Role of O-GlcNAcylation in Central Nervous System Development and Injuries: A Systematic Review.

The development of central nervous system (CNS) can form perceptual, memory, and cognitive functions, while injuries to CNS often lead to severe neurological dysfunction and even death. As one of the prevalent post-translational modifications (PTMs), O-GlcNAcylation has recently attracted great attentions due to its functions in regulating the activity, subcellular localization, and stability of target proteins. It has been indicated that O-GlcNAcylation could interact with phosphorylation, ubiquitination, and methylation to jointly regulate the function and activity of proteins. Furthermore, a growing number of studies have suggested that O-GlcNAcylation played an important role in the CNS. During development, O-GlcNAcylation participated in the neurogenesis, neuronal development, and neuronal function. In addition, O-GlcNAcylation was involved in the progress of CNS injuries including ischemic stroke, subarachnoid hemorrhage (SAH), and intracerebral hemorrhage (ICH) and played a crucial role in the improvement of brain damage such as attenuating cognitive impairment, inhibiting neuroinflammation, suppressing endoplasmic reticulum (ER) stress, and maintaining blood-brain barrier (BBB) integrity. Therefore, O-GlcNAcylation showed great promise as a potential target in CNS development and injuries. In this article, we presented a review highlighting the role of O-GlcNAcylation in CNS development and injuries. Hence, on the basis of these properties and effects, intervention with O-GlcNAcylation may be developed as therapeutic agents for CNS diseases.

Human umbilical cord mesenchymal stem cell-derived exosomes provide neuroprotection in traumatic brain injury through the lncRNA TUBB6/Nrf2 pathway.

Recently, human umbilical cord mesenchymal stem cell (HucMSC) is a new focus of research in neurological diseases, and the beneficial effect of HucMSC is mediated by paracrine factors which are transported by exosome. Our previous study has shown that HucMSC-derived exosome could provide neuroprotection after traumatic brain injury (TBI). However, the underlying mechanisms were not fully understood. In the present study, we found that administration of exosome suppressed TBI-induced inflammation and ferroptosis. In addition, exosome activated the long non-coding ribonucleic acid (lncRNA) TUBB6/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway after TBI. However, exosome partly failed to provide neuroprotection following TBI when TUBB6 was knockdown. Importantly, exosome treatment also decreased neuron cell death, suppressed inflammation, inhibited ferroptosis and activated the lncRNA TUBB6/Nrf2 pathway after TBI in vitro. Taken together, our results provided the first evidence that HucMSC-derived exosome played a key role in neuroprotection after TBI through the lncRNA TUBB6/Nrf2 pathway.

Crosstalk among mitophagy, pyroptosis, ferroptosis, and necroptosis in central nervous system injuries.

Central nervous system injuries have a high rate of resulting in disability and mortality; however, at present, effective treatments are lacking. Programmed cell death, which is a genetically determined form of active and ordered cell death with many types, has recently attracted increasing attention due to its functions in determining the fate of cell survival. A growing number of studies have suggested that programmed cell death is involved in central nervous system injuries and plays an important role in the progression of brain damage. In this review, we provide an overview of the role of programmed cell death in central nervous system injuries, including the pathways involved in mitophagy, pyroptosis, ferroptosis, and necroptosis, and the underlying mechanisms by which mitophagy regulates pyroptosis, ferroptosis, and necroptosis. We also discuss the new direction of therapeutic strategies targeting mitophagy for the treatment of central nervous system injuries, with the aim to determine the connection between programmed cell death and central nervous system injuries and to identify new therapies to modulate programmed cell death following central nervous system injury. In conclusion, based on these properties and effects, interventions targeting programmed cell death could be developed as potential therapeutic agents for central nervous system injury patients.

Fucoxanthin ameliorates traumatic brain injury by suppressing the blood-brain barrier disruption.

