PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing Th17-cell differentiation and regulating cytokine production.

Experimental autoimmune neuritis (EAN) is a CD4+ T-cell-mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system. It has been replicated in an animal model of human inflammatory demyelinating polyradiculoneuropathy, Guillain-Barré syndrome. In this study, we evaluated the therapeutic efficacy of a selective inhibitor of the immunoproteasome subunit, low-MW polypeptide 7 (PR-957) in rats with EAN. Our results showed that PR-957 significantly delayed onset day, reduced severity and shortened duration of EAN, and alleviated demyelination and inflammatory infiltration in sciatic nerves. In addition to significantly regulating expression of the cytokine profile, PR-957 treatment down-regulated the proportion of proinflammatory T-helper (Th)17 cells in sciatic nerves and spleens of rats with EAN. Data presented show the role of PR-957 in the signal transducer and activator of transcription 3 (STAT3) pathway. PR-957 not only decreased expression of IL-6 and IL-23 but also led to down-regulation of STAT3 phosphorylation in CD4+ T cells. Regulation of the STAT3 pathway led to a reduction in retinoid-related orphan nuclear receptor γ t and IL-17 production. Furthermore, reduction of STAT3 phosphorylation may have directly suppressed Th17-cell differentiation. Therefore, our study demonstrates that PR-957 could potently alleviate inflammation in rats with EAN and that it may be a likely candidate for treating Guillain-Barré syndrome.-Liu, H., Wan, C., Ding, Y., Han, R., He, Y., Xiao, J., Hao, J. PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing Th17-cell differentiation and regulating cytokine production.

Programmed Death Ligand 1 Plays a Neuroprotective Role in Experimental Autoimmune Neuritis by Controlling Peripheral Nervous System Inflammation of Rats.

Programmed death 1 (PD-1; CD279), a member of the CD28 family, is an inhibitory receptor on T cells and is responsible for T cell dysfunction in infectious diseases and cancers. The ligand for PD-1, programmed death ligand 1 (PD-L1; also known as B7-H1, CD274), is a member of the B7 family. The engagement of PD-1 with programmed death ligand can downregulate autoreactive T cells that participate in multiple autoimmune diseases. Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barré syndrome, and the pathogenesis of EAN is mediated principally through T cells and macrophages. In this study, we investigated the effects of PD-L1 in EAN rats. For preventative and therapeutic management, we administered PD-L1, which successfully decreased the severity of EAN; it alleviated the neurologic course of EAN, as well as inhibited the infiltration of inflammatory cells and demyelination of sciatic nerves. Our data revealed that PD-L1 treatment inhibited lymphocyte proliferation and altered T cell differentiation by inducing decreases in IFN-γ+CD4+ Th1 cells and IL-17+CD4+ Th17 cells and increases in IL-4+CD4+ Th2 cells and Foxp3+CD4+ regulatory T cells. The expression levels of p-STAT3 and Foxp3 were significantly different in PD-L1-treated groups compared with the control group. Additionally, PD-L1 regulated the expression of Foxp3 and p-STAT3 in EAN, probably by inhibiting PI3K/AKT/mTOR signaling expression. In summary, PD-L1 is a potentially useful agent for the treatment of EAN because of its anti-inflammatory and neuroprotective effects.

Clinical and electrophysiological features of post-traumatic Guillain-Barré syndrome.

BACKGROUND: Post-traumatic Guillain-Barré syndrome (GBS) is a rarely described potentially life-threatening cause of weakness. We sought to elucidate the clinical features and electrophysiological patterns of post-traumatic GBS as an aid to diagnosis. METHODS: We retrospectively studied six patients diagnosed with post-traumatic GBS between 2014 and 2016 at Tianjin Medical University General Hospital, China. Clinical features, serum analysis, lumbar puncture results, electrophysiological examinations, and prognosis were assessed. RESULTS: All six patients had different degrees of muscular atrophy at nadir and in two, respiratory muscles were involved. Five also had damaged cranial nerves and four of these had serum antibodies against gangliosides. The most common electrophysiological findings were relatively normal distal latency, prominent reduction of compound muscle action potential amplitude, and absence of F-waves, which are consistent with an axonal form of GBS. CONCLUSIONS: It is often overlooked that GBS can be triggered by non-infectious factors such as trauma and its short-term prognosis is poor. Therefore, it is important to analyze the clinical and electrophysiological features of GBS after trauma. Here we have shown that electrophysiological evaluations are helpful for diagnosing post-traumatic GBS. Early diagnosis may support appropriate treatment to help prevent morbidity and improve prognosis.

Dimethyl fumarate attenuates experimental autoimmune neuritis through the nuclear factor erythroid-derived 2-related factor 2/hemoxygenase-1 pathway by altering the balance of M1/M2 macrophages.

