Despite the efficacy of highly active antiretroviral therapy in controlling the incidence and mortality of AIDS, effective interventions for HIV-1-induced neurological damage and cognitive impairment remain elusive. In this study, we found that HIV-1 infection can induce proteolytic cleavage and aberrant aggregation of TAR DNA-binding protein 43 (TDP-43), a pathological protein associated with various severe neurological disorders. The HIV-1 accessory protein Vpu was found to be responsible for the cleavage of TDP-43, as ectopic expression of Vpu alone was sufficient to induce TDP-43 cleavage, whereas HIV-1 lacking Vpu failed to cleave TDP-43. Mechanistically, the cleavage of TDP-43 at Asp89 by HIV-1 relies on Vpu-mediated activation of Caspase 3, and pharmacological inhibition of Caspase 3 activity effectively suppressed the HIV-1-induced aggregation and neurotoxicity of TDP-43. Overall, these results suggest that TDP-43 is a conserved host target of HIV-1 Vpu and provide evidence for the involvement of TDP-43 dysregulation in the neural pathogenesis of HIV-1.

BACKGROUND:Currently, validated biomarkers for assessing hemorrhagic transformation (HT) after intravenous thrombolysis (IVT) are lacking. We aimed to validate a test combining GFAP (glial fibrillary acidic protein) and UCH-L1 (ubiquitin C-terminal hydrolase-L1) to indicate the absence of HT after IVT. METHODS:We prospectively enrolled consecutive patients with stroke treated with IVT from 16 hospitals. Serum GFAP and UCH-L1 levels were measured 24 hours after IVT. Cases from 1 hospital were randomly assigned to the training (70%) and testing (30%) cohorts for internal validation. The external validation cohort included patients from the other 15 hospitals. Cutoff levels of GFAP and UCH-L1 for assessing the absence of HT were established in the training cohort and subjected to internal and external verification. RESULTS:A total of 1063 patients were included. Both GFAP and UCH-L1 levels were independently associated with HT, infarct volume, and 3-month outcome; levels lower than cutoff (12.6 and 63.1 pg/mL, respectively) excluded patients with HT with a negative predictive value of 98.31% (95% CI, 89.70%-99.91%) and detection sensitivity of 98.08% (95% CI, 88.42%-99.90%) in the training cohort. In the testing and validation cohorts, negative predictive value was 100% (95% CI, 75.93%-100%) and 100% (95% CI, 82.19%-100%), respectively, and the sensitivity was 100% (95% CI, 80.76%-100%) and 100% (95% CI, 77.08%-100%), respectively. CONCLUSIONS:Serum GFAP and UCH-L1 levels exhibit high sensitivity and negative predictive value for indicating the absence of HT 24 hours after IVT, which supports their potential role in assessing patients' condition after IVT.

Abstract Background S100β is a biomarker of astroglial damage, the level of which is significantly increased following brain injury. However, the characteristics of S100β and its association with prognosis in patients with acute ischemic stroke following intravenous thrombolysis (IVT) remain unclear. Methods Patients in this multicenter prospective cohort study were prospectively and consecutively recruited from 16 centers. Serum S100β levels were measured 24 h after IVT. National Institutes of Health Stroke Scale (NIHSS) and hemorrhagic transformation (HT) were measured simultaneously. NIHSS at 7 days after stroke, final infarct volume, and modified Rankin Scale (mRS) scores at 90 days were also collected. An mRS score ≥ 2 at 90 days was defined as an unfavorable outcome. Results A total of 1072 patients were included in the analysis. The highest S100β levels (> 0.20 ng/mL) correlated independently with HT and higher NIHSS at 24 h, higher NIHSS at 7 days, larger final infarct volume, and unfavorable outcome at 3 months. The patients were divided into two groups based on dominant and non-dominant stroke hemispheres. The highest S100β level was similarly associated with the infarct volume in patients with stroke in either hemisphere (dominant: β 36.853, 95% confidence interval (CI) 22.659–51.048, P < 0.001; non-dominant: β 23.645, 95% CI 10.774–36.516, P = 0.007). However, serum S100β levels at 24 h were more strongly associated with NIHSS scores at 24 h and 3-month unfavorable outcome in patients with dominant hemisphere stroke (NIHSS: β 3.470, 95% CI 2.392–4.548, P < 0.001; 3-month outcome: odds ratio (OR) 5.436, 95% CI 2.936–10.064, P < 0.001) than in those with non-dominant hemisphere stroke (NIHSS: β 0.326, 95% CI − 0.735–1.387, P = 0.547; 3-month outcome: OR 0.882, 95% CI 0.538–1.445, P = 0.619). The association of S100β levels and HT was not significant in either stroke lateralization group. Conclusions Serum S100β levels 24 h after IVT were independently associated with HT, infarct volume, and prognosis in patients with IVT, which suggests the application value of serum S100β in judging the degree of disease and predicting prognosis.

