The Applications of CircRNA in the Diagnosis and Treatment of Alzheimer's Disease.

Early diagnosis and intervention are key to the treatment of Alzheimer's disease (AD). There is an urgent need for new biomarkers and molecular targets for the detection and treatment of early Alzheimer's pathology. Circular RNA (circRNA) is a newly discovered non-coding RNA with a special type of covalently closed single strand, with potential preventive and therapeutic applications in a variety of diseases. New studies in the field of circRNA in AD have made many exciting new discoveries in recent years, some of which have not received sufficient attention but have important research implications. This review will focus on existing studies of circRNA in AD and discuss future translational perspectives of proposed circRNA strategies for clinical application in AD.

HMGN2 and Histone H1.2: potential targets of a novel probiotic mixture for seasonal allergic rhinitis.

Background: Allergic rhinitis (AR) is a common nasal inflammatory disorder that severely affects an individual's quality of life (QoL) and poses a heavy financial burden. In addition to routine treatments, probiotic intervention has emerged as a promising strategy for preventing and alleviating allergic diseases. The main objective of this study was to determine the effect of a novel multi-strain probiotic mixture on AR symptoms and investigate potential targets underlying the probiotic intervention. Methods: A randomized, double-blind, placebo-controlled clinical study was conducted on AR patients who were allergic to autumnal pollens (n = 31). Placebo or a novel probiotic mixture, composed of Lactobacillus rhamnosus (L. rhamnosus) HN001, L. acidophilus NCFM, Bifidobacterium lactis (B. lactis) Bi-07, L. paracasei LPC-37, and L. reuteri LE16, was administered after 2 months. The therapeutic efficacy was evaluated by a symptom assessment scale. Before and during the pollen season, blood samples were collected, and peripheral blood mononuclear cells (PBMCs) were isolated for further tandem mass tags (TMTs)-based quantitative proteomic analyses. Potential targets and underlying pathological pathways were explored using bioinformatics methods. Results: During the pollen season, the rhinoconjunctivitis symptom score of participants who were administered probiotics (probiotic group, n = 15) was significantly lower than those administered placebo (placebo group, n = 15) (P = 0.037). The proteomic analyses identified 60 differentially expressed proteins (DEPs) in the placebo group, and subsequent enrichment analyses enriched a series of pathways and biological processes, including signaling pathways of inflammation, coagulation cascade, lipid, carbohydrate and amino acid metabolic pathways, and transcription and translation processes. Least Absolute Shrinkage and Selection Operator (LASSO) regression extracted five main elements, namely, GSTO1, ATP2A2, MCM7, PROS1, and TRIM58, as signature proteins. A total of 17 DEPs were identified in the probiotic group, and there was no pathway enriched. Comparison of DEPs in the two groups revealed that the expression levels of the high-mobility group nucleosome-binding domain-containing protein 2 (HMGN2) and Histone H1.2 presented an opposite trend with different interventions. Conclusion: Our data showed that AR symptoms alleviated after treatment with the novel multi-strain probiotic mixture, and the proteomic analyses suggested that HMGN2 and Histone H1.2 might be targets of probiotic intervention for seasonal AR.

Protective Role of AMPK against PINK1B9 Flies' Neurodegeneration with Improved Mitochondrial Function.

Adenosine 5'-monophosphate-activated protein kinase (AMPK)'s effect in PTEN-induced kinase 1 (PINK1) mutant Parkinson's disease (PD) transgenic flies and the related mechanism is seldom studied. The classic MHC-Gal4/UAS PD transgenic flies was utilized to generate the disease characteristics specifically expressed in flies' muscles, and Western blot (WB) was used to measure the expression of the activated form of AMPK to investigate whether activated AMPK alters in PINK1B9 PD flies. MHC-Gal4 was used to drive AMPK overexpression in PINK1B9 flies to demonstrate the crucial role of AMPK in PD pathogenesis. The abnormal wing posture and climbing ability of PINK1B9 PD transgenic flies were recorded. Mitochondrial morphology via transmission electron microscopy (TEM) and ATP and NADH: ubiquinone oxidoreductase core subunit S3 (NDUFS3) protein levels were tested to evaluate the alteration of the mitochondrial function in PINK1B9 PD flies. Phosphorylated AMPKα dropped significantly in PINK1B9 flies compared to controls, and AMPK overexpression rescued PINKB9 flies' abnormal wing posture rate. The elevated dopaminergic neuron number in PPL1 via immunofluorescent staining was observed. Mitochondrial dysfunction in PINK1B9 flies has been ameliorated with increased ATP level, restored mitochondrial morphology in muscle, and increased NDUFS3 protein expression. Conclusively, AMPK overexpression could partially rescue the PD flies via improving PINK1B9 flies' mitochondrial function.