BACKGROUND: Guillain-Barré syndrome (GBS) is an acute, post-infectious, immune-mediated, demyelinating disease of peripheral nerves and nerve roots. Dimethyl fumarate (DMF), a fumaric acid ester, exhibits various biological activities, including multiple immunomodulatory and neuroprotective effects. However, the potential mechanism underlying the effect of DMF in GBS animal model experimental autoimmune neuritis (EAN) is unclear. METHODS: Using EAN, an established GBS model, we investigated the effect of DMF by assessing clinical score, histological staining and electrophysiological studies. Then, we further explored the potential mechanism by Western blot analysis, flow cytometry, fluorescence immunohistochemistry, PCR, and ELISA analysis. The Mann-Whitney U test was used to compare differences between control group and treatment groups where appropriate. RESULTS: DMF treatment reduced the neurological deficits by ameliorating inflammatory cell infiltration and demyelination of sciatic nerves. In addition, DMF treatment decreased the level of pro-inflammatory M1 macrophages while increasing the number of anti-inflammatory M2 macrophages in the spleens and sciatic nerves of EAN rats. In RAW 264.7, a shift in macrophage polarization from M1 to M2 phenotype was demonstrated to be depended on DMF application. In sciatic nerves, DMF treatment elevated the level of the antioxidant transcription factor nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and its target gene hemoxygenase-1 (HO-1) which could facilitate macrophage polarization toward M2 type. Moreover, DMF improved the inflammatory milieu in spleens of EAN rats, characterized by downregulation of messenger RNA (mRNA) of IFN-γ, TNF-α, IL-6, and IL-17 and upregulation of mRNA level of IL-4 and IL-10. CONCLUSIONS: Taken together, our data demonstrate that DMF can effectively suppress EAN, and the mechanism involves altering the balance of M1/M2 macrophages and attenuating inflammation.

Chrysin protects against focal cerebral ischemia/reperfusion injury in mice through attenuation of oxidative stress and inflammation.

Inflammation and oxidative stress play an important part in the pathogenesis of focal cerebral ischemia/reperfusion (I/R) injury, resulting in neuronal death. The signaling pathways involved and the underlying mechanisms of these events are not fully understood. Chrysin, which is a naturally occurring flavonoid, exhibits various biological activities. In this study, we investigated the neuroprotective properties of chrysin in a mouse model of middle cerebral artery occlusion (MCAO). To this end, male C57/BL6 mice were pretreated with chrysin once a day for seven days and were then subjected to 1 h of middle cerebral artery occlusion followed by reperfusion for 24 h. Our data show that chrysin successfully decreased neurological deficit scores and infarct volumes, compared with the vehicle group. The increases in glial cell numbers and proinflammatory cytokine secretion usually caused by ischemia/reperfusion were significantly ameliorated by chrysin pretreatment. Moreover, chrysin also inhibited the MCAO-induced up-regulation of nuclear factor-kappa B (NF-κB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS), compared with the vehicle. These results suggest that chrysin could be a potential prophylactic agent for cerebral ischemia/reperfusion (I/R) injury mediated by its anti-inflammatory and anti-oxidative effects.

Identification and validation of oxidative stress and immune-related hub genes in Alzheimer's disease through bioinformatics analysis.

Alzheimer's disease (AD) is the leading cause of dementia in aged population. Oxidative stress and neuroinflammation play important roles in the pathogenesis of AD. Investigation of hub genes for the development of potential therapeutic targets and candidate biomarkers is warranted. The differentially expressed genes (DEGs) in AD were screened in GSE48350 dataset. The differentially expressed oxidative stress genes (DEOSGs) were analyzed by intersection of DEGs and oxidative stress-related genes. The immune-related DEOSGs and hub genes were identified by weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) analysis, respectively. Enrichment analysis was performed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The diagnostic value of hub genes was assessed by receiver operating characteristic analysis and validated in GSE1297. The mRNA expression of diagnostic genes was determined by qRT-PCR analysis. Finally, we constructed the drug, transcription factors (TFs), and microRNA network of the diagnostic genes. A total of 1160 DEGs (259 up-regulated and 901 down-regulated) were screened in GSE48350. Among them 111 DEOSGs were identified in AD. Thereafter, we identified significant difference of infiltrated immune cells (effector memory CD8 T cell, activated B cell, memory B cell, natural killer cell, CD56 bright natural killer cell, natural killer T cell, plasmacytoid dendritic cell, and neutrophil) between AD and control samples. 27 gene modules were obtained through WGCNA and turquoise module was the most relevant module. We obtained 66 immune-related DEOSGs by intersecting turquoise module with the DEOSGs and identified 15 hub genes through PPI analysis. Among them, 9 hub genes (CCK, CNR1, GAD1, GAP43, NEFL, NPY, PENK, SST, and TAC1) were identified with good diagnostic values and verified in GSE1297. qRT-PCR analysis revealed the downregulation of SST, NPY, GAP43, CCK, and PENK and upregulation of NEFL in AD. Finally, we identified 76 therapeutic agents, 152 miRNAs targets, and 91 TFs regulatory networks. Our study identified 9 key genes associated with oxidative stress and immune reaction in AD pathogenesis. The findings may help to provide promising candidate biomarkers and therapeutic targets for AD.