Abstract Stress induced by glucocorticoids (GC), such as dexamethasone (DEX), has the potential to detrimentally impact the structure and function of the hippocampus and is closely associated with the development and progression of Alzheimer’s disease (AD). However, it remains uncertain whether LEV and TPM can effectively alleviate neuropathological and cognitive deficits in patients with DEX-induced AD by preserving or restoring neuronal network activities. This study aimed to investigate the mechanisms underlying the effect of DEX on AD development and progression and identify the role of NRP1 inflammasome in APP23/MAPTP301S mice. APP23/MAPTP301S mice were treated with DEX in the absence and presence of levetiracetam (LEV). After treatment, the mice were subjected to various cognitive and behavioral tests. DEX accelerated neuronal impairment by promoting the accumulation of β-amyloid protein and phosphorylation of tau in senile plaques and neurofibrillary tangles in APP23/MAPTP301S mice. Moreover, DEX significantly upregulated BACE1 and promoted the phosphorylation of cyclin-dependent kinase-5 and glycogen synthase kinase 3α/β, resulting in synaptic dystrophy and apoptosis. NLRP3 siRNA transfection showed that NLRP1 inflammasome activation is pivotal to the observed DEX effects. To counteract the adverse effects of DEX, LEV was administered to APP23/MAPTP301S mice, and it ameliorated DEX-induced AD via NLRP1-dependent mechanisms. This study underscores the detrimental impact of chronic glucocorticoid exposure on AD pathogenesis and the potential therapeutic benefits of compounds such as LEV in counteracting these effects by regulating neuroinflammation and key pathological markers.

Neuromyelitis optica spectrum disorders (NMOSD) are severe inflammatory disorders of the central nervous system targeting aquaporin‐4 (AQP4). The risk factors for NMOSD remain to be determined, though they may be related to diet and nutrition. This study aimed to explore the possibility of a causal relationship between specific food intake and AQP4-positive NMOSD risk. The study followed a two-sample Mendelian randomization (MR) design. Genetic instruments and self-reported information on the intake of 29 types of food were obtained from a genome-wide association study (GWAS) on 445,779 UK Biobank participants. A total of 132 individuals with AQP4-positive NMOSD and 784 controls from this GWAS were included in our study. The associations were evaluated using inverse-variance-weighted meta-analysis, weighted-median analysis, and MR-Egger regression. A high consumption of oily fish and raw vegetables was associated with a decreased risk of AQP4-positive NMOSD (odds ratio [OR] = 1.78 × 10 −16 , 95% confidence interval [CI] = 2.60 × 10 −25 –1.22 × 10 −7 , p = 0.001; OR = 5.28 × 10 −6 , 95% CI = 4.67 × 10 −11 –0.598, p = 0.041, respectively). The results were consistent in the sensitivity analyses, and no evidence of directional pleiotropy was observed. Our study provides useful implications for the development of AQP4-positive NMOSD prevention strategies. Further research is needed to determine the exact causal relationship and mechanisms underlying the association between specific food intake and AQP4-positive NMOSD.