Fucoxanthin is the most abundant marine carotenoid extracted from seaweed. Our previous study has shown that fucoxanthin inhibited oxidative stress after traumatic brain injury (TBI). However, the effects of fucoxanthin on TBI-induced blood-brain barrier (BBB) destruction have not been well understood. In the present study, we found that fucoxanthin improved neurological dysfunction, reduced brain edema, attenuated cortical lesion volume, and decreased dendrites loss after TBI in vivo. Moreover, fucoxanthin suppressed BBB leakage, preserved tight junction (TJ) and adherens junction (AJ) proteins, and inhibited MMP-9 expression. Furthermore, fucoxanthin alleviated apoptosis and ferroptosis, and activated mitophagy in endothelial cells (ECs) after TBI. However, the protection of fucoxanthin on BBB was attenuated when mitophagy was inhibited. Importantly, fucoxanthin also provided protective effects in bEnd.3 cells after TBI. Taken together, our results suggested that fucoxanthin played a key role in the protection of BBB after TBI through mitophagy.

Human umbilical cord mesenchymal stem cell-derived exosome suppresses programmed cell death in traumatic brain injury via PINK1/Parkin-mediated mitophagy.

AIMS: Recently, human umbilical cord mesenchymal stem cell (HucMSC)-derived exosome is a new focus of research in neurological diseases. The present study was aimed to investigate the protective effects of HucMSC-derived exosome in both in vivo and in vitro TBI models. METHODS: We established both mouse and neuron TBI models in our study. After treatment with HucMSC-derived exosome, the neuroprotection of exosome was investigated by the neurologic severity score (NSS), grip test score, neurological score, brain water content, and cortical lesion volume. Moreover, we determined the biochemical and morphological changes associated with apoptosis, pyroptosis, and ferroptosis after TBI. RESULTS: We revealed that treatment of exosome could improve neurological function, decrease cerebral edema, and attenuate brain lesion after TBI. Furthermore, administration of exosome suppressed TBI-induced cell death, apoptosis, pyroptosis, and ferroptosis. In addition, exosome-activated phosphatase and tensin homolog-induced putative kinase protein 1/Parkinson protein 2 E3 ubiquitin-protein ligase (PINK1/Parkin) pathway-mediated mitophagy after TBI. However, the neuroprotection of exosome was attenuated when mitophagy was inhibited, and PINK1 was knockdown. Importantly, exosome treatment also decreased neuron cell death, suppressed apoptosis, pyroptosis, and ferroptosis and activated the PINK1/Parkin pathway-mediated mitophagy after TBI in vitro. CONCLUSION: Our results provided the first evidence that exosome treatment played a key role in neuroprotection after TBI through the PINK1/Parkin pathway-mediated mitophagy.

Total areola approach for endoscopic thyroidectomy: Six years of experience with the same surgeon.

Background: Scarless endoscopic thyroidectomy (ET) is increasingly accepted by the growing amount of surgeons. The target of this study is to assess the efficacy and summarise the experiences of total areola approach for ET (TAAET). Subjects and Methods: TAAET was performed on 529 patients between January 2016 and October 2021. All operated patients were divided into two groups according to the chronological order. Demographic data, perioperative data and post-operative complications were collected to assess the effectiveness of TAAET. Results: Five hundred and twenty-eight patients were successfully treated with TAAET, while 1 case was converted to open surgery due to bleeding. The surgical approach consists of lobectomy or total thyroidectomy with or without central lymph node dissection. The post-operative pathology of 433 (81.9%) patients was diagnosed with T1 ~2N0M0. The average number of unilateral lymph node dissection was 7.72 ± 2.44 while the bilateral lymph node was 10.70 ± 3.72. In terms of complications, 38 cases had transient hoarseness, 28 cases had tetany and numbness, 3 cases had post-operative bleeding, 1 case had infection and 33 cases had subcutaneous fluid. There were statistically significant differences between the two groups with respect to transient hoarseness (P < 0.001), tetany and numbness (P = 0.005), intraoperative blood loss (P = 0.003) and operation time for malignant tumour (P < 0.001) because of the accumulation of surgical experience and the maturation of technology. Conclusions: TAAET which conforms to the anatomical pathway of open thyroidectomy is a safe, effective and feasible technique and is highly suitable for novices.

Targeting Non-Coding RNA for CNS Injuries: Regulation of Blood-Brain Barrier Functions.

