Emerging functions and therapeutic targets of IL-38 in central nervous system diseases.

Interleukin (IL)-38 is a newly discovered cytokine of the IL-1 family, which binds various receptors (i.e., IL-36R, IL-1 receptor accessory protein-like 1, and IL-1R1) in the central nervous system (CNS). The hallmark physiological function of IL-38 is competitive binding to IL-36R, as does the IL-36R antagonist. Emerging research has shown that IL-38 is abnormally expressed in the serum and brain tissue of patients with ischemic stroke (IS) and autism spectrum disorder (ASD), suggesting that IL-38 may play an important role in neurological diseases. Important advances include that IL-38 alleviates neuromyelitis optica disorder (NMOD) by inhibiting Th17 expression, improves IS by protecting against atherosclerosis via regulating immune cells and inflammation, and reduces IL-1ß and CXCL8 release through inhibiting human microglial activity post-ASD. In contrast, IL-38 mRNA is markedly increased and is mainly expressed in phagocytes in spinal cord injury (SCI). IL-38 ablation attenuated SCI by reducing immune cell infiltration. However, the effect and underlying mechanism of IL-38 in CNS diseases remain inadequately characterized. In this review, we summarize the biological characteristics, pathophysiological role, and potential mechanisms of IL-38 in CNS diseases (e.g., NMOD, Alzheimer's disease, ASD, IS, TBI, and SCI), aiming to explore the therapeutic potential of IL-38 in the prevention and treatment of CNS diseases.

Development of Phormia regina at seven constant temperatures for minimum postmortem interval estimation.

Phormia regina (Meigen, 1826) (Diptera: Calliphoridae) can colonize carcasses quickly, and its immature stages are reliable entomological evidence for the estimation of the minimum postmortem interval (PMImin). There are discrepancies in the developmental data from previous studies on P. regina, and the related PMImin indicators need to be refined. We investigated the accuracy of forensic entomological evidence using development durations, growth accumulated degree hours, and larval body length variations of P. regina at seven constant temperatures ranging from 16 to 34 °C. We also established development models such as the isomorphen diagram, thermal summation model, isomegalen diagram, and body length simulation equation to assist with PMImin estimation. The developmental duration of P. regina from egg to adult at 16, 19, 22, 25, 28, 31, and 34 °C was 840.8 ± 42.8 h, 580.1 ± 10.1 h, 390.4 ± 8.7 h, 316.8 ± 9.4 h, 291.4 ± 21.2 h, 238.4 ± 2.8 h, and 222.5 ± 5.2 h, respectively. The lower threshold temperature TL was 9.97 ± 0.50 °C, while the thermal constant K was 5052.7 ± 229 degree days. The lower developmental thresholds, intrinsic optimum temperature, and upper lethal developmental threshold obtained by the Optim SSI models were 13.15, 21.20, and 36.86 °C, respectively. This study aims to provide developmental models for P. regina aimed at common case-site temperatures in the northern provinces of China, which can be used for accurate PMImin estimation.

Differences in three instars of four carrion nitidulids (Coleoptera, Nitidulidae, Nitidula and Omosita) revealed using SEM.

The genera Omosita and Nitidula from the family Nitidulidae, are often reported to be associated with rotten animal carcasses. However, morphological descriptions of their larval stages are limited and are usually only from the third instar larvae, which does not provide enough systematic data. In this study, the overall structure of three instar larvae from the four Nitidulidae species was compared using optical microscopy, and the resolution was not satisfactory. To compensate, a large number of structures and organs were observed by scanning electron microscopy (SEM). Results showed that the number and distribution of chaetotaxy in different parts, including the macrosetae, setae, and microtrichia, have important identification values between the genera, species, and even instars. We also discuss the possible role of microtrichia in the biology of Nitidulidae larvae. Additionally, we described the number and types of sensilla in three sensory organs, and the morphologic parameters of the head capsule and urogomphi as determined by SEM images, are provided. An identification key with application value for storage products and forensic entomology was also compiled.

Research Progress and Forensic Application of Human Vascular Finite Element Modeling and Biomechanics.

