FGF21 attenuates neuroinflammation following subarachnoid hemorrhage through promoting mitophagy and inhibiting the cGAS-STING pathway.

BACKGROUND: Subarachnoid hemorrhage (SAH) represents a form of cerebrovascular event characterized by a notable mortality and morbidity rate. Fibroblast growth factor 21 (FGF21), a versatile hormone predominantly synthesized by the hepatic tissue, has emerged as a promising neuroprotective agent. Nevertheless, the precise impacts and underlying mechanisms of FGF21 in the context of SAH remain enigmatic. METHODS: To elucidate the role of FGF21 in inhibiting the microglial cGAS-STING pathway and providing protection against SAH-induced cerebral injury, a series of cellular and molecular techniques, including western blot analysis, real-time polymerase chain reaction, immunohistochemistry, RNA sequencing, and behavioral assays, were employed. RESULTS: Administration of recombinant fibroblast growth factor 21 (rFGF21) effectively mitigated neural apoptosis, improved cerebral edema, and attenuated neurological impairments post-SAH. Transcriptomic analysis revealed that SAH triggered the upregulation of numerous genes linked to innate immunity, particularly those involved in the type I interferon (IFN-I) pathway and microglial function, which were notably suppressed upon adjunctive rFGF21 treatment. Mechanistically, rFGF21 intervention facilitated mitophagy in an AMP-activated protein kinase (AMPK)-dependent manner, thereby preventing mitochondrial DNA (mtDNA) release into the cytoplasm and dampening the activation of the DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Conditional knockout of STING in microglia markedly ameliorated the inflammatory response and mitigated secondary brain injuries post-SAH. CONCLUSION: Our results present the initial evidence that FGF21 confers a protective effect against neuroinflammation-associated brain damage subsequent to SAH. Mechanistically, we have elucidated a novel pathway by which FGF21 exerts this neuroprotection through inhibition of the cGAS-STING signaling cascade.

Anti-GABAB receptor encephalitis in a patient with gastric adenocarcinoma.

Anti-γ-aminobutyric acid-B (GABAB) receptor encephalitis is an autoimmune encephalitis associated with antibodies against neuronal cell surface antigens, which are primarily observed with small-cell lung cancer, melanoma, and thymoma. Here, we first report a case on the association between a relatively frequent cancer, gastric adenocarcinoma (GAC), and a rare GABAB receptor antibody limbic encephalitis. The patient was treated with immunotherapy and combined-drug chemotherapy, which were partially effective in terms of stabilizing the tumor and relieving neurological symptoms. This report indicates that, when patients present with GABAB receptor antibody limbic encephalitis, regular and broad screening for tumors including gastric adenocarcinoma should also be considered.

Down-regulation of Homer1b/c protects against chemically induced seizures through inhibition of mTOR signaling.

BACKGROUND: Homer is a family of post synaptic density proteins functionally and physically attached to target proteins at proline-rich sequences. Reducing Homer1b/c expression has been shown in previous studies to be protective against excitotoxic insults, implicating Homer1b/c in the physiological regulation of aberrant neuronal excitability. METHODS: To test the efficacy of a Homer1b/c reducing therapy for disorders with a detrimental hyperexcitability profile in mice, we used small interfere RNA (siRNA) to decrease endogenous Homer1b/c expression in mouse hippocampus. The baseline motor and cognitive behavior was measured by sensorimotor tests, Morris water maze and elevated plus maze tasks. The anti-epileptic effects of Homer1b/c knockdown were determined in two chemically induced seizure models induced by Picrotoxin (PTX) or pentylenetetrazole (PTZ) administration. RESULTS: The results of sensorimotor tests, Morris water maze and elevated plus maze tasks showed that Homer1b/c reduction had no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced Homerb/c protein had less severe seizures than control mice. Total Homer1b/c protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of Homer1b/c. In addition, the phosphorylation of mammalian target of rapamycin (mTOR) and its target protein S6 was significantly inhibited in Homer1b/c down-regulated mice. Homer1b/c knockdown-induced inhibition of mTOR pathway was partially ablated by the metabotropic glutamate receptor 5 (mGluR5) agonist CHPG. CONCLUSION: Our results demonstrate that endogenous Homer1b/c is integral for regulating neuronal hyperexcitability in adult animals and suggest that reduction of Homer1b/c could protect against chemically induced seizures through inhibition mTOR pathway.

