Revealing the mechanisms of blood-brain barrier in chronic neurodegenerative disease: an opportunity for therapeutic intervention.

The brain microenvironment is tightly regulated, and the blood-brain barrier (BBB) plays a pivotal role in maintaining the homeostasis of the central nervous system. It effectively safeguards brain tissue from harmful substances in peripheral blood. However, both acute pathological factors and age-related biodegradation have the potential to compromise the integrity of the BBB and are associated with chronic neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), as well as Epilepsy (EP). This association arises due to infiltration of peripheral foreign bodies including microorganisms, immune-inflammatory mediators, and plasma proteins into the central nervous system when the BBB is compromised. Nevertheless, these partial and generalized understandings do not prompt a shift from passive to active treatment approaches. Therefore, it is imperative to acquire a comprehensive and in-depth understanding of the intricate molecular mechanisms underlying vascular disease alterations associated with the onset and progression of chronic neurodegenerative disorders, as well as the subsequent homeostatic changes triggered by BBB impairment. The present article aims to systematically summarize and review recent scientific work with a specific focus on elucidating the fundamental mechanisms underlying BBB damage in AD, PD, and EP as well as their consequential impact on disease progression. These findings not only offer guidance for optimizing the physiological function of the BBB, but also provide valuable insights for developing intervention strategies aimed at early restoration of BBB structural integrity, thereby laying a solid foundation for designing drug delivery strategies centered around the BBB.

Effects of Intranasal Insulin Pretreatment on Preoperative Sleep Quality and Postoperative Delirium in Patients Undergoing Valve Replacement for Rheumatic Heart Disease.

Background: Postoperative delirium (POD) is a common neurological complication associated with valve replacement. Preoperative sleep disturbance is a risk factor for POD development, and nasal insulin modulates the sleep-wake cycle. This study investigated the beneficial effects of intranasal insulin pretreatment on preoperative sleep quality and reducing POD in patients undergoing valve replacement for rheumatic heart disease. Patients and Methods: This prospective, single-center, randomized controlled trial (RCT) included 76 adult patients aged 18-65 years undergoing valve surgery with cardiopulmonary bypass who were randomly allocated to receive intranasal insulin or normal saline interventions two days before surgery. POD incidence was on postoperative days 1 (T3), 2 (T4), and 3 (T5). Before the first intervention (T0), 1 d before surgery (T1), and before anesthesia on the day of surgery (T2), sleep quality was assessed and serum cortisol concentrations were measured. At T1 and T2, sleep quality related indicators monitored by sleep monitoring watches from the previous night were recorded. Results: Compared with the normal saline group, 3 days after surgery, the insulin group showed a significantly reduced incidence of POD; significantly increased deep sleep, REM sleep, deep sleep continuity, and total sleep quality scores at T1 and T2; and significantly reduced serum cortisol concentration, PSQI scale, light sleep ratio, and wakefulness at T1 and T2. Conclusion: The administration of 20 U of intranasal insulin twice daily, from 2 days preoperatively until 10 minutes preanesthesia on the day of surgery, can improved preoperative sleep quality significantly and reduced POD incidence in patients with rheumatic heart disease undergoing valve replacement. Clinical Trial Registration: This study was registered with the Chinese Clinical Trial Registry (www.chictr.org.cn, with the unique identifier ChiCTR2100048515; July 9, 2021).

Challenges and prospects in geriatric epilepsy treatment: the role of the blood-brain barrier in pharmacotherapy and drug delivery.

The blood-brain barrier (BBB) is pivotal in maintaining neuronal physiology within the brain. This review delves into the alterations of the BBB specifically in the context of geriatric epilepsy. We examine how age-related changes in the BBB contribute to the pathogenesis of epilepsy in the elderly and present significant challenges in pharmacotherapy. Subsequently, we evaluate recent advancements in drug delivery methods targeting the BBB, as well as alternative approaches that could bypass the BBB's restrictive nature. We particularly highlight the use of neurotropic viruses and various synthetic nanoparticles that have been investigated for delivering a range of antiepileptic drugs. Additionally, the advantage and limitation of these diverse delivery methods are discussed. Finally, we analyze the potential efficacy of different drug delivery approaches in the treatment of geriatric epilepsy, aiming to provide insights into more effective management of this condition in the elderly population.