The finite element method (FEM) is a mathematical method for obtaining approximate solutions to a wide variety of engineering problems. With the development of computer technology, it is gradually applied to the study of biomechanics of human body. The application of the combination of FEM and biomechanics in exploring the relationship between vascular injury and disease, and pathological mechanisms will be a technological innovation for traditional forensic medicine. This paper reviews the construction and development of human vascular FEM modeling, and its research progress on the vascular biomechanics. This paper also looks to the application prospects of FEM modeling in forensic pathology.

Cognitive control subprocess deficits and compensatory modulation mechanisms in patients with frontal lobe injury revealed by EEG markers: a basic study to guide brain stimulation.

Background: Frontal lobe injury (FLI) is related to cognitive control impairments, but the influences of FLI on the internal subprocesses of cognitive control remain unclear. Aims: We sought to identify specific biomarkers for long-term dysfunction or compensatory modulation in different cognitive control subprocesses. Methods: A retrospective case-control study was conducted. Event-related potentials (ERP), oscillations and functional connectivity were used to analyse electroencephalography (EEG) data from 12 patients with unilateral frontal lobe injury (UFLI), 12 patients with bilateral frontal lobe injury (BFLI) and 26 healthy controls (HCs) during a Go/NoGo task, which included several subprocesses: perceptual processing, anticipatory preparation, conflict monitoring and response decision. Results: Compared with the HC group, N2 (the second negative peak in the averaged ERP waveform) latency, and frontal and parietal oscillations were decreased only in the BFLI group, whereas P3 (the third positive peak in the averaged ERP waveform) amplitudes and sensorimotor oscillations were decreased in both patient groups. The functional connectivity of the four subprocesses was as follows: alpha connections of posterior networks in the BFLI group were lower than in the HC and UFLI groups, and these alpha connections were negatively correlated with neuropsychological tests. Theta connections of the dorsal frontoparietal network in the bilateral hemispheres of the BFLI group were lower than in the HC and UFLI groups, and these connections in the uninjured hemisphere of the UFLI group were higher than in the HC group, which were negatively correlated with behavioural performances. Delta and theta connections of the midfrontal-related networks in the BFLI group were lower than in the HC group. Theta across-network connections in the HC group were higher than in the BFLI group but lower than in the UFLI group. Conclusions: The enhancement of low-frequency connections reflects compensatory mechanisms. In contrast, alpha connections are the opposite, therefore revealing more abnormal neural activity and less compensatory connectivity as the severity of injury increases. The nodes of the above networks may serve as stimulating targets for early treatment to restore corresponding functions. EEG biomarkers can measure neuromodulation effects in heterogeneous patients.

Developmental Indicators of Chrysomya nigripes Aubertin under Different Constant Temperature Conditions and an Application Case for Estimating the PMImin.

Chrysomya nigripes Aubertin, 1932, is a Calliphoridae species that colonize the carcass after the bloat phase and remains for long periods. Some early sarcosaprophagous insects complete one generation of development and are no longer associated with the corpse and surrounding environment, while C. nigripes larvae and pupae remain, providing a basis for the estimation of the minimum postmortem interval (PMImin) for highly decomposed or skeletonized carcasses. However, data on the growth and development of this species are not yet complete. As a result, we studied the developmental patterns of C. nigripes at eight constant temperatures ranging from 16-37 °C and constructed various developmental models, including the isomorphen diagram, isomegalen diagram, linear thermal summation model, nonlinear thermodynamic Optim SSI model, and logistic regression model. Chrysomya nigripes could not complete the entire developmental process at 16 °C, although it could be completed at other temperatures. The mean developmental times (±SD) of C. nigripes from egg to adult at 19 °C, 22 °C, 25 °C, 28 °C, 31 °C, 34 °C, and 37 °C were 644.9 ± 36.8 h, 422.9 ± 20.1 h, 323.1 ± 13.9 h, 246.6 ± 11.2 h, 202.5 ± 1.8 h, 191.5 ± 3.8 h, and 191.8 ± 2.0 h, respectively. The thermal summation constant (K) and lower critical thermal threshold (TL) derived from the linear thermal summation models were 4083.00 ± 293.39 degree hours and 12.52 ± 0.83 °C, respectively. In addition, TL, intrinsic optimum temperature (TΦ), and upper critical thermal threshold (TH) estimated by the optimized nonlinear thermodynamic Optim SSI model were 15.76 °C, 24.88 °C, and 38.15 °C, respectively. This study provides more comprehensive developmental data of C. nigripes for PMImin estimation.