Prospective, open, multicentre Phase I/II trial to assess safety and efficacy of neoadjuvant radiochemotherapy with docetaxel and cisplatin for esophageal carcinoma.

OBJECTIVE: Esophageal squamous cell carcinoma is increasingly treated with trimodality therapy. The objective of this Phase I/II clinical study is to assess the efficacy and safety of neoadjuvant radiochemotherapy with docetaxel and cisplatin and radiotherapy in patients with esophagectomy for locally advanced squamous cell carcinoma of the esophagus with neoadjuvant chemoradiotherapy. METHODS: Patients with esophageal squamous cell carcinoma received radiochemotherapy (50 Gy/25 fractions during Weeks 1-5) using a three-dimensional conformal radiation therapy or intensity-modulated radiation therapy technique together with weekly docetaxel (20 mg/m(2) at dose levels 1 and 2, 25 mg/m(2) at dose level 3 on Weeks 1-5) and cisplatin (30 mg/m(2) at dose level 1, 40 mg/m(2) at dose levels 2 and 3 on Weeks 1-5) from January 2009 to December 2011. The dose-limiting toxicities and maximum tolerated dose were the primary endpoints and overall response rate and progression-free survival were the secondary endpoints. RESULTS: Over this timeframe, a total of 49 patients completed trimodality therapy. Thirteen patients were treated at dose level 1, 21 patients at dose level 2 and 15 patients at dose level 3.The maximum tolerated dose for docetaxel was 20 mg/m(2) and cisplatin 40 mg/m(2). The complete response or partial response was observed in 26.5% (13/49) of patients. Thirty-four patients (69.4%) were treated with neoadjuvant radiochemotherapy followed by surgical resection. The median progression-free survival and median overall survival for all patients (n = 49) were 8 and 17.2 months, respectively. The median overall survival was 27.5 months for patients treated at dose level 2. CONCLUSION: Neoadjuvant radiochemotherapy with docetaxel 20 mg/m(2) and cisplatin 40 mg/m(2) was effective and tolerable induction regimen in patients with esophageal tumors.

Anti-inflammatory and antiapoptotic effects of mesenchymal stem cells transplantation in rat brain with cerebral ischemia.

BACKGROUND: Excessive inflammation and apoptosis contribute to the pathogenesis of ischemic brain damage. Nuclear factor-kappa B (NF-κB) is considered to be a key protein complex involved in this cascade of events. The aim of the present study was to clarify the protection mechanism of the mesenchymal stem cells (MSCs). METHODS: Lewis rats (N = 90) were randomly assigned to three groups: (1) the sham-operated group; (2) the saline group, in which the animals underwent rat transient middle cerebral artery occlusion (tMCAO, for 2 hours) and were treated with saline through the tail vein; and (3) the MSCs group, in which the animals underwent tMCAO (for 2 hours) and were infused with cultured human MSCs (4 × 10(6)/0.4 ml PBS) through the tail vein. At days 1 and 3 post-MSCs infusion, real-time PCR, and Western blot, immunohistochemical analyses were applied for tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and P-IKKß, p53, and B-cell lymphoma 2 (Bcl-2) expression levels. RESULTS: TNF-α, IL-1ß messenger RNA (mRNA) and P-IκB-α, P-IKKß, p53 protein expression levels were significantly increased in the saline group compared with the sham group. However, IκB-α and Bcl-2 protein expression levels were markedly decreased in the saline group. After injection of BrdU(+) MSCs, the expression levels of TNF-α, IL-1ß mRNA and P-IκB-α, P-IKKß, p53 protein were significantly decreased. Contrary to these findings, IκB-α, Bcl-2 protein expression levels were markedly increased. In addition, we found that infarct area was significantly reduced in MSCs group. CONCLUSIONS: These results suggest that MSCs' neuroprotection is attributable to its anti-inflammatory and antiapoptotic effect through inhibition of NF-κB.

Dynamin-related protein 1 inhibitors protect against ischemic toxicity through attenuating mitochondrial Ca2+ uptake from endoplasmic reticulum store in PC12 cells.