Central nervous system (CNS) injuries are the most common cause of death and disability around the world. The blood-brain barrier (BBB) is located at the interface between the CNS and the surrounding environment, which protects the CNS from exogenous molecules, harmful agents or microorganisms in the blood. The disruption of BBB is a common feature of CNS injuries and participates in the pathological processes of secondary brain damage. Recently, a growing number of studies have indicated that non-coding RNAs (ncRNAs) play an important role in brain development and are involved in CNS injuries. In this review, we summarize the mechanisms of BBB breakdown after CNS injuries. We also discuss the effects of ncRNAs including long noncoding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs) on BBB damage in CNS injuries such as ischemic stroke, traumatic brain injury (TBI), intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). In addition, we clarify the pharmacotherapies that could regulate BBB function via ncRNAs in CNS injuries, as well as the challenges and perspectives of ncRNAs on modulation of BBB function. Hence, on the basis of these effects, ncRNAs may be developed as therapeutic agents to protect the BBB for CNS injury patients.

Biotransformation of sulfamonomethoxine in a granular sludge system: Pathways and mechanisms.

The biotransformation of sulfamonomethoxine (SMM) was studied in an aerobic granular sludge (AGS) system to understand the role of sorption by microbial cells and extracellular polymeric substances (EPS) and the role of functional microbe/enzyme biodegradation. Biodegradation played a more important role than adsorption, while microbial cells covered with tightly bound EPS (TB-EPS) showed higher adsorption capacity than microbial cells themselves or microbial cells covered with both loosely bound EPS (LB-EPS) and TB-EPS. The binding tests between EPS and SMM and the spectroscopic analyses (3D-EEM, UV-Vis, and FTIR) were performed to obtain more information about the adsorption process. The data showed that SMM could interact with EPS by combining with aromatic protein compounds, fulvic acid-like substances, protein amide II, and nucleic acids. Batch tests with various substances showed that SMM removal rates were in an order of NH2OH (60.43 ± 2.21 µg/g SS) > NH4Cl (52.96 ± 0.30 µg/g SS) > NaNO3 (31.88 ± 1.20 µg/g SS) > NaNO2 (21.80 ± 0.42 µg/g SS). Hydroxylamine and hydroxylamine oxidoreductase (HAO) favored SMM biotransformation and the hydroxylamine-mediated biotransformation of SMM was more effective than others. In addition, both ammonia monooxygenase (AMO) and CYP450 were able to co-metabolize SMM. Analysis of UPLC-QTOF-MS indicated the biotransformation mechanisms, revealing that acetylation of arylamine, glucuronidation of sulfonamide, deamination, SO2 extrusion, and δ cleavage were the five major transformation pathways. The detection of TP202 in the hydroxylamine-fed Group C indicated a new biotransformation pathway through HAO. This study contributes to a better understanding of the biotransformation of SMM.

Expression characteristics of circular RNA in human traumatic brain injury.

Traumatic brain injury (TBI) causes high rates of worldwide mortality and morbidity due to the complex secondary injury cascade. Recently, circular ribonucleic acids (circRNAs) have attracted significant attention in a variety of diseases. However, their expression characteristics in human TBI are still unclear. In this study, we examined brain injury tissues from six severe TBI patients in Jinling Hospital. The TBI tissues and adjacent brain contusion tissues were used to analyze differential expression signatures of circRNAs through full-length transcriptome sequencing, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and ceRNA network construction. Our results found that there were 126 differently expressed circRNAs in TBI. Among them, 64 circRNAs were up-regulated and 62 circRNAs were down-regulated. Moreover, GO and KEGG analyses revealed that the aberrantly expressed circRNAs participated in many pathophysiological processes of TBI, especially regarding microglial cell activation, protein transport, protein processing and inflammation. Furthermore, the ceRNA (circRNA-miRNA-mRNA) network predicted that there existed strong relationship among circRNA, miRNA and mRNA. Taken together, our results indicated for the first time that the expression profiles of circRNAs were different after human TBI. In addition, we found the signaling pathways that were related to circRNAs and predicted a ceRNA network, which provided new insight of circRNAs in human TBI.