Application of omics techniques in forensic entomology research.

With the advent of the post-genome era, omics technologies have developed rapidly and are widely used, including in genomics, transcriptomics, proteomics, metabolomics, and microbiome research. These omics techniques are often based on comprehensive and systematic analysis of biological samples using high-throughput analysis methods and bioinformatics, to provide new insights into biological phenomena. Currently, omics techniques are gradually being applied to forensic entomology research and are useful in species identification, phylogenetics, screening for developmentally relevant differentially expressed genes, and the interpretation of behavioral characteristics of forensic-related species at the genetic level. These all provide valuable information for estimating the postmortem interval (PMI). This review mainly discusses the available omics techniques, summarizes the application of omics techniques in forensic entomology, and their future in the field.

Extended characterization of IL-33/ST2 as a predictor for wound age determination in skin wound tissue samples of humans and mice.

Interleukin (IL)-33, an important inflammatory cytokine, is highly expressed in skin wound tissue and serum of humans and mice, and plays an essential role in the process of skin wound healing (SWH) dependent on the IL-33/suppression of tumorigenicity 2 (ST2) pathway. However, whether IL-33 and ST2 themselves, as well as their interaction, can be applied for skin wound age determination in forensic practice remains incompletely characterized. Human skin samples with injured intervals of a few minutes to 24 hours (hs) and mouse skin samples with injured intervals of 1 h to 14 days (ds) were collected. Herein, the results demonstrated that IL-33 and ST2 are increased in the human skin wounds, and that in mice skin wounds, there is an increase over time, with IL-33 expression peaking at 24 hs and 10 ds, and ST2 expression peaking at 12 hs and 7 ds. Notably, the relative quantity of IL-33 and ST2 proteins < 0.35 suggested a wound age of 3 hs; their relative quantity > 1.0 suggested a wound age of 24 hs post-mouse skin wounds. In addition, immunofluorescent staining results showed that IL-33 and ST2 were consistently expressed in the cytoplasm of F4/80-positive macrophages and CD31-positive vascular endothelial cells with or without skin wounds, whereas nuclear localization of IL-33 was absent in α-SMA-positive myofibroblasts with skin wounds. Interestingly, IL-33 administration facilitated the wound area closure by increasing the proliferation of cytokeratin (K) 14 -positive keratinocytes and vimentin-positive fibroblasts. In contrast, treating with its antagonist (i.e., anti-IL-33) or receptor antagonist (e.g., anti-ST2) exacerbated the aforementioned pathological changes. Moreover, treatment with IL-33 combined with anti-IL-33 or anti-ST2 reversed the effect of IL-33 on facilitating skin wound closure, suggesting that IL-33 administration facilitated skin wound closure through the IL-33/ST2 signaling pathway. Collectively, these findings indicate that the detection of IL-33/ST2 might be a reliable biomarker for the determination of skin wound age in forensic practice.

Ruxolitinib, a promising therapeutic candidate for traumatic brain injury through maintaining the homeostasis of cathepsin B.