Association between Removal of High-Frequency Oscillations and the Effect of Epilepsy Surgery: A Meta-Analysis.

BACKGROUND: High-frequency oscillations (HFOs) are spontaneous electroencephalographic (EEG) events that occur within the frequency range of 80 to 500 Hz and consist of at least four distinct oscillations that stand out from the background activity. They can be further classified into "ripples" (80-250 Hz) and "fast ripples" (FR; 250-500 Hz) based on different frequency bands. Studies have indicated that HFOs may serve as important markers for identifying epileptogenic regions and networks in patients with refractory epilepsy. Furthermore, a higher extent of removal of brain regions generating HFOs could potentially lead to improved prognosis. However, the clinical application criteria for HFOs remain controversial, and the results from different research groups exhibit inconsistencies. Given this controversy, the aim of this study was to conduct a meta-analysis to explore the utility of HFOs in predicting postoperative seizure outcomes by examining the prognosis of refractory epilepsy patients with varying ratios of HFO removal. METHODS: Prospective and retrospective studies that analyzed HFOs and postoperative seizure outcomes in epilepsy patients who underwent resective surgery were included in the meta-analysis. The patients in these studies were grouped based on the ratio of HFOs removed, resulting in four groups: completely removed FR (C-FR), completely removed ripples (C-Ripples), mostly removed FR (P-FR), and partial ripples removal (P-Ripples). The prognosis of patients within each group was compared to investigate the correlation between the ratio of HFO removal and patient prognosis. RESULTS: A total of nine studies were included in the meta-analysis. The prognosis of patients in the C-FR group was significantly better than that of patients with incomplete FR removal (odds ratio [OR] = 6.62; 95% confidence interval [CI]: 3.10-14.15; p < 0.00001). Similarly, patients in the C-Ripples group had a more favorable prognosis compared with those with incomplete ripples removal (OR = 4.45; 95% CI: 1.33-14.89; p = 0.02). Patients in the P-FR group had better prognosis than those with a majority of FR remaining untouched (OR = 6.23; 95% CI: 2.04-19.06; p = 0.001). In the P-Ripples group, the prognosis of patients with a majority of ripples removed was superior to that of patients with a majority of ripples remaining untouched (OR = 8.14; 95% CI: 2.62-25.33; p = 0.0003). CONCLUSIONS: There is a positive correlation between the greater removal of brain regions generating HFOs and more favorable postoperative seizure outcomes. However, further investigations, particularly through clinical trials, are necessary to justify the clinical application of HFOs in guiding epilepsy surgery.

Role of hypoxic exosomes and the mechanisms of exosome release in the CNS under hypoxic conditions.

Hypoxia is characterized by low oxygen levels in the body or environment, resulting in various physiological and pathological changes. The brain, which has the highest oxygen consumption of any organ, is particularly susceptible to hypoxic injury. Exposure to low-pressure hypoxic environments can cause irreversible brain damage. Hypoxia can occur in healthy individuals at high altitudes or in pathological conditions such as trauma, stroke, inflammation, and autoimmune and neurodegenerative diseases, leading to severe brain damage and impairments in cognitive, learning, and memory functions. Exosomes may play a role in the mechanisms of hypoxic injury and adaptation and are a current focus of research. Investigating changes in exosomes in the central nervous system under hypoxic conditions may aid in preventing secondary damage caused by hypoxia. This paper provides a brief overview of central nervous system injury resulting from hypoxia, and aimed to conduct a comprehensive literature review to assess the pathophysio-logical impact of exosomes on the central nervous system under hypoxic conditions.

Research progress in brain-targeted nasal drug delivery.

The unique anatomical and physiological connections between the nasal cavity and brain provide a pathway for bypassing the blood-brain barrier to allow for direct brain-targeted drug delivery through nasal administration. There are several advantages of nasal administration compared with other routes; for example, the first-pass effect that leads to the metabolism of orally administered drugs can be bypassed, and the poor compliance associated with injections can be minimized. Nasal administration can also help maximize brain-targeted drug delivery, allowing for high pharmacological activity at lower drug dosages, thereby minimizing the likelihood of adverse effects and providing a highly promising drug delivery pathway for the treatment of central nervous system diseases. The aim of this review article was to briefly describe the physiological structures of the nasal cavity and brain, the pathways through which drugs can enter the brain through the nose, the factors affecting brain-targeted nasal drug delivery, methods to improve brain-targeted nasal drug delivery systems through the application of related biomaterials, common experimental methods used in intranasal drug delivery research, and the current limitations of such approaches, providing a solid foundation for further in-depth research on intranasal brain-targeted drug delivery systems (see Graphical Abstract).