Background: Previous studies have shown the potential role of vitamin K supplementation in the prevention and treatment of many diseases. However, the effect of vitamin K supplementation on blood glucose remains controversial. The purpose of this study was to assess the effects of vitamin K supplementation on glycemia-related indicators, including Fasting Blood Sugar (FBS), Fasting Insulin (FINS) and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). The potential association between vitamin K and type 2 diabetes mellitus (T2DM) risk was also evaluated. Methods: Up to April 2023, Cochrane, PubMed, Web of Science, Medline and EMBASE databases were searched to assess the effects of vitamin K on blood glucose and the risk of developing T2DM. Results: A meta-analysis of seven studies (813 participants) found vitamin K supplementation significantly reduced FBS (SMD = -0.150 mg dl-1, 95% CI = -0.290, -0.010 mg dl-1) and HOMA-IR (SMD = -0.200, 95% CI = -0.330, -0.060), but not FINS. Five studies with a total of 105 798 participants were included in the meta-analysis of the association between vitamin K and T2DM. The results showed that vitamin K was associated with the reduced risk of developing T2DM (HR = 0.79, 95% CI [0.71-0.88], P < 0.001). Conclusion: The meta-analysis demonstrated that vitamin K supplementation had a significant effect on the regulation of FBS and HOMA-IR in the population. Moreover, vitamin K was associated with the reduced risk of developing T2DM. Considering some limitations found in this study, additional data from large clinical trials are needed.

Dear Editor, Neurologic manifestations associated with many COVID-19 patients,including acute infection with severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)and long COVID,have been proven by increasing evidence.1 To date,most studies have focused on how SARS-CoV-2 invades the nervous system and the consequent neuropathological changes.2,3 In contrast,the specific mechanism by which SARS-CoV-2 infection leads to neurological disease remains unclear.

Biopsy is recommended for patients with primary intracranial lymphoma to confirm the diagnosis, but the effect of tumor resection is still controversial. We conducted this retrospective study to better understand the epidemiology of primary intracranial lymphoma in the USA and explore the relationship between surgical resection and prognosis. Data regarding primary intracranial lymphoma, including incidence, were extracted from the SEER database. We analyzed the difference in incidence between different groups of people. We explored the effect of surgery on the survival of patients by the Kaplan–Meier method and evaluated the possible prognostic indicators by multivariate Cox proportional hazards models. The incidence significantly increased with age. The non-Hispanic Asian or Pacific Islander population exhibited the highest incidence, and the incidence was significantly higher in males than females. A total of 6428 cases were included in the cohort study, and most of the patients were diagnosed in the sixth to seventh decade of life. Sixty percent of tumors were supratentorial tumors. Surgery, especially total resection, significantly improved overall survival and cancer-specific survival. The survival of female patients, patients diagnosed before reaching 60 years of age, patients diagnosed after 2010, and patients with supratentorial lymphomas was better than that of their counterparts. The survival of patients with diffuse large B-cell lymphoma was worse than that of their counterparts. We conducted a comprehensive retrospective analysis of patients with primary intracranial lymphoma. We analyzed the difference in incidence between different groups of people. Surgery significantly improved overall and cancer-specific survival. The results of our research can help clinicians and patients better understand the epidemiology and management of primary intracranial lymphoma.

Ischemic stroke, caused by a lack of blood supply in brain tissues, is the third leading cause of human death and disability worldwide, and usually results in sensory and motor dysfunction, cognitive impairment, and in severe cases, even death. Autophagy is a highly conserved lysosome-dependent process in which eukaryotic cells removal misfolded proteins and damaged organelles in cytoplasm, which is critical for energy metabolism, organelle renewal, and maintenance of intracellular homeostasis. Increasing evidence suggests that autophagy plays important roles in pathophysiological mechanisms under ischemic conditions. However, there are still controversies about whether autophagy plays a neuroprotective or damaging role after ischemia. G-protein-coupled receptors (GPCRs), one of the largest protein receptor superfamilies in mammals, play crucial roles in various physiological and pathological processes. Statistics show that GPCRs are the targets of about one-fifth of drugs known in the world, predicting potential values as targets for drug research. Studies have demonstrated that nutritional deprivation can directly or indirectly activate GPCRs, mediating a series of downstream biological processes, including autophagy. It can be concluded that there are interactions between autophagy and GPCRs signaling pathway, which provides research evidence for regulating GPCRs-mediated autophagy. This review aims to systematically discuss the underlying mechanism and dual roles of autophagy in cerebral ischemia, and describe the GPCRs-mediated autophagy, hoping to probe promising therapeutic targets for ischemic stroke through in-depth exploration of the GPCRs-mediated autophagy signaling pathway.