Traumatic brain injury (TBI) is one of the main causes of death and disability in the world. Owing to the heterogeneity and complexity of TBI pathogenesis, there is still no specific drug. Our previous studies have proved the neuroprotective effect of Ruxolitinib (Ruxo) on TBI, but further are needed to explore the potent mechanisms and potential translational application. Compelling evidence indicates that Cathepsin B (CTSB) plays an important role in TBI. However, the relationships between Ruxo and CTSB upon TBI remain non-elucidated. In this study, we established a mouse model of moderate TBI to clarify it. The neurological deficit in the behavioral test was alleviated when Ruxo administrated at 6 h post-TBI. Additionally, Ruxo significantly reduced the lesion volume. As for the pathological process of acute phase, Ruxo remarkably reduced the expression of proteins associated with cell demise, neuroinflammation, and neurodegeneration. Then the expression and location of CTSB were detected respectively. We found that the expression of CTSB exhibits a transient decrease and then persistent increase following TBI. The distribution of CTSB, mainly located at NeuN-positive neurons was unchanged. Importantly, the dysregulation of CTSB expression was reversed with the treatment of Ruxo. The timepoint was chosen when CTSB decreased, to further analyze its change in the extracted organelles; and Ruxo maintained the homeostasis of it in sub-cellular. In summary, our results demonstrate that Ruxo plays neuroprotection through maintaining the homeostasis of CTSB, and will be a promising therapeutic candidate for TBI in clinic.

Melatonin ameliorates neurological deficits through MT2/IL-33/ferritin H signaling-mediated inhibition of neuroinflammation and ferroptosis after traumatic brain injury.

Although traumatic brain injury (TBI) is a common cause of death and disability worldwide, there is currently a lack of effective therapeutic drugs and targets. To reveal the complex pathophysiologic mechanisms of TBI, we performed transcriptome analysis of the mouse cerebral cortex and immunohistochemical analysis of human cerebral tissues. The genes Mt1, Mt2, Il33, and Fth1 were upregulated post-TBI and enriched in pathways associated with the inflammatory response, oxidative phosphorylation, and ferroptosis. As an agonist of MT1/2, melatonin (MLT) confers anti-oxidant, anti-inflammatory, and anti-ferroptosis effects after TBI. However, whether these upregulated genes and their corresponding pathways are involved in the neuroprotective effect of MLT remains unclear. In this study, interventions to inhibit MT1/2, IL-33, and ferroptosis (i.e., ferritin H (Fth)-KO) were applied post-TBI. The results showed that MLT attenuated TBI-induced cerebral edema and neurological outcomes by inhibiting inflammation and ferroptosis. Mechanistically, MLT mainly suppressed inflammatory responses and ferroptosis via the activation of MT2 and IL-33 pathways. Building on the previous finding that Fth deletion increases susceptibility to ferroptosis post-TBI, we demonstrated that Fth depletion remarkably exacerbated the post-TBI inflammatory response, and abolished the anti-inflammatory effects of MLT both in vivo and in vitro. Furthermore, the post-TBI anti-inflammatory effect of MLT, which occurs by promoting the polarization of CD206+ macrophages, was dependent on Fth. Taken together, these results clarified that MLT alleviates inflammation- and ferroptosis-mediated brain edema and neurological deficits by activating the MT2/IL-33/Fth pathway, which provides a novel target and theoretical basis for MLT to treat TBI patients.

TrkB agonist N-acetyl serotonin promotes functional recovery after traumatic brain injury by suppressing ferroptosis via the PI3K/Akt/Nrf2/Ferritin H pathway.

Ferroptosis is a form of regulated cell death that is mainly triggered by iron-dependent lipid peroxidation. A growing body of evidence suggests that ferroptosis is involved in the pathophysiology of traumatic brain injury (TBI), and tropomyosin-related kinase B (TrkB) deficiency would mediate TBI pathologies. As an agonist of TrkB and an immediate precursor of melatonin, N-acetyl serotonin (NAS) exerts several beneficial effects on TBI, but there is no information regarding the role of NAS in ferroptosis after TBI. Here, we examined the effect of NAS treatment on TBI-induced functional outcomes and ferroptosis. Remarkably, the administration of NAS alleviated TBI-induced neurobehavioral deficits, lesion volume, and neurodegeneration. NAS also rescued TBI-induced mitochondrial shrinkage, the changes in ferroptosis-related molecule expression, and iron accumulation in the ipsilateral cortex. Similar results were obtained with a well-established ferroptosis inhibitor, liproxstatin-1. Furthermore, NAS activated the TrkB/PI3K/Akt/Nrf2 pathway in the mouse model of TBI, while inhibition of PI3K and Nrf2 weakened the protection of NAS against ferroptosis both in vitro and in vivo, suggesting that a possible pathway linking NAS to the action of anti-ferroptosis was TrkB/PI3K/Akt/Nrf2. Given that ferritin H (Fth) is a known transcription target of Nrf2, we then investigated the effects of NAS on neuron-specific Fth knockout (Fth-KO) mice. Strikingly, Fth deletion almost abolished the protective effects of NAS against TBI-induced ferroptosis and synaptic damage, although Fth deletion-induced susceptibility toward ferroptosis after TBI was reversed by an iron chelator, deferoxamine. Taken together, these data indicate that the TrkB agonist NAS treatment appears to improve brain function after TBI by suppressing ferroptosis, at least in part, through activation of the PI3K/Akt/Nrf2/Fth pathway, providing evidence that NAS is likely to be a promising anti-ferroptosis agent for further treatment for TBI.

