Bioengineered Neutrophils for Smart Response in Brain Infection Management.

Brain infections, frequently accompanied by significant inflammation, necessitate comprehensive therapeutic approaches targeting both infections and associated inflammation. A major impediment to such combined treatment is the blood-brain barrier (BBB), which significantly restricts therapeutic agents from achieving effective concentrations within the central nervous system. Here, a neutrophil-centric dual-responsive delivery system, coined "CellUs," is pioneered. This system is characterized by live neutrophils enveloping liposomes of dexamethasone, ceftriaxone, and oxygen-saturated perfluorocarbon (Lipo@D/C/P). CellUs is meticulously engineered to co-deliver antibiotics, anti-inflammatory agents, and oxygen, embodying a comprehensive strategy against brain infections. CellUs leverages the intrinsic abilities of neutrophils to navigate through BBB, accurately target infection sites, and synchronize the release of Lipo@D/C/P with local inflammatory signals. Notably, the incorporation of ultrasound-responsive perfluorocarbon within Lipo@D/C/P ensures the on-demand release of therapeutic agents at the afflicted regions. CellUs shows considerable promise in treating Staphylococcus aureus infections in mice with meningitis, particularly when combined with ultrasound treatments. It effectively penetrates BBB, significantly eliminates bacteria, reduces inflammation, and delivers oxygen to the affected brain tissue, resulting in a substantial improvement in survival rates. Consequently, CellUs harnesses the natural chemotactic properties of neutrophils and offers an innovative pathway to improve treatment effectiveness while minimizing adverse effects.

Radiomics Nomogram Model Based on TOF-MRA Images: A New Effective Method for Predicting Microaneurysms.

Objective: To develop a radiomics nomogram model based on time-of-flight magnetic resonance angiography (TOF-MRA) images for preoperative prediction of true microaneurysms. Methods: 118 patients with Intracranial Aneurysm Sac (40 positive and 78 negative) were enrolled and allocated to training and validation groups (8:2 ratio). Findings of clinical characteristics and MRA features were analyzed. A radiomics signature was built on the basis of reproducible features by using the least absolute shrinkage and selection operator (LASSO) regression algorithm in the training group. The radiomics nomogram model was constructed by combining clinical risk factors and radiomics signature. In order to compare the classification performance of clinical models, radiomics model and radiomics nomogram model, AUC was used to evaluate them. The performance of the radiomics nomogram model was evaluated by calibration curve and decision curve analysis. Results: Eleven features were selected to develop radiomics model with AUC of 0.875 (95% CI 0.78-0.97), sensitivity of 0.84, and specificity of 0.68. The radiomics model achieved a better diagnostic performance than the clinic model (AUC = 0.75, 95% CI: 0.53-0.97) and even radiologists. The radiomics nomogram model, which combines radiomics signature and clinical risk factors, is effective too (AUC = 0.913, 95% CI: 0.87-0.96). Furthermore, the decision curve analysis demonstrated significantly better net benefit in the radiomics nomogram model. Conclusion: Radiomics features derived from TOF-MRA can reliably be used to build a radiomics nomogram model for effectively differentiating between pseudo microaneurysms and true microaneurysms, and it can provide an objective basis for the selection of clinical treatment plans.

Anti-leucine-rich glioma inactivated protein 1 encephalitis with sleep disturbance as the first symptom: A case report and review of literature.