Integrated pan-cancer analysis of centromere protein F and experimental verification of its role and clinical significance in cholangiocarcinoma.

Centromere protein F (CENPF), a protein related to the cell cycle, is a key part of the kinetochore-centromere complex involved in cell division, differentiation, and proliferation. CENPF expression is upregulated in various types of cancer and plays a role in oncogenesis and tumor progression. However, the expression pattern, prognostic significance, and biological role of CENPF in these cancer types are poorly understood. Therefore, in this study, we conducted a pan-cancer analysis of the role of CENPF, which we considered a cut point, to investigate its utility as a prognostic and immunological indicator for malignancies, especially cholangiocarcinoma (CCA). Using systematic bioinformatics analysis, we investigated the expression patterns, prognostic relevance, molecular function, signaling pathways, and immune infiltration patterns of CENPF in the pan-cancer analysis. Western blot and immunohistochemistry staining assays were performed to evaluate the expression profiles of CENPF in CCA tissues and cell lines. Furthermore, Cell Counting Kit-8, colony formation, wound healing, and Transwell assays, as well as CCA xenograft mouse models, were employed to determine the role and function of CENPF in CCA. The results showed that CENPF expression was upregulated and strongly linked to a worse prognosis in most cancer types. CENPF expression was substantially associated with immune cell infiltration, tumor microenvironment, genes related to immune checkpoints, tumor mutational burden, microsatellite instability, and immunotherapy response in diverse malignancies. CENPF was considerably overexpressed in CCA tissues and cells. Functionally, inhibiting CENPF expression significantly reduced the proliferating, migrating, and invading abilities of CCA cells. CENPF expression also affects the prognosis of multiple malignancies, which is highly associated with immunotherapy response and tumor immune cell infiltration. In conclusion, CENPF may act as an oncogene and an immune infiltration-related biomarker and can accelerate tumor development in CCA.

Impact of Air Pollution on Atopic Dermatitis: A Comprehensive Review.

Air pollution is associated with multiple health problems worldwide, contributing to increased morbidity and mortality. Atopic dermatitis (AD) is a common allergic disease, and increasing evidence has revealed a role of air pollution in the development of atopic dermatitis. Air pollutants are derived from several sources, including harmful gases such as nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO), as well as particulate matter (PM) of various sizes, and bioaerosols. Possible mechanisms linking air pollution to atopic dermatitis include damage to the skin barrier through oxidative stress, increased water loss, physicochemical injury, and an effect on skin microflora. Furthermore, oxidative stress triggers immune dysregulation, leading to enhanced sensitization to allergens. There have been multiple studies focusing on the association between various types of air pollutants and atopic dermatitis. Since there are many confounders in the current research, such as climate, synergistic effects of mixed pollutants, and diversity of study population, it is not surprising that inconsistencies exist between different studies regarding AD and air pollution. Still, it is generally accepted that air pollution is a risk factor for AD. Future studies should focus on how air pollution leads to AD as well as effective intervention measures.

Integrated metabolomics and lipidomics study of patients with atopic dermatitis in response to dupilumab.

Background: Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. Dupilumab, a monoclonal antibody that targets the interleukin (IL)-4 and IL-13 receptors, has been widely used in AD because of its efficacy. However, metabolic changes occurring in patients with AD in response to dupilumab remains unknown. In this study, we integrated metabolomics and lipidomics analyses with clinical data to explore potential metabolic alterations associated with dupilumab therapeutic efficacy. In addition, we investigated whether the development of treatment side effects was linked to the dysregulation of metabolic pathways. Methods: A total of 33 patients with AD were included in the current study, with serum samples collected before and after treatment with dupilumab. Comprehensive metabolomic and lipidomic analyses have previously been developed to identify serum metabolites (including lipids) that vary among treatment groups. An orthogonal partial least squares discriminant analysis model was established to screen for differential metabolites and metabolites with variable importance in projection > 1 and p < 0.05 were considered potential metabolic biomarkers. MetaboAnalyst 5.0 was used to identify related metabolic pathways. Patients were further classified into two groups, well responders (n = 19) and poor responders (n = 14), to identify differential metabolites between the two groups. Results: The results revealed significant changes in serum metabolites before and after 16 weeks of dupilumab treatment. Variations in the metabolic profile were more significant in the well-responder group than in the poor-responder group. Pathway enrichment analysis revealed that differential metabolites derived from the well-responder group were mainly involved in glycerophospholipid metabolism, valine, leucine and isoleucine biosynthesis, the citrate cycle, arachidonic acid metabolism, pyrimidine metabolism, and sphingolipid metabolism. Conclusion: Serum metabolic profiles of patients with AD varied significantly after treatment with dupilumab. Differential metabolites and their related metabolic pathways may provide clues for understanding the effects of dupilumab on patient metabolism.