Brain-specific loss of Abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury.

Based on accumulating evidence, cholesterol metabolism dysfunction has been suggested to contribute to the pathophysiological process of traumatic brain injury (TBI) and lead to neurological deficits. As a key transporter of cholesterol that efflux from cells, the ATP-binding cassette (ABC) transporter family exerts many beneficial effects on central nervous system (CNS) diseases. However, there is no study regarding the effects and mechanisms of ABCG1 on TBI. As expected, TBI resulted in the different time-course changes of cholesterol metabolism-related molecules in the injured cortex. Considering ABCG1 is expressed in neuron and glia post-TBI, we generated nestin-specific Abcg1 knockout (Abcg1-KO) mice using the Cre/loxP recombination system. These Abcg1-KO mice showed reduced plasma high-density lipoprotein cholesterol levels and increased plasma lower-density lipoprotein cholesterol levels under the base condition. After TBI, these Abcg1-KO mice were susceptible to cholesterol metabolism turbulence. Moreover, Abcg1-KO exacerbated TBI-induced pyroptosis, apoptosis, neuronal cell insult, brain edema, neurological deficits, and brain lesion volume. Importantly, we found that treating with retinoid X receptor (RXR, the upstream molecule of ABCG1) agonist, bexarotene, in Abcg1-KO mice partly rescued TBI-induced neuronal damages mentioned above and improved functional deficits versus vehicle-treated group. These data show that, in addition to regulating brain cholesterol metabolism, Abcg1 improves neurological deficits through inhibiting pyroptosis, apoptosis, neuronal cell insult, and brain edema. Moreover, our findings demonstrate that the cerebroprotection of Abcg1 on TBI partly relies on the activation of the RXRalpha/PPARgamma pathway, which provides a potential therapeutic target for treating TBI.

Surface-fill H2S-releasing silk fibroin hydrogel for brain repair through the repression of neuronal pyroptosis.