Background:Patients with Alzheimer's disease (AD) have a significantly higher risk of seizures than other individuals in an age-matched population, suggesting a close association between epilepsy and AD. We aimed to examine the effects of levetiracetam (LEV)-a drug for treating seizures-on learning and memory and the neuropathological features of AD.Methods:We crossbred APP23 mice with microtubule-associated protein tau (MAPT) transgenic mice to generate APP23/MAPT mice. These mice were treated with different concentrations of LEV in the presence of kainic acid (KA) for 3 months.Results:Low doses of LEV alleviated the effects of KA on memory defects in APP23/MAPT mice. Mechanistic investigations showed that low concentrations of LEV decreased tau phosphorylation by reducing the activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3α/β, thus rescuing neurons from synaptic dystrophy and apoptosis. Low doses of LEV inhibited the effects of KA (i.e., inducing neuroinflammation and impairing the autophagy of amyloid β-peptide), thus improving cognitive decline. High concentrations of LEV decreased the production and deposition of amyloid β-peptide (Aβ) by reducing the expression of β-site APP-cleaving enzyme 1 and presenilin 1. However, high concentrations of LEV also induced neuronal apoptosis, decreased movement ability in mice, and did not alleviate cognitive decline in AD mice.Conclusion:Our results support the hypothesis that aberrant network activity contributes to the synaptic and cognitive deficits in APP23/MAPT mice. A low concentration of LEV may help ameliorate abnormalities of AD; however, a high LEV concentration did not induce similar results.

Objective cognitive dysfunction has been commonly found in patients with insomnia, such as attention, memory, speed of information processing, and executive functions. Auditory steady-state responses (ASSRs), P50, mismatch negativity (MMN) can meet varied need and estimate such different cognitive dysfunction. Thus, we can examine whether insomnia is associated with different cognitive dysfunction by such multiple event-related potential (ERP) tasks. Methods we used polysomnography (PSG) to record such objective PSG parameters. ASSR, P50, and MMN were performed in sequence, different ERP components have been analyzed such as latency or amplitude between insomnia group and control group. And we chosed person correlation to make correlation analysis between different ERP components and gender, education, and sleep characteristics. Results there is a significant gender difference of ASSR latency found in insomnia group, and the similar result has been found in suppression ratio of amplitudes (S2:S1) for P50. Additionally, a significant correlation between sleep characteristics and ASSR, P50 has been found. Furthermore, there was a significant difference of MMN latency between insomnia and control group, and between sleep characteristics and varied MMN parameters as latency and amplitude. Discussion our results suggested robust electrophysiological abnormalities as ASSR, P50, and MMN in insomnia patients. Such abnormalities included gender difference, education difference, difference in depressive tendency, and difference in sleep parameters. That results revealed varied cognitive dysfunction involving inputs and processing in insomnia patients. And at the same time, we have also explored the neuropsychological mechanisms underlying the cognitive dysfunction with such different ERP tasks.

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases and accumulating evidences suggest a key role of amyloid-β (Aβ) peptide in the pathogenesis of AD. According to the amyloid cascade hypothesis, the imbalance of producing and clearing Aβ is the beginning of neurodegeneration and dementia. Consequently, immunotherapy becomes popular through using antibodies against Aβ. However, many studies of monoclonal antibodies were stopped because adverse effects appeared or there were no evident benefits observed. Some antibody fragments have many advantages over monoclonal antibodies, such as small sizes, lack of the crystallizable fraction (Fc) and so on. There are three main antibody fragments, including single chain variable fragments (scFvs), Fab fragments and single-domain antibody fragments. Nanoparticles can facilitate the entry of drug molecules across the blood-brain barrier, making them become excellent carriers. Various kinds of nanoparticles have been applied in the treatment of AD. The combination of nanoparticles and antibody fragments against amyloid-β can be used in the diagnosis and treatment of Alzheimer’s disease. In this review, we summarize the progress of antibody fragments against amyloid-β in AD, focusing on the combined application with nanoparticles in the diagnosis and treatment of AD.