Intracellular calcium homeostasis disorder and mitochondrial dysfunction are involved in many acute and chronic brain diseases, including ischemic brain injury. An imbalance in mitochondrial fission and fusion is one of the most important structural abnormalities found in a large number of mitochondrial dysfunction related diseases. Here, we investigated the effects of mitochondrial division inhibitor A (mdivi A) and mdivi B, two small molecule inhibitors of mitochondrial fission protein dunamin-related protein 1 (Drp-1), in neuronal injury induced by oxygen-glucose deprivation (OGD) in PC12 cells. We found that mdivi A and mdivi B inhibited OGD-induced neuronal injury through attenuating apoptotic cell death. These two inhibitors also preserved mitochondrial function, as evidenced by reduced reactive oxygen species (ROS) generation and cytochrome c release, as well as prevented loss of mitochondrial membrane potential (MMP). Moreover, mdivi A and mdivi B significantly suppressed mitochondrial Ca(2+) uptake, but had no effect on cytoplasmic Ca(2+) after OGD injury. The results of calcium imaging and immunofluorescence staining showed that Drp-1 inhibitors attenuated endoplasmic reticulum (ER) Ca(2+) release and prevented ER morphological changes induced by OGD. These results demonstrate that Drp-1 inhibitors protect against ischemic neuronal injury through inhibiting mitochondrial Ca(2+) uptake from the ER store and attenuating mitochondrial dysfunction.

Bilateral pontine brachium lesions in one autoantibodies directed against MOG positive patient: A case report.

RATIONALE: Myelin oligodendrocyte glycoprotein (MOG) antibody-related disease is a relatively recent entity in inflammatory demyelinating disease. Its clinical presentation varies in severity and the lack of specific imaging features makes it easy to misdiagnose. We now report the case of a MOG antibody-positive patient who presented with diplopia and dizziness, and whose brain magnetic resonance imaging (MRI) showed abnormal signals in the bilateral pontine brachium. PATIENT CONCERNS: A previously healthy 52-year-old woman presented with diplopia and dizziness, and was hospitalized 4 days after onset. DIAGNOSES: Brain MRI demonstrated abnormal hyperintense signals in the bilateral pontine brachium on T2-weighted fluid attenuated inversion recovery imaging. MRI enhancement showed abnormal enhancement foci in bilateral pontine brachium and pons. Cerebrospinal fluid examination showed Oligoclonal IgG bands were negative. The IgG index was normal, and serum aquaporin-4 antibody was negative, while serum MOG-Ab was positive (1:100). In conjunction with a positive serum MOG antibody and exclusion of other diseases, diagnosis of MOG antibody-related disease was made. INTERVENTIONS: Intravenous methylprednisolone followed by oral corticosteroids. OUTCOMES: Symptoms resolved completely. At 4-month follow-up. Follow-up after 4 months showed disappearance of the abnormal signal in the left pontine brachium and diminution of abnormal high signal in the right compared to the previous one, and there was no recurrence 1 year after the onset of the disease. LESSONS: If brain MRI indicating bilateral, multiple, and diffuse abnormal signals in the pontine brachium, and a discrepancy between the clinical symptoms and the imaging severity, a diagnosis of demyelinating disease should be considered highly probable. In such cases, anti-MOG antibody testing is essential for further defining the etiology. The clinical phenotype and imaging manifestations of MOG antibody-positive brainstem encephalitis may lack sufficient specificity to be readily identifiable. Timely diagnosis and early glucocorticoid therapy are beneficial in improving prognosis and preventing recurrence.

Machine learning-based nomogram: integrating MRI radiomics and clinical indicators for prognostic assessment in acute ischemic stroke.