Identification and Experimental Validation of Marker Genes between Diabetes and Alzheimer's Disease.

Currently, Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are widely prevalent in the elderly population, and accumulating evidence implies a strong link between them. For example, patients with T2DM have a higher risk of developing neurocognitive disorders, including AD, but the exact mechanisms are still unclear. This time, by combining bioinformatics analysis and in vivo experimental validation, we attempted to find a common biological link between AD and T2DM. We firstly downloaded the gene expression profiling (AD: GSE122063; T2DM: GSE161355) derived from the temporal cortex. To find the associations, differentially expressed genes (DEGs) of the two datasets were filtered and intersected. Based on them, enrichment analysis was carried out, and the least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms were used to identify the specific genes. After verifying in the external dataset and in the samples from the AD and type 2 diabetes animals, the shared targets of the two diseases were finally determined. Based on them, the ceRNA networks were constructed. Besides, the logistic regression and single-sample gene set enrichment analysis (ssGSEA) were performed. As a result, 62 DEGs were totally identified between AD and T2DM, and the enrichment analysis indicated that they were much related to the function of synaptic vesicle and MAPK signaling pathway. Based on the evidence from external dataset and RT-qPCR, CARTPT, EPHA5, and SERPINA3 were identified as the marker genes in both diseases, and their clinical significance and biological functions were further analyzed. In conclusion, discovering and exploring the marker genes that are dysregulated in both 2 diseases could help us better comprehend the intrinsic relationship between T2DM and AD, which may inspire us to develop new strategies for facing the dilemmas of clinical or basic research in cognitive dysfunction.

TGFß-Associated Signature Predicts Prognosis and Tumor Microenvironment Infiltration Characterization in Gastric Carcinoma.

Background: Gastric carcinoma (GC) is a carcinoma with a high incidence rate, and it is a deadly carcinoma globally. An effective tool, that is, able to predict different survival outcomes for GC patients receiving individualized treatments is deeply needed. Methods: In total, data from 975 GC patients were collected from TCGA-STAD, GSE15459, and GSE84437. Then, we performed a comprehensive unsupervised clustering analysis based on 54 TGFß-pathway-related genes and correlated these patterns with tumor microenvironment (TME) cell-infiltrating characteristics. WGCNA was then applied to find the module that had the closest relation with these patterns. The least absolute shrinkage and selection operator (LASSO) algorithm was combined with cross validation to narrow down variables and random survival forest (RSF) was used to create a risk score. Results: We identified two different TGFß regulation patterns and named them as TGFß Cluster 1 and Cluster 2. TGFß Cluster 1 was linked to significantly poorer survival outcomes and represented an inflamed TME subtype of GC. Using WGCNA, a module (magenta) with the closest association with the TGFß clusters was identified. After narrowing down the gene list by univariate Cox regression analysis, the LASSO algorithm and cross validation, four of the 243 genes in the magenta module were applied to build a risk score. The group with a higher risk score exhibited a considerably poorer survival outcome with high predictive accuracy. The risk score remained an independent risk factor in multivariate Cox analysis. Moreover, we validated this risk score using GSE15459 and GSE84437. Furthermore, we found that the group with a higher risk score represented an inflamed TME according to the evidence that the risk score was remarkably correlated with several steps of cancer immunity cycles and a majority of the infiltrating immune cells. Consistently, the risk score was significantly related to immune checkpoint genes and T cell-inflamed gene expression profiles (GEPs), indicating the value of predicting immunotherapy. Conclusions: We have developed and validated a TGFß-associated signature, that is, capable of predicting the survival outcome as well as depicting the TME immune characteristics of GC. In summary, this signature may contribute to precision medicine for GC.

TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling.

