Citrate synthase lysine K215 hypoacetylation contributes to microglial citrate accumulation and pro-inflammatory functions after traumatic brain injury.

AIMS: This study aimed to investigate the relationship between microglial metabolism and neuroinflammation by examining the impact of citrate accumulation in microglia and its potential regulation through Cs K215 hypoacetylation. METHODS: Experimental approaches included assessing Cs enzyme activity through Cs K215Q mutation and investigating the inhibitory effects of hesperidin, a natural flavanone glycoside, on citrate synthase. Microglial phagocytosis and expression of pro-inflammatory cytokines were also examined in relation to Cs K215Q mutation and hesperidin treatment. RESULTS: Cs K215Q mutation and hesperidin exhibited significant inhibitory effects on Cs enzyme activity, microglial citrate accumulation, phagocytosis, and pro-inflammatory cytokine expression. Interestingly, Sirt3 knockdown aggravated microglial pro-inflammatory functions during neuroinflammation, despite its proven role in Cs deacetylation. CONCLUSION: Cs K215Q mutation and hesperidin effectively inhibited microglial pro-inflammatory functions without reversing the metabolic reprogramming. These findings suggest that targeting Cs K215 hypoacetylation and utilizing hesperidin may hold promise for modulating neuroinflammation in microglia.

Study on Synergistic Effect of Xanthan Gum and Sodium Methylsiliconate on Mechanical Strength and Water Stability of Phosphogypsum Road-Based Materials.

To address the issues of low strength, poor water stability, and hazardous substance leaching associated with using phosphogypsum (PG) as a direct road-based material, the traditional approach involves employing inorganic cementing materials to stabilize PG, effectively addressing the problems. This study innovatively utilizes the xanthan gum (XG) and sodium methylsiliconate (SM) as curing agents for PG to solve the above problems. An organic curing agent stabilized PG was prepared by dry mixing XG and PG. The unconfined compressive strength, water stability, and leaching behavior of stabilized PG were investigated, the leaching behavior was characterized by ion leaching concentration, and the mechanisms behind the strength development of stabilized PG were explored by SEM and FTIR. The experimental results indicate that the single incorporation of XG reduced the strength and water stability of stabilized PG, while the single incorporation of SM had a limited effect on strength and water stability. In addition, the dual incorporation of XG and SM significantly improved the strength and water stability of stabilized PG. At the same time, the dual incorporation of XG and SM greatly reduced the leaching of hazardous substances from stabilized PG. These results demonstrate the feasibility of using stabilized PG for road base materials.

Hypothermia impairs glymphatic drainage in traumatic brain injury as assessed by dynamic contrast-enhanced MRI with intrathecal contrast.

Introduction: The impact of hypothermia on the impaired drainage function of the glymphatic system in traumatic brain injury (TBI) is not understood. Methods: Male Sprague-Dawley rats undergoing controlled cortical impact injury (CCI) were subjected to hypothermia or normothermia treatment. The rats undergoing sham surgery without CCI were used as the control. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with intrathecal administration of low- and high-molecular-weight contrast agents (Gd-DTPA and hyaluronic acid conjugated Gd-DTPA) was performed after TBI and head temperature management. The semiquantitative kinetic parameters characterizing the contrast infusion and cleanout in the brain, including influx rate, efflux rate, and clearance duration, were calculated from the average time-intensity curves. Results and discussion: The qualitative and semiquantitative results of DCE-MRI obtained from all examined perivascular spaces and most brain tissue regions showed a significantly increased influx rate and efflux rate and decreased clearance duration among all TBI animals, demonstrating a significant impairment of glymphatic drainage function. This glymphatic drainage dysfunction was exacerbated when additional hypothermia was applied. The early glymphatic drainage reduction induced by TBI and aggravated by hypothermia was linearly related to the late increased deposition of p-tau and beta-amyloid revealed by histopathologic and biochemical analysis and cognitive impairment assessed by the Barnes maze and novel object recognition test. The glymphatic system dysfunction induced by hypothermia may be an indirect alternative pathophysiological factor indicating injury to the brain after TBI. Longitudinal studies and targeted glymphatic dysfunction management are recommended to explore the potential effect of hypothermia in TBI.

Ketogenic Diet Modulates Neuroinflammation via Metabolites from Lactobacillus reuteri After Repetitive Mild Traumatic Brain Injury in Adolescent Mice.

