif chemokine ligand 10, matrix metalloproteinase 9, and tumor necrosis factor-α, as well as the secretion of inflammatory factors interleukin (IL)-1ß and IL-6, were significantly decreased. By further investigation of the mechanisms, the results showed that sDR5-Fc can recover the LPS and IFN-γ induced pH reduction, lactic acid elevation, and increased expression of hexokinase 2 and glucose transporter 1, which were markers of glycolysis in macrophages. CONCLUSIONS: sDR5-Fc inhibits the M1 polarization of macrophages by blocking the glycolysis, which provides a new direction for the development of strategies in the treatment of myocardial ischemia reperfusion injury.

Cell Models for Birth Defects Caused by Chloroethyl Nitrosourea-Induced DNA Lesions.

ABSTRACT: Birth defects have been linked to administration of alkylating agents during pregnancy. The anti-tumor efficacy of alkylating agents correlate with their ability to induce DNA lesions, especially interstrand crosslinks (ICLs). Yet the role of DNA damages in birth defects remains to be clarified, owing, in part, to a lack of cell models. Here we generate DNA lesions in NIH/3T3 cells to mimic defects in fetus triggered by 3-Bis(2-chloroethyl)-1-nitrosourea (BCNU, carmustine). CCK-8 assay suggests that BCNU-induced cell death was dose-dependent. Alkaline comet tests and γ-H2AX staining confirm DNA ICLs and other forms of DNA damages caused by BCNUs. The cell cycle analysis shows cells arrest in G2/M phase until crosslinks repair is complete. Taken together, all these experiments demonstrate we have successfully established normal cell models for birth defects caused by BCNU-mediated DNA damages. The model can not only guide the development of effective and low-toxicity anticancer drugs, but also be of great significance for the study of neonatal malformation triggered by BCNUs.

Candesartan modulates microglia activation and polarization via NF-κB signaling pathway.

Microglia are diverse cells that acquire different functional phenotypes in response to microenvironment in which they reside. Several transcriptional regulators have been identified that regulate different microglia phenotypes. They are mainly stimulated into two opposing phenotypes, classically (M1) and alternatively (M2) phenotype. Regulating microglia polarization from M1 to M2 state has been suggested as a potential therapeutic approach in treatment of CNS disorders. Candesartan, an angiotensin II type I receptors antagonist, exerts beneficial effects for antioxidant, anti-inflammation, neurotrophic, and anti-apoptotic function. However, the effect of candesartan on microglia polarization and underlying mechanisms remain unknown. In this study, the resting microglia were stimulated to M1 microglia with lipopolysaccharide (LPS) and interferon-γ (IFN-γ), and then treated with vehicle or candesartan for 24 h. RT-PCR was utilized to detect the mRNA expression of microglia phenotype markers and inflammatory cytokines. Microglia phenotype markers and toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathway were determined by western blot. A neuron-microglia co-culture system was used to determine whether candesartan could ameliorate the neurotoxic effect of M1 microglia to oxygen-glucose deprivation (OGD) neuron. Candesartan treatment reduced the expression of M1 markers, and increased M2 markers. Meanwhile, candesartan reduced fluorescence intensity and protein level of M1 marker and enhanced M2 marker. Candesartan also regulated the neuroinflammatory response via reducing the release of pro-inflammatory cytokines and increasing anti-inflammatory cytokines in LPS + IFN-γ stimulated BV2 cells. Candesartan markedly inhibited the protein level of TLR4, the phosphorylation of IKBα and p65, and suppressed nuclear translocation of NF-κB p65. BAY 11-7085, a NF-κB inhibitor, remarkably enlarged the inhibitory effect of candesartan on NF-κB pathway. In addition, M1 phenotype microglia exacerbated post-OGD N2a cells death and LDH release, whereas candesartan reversed such neurotoxic effect. Candesartan treatment may ameliorate stroke-induced neuronal damage through shifting microglia to M2 phenotype in a TLR4/NF-κB-dependent manner.