BACKGROUND: Anti-leucine-rich glioma inactivated protein 1 (anti-LGI1) encephalitis is an infrequent type of autoimmune encephalitis (AE) characterized by acute or subacute cognitive and psychiatric disturbance, facio-brachial dystonic seizures (FBDSs), and hyponatremia. Anti-LGI1 AE has increasingly been considered a primary form of AE. Early identification and treatment of this disease are clearly very important. CASE SUMMARY: Here, we report that a male patient developed severe anti-LGI1 encephalitis, which was initially misdiagnosed as a sleep disturbance. He was hospitalized for epileptic seizures and typical FBDSs half a month after he developed sleep disturbances. LGI1 antibodies were detected in his cerebrospinal fluid and serum (1:100 and 1:3.2, respectively), which led to the diagnosis of classic anti-LGI1 AE. No obvious abnormality was observed on brain computed tomography images. T2-weighted fluid-attenuated inversion recovery and T2-weighted scans of brain magnetic resonance imaging (MRI) showed slightly elevated signals within the left basal ganglia area. No tumor was detected within the brain of this patient using MRI. After hormone and antiepileptic drug treatment, the patient's symptoms improved significantly. CONCLUSION: Anti-LGI1 antibody-associated encephalitis has characteristic clinical manifestations, such as cognitive impairment, psychiatric symptoms, seizures, sleep disorders, hyponatremia, and FBDSs. LGI1 antibodies are present in the serum and/or cerebrospinal fluid, but their production is sensitive to immunosuppressants, and this disease has a relatively good prognosis. In particular, we should be aware of the possibility of anti-LGI1 antibody-associated encephalitis in adolescents with sleep disorders to avoid missed diagnoses and misdiagnoses.

Upregulation of MDH1 acetylation by HDAC6 inhibition protects against oxidative stress-derived neuronal apoptosis following intracerebral hemorrhage.

Oxidative stress impairs functional recovery after intracerebral hemorrhage (ICH). Histone deacetylase 6 (HDAC6) plays an important role in the initiation of oxidative stress. However, the function of HDAC6 in ICH and the underlying mechanism of action remain elusive. We demonstrated here that HDAC6 knockout mice were resistant to oxidative stress following ICH, as assessed by the MDA and NADPH/NADP+ assays and ROS detection. HDAC6 deficiency also resulted in reduced neuronal apoptosis and lower expression levels of apoptosis-related proteins. Further mechanistic studies showed that HDAC6 bound to malate dehydrogenase 1 (MDH1) and mediated-MDH1 deacetylation on the lysine residues at position 121 and 298. MDH1 acetylation was inhibited in HT22 cells that were challenged with ICH-related damaging agents (Hemin, Hemoglobin, and Thrombin), but increased when HDAC6 was inhibited, suggesting an interplay between HDAC6 and MDH1. The acetylation-mimetic mutant, but not the acetylation-resistant mutant, of MDH1 protected neurons from oxidative injury. Furthermore, HDAC6 inhibition failed to alleviate brain damage after ICH when MDH1 was knockdown. Taken together, our study showed that HDAC6 inhibition protects against brain damage during ICH through MDH1 acetylation.

Genomic deletion of TLR2 induces aggravated white matter damage and deteriorated neurobehavioral functions in mouse models of Alzheimer's disease.

Toll-like receptor-2 (TLR2), a member of the TLR family, plays an important role in the initiation and regulation of immune/inflammation response, which is a critical mechanism underlying Alzheimer's disease (AD). To clarify the role of TLR2 in the pathological process of AD, in the present study, TLR2 knockout plus APPswe/PSEN1dE9 transgenic mice (AD-TLR2KO) were generated. Neurobehavioral tests and brain MRI scan were conducted on mice at the age of 12 months. Additionally, neuron loss was evaluated using NeuN staining. Amyloid ß protein (Aß), glial fibrillary acidic protein (GFAP), endogenous ligands for TLR2, and the activation of downstream signaling of TLR2 in mouse brains were detected by immunohistochemistry and Western blots. The results demonstrated that TLR2 deficit induced learning disabilities, decreased spontaneous activity, increased anxiety and depression, and led to white matter damage (WMD), brain atrophy, loss of neurons, and glial activation. Moreover, TLR2 deficit aggravated impaired neurobehavioral functions and WMD in AD mice, but did not affect the Aß deposition in mouse brains. Our data indicate that the genomic deletion of TLR2 impairs neurobehavioral functions, induces WMD and brain atrophy, and increases the activation of astrocytes, which in turn aggravate the symptoms of AD through a non-Aß mechanism.

Role of Toll-like receptor mediated signaling in traumatic brain injury.