Thrombospondin-2 promotes the proliferation and migration of glioma cells and contributes to the progression of glioma.

BACKGROUND: Gliomas, especially high-grade gliomas, are highly malignant with a poor prognosis. Although existing treatments have improved the survival rate of patients with glioma, the recurrence and mortality rates are still not ideal. The molecular mechanisms involved in the occurrence and development of glioma are still poorly understood. We previously reported that thrombospondin-2 (TSP2) expression was increased in tumor specimens from rat models, promoting excitatory synapse formation. However, little is known about the effect of TSP2 on the biological characteristics of glioma. METHODS: Glioma and cerebral cortex tissues were collected from 33 patients, and the expression of TSP2 in them was analyzed. Next, the proliferation and migration of TSP2 on glioma cells were analyzed in vitro. At last, a glioma transplantation model was constructed to explore the growth of TSP2 on glioma in vivo. RESULTS: The expression of TSP2 in surgical glioma specimens was increased compared to that in the normal cortex. Interestingly, the TSP2 protein level was higher in high-grade glioma (HGG, World Health Organization (WHO) grades 3-4) than in low-grade glioma (LGG, WHO grades 1-2) tissues. Exogenous addition of the TSP2 protein at an appropriate concentration promoted the migration of glioma cells but did not significantly affect their proliferation. Surprisingly, overexpression of TSP2 promoted both the migration and proliferation of cultured glioma cells. Moreover, in vivo experimental data implied that overexpression of TSP2 in C6 cells promoted the malignant growth of gliomas, while knockout of TSP2 slowed glioma growth. CONCLUSIONS: TSP2 promotes the migration and proliferation of glioma cells, which may provide new ideas for blocking glioma progression.

HMGB1-RAGE Pathway Contributes to the Abnormal Migration of Endogenous Subventricular Zone Neural Progenitors in an Experimental Model of Focal Microgyria.

Abnormal migration of subventricular zone (SVZ)-derived neural progenitor cells (SDNPs) is involved in the pathological and epileptic processes of focal cortical dysplasias (FCDs), but the underlying mechanisms are not clear. Recent studies indicated that high mobility group box 1 (HMGB1)/receptor for advanced glycation end products (RAGE) are widely expressed in epileptic specimens of FCDs, which suggests that the HMGB1-RAGE pathway is involved in the pathological and/or epileptic processes of FCDs. The present study used Nestin-GFPtg/+ transgenic mice, and we established a model of freezing lesion (FL), as described in our previous report. A "migrating stream" composed of GFP-Nestin+ SDNPs was derived from the SVZ region and migrated to the cortical FL area. We found that translocated HMGB1 and RAGE were expressed in cortical lesion in a clustered distribution pattern, which was especially obvious in the early stage of FL compared to the sham group. Notably, the number of GFP-Nestin+ SDNPs within the "migrating stream" was significantly decreased when the HMGB1-RAGE pathway was blocked by a RAGE antagonist or deletion of the RAGE gene. The absence of RAGE also decreased the activity of pentylenetetrazol-induced cortical epileptiform discharge. In summary, this study provided experimental evidence that the levels of extranuclear HMGB1 and its receptor RAGE were increased in cortical lesion in the early stage of the FL model. Activation of the HMGB1-RAGE pathway may contribute to the abnormal migration of SDNPs and the hyperexcitability of cortical lesion in the FL model.

Glioma-Derived TSP2 Promotes Excitatory Synapse Formation and Results in Hyperexcitability in the Peritumoral Cortex of Glioma.