Repetitive mild traumatic brain injury (rmTBI) is associated with a range of neural changes which is characterized by axonal injury and neuroinflammation. Ketogenic diet (KD) is regarded as a potential therapy for facilitating recovery after moderate-severe traumatic brain injury (TBI). However, its effect on rmTBI has not been fully studied. In this study, we evaluated the anti-neuroinflammation effects of KD after rmTBI in adolescent mice and explored the potential mechanisms. Experimentally, specific pathogen-free (SPF) adolescent male C57BL/6 mice received a sham surgery or repetitive mild controlled cortical impacts consecutively for 7 days. The uninjured mice received the standard diet, and the mice with rmTBI were fed either the standard diet or KD for 7 days. One week later, all mice were subjected to behavioral tests and experimental analysis. Results suggest that KD significantly increased blood beta-hydroxybutyrate (ß-HB) levels and improved neurological function. KD also reduced white matter damage, microgliosis, and astrogliosis induced by rmTBI. Aryl hydrocarbon receptor (AHR) signaling pathway, which was mediated by indole-3-acetic acid (3-IAA) from Lactobacillus reuteri (L. reuteri) in gut and activated in microglia and astrocytes after rmTBI, was inhibited by KD. The expression level of the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88) in inflammatory cells, which mediates the NF-κB pathway, was also attenuated by KD. Taken together, our results indicated that KD can promote recovery following rmTBI in adolescent mice. KD may modulate neuroinflammation by altering L. reuteri in gut and its metabolites. The inhibition of indole/AHR pathway and the downregulation of TLR4/MyD88 may play a role in the beneficial effect of KD against neuroinflammation in rmTBI mice.

Hypothermia reduces glymphatic transportation in traumatic edematous brain assessed by intrathecal dynamic contrast-enhanced MRI.

The glymphatic system has recently been shown to clear brain extracellular solutes and can be extensively impaired after traumatic brain injury (TBI). Despite hypothermia being identified as a protective method for the injured brain via minimizing the formation of edema in the animal study, little is known about how hypothermia affects the glymphatic system following TBI. We use dynamic contrast-enhanced MRI (DCE-MRI) following cisterna magna infusion with a low molecular weight contrast agent to track glymphatic transport in male Sprague-Dawley rats following TBI with hypothermia treatment and use diffusion-weighted imaging (DWI) sequence to identify edema after TBI, and further distinguish between vasogenic and cytotoxic edema. We found that hypothermia could attenuate brain edema, as demonstrated by smaller injured lesions and less vasogenic edema in most brain subregions. However, in contrast to reducing cerebral edema, hypothermia exacerbated the reduction of efficiency of glymphatic transportation after TBI. This deterioration of glymphatic drainage was present brain-wide and showed hemispherical asymmetry and regional heterogeneity across the brain, associated with vasogenic edema. Moreover, our data show that glymphatic transport reduction and vasogenic edema are closely related to reducing perivascular aquaporin-4 (AQP4) expression. The suppression of glymphatic transportation might eliminate the benefits of brain edema reduction induced by hypothermia and provide an alternative pathophysiological factor indicating injury to the brain after TBI. Thus, this study poses a novel emphasis on the potential role of hypothermia in managing severe TBI.

EP-ADTA: Edge Prediction-Based Adaptive Data Transfer Algorithm for Underwater Wireless Sensor Networks (UWSNs).

The underwater wireless sensor network is an important component of the underwater three-dimensional monitoring system. Due to the high bit error rate, high delay, low bandwidth, limited energy, and high dynamic of underwater networks, it is very difficult to realize efficient and reliable data transmission. Therefore, this paper posits that it is not enough to design the routing algorithm only from the perspective of the transmission environment; the comprehensive design of the data transmission algorithm should also be combined with the application. An edge prediction-based adaptive data transmission algorithm (EP-ADTA) is proposed that can dynamically adapt to the needs of underwater monitoring applications and the changes in the transmission environment. EP-ADTA uses the end-edge-cloud architecture to define the underwater wireless sensor networks. The algorithm uses communication nodes as the agents, realizes the monitoring data prediction and compression according to the edge prediction, dynamically selects the transmission route, and controls the data transmission accuracy based on reinforcement learning. The simulation results show that EP-ADTA can meet the accuracy requirements of underwater monitoring applications, dynamically adapt to the changes in the transmission environment, and ensure efficient and reliable data transmission in underwater wireless sensor networks.

Dematin inhibits glioblastoma malignancy through RhoA-mediated CDKs downregulation and cytoskeleton remodeling.