FastTalker: A neural text-to-speech architecture with shallow and group autoregression.

Non-autoregressive architecture for neural text-to-speech (TTS) allows for parallel implementation, thus reduces inference time over its autoregressive counterpart. However, such system architecture does not explicitly model temporal dependency of acoustic signal as it generates individual acoustic frames independently. The lack of temporal modeling often adversely impacts speech continuity, thus voice quality. In this paper, we propose a novel neural TTS model that is denoted as FastTalker. We study two strategies for high-quality speech synthesis at low computational cost. First, we add a shallow autoregressive acoustic decoder on top of the non-autoregressive context decoder to retrieve the temporal information of the acoustic signal. Second, we further implement group autoregression to accelerate the inference of the autoregressive acoustic decoder. The group-based autoregression acoustic decoder generates acoustic features as a sequence of groups instead of frames, each group having multiple consecutive frames. Within a group, the acoustic features are generated in parallel. With the shallow and group autoregression, FastTalker retrieves the temporal information of the acoustic signal, while keeping the fast-decoding property. The proposed FastTalker achieves a good balance between speech quality and inference speed. Experiments show that, in terms of voice quality and naturalness, FastTalker outperforms the non-autoregressive FastSpeech baseline significantly, and is on par with the autoregressive baselines. It also shows a considerable inference speedup over Tacotron2 and Transformer TTS.

Activation of the Nrf2-ARE signal pathway after blast induced traumatic brain injury in mice.

Background: Treatment of blast-induced traumatic brain injury (bTBI) has been hindered. Previous studies have demonstrated that oxidative stress may contribute to the pathophysiological process. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway exhibits a protective effect after traumatic brain injury (TBI). This study explored whether the Nrf2-ARE pathway was activated in a modified bTBI mouse model. Method: Mice were randomly divided into six groups: the 6 h, 1 d, 3 d, 7 d and 14 d after bTBI groups and a sham group. The protein levels of nuclear Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1) were detected using western blot, and HO-1 and NQO1 mRNA levels were determined by real-time quantitative polymerase chain reaction. Moreover, HO-1 and Nrf2 were localized using histological staining. Results: The protein level of the Nrf2-ARE pathway in the frontal lobe increased significantly in the 3 d after bTBI. The HO-1 and NQO1 mRNA levels also reached a peak in the frontal lobe 3 d after bTBI. The histological staining demonstrated higher expression of HO-1 in the frontal lobe and hippocampus 3 d after bTBI, when nuclear import of Nrf2 reached a peak in the frontal lobe. Conclusions: bTBI activated the Nrf2-ARE signaling pathway in the brain. The peak activation time in the frontal lobe may be 3 d after injury, and activating the Nrf2 pathway could be a new direction for treatment.

The microglial activation profile and associated factors after experimental spinal cord injury in rats.

BACKGROUND: Spinal cord injury (SCI) has imposed a great impact on the quality of life of patients due to its relatively young age of onset. The pathophysiology of SCI has been proven to be complicated. Microglia plays an important role in neuroinflammation and second injuries after SCI. Different environment and other factors may determine the microglial activation profile and what role they play. However, neither accurate time-course profiles of microglial activation nor influence factors have been demonstrated in varied SCI models. METHODS: A rat compressive SCI model was used. Microglial activation profile and contents of inflammatory factors including IL-1ß, IL-6 and TNF-α were detected. Myelination status as well as levels of iron and glutamate concentration, adenosine triphosphate (ATP) and potassium are also assessed. RESULTS: Our results showed that the activated microglia participating in immune-mediated responses peaked at day 7 post SCI and gradually decreased during the following 3 weeks. Contrarily, myelination and oligodendroglia showed an opposite trend, indicating that microglia may be a key factor partly through inflammatory reaction. Iron and glutamate concentration were found to be the highest at day 7 after SCI while both ATP and potassium reached a low valley at the same time. CONCLUSION: These findings showed a microglial activation profile and the alterations of associated factors after experiment SCI model. Moreover, our data suggest that high iron and glutamate concentration may be released by damaged oligodendroglia and contribute to the activation of microglial after SCI.