Seizures are common in patients with glioma, especially low-grade glioma (LGG). However, the epileptogenic mechanisms are poorly understood. Recent evidence has indicated that abnormal excitatory synaptogenesis plays an important role in epileptogenesis. The thrombospondin (TSP) family is a key regulator of synaptogenesis. Thus, this study aimed to elucidate the role of TSP2 in epileptogenesis in glioma-related epilepsy. The expression of TSP2 was increased in tumor tissue specimens from LGG patients, and this increase may have contributed to an increase in the density of spines and excitatory synapses in the peritumoral area. A glioma cell-implanted rat model was established by stereotactic implantation of wild-type TSP2-expressing, TSP2-overexpressing or TSP2-knockout C6 cells into the neocortex. Similarly, an increase in the density of excitatory synapses was also observed in the peritumoral area of the implanted tumor. In addition, epileptiform discharges occurred in the peritumoral cortex and were positively correlated with the TSP2 level in glioma tissues. Moreover, α2δ1/Rac1 signaling was enhanced in the peritumoral region, and treatment with the α2δ1 antagonist gabapentin inhibited epileptiform discharges in the peritumoral cortex. In conclusion, glioma-derived TSP2 promotes excitatory synapse formation, probably via the α2δ1/Rac1 signaling pathway, resulting in hyperexcitability in the peritumoral cortical networks, which may provide new insight into the epileptogenic mechanisms underlying glioma-related epilepsy.

The Role of BDNF on Neural Plasticity in Depression.

Using behavioral, pharmacological, and molecular methods, lots of studies reveal that depression is closely related to the abnormal neural plasticity processes occurring in the prefrontal cortex and limbic system such as the hippocampus and amygdala. Meanwhile, functions of the brain-derived neurotrophic factor (BDNF) and the other neurotrophins in the pathogenesis of depression are well known. The maladaptive neuroplastic in depression may be related to alterations in the levels of neurotrophic factors, which play a central role in plasticity. Enhancement of neurotrophic factors signaling has great potential in therapy for depression. This review highlights the relevance of neurotrophic factors mediated neural plasticity and pathophysiology of depression. These studies reviewed here may suggest new possible targets for antidepressant drugs such as neurotrophins, their receptors, and relevant signaling pathways, and agents facilitating the activation of gene expression and increasing the transcription of neurotrophic factors in the brain.

The Nogo receptor inhibits proliferation, migration and axonal extension by transcriptionally regulating WNK1 in PC12 cells.

Neuronal regeneration and axonal regrowth mechanisms in the injured mammalian central nervous system are largely unknown. As part of a major pathway for inhibiting axonal regeneration, activated neuronal glycosylphosphatidylinositol-anchored Nogo receptor (NgR) interacts with LINGO-1 and p75NTR to form a complex at the cell surface. However, it was found in our previous report that upregulation of NgR stimulated by injury plays a key role in neuronal regeneration in the neonatal cortex freeze-lesion model, but its downstream signalling remains elusive. In the present study, the novel regulatory role of NgR in a serine-threonine kinase WNK1 was identified. NgR's transcriptional regulation of WNK1 was identified by RT-qPCR and semiquantitative western blot after the overexpression or knockdown of NgR, and the regulation is specific to WNK1, which is not the same for its family members, WNK2, WNK3 and WNK4. Furthermore, NgR inhibition by NEP fails to affect WNK1, which indicates that WNK1 functions outside of the Nogo-A/NgR pathway. By performing a proliferation, migration and axonal extension assay, we also identified that overexpressed NgR critically regulated these processes and impairment by overexpressing NgR was rescued with coexpression of WNK1, indicating the partial role of WNK1 in NgR-mediated morphological regulation. Our study identifies a separation of functions for the NgR-regulated WNK1 in mediating proliferation, migration and axonal extension in PC12 cells as well as a specific regulatory role between NgR and WNK1 that is important for recovery from central nervous system injury.

Expression of pannexin 1 and 2 in cortical lesions from intractable epilepsy patients with focal cortical dysplasia.

Focal cortical dysplasia (FCD) is a major cause of intractable epilepsy in children however the mechanisms underlying the pathogenesis of FCD and FCD induced epilepsy remain unclear. Increasing evidence suggests that the large-pore ion channels, pannexin 1 (Panx1) and 2 (Panx2), are involved in epilepsy and brain development. In this study, we investigated the expression of Panx1 and Panx2 in surgical samples from patients with FCD type Ia (FCDIa), type IIa (FCDIIa), and type IIb (FCDIIb) and in age-matched autopsy control samples. We found Panx1 mRNA and protein levels were both increased in all these FCD samples. Immunohistochemical analyses revealed that Panx1 was mainly distributed in microcolumn neurons, dysmorphic neurons (DNs), balloon cells (BCs) and reactive astrocytes. Double-labeled staining showed that the Panx1-positive neurons were mostly glutamatergic DNs and occasionally GABAergic normal-appearing neurons. Importantly, the protein levels of Panx1 positively correlated with the frequency of seizures. Intriguingly, the Panx2 mRNA and protein levels were only upregulated in FCDIIb lesions and characteristically expressed on SOX2-positive multipotential BCs. Immunofluorescent experiments identified that Panx2-positive BCs mainly expressed the neuronal differentiation transcription factor MASH1 but not the immature glial marker vimentin. Taken together, our results established a potential role of the specific expression and cellular distribution patterns of Panx1 and Panx2 in FCD-associated epileptogenesis and pathogenesis.