BACKGROUND: Liver fibrosis represent a major global health care burden. Data emerging from recent advances suggest TRPM8, a member of the transient receptor potential (TRP) family of ion channels, plays an essential role in various chronic inflammatory diseases. However, its role in liver fibrosis remains unknown. Herein, we assessed the potential effect of TRPM8 in liver fibrosis. METHODS: The effect of TRPM8 was evaluated using specimens obtained from classic murine models of liver fibrosis, namely wild-type (WT) and TRPM8-/- (KO) fibrotic mice after carbon tetrachloride (CCl4) or bile duct ligation (BDL) treatment. The role of TRPM8 was systematically evaluated using specimens obtained from the aforementioned animal models after various in vivo and in vitro experiments. RESULTS: Clinicopathological analysis showed that TRPM8 expression was upregulated in tissue samples from cirrhosis patients and fibrotic mice. TRPM8 deficiency not only attenuated inflammation and fibrosis progression in mice but also helped to alleviate symptoms of cholangiopathies. Moreover, reduction in S100A9 and increase in HNF4α expressions were observed in liver of CCl4- and BDL- treated TRPM8-/- mice. A strong regulatory linkage between S100A9 and HNF4α was also noticed in L02 cells that underwent siRNA-mediated S100A9 knockdown and S100A9 overexpressing plasmid transfection. Lastly, the alleviative effect of a selective TRPM8 antagonist was confirmed in vivo. CONCLUSIONS: These findings suggest TRPM8 deficiency may exert protective effects against inflammation, cholangiopathies, and fibrosis through S100A9-HNF4α signaling. M8-B might be a promising therapeutic candidate for liver fibrosis.

Circular RNA circ-FoxO3 attenuates blood-brain barrier damage by inducing autophagy during ischemia/reperfusion.

Blood-brain barrier (BBB) damage can be a result of central nervous system (CNS) diseases and may be a cause of CNS deterioration. However, there are still many unknowns regarding effective and targeted therapies for maintaining BBB integrity during ischemia/reperfusion (I/R) injury. In this study, we demonstrate that the circular RNA of FoxO3 (circ-FoxO3) promotes autophagy via mTORC1 inhibition to attenuate BBB collapse under I/R. Upregulation of circ-FoxO3 and autophagic flux were detected in brain microvessel endothelial cells in patients with hemorrhagic transformation and in mice models with middle cerebral artery occlusion/reperfusion. In vivo and in vitro studies indicated that circ-FoxO3 alleviated BBB damage principally by autophagy activation. Mechanistically, we found that circ-FoxO3 inhibited mTORC1 activity mainly by sequestering mTOR and E2F1, thus promoting autophagy to clear cytotoxic aggregates for improving BBB integrity. These results demonstrate that circ-FoxO3 plays a novel role in protecting against BBB damage, and that circ-FoxO3 may be a promising therapeutic target for neurological disorders associated with BBB damage.

Linking Diabetes Mellitus with Alzheimer's Disease: Bioinformatics Analysis for the Potential Pathways and Characteristic Genes.

As the surging epidemics with significant disability, Alzheimer's disease (AD) and type II diabetes mellitus (T2DM) with microvascular complications are widely prevalent, sharing considerable similarities in putative pathomechanism. Despite a spurt of researches on the biology, knowledge about their interactive mechanisms is still rudimentary. Applying bioinformatics ways to explore the differentially co-expressed genes contributes to achieve our objectives to find new therapeutic targets. In this study, we firstly integrated gene expression omnibus datasets (GSE28146 and GSE43950) to identify differentially expressed genes. The enrichment analysis of pivotal genes, like gene ontology and pathway signaling proceeded subsequently. Besides, the related protein-protein interaction (PPI) network was then constructed. To further explain the inner connections, we ended up unearthing the biological significance of valuable targets. As a result, a set of 712, 630, 487, and 997 genes were differentially identified in T2DM with microvascular complications and AD at incipient, moderate, and severe, respectively. The enrichment analysis involving both diseases implicated the dominance of immune system, especially the noteworthy chemokine signaling. Multiple comparisons confirmed that CACNA2D3, NUMB, and IER3 were simultaneously participate in these two conditions, whose respective associations with neurological and endocrine diseases, and regulators including interacting chemicals, transcription factors, and miRNAs were analyzed. Bioinformatics analysis eventually concluded that immune-related biological functions and pathways closely link AD and T2DM with microvascular complications. Further exploration of the regulatory factors about CACNA2D3, NUMB, and IER3 in neuroendocrine field may provide us a promising direction to discover potential strategies for the comorbidity status.