BACKGROUND:Non-convulsive status epileptics (NCSE) is a common neurological emergency necessitating rapid assessment and management, but is often underdiagnosed as it lacks specific electroencephalographic features. The diagnostic value of periodic lateralized epileptiform discharges (PLEDs) in NCSE is still unclear. Herein, we reported a case with NCSE manifesting as PLEDs and coma.CASE REPORT:A 62-year-old man presented with epileptic seizures. Based on clinical and radiological profiles, he was diagnosed with frontal hemorrhage, coma, and NCSE. An electroencephalogram (EEG) revealed PLEDs. A combined antiepileptic regimen was initiated and, over a follow-up period of 2 months, a favorable outcome was achieved.CONCLUSION:EEG may help identify potential NCSE in comatose patients, and PLEDs can be an atypical manifestation of NCSE, which can be effectively treated with antiepileptic drugs. The emphasis in NCSE is on early identification and individualized therapeutic regimens.

Diabetic cardiomyopathy (DCM) is a serious diabetic complication that lacks effective preventive or therapeutic approaches. Wild-type and Klf15 knockout (Klf15-KO) mice were fed with either high fat diet (HFD, 60% kcal from fat) or normal diet (ND, 10% kcal from fat) for 3 months and then injected with streptozotocin or vehicle, to induce type 2 diabetes (T2D). All T2D and age-matched control mice were treated with or without SDF-1β at 5 mg/kg body-weight twice a week and also continually received HFD or ND for 3 months. At the end of 6-month study, after cardiac functions were measured, mice were euthanized to collect heart tissue. For in vitro mechanistic study, H9c2 cells were exposed to palmitate to mimic in vivo condition of T2D. SDF-1β prevented T2D-induced cardiac dysfunction and fibrosis and T2D-down-regulated KLF15 expression in wild-type diabetic heart tissue. However, the preventive effects of SDF-1β on both KLF15 expression and fibrosis was abolished, with partial cardiac protection in Klf15-KO/T2D mice. These results demonstrate partial KLF15-dependence for SDF-1β's cardiac fibrotic protection from T2D, but not on SDF-1β's protective effects on T2D-induced cardiac dysfunction. Further study showed that SDF-1β inhibited palmitate-induced cardiomyocyte fibrosis through its receptor CXCR7-mediated activation of p38β MAPK signaling pathway.

Axonal variants of Guillain–Barré syndrome (GBS) mainly include acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, and pharyngeal-cervical-brachial weakness. Molecular mimicry of human gangliosides by a pathogen's lipooligosaccharides is a well-established mechanism for Campylobacter jejuni -associated GBS. New triggers of the axonal variants of GBS (axonal GBS), such as Zika virus, hepatitis viruses, intravenous administration of ganglioside, vaccination, and surgery, are being identified. However, the pathogenetic mechanisms of axonal GBS related to antecedent bacterial or viral infections other than Campylobacter jejuni remain unknown. Currently, autoantibody classification and serial electrophysiology are cardinal approaches to differentiate axonal GBS from the prototype of GBS, acute inflammatory demyelinating polyneuropathy. Newly developed technologies, including metabolite analysis, peripheral nerve ultrasound, and feature selection via artificial intelligence are facilitating more accurate diagnosis of axonal GBS. Nevertheless, some key issues, such as genetic susceptibilities, remain unanswered and moreover, current therapies bear limitations. Although several therapies have shown considerable benefits to experimental animals, randomized controlled trials are still needed to validate their efficacy.