Activation of LILRB2 signal pathway in temporal lobe epilepsy patients and in a pilocarpine induced epilepsy model.

Temporal lobe epilepsy (TLE) is a frequent form of focal intractable epilepsy in adults, but the specific mechanism underlying the epileptogenesis of TLE is still unknown. Human leukocyte immunoglobulin-like receptor B2 (LILRB2) (the murine homolog gene called paired immunoglobulin-like receptor B, or PirB), participates in the process of synaptic plasticity and neurite growth in the central nervous system (CNS), suggesting a potential role of LILRB2 in epilepsy. However, the expression pattern of LILRB2 and the downstream molecular signal in intractable TLE remains poorly understood. In the present study, western blotting and immunohistochemistry results showed that LILRB2 expression was upregulated in the temporal neocortex of patients with TLE. Moreover, protein levels of LILRB2 negatively correlated with the frequency of seizures in TLE patients. In the pilocarpine-induced C57BL/6 mouse model, PirB upregulation in the hippocampus began 12h after status epilepticus (SE), reached a peak at 7days and then maintained a significantly high level until day 60. Similarly, we found a remarkable increase in PirB expression at 1day, 7days and30days post-SE in the temporal cortex. Double-labeled immunofluorescence showed that LILRB2/PirB were highly expressed in neurons and astrocytes but not microglia. In addition, protein levels of POSH, SHROOM3, ROCK1 and ROCK2, the important downstream factors of the LILRB2 pathway, were significantly increased in the epileptic foci of TLE patients and located on the NeuN-positive neurons and GFAP-positive astrocytes. Taken together, our results indicate that LILRB2/PirB may be involved in the process of TLE.

Upregulated expression of Nogo-A and NgR in an experimental model of focal microgyria regulates the migration, proliferation and self-renewal of subventricular zone neural progenitors.

Nogo-A and its receptor (NgR) were first described as myelin-associated inhibitors of neuronal regeneration in response to injury. In recent years, knowledge about the important role of the Nogo-A protein in several neuronal pathologies has grown considerably. Here, we employed a neonatal cortex freeze-lesion (NFL) model in neonatal rats and measured the expression of Nogo-A and NgR in the resulting cerebrocortical microdysgenesis 5-75 days after freezing injury. We observed marked upregulation of Nogo-A and NgR in protein levels. Furthermore, the migration of neural precursor cells (NPCs) derived from the subventricular zone (SVZ) toward the sits of injury was perturbed by treatment of NgR antagonist peptide NEP1-40. In vitro analysis showed that the knockdown of NgR by lentivirus-delivered siRNA promoted in axonal regeneration and SVZ-derived neural stem cell/progenitor cell (SVZ-NPCs) adhesion and migration, findings which were similar to the effects of NEP1-40. Taken together, our results indicate an important role for NgR in regulating the physiological processes of SVZ-NPCs. The observation of upregulated Nogo-A/NgR in lesion sites in the NFL model suggest that the effects of the perturbed Nogo-A are a key feature during the development and/or the progression of cortical malformation.

Emodin plays an interventional role in epileptic rats via multidrug resistance gene 1 (MDR1).