Vitamin K2 protects against Aß42-induced neurotoxicity by activating autophagy and improving mitochondrial function in Drosophila.

OBJECTIVE: Alzheimer disease is characterized by progressive decline in cognitive function due to neurodegeneration induced by accumulation of Aß and hyperphosphorylated tau protein. This study was conducted to explore the protective effect of vitamin K2 against Aß42-induced neurotoxicity. METHODS: Alzheimer disease transgenic Drosophila model used in this study was amyloid beta with the arctic mutation expressed in neurons. Alzheimer disease flies were treated with vitamin K2 for 28 days after eclosion. Aß42 level in brain was detected by ELISA. Autophagy-related genes and NDUFS3, the core subunit of mitochondrial complex I, were examined using real-Time PCR (RT-PCR) and western blot analysis. RESULTS: Vitamin K2 improved climbing ability (P = 0.0105), prolonged lifespan (P < 0.0001) and decreased Aß42 levels (P = 0.0267), upregulated the expression of LC3 and Beclin1(P = 0.0012 and P = 0.0175, respectively), increased the conversion of LC3I to LC3II (P = 0.0206) and decreased p62 level (P =0.0115) in Alzheimer disease flies. In addition, vitamin K2 upregulated the expression of NDUFS3 (P = 0.001) and increased ATP production (P = 0.0033) in Alzheimer disease flies. CONCLUSION: It seems that vitamin K2 protect against Aß42-induced neurotoxicity by activation of autophagy and rescue mitochondrial dysfunction, which suggests that it may be a potential valuable therapeutic approach for Alzheimer disease.

Local IL-17 positive T cells are functionally associated with neutrophil infiltration and their development is regulated by mucosal microenvironment in nasal polyps.

OBJECTIVE AND DESIGN: IL-17 plays essential roles in neutrophilic inflammation in the lower respiratory tract, however, the characteristics of local IL-17+ T cells in nasal inflammatory mucosa are not fully understood. We investigated the roles of IL-17+ T cells in regulating neutrophil infiltration and the effect of the mucosal microenvironment in modulating IL-17+ T cell differentiation in CRSwNP tissues. SUBJECTS: 47 polyp tissues from chronic rhinosinusitis with nasal polyps (CRSwNP) patients without corticosteroid therapy and 26 tissues from healthy mucosa were obtained. METHODS: Immunohistochemistry and flow cytometry were used to analyze the neutrophil infiltration, local IL-17+ T cell subsets, as well as cytokine producing profiles of IL-17+ T cell; tissue homogenates were used to study neutrophil migration and IL-17+ T cell differentiation. RESULTS: Increase of IL-17+ cells and IL-17+ T cell subsets was significant in polyp tissues versus controls, IL-17+ cell number was positively correlated with neutrophil infiltration; while homogenates from polyp tissues with high IL-17 promoted neutrophil migration in vitro. IL-17 response was found in polyp-derived T cells upon Staphylococcus aureus infection. IL-17+ T cells were also down-regulated in polyps from patients treated with glucocorticoid steroids, and exhibited poly-functionality patterns in polyp tissues. Finally, IL-17+ T cell differentiation could be induced by IL-23, and homogenates from polyps could enhance IL-17+ T cell development. CONCLUSIONS: This study determined a functional association of IL-17+ T cells with neutrophils in CRSwNP, and revealed that polyp microenvironment could promote IL-17+ T cell differentiation, suggesting a potential feedback role for IL-17+ T cell development and local neutrophilic inflammation.

Overexpressed PERK suppresses the neurodegenerative phenotypes in PINK1B9 flies by enhancing mitochondrial function.