Abstract Background: Diabetic cardiomyopathy (DCM) is a common complication in diabetic patients. Cardiac fibrosis is the major pathologic changes, for which the effective and safe approaches remain not available. Methods: Wild-type mice and conditional knockout of cardiac specific Klf15 gene (Klf15-cKO) mice were fed with either high fat diet (HFD, 60% kcal from fat) or normal diet (ND, 10% kcal from fat) for 3 months and then injected with streptozotocin or vehicle. Five days later mice with hyperglycemia (3 h fasting blood glucose level ≥ 250 mg/dL) were defined as type 2 diabetes (T2D). All T2D and age-matched control mice that were continually received their HFD or ND for 6 months were treated with or without SDF-1β at 5 mg/kg body-weight twice a week for 3 months. At the end of 9-month study, after cardiac functions measured, mice were euthanized, for collecting heart tissue. For the in vitro study, H9C2 cells were exposed to palmitate to mimic in vivo condition of T2D.Results: SDF-1β treatment attenuated T2D-induced cardiac dysfunction and fibrosis and down-regulated KLF15 expression in wild type diabetic mice. The inhibitory effect of SDF-1β on cardiac fibrosis was abolished in Klf15-cKO/T2D mice, demonstrating the KLF15-dependence for this protection. Pre-treatment of H9C2 cells with the relevant siRNAs, followed by treatment with palmitate or SDF-1b or palmitate/SDF-1b demonstrated that SDF-1β inhibited palmitate-induced myocardial fibrosis through its receptor CXCR7 mediated activation of p38β MAPK and subsequent blockade of KLF15 down-regulation. Conclusions: T2D-promoted cardiac fibrosis and dysfunction were prevented with SDF-1β treatment by up-regulating KLF15 expression. Conditional knockout of cardiac specific Klf15 gene abolishes SDF-1β prevention of cardiac fibrosis but not cardiac dysfunction. The SDF-1β’s anti-fibrosis effect in the heart of T2D is probably mediated through CXCR7-mediated p38β MAPK activation of KLF15 function.

The aim of this study is to examine the antidepressant-like effect of EGCG and get deeper insights into implications of modulating serotonin (5-HT) in the colon and brain. A total of 24 stochastically-selected rats were subdivided into three groups: one group served as the control group, and other two groups were subjected to chronic unpredictable mild stress interventions (CUMS group and CUMS + EGCG group respectively). Before conducting a designed set of behavior tests, all rats were weighed and then forced swimming test (FST) and open field test (OPT) were performed in all rats for the measurement and analysis of central and colonic serotonin levels. In order to determine the extent of CUMS-induced injuries and examine neurological deficits, the method of Nissl staining was implemented accordingly. Meanwhile, haematoxylin-eosin (H&E) staining was employed to detect the structure of the colon. The study found that, due to the involvement of CUMS, the body weight of experimental rats declined, their time of immobility in FST was greater, and the avoidance of central sections in OPT was also greater and more obvious. However, through intervention of the EGCG treatment, either weight loss or depression-related behavior induced by the involvement of CUMS was alleviated in the experimental rats. Comparison of both CUMS and CUMS + EGCG groups indicated that EGCG administration may decrease the level of serotonin (5-HT) in the colon but increase the level of serotonin (5-HT) in the hippocampus. However, it should be noted that the level of 5-HT in peripheral blood did not show any significant difference between both groups. Furthermore, CUMS caused the morphological changes of the hippocampus and structural changes of the colon were noteworthy. Summarily, the investigation results of this experimental study indicated that the intervention of EGCG treatment might have considerable implications in several aspects such as anti-depression, regulation of 5-HT concentration, enhancement of intestinal hyper-permeability, and neuroprotection in the hippocampus.