Traumatic brain injury (TBI) remains the major cause of disability and mortality worldwide due to the persistent neuroinflammation and neuronal death induced by TBI. Among them, pyroptosis, a specific type of programmed cell death (PCD) triggered by inflammatory signals, plays a significant part in the pathological process after TBI. Inhibition of neuroinflammation and pyroptosis is considered a possible strategy for the treatment of TBI. In our previous study, exogenous hydrogen sulfide(H2S) exerted a neuroprotective effect after TBI. Here, we developed a surface-fill H2S-releasing silk fibroin (SF) hydrogel (H2S@SF hydrogel) to achieve small-dose local administration and avoid volatile and toxic side effects. We used a controlled cortical impact (CCI) to establish a mild TBI model in mice to examine the effect of H2S@SF hydrogel on TBI-induced pyroptosis. We found that H2S@SF hydrogel inhibited the expression of H2S synthase in neurons after TBI and significantly inhibited TBI-induced neuronal pyroptosis. In addition, immunofluorescence staining results showed that the necroptosis protein receptor-interacting serine/threonine-protein kinase 1 (RIPK1) partially colocalized with the pyroptosis protein Gasdermin D (GSDMD) in the same cells. H2S@SF hydrogel can also inhibit the expression of the necroptosis protein. Moreover, H2S@SF hydrogel also alleviates brain edema and the degree of neurodegeneration in the acute phase of TBI. The neuroprotective effect of H2S@SF hydrogel was further confirmed by wire-grip test, open field test, Morris water maze, beam balance test, radial arm maze, tail suspension, and forced swimming test. Lastly, we also measured spared tissue volume, reactive astrocytes and activated microglia to demonstrate H2S@SF hydrogel impacts on long-term prognosis in TBI. Our study provides a new theoretical basis for the treatment of H2S after TBI and the clinical application of H2S@SF hydrogel. STATEMENT OF SIGNIFICANCE: Silk fibroin (SF) hydrogel controls the release of hydrogen sulfide (H2S) to inhibit neuronal pyroptosis and neuroinflammation in injured brain tissue. In this study, we synthesized a surface-fill H2S-releasing silk fibroin hydrogel, which could slowly release H2S to reshape the homeostasis of endogenous H2S in injured neurons and inhibit neuronal pyroptosis in a mouse model of traumatic brain injury. Meanwhile, H2S@SF hydrogel could alleviate brain edema and the degree of neurodegeneration, improve motor dysfunction, anxious behavior and memory impairment caused by TBI, reduce tissue loss and ameliorate neuroinflammation. Our study provides a new theoretical basis for the treatment of H2S after TBI and the clinical application of H2S@SF hydrogel.

Emerging Effects of IL-33 on COVID-19.

Since the start of COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more than 6 million people have lost their lives worldwide directly or indirectly. Despite intensified efforts to clarify the immunopathology of COVID-19, the key factors and processes that trigger an inflammatory storm and lead to severe clinical outcomes in patients remain unclear. As an inflammatory storm factor, IL-33 is an alarmin cytokine, which plays an important role in cell damage or infection. Recent studies have shown that serum IL-33 is upregulated in COVID-19 patients and is strongly associated with poor outcomes. Increased IL-33 levels in severe infections may result from an inflammatory storm caused by strong interactions between activated immune cells. However, the effects of IL-33 in COVID-19 and the underlying mechanisms remain to be fully elucidated. In this review, we systematically discuss the biological properties of IL-33 under pathophysiological conditions and its regulation of immune cells, including neutrophils, innate lymphocytes (ILCs), dendritic cells, macrophages, CD4+ T cells, Th17/Treg cells, and CD8+ T cells, in COVID-19 phagocytosis. The aim of this review is to explore the potential value of the IL-33/immune cell pathway as a new target for early diagnosis, monitoring of severe cases, and clinical treatment of COVID-19.

Implantation of injectable SF hydrogel with sustained hydrogen sulfide delivery reduces neuronal pyroptosis and enhances functional recovery after severe intracerebral hemorrhage.

Hydrogen sulfide (H2S), an important endogenous signaling molecule, plays an important neuroprotective role in the central nervous system. However, there is no ideal delivery material or method involving the sustained and controlled release of H2S for clinical application in brain diseases. Silk fibroin (SF)-based hydrogels have become a potentially promising strategy for local, controlled, sustained drug release in the treatment of various disorders. Here, we show a silk fibroin (SF)-based hydrogel with sustained H2S delivery (H2S@SF hydrogel) is effective in treating brain injury through stereotactic orthotopic injection in a severe intracerebral hemorrhage (ICH) mouse model. In this study, we observed H2S@SF hydrogel sustained H2S release in vitro and in vivo. The physicochemical properties of H2S@SF hydrogel were studied using FE-SEM, Raman spectroscopy and Rheological analysis. Treatment with H2S@SF hydrogel attenuated brain edema, reduced hemorrhage volume and improved the recovery of neurological deficits after severe ICH following stereotactic orthotopic injection. Double immunofluorescent staining also revealed that H2S@SF hydrogel may reduce cell pyroptosis in the striatum, cortex and hippocampus. However, when using endogenous H2S production inhibitor AOAA, H2S@SF hydrogel could not suppress ICH-induced cell pyroptosis. Hence, the therapeutic effect of the H2S@SF hydrogel may be partly the result of the slow-release of H2S and/or the effect of the SF hydrogel on the production of endogenous H2S. Altogether, the results exhibit promising attributes of injectable silk fibroin hydrogel and the utility of H2S-loaded injectable SF hydrogel as an alternative biomaterial toward brain injury treatment for clinical application.