OBJECTIVE: To observe the interventional effects of emodin in epileptic rats and elucidate its possible mechanism of action. METHODS: Thirty-six female Wistar rats were randomly divided into normal control group, model group (intraperitoneal injection of kainic acid) and emodin group (intraperitoneal injection of kainic acid+emodin intervention). The rat epilepsy model was confirmed by behavioral tests and electroencephalography. The protein levels of P-glycoprotein and N-methyl-D-aspartate (NMDA) receptor in cerebral vascular tissue were analyzed by western blotting, and mRNA levels of multidrug resistance gene 1 (MDR1) and cyclooxygenase-2 (COX-2) were analyzed by real-time PCR. COX-2 and P-glycoprotein levels in the brains were detected by immunohistochemical assay. RESULTS: The seizures were relieved in emodin group. Laser scanning confocal microscopy showed P-glycoprotein fluorescence increased significantly after seizures, indicating that epilepsy can induce overexpression of P-glycoprotein. Compared with control group, protein levels of P-glycoprotein and NMDA receptor in cerebral vascular tissue were significantly higher in model group, and mRNA levels of MDR1 and COX-2 were also significantly increased. Compared with model group, P-glycoprotein and NMDA receptor levels in cerebral vascular tissue were significantly decreased in emodin group (P<0.05), and the levels of MDR1 and COX-2 were down-regulated (P<0.05). In the rat brain, seizures could significantly increase COX-2 and P-glycoprotein levels, while emodin intervention was able to significantly reduce the levels of both. DISCUSSION: These findings suggest that epileptic seizures are tightly associated with up-regulated MDR1 gene, and emodin shows good antagonistic effects on epileptic rats, possibly through inhibition of MDR1 gene and its associated genes.

Osteosarcoma cell proliferation and migration are partly regulated by redox-activated NHE-1.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. OS is associated with locally aggressive growth and high metastatic potential. The mechanisms that underlie these processes are currently elusive. Reactive oxygen species (ROS) and Na+/H+ exchanger 1 (NHE1) have been suggested to regulate proliferation and migration of tumor cells. However, the relationship between NHE1 and ROS in OS proliferation and migration has not been investigated before. AIM: To investigate the role of NHE1 and ROS in the proliferation and migration of OS. METHODS: ROS levels and NHE1 expression were studied in cultured human OS cells and human OS xenografts in nude mice. In vitro, OS cells were treated with different doses of tert-butyl hydroperoxide (tBHP), a ROS inducer, and cariporide, an NHE1 inhibitor, to study the effect on cell proliferation and migration. In vivo, nude mice bearing OS cells were administrated with NHE1 inhibitor or antioxidant and the tumor weights were measured. RESULTS: This study reported for the first time that the expression of NHE1 and intracellular ROS level were both increased in OS tissues and cells. Exposure of OS cell to ROS derived from tBHP was able to accelerate cell proliferation and migration and also up-regulate NHE1 protein expression. Moreover, tBHP significantly increased intracellular pH (pHi), decreased extracellular pH (pHe) and induced upregulation of ERK, MMP2, and MMP9. Lowering of ROS levels with the anti-oxidant DMTU or inhibiting NHE1 activity via cariporide abolished the stimulatory effect of tBHP. However, there cariporide did not affect intracellular ROS levels. In vivo study we further confirmed that cariporide could inhibit tumor growth in the nude mouse xenografts of OS cells. CONCLUSIONS: The data demonstrate that up-regulation of NHE1 was induced by low concentrations of ROS contributes to the regulation of tumor proliferation and invasion of OS. RELEVANCE FOR PATIENTS: There is potential application for cariporide as an effective antitumor agent during the development of human osteosarcoma. In addition, redox modulation on proton transport may represent a novel target of osteosarcoma prevention, and open a new avenues for future research.

Aerobic exercise for Parkinson's disease: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Although some trials assessed the effectiveness of aerobic exercise for Parkinson's disease (PD), the role of aerobic exercise in the management of PD remained controversial. OBJECTIVE: The purpose of this systematic review is to evaluate the evidence about whether aerobic exercise is effective for PD. METHODS: Seven electronic databases, up to December 2013, were searched to identify relevant studies. Two reviewers independently extracted data and assessed methodological quality based on PEDro scale. Standardised mean difference (SMD) and 95% confidence intervals (CI) of random-effects model were calculated. And heterogeneity was assessed based on the I2 statistic. RESULTS: 18 randomized controlled trials (RCTs) with 901 patients were eligible. The aggregated results suggested that aerobic exercise should show superior effects in improving motor actions (SMD, -0.57; 95% CI -0.94 to -0.19; p = 0.003), balance (SMD, 2.02; 95% CI 0.45 to 3.59; p = 0.01), and gait (SMD, 0.33; 95% CI 0.17 to 0.49; p<0.0001) in patients with PD, but not in quality of life (SMD, 0.11; 95% CI -0.23 to 0.46; p = 0.52). And there was no valid evidence on follow-up effects of aerobic exercise for PD. CONCLUSION: Aerobic exercise showed immediate beneficial effects in improving motor action, balance, and gait in patients with PD. However, given no evidence on follow-up effects, large-scale RCTs with long follow-up are warrant to confirm the current findings.