Bibliometric and Visualized Analysis of Global Evolution of Research in Lung Ultrasound: A Rapidly Developing Field.

BACKGROUND: Lung ultrasound (LUS) is gaining recognition as an indispensable diagnostic tool in critical care. OBJECTIVE: The study aimed to characterize the global research landscape and trend of LUS with quantification and visualization approaches. METHODS: Documents related to LUS published between 2007 and 2023 were selected from the Web of Science Core Collection and identified. Visualization and statistical analysis were conducted with the VOSviewer 1.6.18, CiteSpace 5.7.R5, and Bibliometrix 4.1.0 Package, including analysis of the trend of global publications, prominent countries, active institutions, and funding agencies, key authors and journals, co-cited references, and keywords. RESULTS: A total of 3010 publications, including 2434 articles and 576 reviews, were retrieved. The output of LUS-related research has increased steadily over the years, especially after 2018. Italy (n=756; 25.12%) has shown the highest output, being the country with the highest total citations (23423 times). The most influential author was Gargani Luna with 52 documents, who worked at the Consiglio Nazionale delle Ricerche. Chest and Intensive Care Medicine with high citations and impact factor scores were the most influential journals. Besides "lung ultrasonography", the keywords developed included "coronavirus disease 2019 (COVID-19)", "acute respiratory distress syndrome", and "acute heart failure". CONCLUSION: Research output on LUS has increased steadily, especially after 2018. Italy and the United States are staying ahead in this field. Research collaboration still needs to be strengthened. This comprehensive analysis has presented the global research landscape and trends of LUS-related research, providing valuable information for researchers to pursue further exploration.

Integrated analysis of C3AR1 and CD163 associated with immune infiltration in intracranial aneurysms pathogenesis.

Background: To identify potential immune-related biomarkers, molecular mechanism, and therapeutic agents of intracranial aneurysms (IAs). Methods: We identified the differentially expressed genes (DEGs) between IAs and control samples from GSE75436, GSE26969, GSE6551, and GSE13353 datasets. We used weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) analysis to identify immune-related hub genes. We evaluated the expression of hub genes by using qRT-PCR analysis. Using miRNet, NetworkAnalyst, and DGIdb databases, we analyzed the regulatory networks and potential therapeutic agents targeting hub genes. Least absolute shrinkage and selection operator (LASSO) logistic regression was performed to identify optimal biomarkers among hub genes. The diagnostic value was validated by external GSE15629 dataset. Results: We identified 227 DEGs and 22 differentially infiltrating immune cells between IAs and control samples from GSE75436, GSE26969, GSE6551, and GSE13353 datasets. We further identified 41 differentially expressed immune-related genes (DEIRGs), which were primarily enriched in the chemokine-mediated signaling pathway, myeloid leukocyte migration, endocytic vesicle membrane, chemokine receptor binding, chemokine activity, and viral protein interactions with cytokines and their receptors. Among 41 DEIRGs, 10 hub genes including C3AR1, CD163, CCL4, CXCL8, CCL3, TLR2, TYROBP, C1QB, FCGR3A, and FCGR1A were identified with good diagnostic values (AUC >0.7). Hsa-mir-27a-3p and transcription factors, including YY1 and GATA2, were identified the primary regulators of hub genes. 92 potential therapeutic agents targeting hub genes were predicted. C3AR1 and CD163 were finally identified as the best diagnostic biomarkers using LASSO logistic regression (AUC = 0.994). The diagnostic value of C3AR1 and CD163 was validated by the external GSE15629 dataset (AUC = 0.914). Conclusions: This study revealed the importance of C3AR1 and CD163 in immune infiltration in IAs pathogenesis. Our finding provided a valuable reference for subsequent research on the potential targets for molecular mechanisms and intervention of IAs.

Identifying global research trends on inflammation associated with traumatic brain injury by bibliometric and visualized analysis.