Chiari type I malformation with occult tethered cord syndrome in a child: A case report.

RATIONALE: Chiari type I malformation (CM1) and occult tethered cord syndrome (OTCS) are considered to be malformations associated with subtle structural abnormalities of the terminal filum. Few studies have reported patients with CM1 and OTCS. Treatment strategy for patients of CM1 associated with OTCS is controversial. PATIENT CONCERNS: A 14-year-old child was admitted with intermittent pain and numbness in the right upper limb. And he had urinary frequency, neck pain, back pain, and numbness simultaneously. The imaging examinations showed CM1, syringomyelia, small fat in the filum at the level of the L2 vertebral body but the conus medullaris at the aspect of the L1 vertebral body. DIAGNOSES: The child was diagnosed with CM1 associated with OTCS. INTERVENTIONS: Patient underwent sectioning of filum terminale (SFT) under electrophysiological monitoring during the first hospital and posterior fossa decompression (PFD) during the second hospital. OUTCOMES: After first discharge pain of the right upper limb was relieved, but he still felt numbness. And his numbness was relieved after second discharge. The imaging examinations also showed corresponding improvement during the 2-year follow-up period. LESSONS: For pediatric patients with CM1 and TCS, treatment trouble is not only to choose the staging operation or simultaneous operation but also staging procedures for treatment of 2 lesions. Detailed preoperative evaluation is essential for development of individualized surgical plan. Staging operation of firstly minimally invasive SFT and later PFD may be helpful for such cases owing to its positive effect on both the symptoms and imaging findings.

Constriction and dysfunction of pial arterioles after regional hemorrhage in the subarachnoid space.

Increasing evidence indicates that poor outcomes after brain hemorrhage, especially after subarachnoid hemorrhage (SAH), can be attributed largely to dysfunction of the cerebral microcirculation. However, the cause of this dysfunction remains unclear. Here, we investigated changes in the cerebral microcirculation after regional hemorrhage in the subarachnoid space using the closed cranial window technique in mice. A single pial arteriole on the surface of the brain was punctured to induce a regional hemorrhage in the subarachnoid space. Physiological parameters were monitored during the procedure, and microvessel diameter was measured after hemorrhage. The vasoreactivity of the arterioles in response to hypercapnia as well as to topical application of the vasodilator acetylcholine (ACh) and S-nitroso-N-acetyl-penicillamine (SNAP) were assessed. The constriction of pial arterioles was detected without changes in other physiological parameters. Decreased reactivity of pial arterioles to all of the applied vasodilatory stimuli was observed after hemorrhage. Our results indicate that regional hemorrhage in the subarachnoid space can induce the vasospasm of microvessels and also reduce the vasoreactivity of pial arterioles.

Targeting the NF-E2-related factor 2 pathway: a novel strategy for glioblastoma (review).

Glioblastoma is the most common and malignant subtype among all brain tumors. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential component of cellular defense against a variety of endogenous and exogenous stresses. A marked increase in research over the past few decades focusing on Nrf2 and its role in regulating glioblastoma has revealed the potential value of Nrf2 in the treatment of glioblastoma. In the present review, we discuss a novel framework of Nrf2 in the regulation of glioblastoma and the mechanisms regarding the downregulation of Nrf2 in treating glioblastoma. The candidate mechanisms include direct and indirect means. Direct mechanisms target tumor molecular pathways in order to overcome resistance to chemotherapy and radiotherapy, to inhibit proliferation, to block invasion and migration, to induce apoptosis, to promote differentiation, to enhance autophagy and to target glioblastoma stem cells. Indirect mechanisms target the reaction between glioblastoma cells and the surrounding microenvironment. Overall, the value of the Nrf2 pathway in glioblastoma provides a promising opportunity for new approaches by which to treat glioblastoma.