The mechanisms underlying secondary brain damage following traumatic brain injury (TBI) remain unclear. A great many studies have demonstrated that inflammatory cascades contribute to brain damage through the activation of immune/inflammatory responses, including the increased release of cytokines and chemokines, and the recruitment of leukocytes. The cells and tissues damaged by primary mechanical injury release a number of endogenous factors acting as damage-associated molecular patterns (DAMPs), which initiate and perpetuate noninfectious inflammatory responses through transduction signaling pathways. Toll-like receptors (TLRs) are a transmembrane receptor family that can recognize the specific DAMPs released from damaged cells and recruit a set of adaptors leading to the activation of downstream kinases and nuclear factors which regulate the expression of inflammatory genes. The activation of inflammatory responses mediated by TLR signaling is closely associated with brain tissue damage and neurological dysfunction following TBI. TLRs and their downstream protein kinases may be potential targets for the treatment of TBI. Modulation of TLR-mediated signaling may attenuate brain damage and improve TBI outcome. In this review, we briefly discuss the role of TLR-mediated signaling in TBI and the new treatments targeting TLR signaling. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".

Gender difference in the effect of progesterone on neonatal hypoxic/ischemic brain injury in mouse.

This study investigated the effects of progesterone (PROG) on neonatal hypoxic/ischemic (NHI) brain injury, the differences in effects between genders, and the underlying mechanisms. NHI brain injury was established in both male and female neonatal mice induced by occlusion of the left common carotid artery followed by hypoxia. The mice were treated with PROG or vehicle. Fluoro-Jade B staining (F-JB), long term behavior testing, and brain magnetic resonance image (MRI) were applied to evaluate neuronal death, neurological function, and brain damage. The underlying molecular mechanisms were also investigated by Western blots. The results showed that, in the male mice, administration of PROG significantly reduced neuronal death, improved the learning and memory function impaired by cerebral HI, decreased infarct size, and maintained the thickness of the cortex after cerebral HI. PROG treatment, however, did not show significant neuroprotective effects on female mice subjected to HI. In addition, the data demonstrated a gender difference in the expression of tumor necrosis factor receptor 1 (TNFR1), TNF receptor associated factor 6 (TRAF6), Fas associated protein with death domain (FADD), and TIR-domain-containing adapter-inducing interferon-ß (TRIF) between males and females. Our results indicated that treatment with PROG had beneficial effects on NHI injured brain in acute stage and improved the long term cognitive function impaired by cerebral HI in male mice. In addition, the activation of TNF and TRIF mediated signaling in response to cerebral HI and the treatment of PROG varied between genders, which highly suggested that gender differences should be emphasized in evaluating neonatal HI brain injury and PROG effects, as well as the underlying mechanisms.

MyD88 contributes to neuroinflammatory responses induced by cerebral ischemia/reperfusion in mice.

Myeloid differentiation primary-response protein-88 (MyD88) is one of adaptor proteins mediating Toll-like receptors (TLRs) signaling. Activation of MyD88 results in the activation of nuclear factor kappa B (NFκB) and the increase of inflammatory responses. Evidences have demonstrated that TLRs signaling contributes to cerebral ischemia/reperfusion (I/R) injury. However, the role of MyD88 in this mechanism of action is disputed and needs to be clarified. In the present study, in a mouse model of cerebral I/R, we examined the activities of NFκB and interferon factor-3 (IRF3), and the inflammatory responses in ischemic brain tissue using ELISA, Western blots, and real-time PCR. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. Our results showed that NFκB activity increased in ischemic brains, but IRF3 was not activated after cerebral I/R, in wild-type (WT) mice. MyD88 deficit inhibited the activation of NFκB, and the expression of interleukin-1ß (IL-1ß), IL-6, Beclin-1 (BECN1), pellino-1, and cyclooxygenase-2 (COX-2) increased by cerebral I/R compared with WT mice. Interestingly, the expression of interferon Beta 1 (INFB1) and vascular endothelial growth factor (VEGF) increased in MyD88 KO mice. Unexpectedly, although the neurological function improved in the MyD88 knockout (KO) mice, the deficit of MyD88 failed to reduce cerebral infarct size compared to WT mice. We concluded that MyD88-dependent signaling contributes to the inflammatory responses induced by cerebral I/R. MyD88 deficit may inhibit the increased inflammatory response and increase neuroprotective signaling.