Silk Fibroin Hydrogels Could Be Therapeutic Biomaterials for Neurological Diseases.

Silk fibroin, a natural macromolecular protein without physiological activity, has been widely used in different fields, such as the regeneration of bones, cartilage, nerves, and other tissues. Due to irrevocable neuronal injury, the treatment and prognosis of neurological diseases need to be investigated. Despite attempts to propel neuroprotective therapeutic approaches, numerous attempts to translate effective therapies for brain disease have been largely unsuccessful. As a good candidate for biomedical applications, hydrogels based on silk fibroin effectively amplify their advantages. The ability of nerve tissue regeneration, inflammation regulation, the slow release of drugs, antioxidative stress, regulation of cell death, and hemostasis could lead to a new approach to treating neurological disorders. In this review, we introduced the preparation of SF hydrogels and then delineated the probable mechanism of silk fibroin in the treatment of neurological diseases. Finally, we showed the application of silk fibroin in neurological diseases.

Spatiotemporal Dynamics of Covert Attention With Different Degrees of Central Visual Field Defects: An ERP and sLORETA Study.

Purpose: The present study aimed to investigate the spatiotemporal dynamics of covert attention by simulating different degrees of central visual field defects in healthy subjects. Methods: An electroencephalogram (EEG) was recorded while 40 normal-sighted subjects performed a target discrimination task. Target stimuli simulated different defect degrees of the central visual field by artificially central scotomas (5, 10, 20, and 30 degrees of visual angle) masked on the center of black-and-white checkerboards. Event-related potentials (ERPs) and standardized low-resolution brain electromagnetic tomography (sLORETA) based on ERPs were analyzed. Results: ERP results indicated that during early perceptual processes, compared with 5-degree and 10-degree defects, N1 amplitudes of 20-degree and 30-degree defects decreased, whereas P2 amplitudes significantly reduced in 30-degree defects. During later discrimination and decision processing, N2 amplitudes gradually increased from 5-degree to 30-degree defects, whereas P3 amplitudes gradually decreased. Source localization indicated that 5-degree and 10-degree defects had stronger activations than 20-degree and 30-degree defects from the occipital cortex to the ventral stream and dorsal streams. Especially, 30-degree defects primarily recruited additional activations in the ventrolateral prefrontal cortex and ventral stream and later caused the disconnection of dorsolateral prefrontal-posterior parietal cortices in the dorsal stream. Conclusions: Different degrees of central visual field defects differed in distinct spatiotemporal characteristics at multiple stages of covert attention, from top-down forward feedback and attentional allocation to executive controls through ventral and dorsal processing streams, suggesting that the combination of ERP and source localization can reveal the spatiotemporal control capacity of the cortex on central visual field defects.

Interleukin-13 Affects the Recovery Processes in a Mouse Model of Hemorrhagic Stroke with Bilateral Tibial Fracture.

As one form of stroke, intracerebral hemorrhage (ICH) is a fatal cerebrovascular disease, which has high morbidity and mortality and lacks effective medical treatment. Increased infiltration of inflammatory cytokines coupled with pyroptotic cell death is involved in the pathophysiological process of ICH. However, little is known about whether concomitant fracture patients have the same progression of inflammation and pyroptosis. Hence, we respectively established the mouse ICH model and ICH with bilateral tibial fracture model (MI) to explore the potential cross-talk between the above two injuries. We found that MI obviously reversed the expressions of pyroptosis-associated proteins, which were remarkably up-regulated at the acute phase after ICH. Similar results were observed in neuronal expressions via double immunostaining. Furthermore, brain edema was also significantly alleviated in mice who suffered MI, when compared with ICH alone. To better clarify the potential mechanisms that mediated this cross-talk, recombinant mouse interleukin-13 (IL-13) was used to investigate its effect on pyroptosis in the mouse MI model, in which a lower level of IL-13 was observed. Remarkably, IL-13 administration re-awakened cell death, which was mirrored by the re-upregulation of pyroptosis-associated proteins and PI-positive cell counts. The results of hemorrhage volume and behavioral tests further confirmed its critical role in regulating neurological functions. Besides, the IL-13-treated MI group showed poor outcomes of fracture healing. To sum up, our research indicates that controlling the IL-13 content in the acute phase would be a promising target in influencing the outcomes of brain injury and fracture, and meanwhile, provides new evidence in repairing compound injuries in clinics.