MicroRNA-23a promotes neuroblastoma cell metastasis by targeting CDH1.

CDH1 inactivation is important in tumor metastasis. In the present study, it was suggested that the mRNA and protein levels of CDH1 decreased in metastatic neuroblastoma (NB) tissues compared with those in primary NB tissues. The aim of the study was to explore the regulatory mechanisms of CDH1 downregulation in metastatic NB. MicroRNAs are small non-coding RNAs (~22 nt in length) that negatively regulate target mRNAs and are involved in various cancer-related processes, including metastasis. In the current study, miR-23a was shown to be upregulated in human metastatic NB tissues compared with primary NB tissues. Inhibition of miR-23a may significantly suppress NB cell migration and invasion. In vitro reporter assay suggested that CDH1 is a direct target gene of miR-23a. Furthermore, blocking the expression of miR-23a partly restored the expression of CDH1 in NB cells. These findings provide evidence that miR-23a is key in promoting NB cell migration and invasion through targeting CDH1, and suggest that exogenous miR-23a may have therapeutic value in treating NB metastasis.

Endogenous subventricular zone neural progenitors contribute to the formation and hyperexcitability of experimental model of focal microgyria.

Microgyria is associated with epilepsy and due to developmental disruption of neuronal migration. However, the role of endogenous subventricular zone-derived neural progenitors (SDNPs) in formation and hyperexcitability has not been fully elucidated. Here, we establish a neonatal cortex freeze-lesion (FL) model, which was considered as a model for focal microgyria, and simultaneously label SDNPs by CM-DiI. Morphological investigation showed that SDNPs migrated into FL and differentiated into neuronal and glia cell types, suggesting the involvement of endogenous SDNPs in the formation of FL-induced microgyria. Patch-clamp recordings in CM-DiI positive (CM-DiI(+)) pyramidal neurons within FL indicated an increase in frequency of spontaneous action potentials, while the resting membrane potential did not differ from the controls. We also found that spontaneous excitatory postsynaptic currents (EPSCs) increased in frequency but not in amplitude compared with controls. The evoked EPSCs showed a significant increase of 10-90% in rise time and decay time in the CM-DiI(+) neurons. Moreover, paired-pulse facilitation was dramatically larger in CM-DiI(+) pyramidal neurons. Western blotting data showed that AMPA and NMDA receptors were increased to some extent in the FL cortex compared with controls, and the NMDA/AMPA ratio of eEPSCs at CM-DiI(+) pyramidal neurons was significantly increased. Taken together, our findings provide novel evidence for the contribution of endogenous SDNPs in the formation and epileptogenicity of FL-induced focal microgyria.

Overexpression of MACC1 protein and its clinical implications in patients with glioma.

Metastasis associated in colon cancer 1 (MACC1) has been regarded as a novel potential therapeutic target for multiple cancers. However, the impact of MACC1 in glioma remains unclear. The aim of this study was to analyze the correlation of MACC1 expression with the clinicopathological features of glioma. MACC1 mRNA and protein expression levels in human glioma tissues were detected by quantitative real-time polymerase chain reaction and immunohistochemistry assays, respectively. MACC1 mRNA and protein expression were both significantly higher in glioma tissues than in corresponding noncancerous brain tissues (both P < 0.001). In addition, statistical analysis suggested that high MACC1 expression was significantly correlated with advanced pathological grade (P = 0.004) and that patients with high expression of MACC1 protein exhibited a poorer prognosis than those with low MACC1 expression. Furthermore, Cox multivariate analysis showed that MACC1 overexpression was an independent prognostic factor for predicting the overall survival of glioma patients. In conclusion, expression of MACC1 in glioma could be adopted as a candidate biomarker for the diagnosis of clinical stage and for assessing prognosis, indicating for the first time that MACC1 may play an important role in the tumor development and progression in glioma. MACC1 might be considered as a novel therapeutic target against this cancer.