PTEN-induced putative kinase 1 (PINK1) mutation induces autosomal recessive Parkinson's Disease (PD), mitochondrial dysfunction is the central pathogenic process. However, more and more studies presented the bulk of the damage to neurons with mitochondrial dysfunction stems from the endoplasmic reticulum (ER) stress. In mitochondria damaged PINK1B9 fly model how protein kinase RNA-like ER kinase (PERK) arm of ER stress functions remains a mystery. Thus, we generated both PERK overexpressed (PEK OE) and down expressed (PEK RNAi) PINK1B9 flies and monitored their motor activity. We found PEK OE decreased the abnormal wing posture rate and rescued PINK1B9 flies' motor activity. Furthermore, we observed the increased number of dopaminergic neurons of protocerebral posterior lateral 1 (PPL1) and the tyrosine hydroxylase (TH) protein levels in PINK1B9 flies. When testing the mitochondrial morphology in flight muscle with TEM, we found that the shape of the mitochondria became normal. The ATP levels of flight muscle tissues were significantly elevated in PEK OE PINK1B9 flies with the increased function of mitochondrial Electron Transport Chain (ETC) Complex I (CI) but not Complex Ⅱ (CⅡ) which is further confirmed by oxygen consumption experiments, Western Blot, and RT-PCR to examine the corresponding subunits. We suggest that overexpression of PERK can rescue PINK1B9 PD flies' pathogenic phenotypes and it is linked with the improved mitochondrial function especially CI of ETC but not CⅡ. Our findings may pave a way for the target of the drug for alleviating the suffering of PINK1 mutant autosomal recessive PD patients.

Wnt2 overexpression protects against PINK1 mutant­induced mitochondrial dysfunction and oxidative stress.

The PTEN induced putative kinase 1 (PINK1) mutation is the second most common cause of autosomal recessive adolescent Parkinson's disease (PD). Furthermore, mitochondrial disorders and oxidative stress are important mechanisms in the pathogenesis of PD. Numerous members of the Wnt family have been found to be associated with neurodegenerative diseases. Therefore, the present study investigated the role of the Wnt2 gene in PINK1B9 transgenic flies, which is a PD model, and its underlying mechanism. It was identified that overexpression of Wnt2 reduced the abnormality rate of PD transgenic Drosophila and improved their flight ability, while other intervention groups had no significant effect. Furthermore, an increase in ATP concentration normalized mitochondrial morphology, and increased the mRNA expression levels of NADH­ubiquinone oxidoreductase chain 1 (ND1), ND42, ND75, succinate dehydrogenase complex subunits B, Cytochrome b and Cyclooxygenase 1, which are associated with Wnt2 overexpression. Moreover, overexpression of Wnt2 in PD transgenic Drosophila resulted in the downregulation of reactive oxygen species and malondialdehyde production, and increased manganese superoxide dismutase (MnSOD), while glutathione was not significantly affected. It was found that overexpression of Wnt2 did not alter the protein expression of ß­catenin in PINK1B9 transgenic Drosophila, but did increase the expression levels of PPARG coactivator 1α (PGC­1α) and forkhead box sub­group O (FOXO). Collectively, the present results indicated that the Wnt2 gene may have a protective effect on PD PINK1B9 transgenic Drosophila. Thus, it was speculated that the reduction of oxidative stress and the restoration of mitochondrial function via Wnt2 overexpression may be related to the PGC­1α/FOXO/MnSOD signaling pathway in PINK1 mutant transgenic Drosophila.

Withaferin A alleviates traumatic brain injury induced secondary brain injury via suppressing apoptosis in endothelia cells and modulating activation in the microglia.

Traumatic brain injury (TBI) is a major public health concern with high rates of morbidity and mortality worldwide. Currently used medications, though effective, are also associated with several adverse effects. Development of effective neuroprotective agents with fewer side-effects would be of clinical value. Previous studies have shown that withaferin compounds have a potential neuroprotective effect in nervous system disorders. However, the effect of withaferin compounds, especially withaferin A (WFA), on traumatic brain injury is unclear. In the present study, both in vivo and in vitro models were used to assess whether WFA could exert a neuroprotective effect after TBI and were used to explore the associated mechanisms. The results showed that WFA significantly improved neurobehavioral function in a dose-dependent fashion and alleviated histological alteration of injury to tissues in TBI mice. In vitro models of TBI revealed that dose-dependent WFA treatment increased the viability of SH-SY5Y cells. In addition, WFA treatment could attenuate blood-brain barrier disruption and brain edema via suppressing apoptosis in endothelial cells. Furthermore, both our in vivo and in vitro results reveal that WFA treatment could significantly reduce levels of several neuroinflammation cytokines (IL-1ß, IL-6, and TNF-α), which correlate with an overall reduction in microglial activation. These data suggest that the neuroprotection by WFA is, at least in part, related to regulation of microglial activation and inhibition of vascular endothelial cell apoptosis. Taken together, these findings support further investigation of WFA as a promising therapeutic agent for promoting functional recovery after traumatic brain injury.