Restraint Stress Delays the Recovery of Neurological Impairments and Exacerbates Brain Damages through Activating Endoplasmic Reticulum Stress-mediated Neurodegeneration/Autophagy/Apopotosis post Moderate Traumatic Brain Injury.

Based on accumulating evidence, patients recovering from mild and moderate traumatic brain injury (TBI) often experience increased sensitivity to stressful events. However, few studies have assessed on the effects and pathophysiological mechanisms of stress on TBI. In the current study, using a mouse model of moderate TBI, we investigated whether restraint stress (RS) regulates secondary neurodegeneration and neuronal cell death, which are commonly associated with neurological dysfunctions. Our data showed that RS significantly reduced body weight recovery, delayed the recovery of neurological functions (motor function, cognitive function and anxiety-like behavior) and exacerbated the brain lesion volume after moderate TBI. Immunofluorescence results indicated that moderate TBI-induced cell insults and blood-brain barrier leakage were aggravated by RS. Further Western blotting experiments showed that RS activated endoplasmic reticulum (ER) stress excessively after moderate TBI and decreased the number of NeuN-positive cells, but increased the number of CHOP/NeuN-co-positive cells by performing immunostaining in the injured cortex after moderate TBI. Moreover, RS increased the ratios of CHOP/Aß and CHOP/p-Tau co-positive cells in the injured cortex after moderate TBI. However, blocking ER stress with the classic ER stress inhibitor salubrinal remarkably decreased apoptosis and the levels of autophagy-related proteins in the mouse model of moderate TBI plus RS. Collectively, RS delays the recovery of neurological function and deteriorates morphological damage by excessively activating ER stress-mediated neurodegeneration, apoptosis and autophagy after moderate TBI. Thus, monitoring stress levels in patients recovering from non-severe TBI may merit consideration in the future.

The effect of traumatic brain injury on bone healing from a novel exosome centered perspective in a mice model.

BACKGROUND: In patients with traumatic brain injury (TBI) combined with long bone fracture, the fracture healing is always faster than that of patients with single fracture, which is characterized by more callus growth at the fracture site and even ectopic ossification. Exosomes are nanoscale membrane vesicles secreted by cells, which contain cell-specific proteins, miRNAs, and mRNAs. METHODS: In this study, we used exosomes as the entry point to explore the mechanism of brain trauma promoting fracture healing. We established a model of tibia fracture with TBI in mice to observe the callus growth and expression of osteogenic factors at the fracture site. Blood samples of model mice were further collected, exosomes in plasma were extracted by ultra-centrifugation method, and then identified and acted on osteoblasts cultured in vitro. The effects of exosomes on osteoblast differentiation at the cell, protein and gene levels were investigated by Western Blot and q-PCR, respectively. Furthermore, miRNA sequencing of exosomes was performed to identify a pattern of miRNAs that were present at increased or decreased levels. RESULTS: The results suggested that plasma exosomes after TBI had the ability to promote the proliferation and differentiation of osteoblasts, which might be due to the increased expression of osteoblast-related miRNA in exosomes. They were transmitted to the osteoblasts at the fracture site, so as to achieve the role of promoting osteogenic differentiation. CONCLUSION: The TBI-derived exosomes may have potential applications for promoting fracture healing in future. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Plasma exosomes early after TBI have the ability to promote osteoblast proliferation and differentiation. The mechanism may be achieved by miRNA in exosomes. Plasma exosomes may be used as breakthrough clinical treatment for delayed or non-union fractures.