The excitotoxicity induced by kainic acid (KA) is thought to contribute to the development of Alzheimer's disease (AD); however, the mechanisms underlying this excitotoxicity remain unknown. In the current study, we investigated the dynamic changes in tau phosphorylation and their associations with the excitotoxicity induced by intraperitoneal injection of KA in the mouse brain. We found that KA-induced excitotoxicity led to sustained hyperphosphorylation of tau in MAPT transgenic (Tg) mice. By using cultured microglia and mouse brains, we showed that KA treatment specifically induced endoplasmic reticulum (ER) stress, which was characterized by activation of the major biomarkers of ER, such as ATF6, GRP78, and IRE1, and resulted in stimulation of inflammasomes. KA receptors (KARs), such as Girk1, were determined to be involved in this KA-induced ER stress. ER stress was also shown to activate inflammasomes by stimulating the expression of the two major components of inflammasomes, nucleotide binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3) and nuclear factor (NF)-κB, and eventually causing the production of interleukin-1β (IL-1β). Inhibition of NLRP3 or NF-κB by Bay11-7082 resulted in reduction of KA-induced IL-1β production. Our results also revealed the positive effects of IL-1β on tau phosphorylation, which was blocked by Bay11-7082. Notably, the results indicate that Bay11-7082 acts against KA-induced neuronal degeneration, tau phosphorylation, and memory defects via inflammasomes, which further highlight the protective role of Bay11-7082 in KA-induced neuronal defects.

Hypoxia inducible factors (HIFs) mediate angiogenesis via up-regulation of various pro-angiogenic factors (particularly VEGF) in response to hypoxia. Here, we report that hypoxia unexpectedly induced robust production of the pro-inflammatory factor TNFα by endothelial cells (ECs), suggesting an autocrine loop that in turn activated HIFs via an NF-κB-dependent process, resulting in production of VEGF and thereby promotion of angiogenesis. In contrast, low-density lipoprotein (LDL) prevented expression of HIFs in ECs exposed to either hypoxia or TNFα, while knockdown of either HIF-1α or HIF-2α strikingly attenuated hypoxia-induced production of VEGF by ECs as well as EC colony formation and tube formation. Significantly, LDL attenuated hypoxia-induced angiogenesis by disrupting the TNFα/NF-κB/HIF/VEGF signaling cascade via down-regulation of the TNF receptor TNF-R1, rather than TNFα itself, and multiple key components of both canonical and non-canonical NF-κB pathways. By doing so, LDL was able to either inhibit or down-regulate a wide spectrum of HIF-dependent pro-angiogenic downstream targets and signals. Together, these findings argue existence of a self-regulatory TNFα/NF-κB/HIF/VEGF signaling network in ECs, which mediates and fine-tones angiogenesis, at least in response to hypoxia. They also suggest that LDL impairs angiogenesis by disrupting this network, which might represent a novel mechanism underlying anti-angiogenic property of LDL.

The diagnosis of autoimmune epilepsy is often challenging, and may be misdiagnosed as epileptic disorders or viral encephalitis. Autoimmune epilepsy has a strong association with other autoimmune diseases, especially systemic lupus erythematosus (SLE). In addition, autoimmune epilepsy was reported to present with complex partial seizure (CPS), simple partial seizure (SPS), and secondarily generalized tonic-clonic seizure (sGTCS). In our case, we present a different seizure type of tonic seizure in autoimmune epilepsy caused by SLE, which has not been reported, and it will provide with a new understanding of autoimmune epilepsy. A 17-year-old Chinese girl was diagnosed as having SLE for 1 month but with no epilepsy history. After this admission, she presented with different seizure types. Then EEG, magnetic resonance imaging, and lumbar puncture were performed. We have found generalized tonic seizure and excluded CNS infection and lupus encephalopathy. After antiepileptic therapy, no improvement has been found in seizure control. According to the previous history, clinical manifestation, and relevant examinations, we have made a clinical diagnosis of autoimmune epilepsy (tonic seizure) and SLE has been confirmed again by the immunological test. After the hormonotherapy, anti-inflammatory, and anti-tuberculosis therapy, the tonic seizure decreased significantly, and patient's consciousness improved. Autoimmune epilepsy should call the attentions of the clinicians, especially when the patient presented with SLE. Tonic seizure has not been described in autoimmune epilepsy before, which was different from other seizures reported, such as SPS, CPS, and sGTCS, and may bring a new insight into the autoimmune epilepsy.