Background: Traumatic brain injury (TBI) is a catastrophic disease involving complex inflammatory processes. This study aimed to quantitatively analyze and visualize the global research trends on inflammation associated with TBI. Methods: All publications concerning TBI and inflammation published from 2007 to 2021 were retrieved from the Web of Science Core Collection database. Key visualization and statistical analysis were calculated and evaluated using VOSviewer, CiteSpace, R package "bibliometrix," and an online bibliometric analysis platform. Results: From 2007 to 2021, 15,138 authors from 2860 institutions in 77 countries/regions published 3154 articles on inflammation associated with TBI in 786 academic journals. The research output has significantly increased over the years despite a minor fluctuation. Among the countries, the United States showed the highest output (43.50%) with the most total citations (62,791). The author with the most published articles was Cox CS (30 articles with h-index = 20), and the most popular journal in the field was the Journal of Neurotrauma (190 papers, cited 6433 times). The high-frequency keywords were "post-traumatic brain injury," "brain edema," and "glial activation." Moreover, high-frequency keywords analysis indicated that various inflammatory cells contributed to neuroinflammation, neuroprotection, and oxidative stress after TBI. Conclusion: This study revealed the research trends, hotspots, and emerging topics in inflammation associated with TBI by quantitative and visualized analysis. The current research focuses on the crosstalk between various inflammatory cells and the brain and the associated mechanisms. This study presents the research landscape and inspires future research on inflammation associated with TBI.

Individualized CT image-guided free-hand catheter technique: A new and reliable method for minimally invasive evacuation of basal ganglia hematoma.

Objective: To validate the clinical reliability of an individualized CT image-guided' free-hand catheter technique (CTGFC) for basal ganglia hematoma (BGH) evacuation. Methods: From January 2017 to December 2020, 58 cases of patients with BGH who underwent catheter evacuation were enrolled. The surgery was conducted using the CTGFC (n = 31) or stereotactic catheter technique (STC, n = 27). The authors evaluated the baseline characteristics, operation-related indicators, postoperative complications, hospitalization-related indicators, short-term and long-term functional outcomes, and mortality rate 1 year after surgery. Results: All patients underwent BGH evacuation under non-general anesthesia in the CTGFC group. The operative time (p < 0.01) and operation costs (p < 0.05) were significantly shorter in the CTGFC group than that in the STC group (p < 0.01). Comparable results were found in the catheter indwelling duration, residual hematoma volume, hematoma evacuation rate, incidence of postoperative complications, hospital ICU stay, and hospital costs between these two groups (p > 0.05). The duration of hospital stay was remarkably shorter in the CTGFC group than that in the STC group (p < 0.01). There were no differences in terms of the short-time functional outcomes score at discharge, including the Glasgow outcome scale (GOS) score, the activities of daily living (ADL) score, and the Karnofsky performance score (KPS). Moreover, comparable findings were also found in the 1-year postoperative GOS score, ADL score, KPS score, and mortality rate between these two groups. Conclusion: The simple CTGFC-assisted surgery was a safe and reliable option for BGH evacuation, especially in primary medical institutes and emergency situations with limited medical resources.

RAD001 (everolimus) attenuates experimental autoimmune neuritis by inhibiting the mTOR pathway, elevating Akt activity and polarizing M2 macrophages.

Guillain-Barre' syndrome (GBS) is an acute, postinfectious, immune-mediated, demyelinating disease of peripheral nerves and nerve roots. As a classical animal model of GBS, experimental autoimmune neuritis (EAN) has become well-accepted. Additionally, the potent immune modulation exerted by mammalian target of rapamycin (mTOR) inhibitors has been used to treat cancers and showed beneficial effects. Here we demonstrate that the mTOR inhibitor RAD001 (everolimus) protected rats from the symptoms of EAN, as shown by decreased paralysis, diminished inflammatory cell infiltration, reductions in demyelination of peripheral nerves and improved nerve conduction. Furthermore, RAD001 shifted macrophage polarization toward the protective M2 phenotype and modified the inflammatory milieu by downregulating the production of pro-inflammatory cytokines including IFN-γ and IL-17as well as upregulating the release of anti-inflammatory cytokines such as IL-4 and TGF-ß. Amounts of the mTOR downstream targets p-P70S6K and p-4E-BP1 in sciatic nerves decreased, whereas the level of its upstream protein p-Akt was elevated. This demonstrated that RAD001 inhibited the mTOR pathway and encouraged the expression of p-Akt, which led to M2 macrophage polarization, thus improved the outcome of EAN in rats. Consequently, RAD001 exhibits strong potential as a therapeutic strategy for ameliorating peripheral poly-neuropathy.

New strategies in the management of Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an acute and usually monophasic, neurological, demyelinating disease. Although most patients have good outcomes without sequelae after conventional plasma exchange and intravenous immunoglobulin therapy, 20% of patients continue to have severe disease and 5% die of their disease. Therefore, there is an obvious need for more acceptable and efficacious therapies. Experimental autoimmune neuritis (EAN) is the classical animal model for GBS. As there is no specific drug for GBS, several drugs targeting the humoral and cellular components of the immune response have been used to treat EAN in the endeavour to find new treatment alternatives for GBS. This review focused on some new strategies for GBS, which have been reported but have not yet been widely used, and on the main drugs which have been investigated in EAN.