Efficacy and safety of endovascular treatment versus intravenous thrombolysis for acute ischemic stroke: a meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: Although endovascular therapy (ET) is increasingly used in patients with moderate to severe acute ischemic stroke, its efficacy and safety remains controversial. We performed a meta-analysis aiming to compare the benefits and safety of endovascular treatment and intravenous thrombolysis in the treatment of acute ischemic stroke. METHODS: We systematically searched PubMed, Embase, Science direct and Springer unitil July, 2013. The primary outcomes included good outcome (mRS ≤ 2) and excellent outcome (mRS ≤ 1) at 90 days or at trial end point. Secondary outcomes were occurrence of symptomatic hemorrhage and all-cause mortality. RESULTS: Using a prespecified search strategy, 5 RCTs with 1106 patients comparing ET and intravenous thrombolysis (IVT) were included in the meta-analysis. ET and IVT were associated with similar good (43.06% vs 41.78%; OR=1.14; 95% CI, 0.77 to 1.69; P=0.52;) and excellent (30.43% vs 30.42%; OR=1.05; 95% CI, 0.80 to 1.38; P=0.72;) outcome. For additional end points, ET was not associated with increased occurrence of symptomatic hemorrhage (6.25% vs. 6.22%; OR=1.03; 95% CI, 0.62 to 1.69; P=0.91;), or all-cause mortality (18.45% vs. 17.35%; OR=1.00; 95% CI, 0.73 to 1.39; P=0.99;). CONCLUSIONS: Formal meta-analysis indicates that there are similar safety outcomes and functional independence with endovascular therapy and intravenous thrombolysis for acute ischemic stroke.

Intracisternal administration of SB203580, a p38 mitogen-activated protein kinase inhibitor, attenuates cerebral vasospasm via inhibition of tumor-necrosis factor-α.

Tumor-necrosis factor-α (TNF-α) is critical to the development of cerebral vasospasm after subarachnoid hemorrhage (SAH). Hence, therapeutic strategies targeting TNF-α can attenuate cerebral vasospasm. This study investigated the effects of SB203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor, on TNF-α concentration in the cerebral arteries and the cerebrospinal fluid (CSF) after SAH and on subsequent cerebral vasospasm. Twenty-three rabbits were divided into four groups: (i) control (without SAH), (ii) SAH (SAH only), (iii) dimethylsulfoxide (DMSO, vehicle), and (iv) SB203580. The severity of vasospasm and the immunoreactivities of TNF-α and phosphorylated p38 MAPK in the brain vessels were determined in all animals, and the concentrations of TNF-α in the CSF were also assessed. Severe vasospasm was observed in the rabbits from the SAH and DMSO groups. SB203580 reversed vasospasm after SAH. Lower immunoreactivities of TNF-α and phosphorylated p38 MAPK were found in the basilar artery in the SB203580 group than in the DMSO group. The concentration of TNF-α in the CSF increased after SAH, but treatment with SB203080 after SAH suppressed this increase. Our data show that SB203580 reversed cerebral vasospasm by inhibiting the phosphorylation of p38 MAPK in the basilar artery and by suppressing the increase in TNF-α in the basilar artery and CSF after SAH. SB203580 could therefore potentially be used for the treatment of cerebral vasospasm after SAH.

N-acetylcysteine suppresses oxidative stress in experimental rats with subarachnoid hemorrhage.

The neuroprotective effect of N-acetylcysteine (NAC), a sulfhydryl-containing antioxidant, on experimentally induced subarachnoid hemorrhage (SAH) in rats was assessed. NAC was administered to rats after the induction of SAH. Neurological deficits and brain edema were investigated. The activity of antioxidant defense enzymes, copper/zinc superoxide dismutase (CuZn-SOD) and glutathione peroxidase (GSH-Px), were measured in the brain cortex by spectrophotometer. The content of the lipid peroxidation product malondialdehyde (MDA) was also analyzed. We found that NAC markedly reversed the SAH-induced neurological deficit and brain edema. We further investigated the mechanism involved in the neuroprotective effects of NAC on rat brain tissue and found that NAC significantly increased CuZn-SOD and GSH-Px activity and decreased MDA content in the SAH brain. NAC has the potential to be a novel therapeutic strategy for the treatment of SAH, and its neuroprotective effect may be partly mediated via enhancing the activity of endogenous antioxidant enzymes and inhibiting free radical generation.