Glioblastoma multiforme (GBM) is well known as a highly aggressive brain tumor subtype. Here, we show that overexpression (OE) of dematin actin-binding protein (DMTN) inhibits GBM proliferation and invasion by affecting cell cycle regulation and actin remodeling, respectively. RT-qPCR, western blotting, and immunohistochemical (IHC) staining demonstrated a significant reduction in DMTN expression in gliomas, especially in high-grade gliomas (HGG) compared with normal brains, which correlates with worse survival in HGG patients. Functional studies revealed inhibitory effects of DMTN on tumor proliferation and migratory capacities. The attenuation in tumor proliferative ability upon DMTN OE was accompanied by RhoA suppression and CDK1, CDK2, CDK4, and cyclin D1 downregulation, while RhoA rescue restored the proliferative phenotype. Meanwhile, overexpression of DMTN produced profoundly disorganized stress fibers, which led to impaired tumor invasion. Furthermore, DMTN overexpression produced substantial suppression of tumor growth upon subcutaneous and intracranial implantation in mice, and this was accompanied by significantly reduced vinculin expression and Ki67 positivity. Taken together, these findings demonstrate the role of DMTN in regulating GBM cell proliferation, actin cytoskeleton, and cell morphology and identify DMTN as a vital tumor suppressor in GBM progression.

Moderate hypothermia inhibits microglial activation after traumatic brain injury by modulating autophagy/apoptosis and the MyD88-dependent TLR4 signaling pathway.

BACKGROUND: Complex mechanisms participate in microglial activation after a traumatic brain injury (TBI). TBI can induce autophagy and apoptosis in neurons and glial cells, and moderate hypothermia plays a protective role in the acute phase of TBI. In the present study, we evaluated the effect of TBI and moderate hypothermia on microglial activation and investigated the possible roles of autophagy/apoptosis and toll-like receptor 4 (TLR4). METHODS: The TBI model was induced with a fluid percussion TBI device. Moderate hypothermia was achieved under general anesthesia by partial immersion in a water bath for 4 h. All rats were killed 24 h after the TBI. RESULTS: Our results showed downregulation of the microglial activation and autophagy, but upregulation of microglial apoptosis, upon post-TBI hypothermia treatment. The expression of TLR4 and downstream myeloid differentiation primary response 88 (MyD88) was attenuated. Moderate hypothermia reduced neural cell death post-TBI. CONCLUSIONS: Moderate hypothermia can reduce the number of activated microglia by inhibiting autophagy and promoting apoptosis, probably through a negative modulation between autophagy and apoptosis. Moderate hypothermia may attenuate the pro-inflammatory function of microglia by inhibiting the MyD88-dependent TLR4 signaling pathway.

Proton Magnetic Resonance Spectroscopy (H1-MRS) Study of the Ketogenic Diet on Repetitive Mild Traumatic Brain Injury in Adolescent Rats and Its Effect on Neurodegeneration.

OBJECTIVE: A ketogenic diet (KD) improves cellular metabolism and functional recovery after moderate-to-severe traumatic brain injury. Here, we evaluated the changes of neurochemical metabolites after KD therapy for repetitive mild traumatic brain injury (rmTBI) and its possible role in neurodegeneration. METHODS: Postnatal day 35 rats were randomly divided into 3 groups: sham, control, and KD groups. Rats in control and KD groups were given 3 rmTBI by a fluid percussion traumatic brain injury device 24 hours apart. All rats were killed at 7 days after the last injury. The ipsilateral cortex were analyzed with hematoxylin and eosin staining; beta-hydroxybutyrate was measured; conventional magnetic resonance imaging and the dry-wet weight method were used to assess the brain edema; changes of neurochemical metabolites were assessed using the ratio of N-acetylaspartate (NAA)/creatine (Cr), choline compound (Cho)/Cr, and NAA/Cho with magnetic resonance spectroscopy; the effect of KD therapy on neurodegeneration was evaluated with double immunofluorescence staining of Iba-1/beclin-1; behavioral outcome was assessed with beam walk/beam balance tests. RESULTS: KD significantly elevated beta-hydroxybutyrate levels, and there was no brain edema associated with rmTBI and KD therapy; behavioral assessment showed KD therapy significantly improved motor performance; magnetic resonance spectroscopy showed that rmTBI reduced the ratio of NAA/Cr and had no effect on the ratios of Cho/Cr and NAA/Cho whereas KD increased the ratio of NAA/Cr; double immunofluorescence staining showed KD therapy could significantly decrease microglial beclin-1 expression in the ipsilateral cortex. CONCLUSIONS: These results suggest the effect of KD on metabolic status and its possible role in preventing neurodegeneration in adolescent rats after rmTBI.