Background: Acute Ischemic Stroke (AIS) remains a leading cause of mortality and disability worldwide. Rapid and precise prognostication of AIS is crucial for optimizing treatment strategies and improving patient outcomes. This study explores the integration of machine learning-derived radiomics signatures from multi-parametric MRI with clinical factors to forecast AIS prognosis. Objective: To develop and validate a nomogram that combines a multi-MRI radiomics signature with clinical factors for predicting the prognosis of AIS. Methods: This retrospective study involved 506 AIS patients from two centers, divided into training (n = 277) and validation (n = 229) cohorts. 4,682 radiomic features were extracted from T1-weighted, T2-weighted, and diffusion-weighted imaging. Logistic regression analysis identified significant clinical risk factors, which, alongside radiomics features, were used to construct a predictive clinical-radiomics nomogram. The model's predictive accuracy was evaluated using calibration and ROC curves, focusing on distinguishing between favorable (mRS ≤ 2) and unfavorable (mRS > 2) outcomes. Results: Key findings highlight coronary heart disease, platelet-to-lymphocyte ratio, uric acid, glucose levels, homocysteine, and radiomics features as independent predictors of AIS outcomes. The clinical-radiomics model achieved a ROC-AUC of 0.940 (95% CI: 0.912-0.969) in the training set and 0.854 (95% CI: 0.781-0.926) in the validation set, underscoring its predictive reliability and clinical utility. Conclusion: The study underscores the efficacy of the clinical-radiomics model in forecasting AIS prognosis, showcasing the pivotal role of artificial intelligence in fostering personalized treatment plans and enhancing patient care. This innovative approach promises to revolutionize AIS management, offering a significant leap toward more individualized and effective healthcare solutions.

Identifying New Subtypes of Multiple System Atrophy Using Cluster Analysis.

Background: Multiple system atrophy (MSA) is a disease with diverse symptoms and the commonly used classifications, MSA-P and MSA-C, do not cover all the different symptoms seen in MSA patients. Additionally, these classifications do not provide information about how the disease progresses over time or the expected outcome for patients. Objective: To explore clinical subtypes of MSA with a natural disease course through a data-driven approach to assist in the diagnosis and treatment of MSA. Methods: We followed 122 cases of MSA collected from 3 hospitals for 3 years. Demographic characteristics, age of onset, clinical signs, scale assessment scores, and auxiliary examination were collected. Age at onset; time from onset to assisted ambulation; and UMSARS I, II, and IV, COMPASS-31, ICARS, and UPDRS III scores were selected as clustering elements. K-means, partitioning around medoids, and self-organizing maps were used to analyze the clusters. Results: The results of all three clustering methods supported the classification of three MSA subtypes: The aggressive progression subtype (MSA-AP), characterized by mid-to-late onset, rapid progression and severe clinical symptoms; the typical subtype (MSA-T), characterized by mid-to-late onset, moderate progression and moderate severity of clinical symptoms; and the early-onset slow progression subtype (MSA-ESP), characterized by early-to-mid onset, slow progression and mild clinical symptoms. Conclusions: We divided MSA into three subtypes and summarized the characteristics of each subtype. According to the clustering results, MSA patients were divided into three completely different types according to the severity of symptoms, the speed of disease progression, and the age of onset.

[A cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy pedigree: clinical pathology, neuroimaging and molecular genetics studies].

OBJECTIVE: To explore the clinical presentations, pathological features, imaging manifestation and genetic mutation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: A systematic study on the clinical manifestations, neuroimaging characteristics, pathology and molecular genetics was performed in the proband and 16 members of the family. An investigation on the hereditary pattern of the family tree of the proband was also conducted. RESULTS: The main clinical features including history of ischemic stroke attack, migraine, psychological disoders and dementia were noted. No risk factors of hypertension and arteriosclerosis were found. Pedigree maps of the index case were consistent with classical autosomal dominant inheritance. Subcortical multi-infarct lesions, leukoencephalopathy, O'Sullivan sign and "Herringbone pattern"shape sign were observed via cranial MRI analysis. By electron microscopy, skin biopsy indicated the characteristic deposition of granular osmiophilic material (GOM) on the basement of smooth muscle cells of arterioles in the proband. The mutation of C144Y in the fourth exon of notch 3 gene was revealed in three cases, including 1 patient with normal MRI. CONCLUSION: The pedigree is diagnosed with CADASIL. The main cause can be attributed to a mutation of C144Y in the fourth exon of Notch 3 gene. The pedigree has enriched Chinese database of CADASIL.

miR­497/MIR497HG inhibits glioma cell proliferation by targeting CCNE1 and the miR­588/TUSC1 axis.

Emerging evidence has shown that microRNA (miR)­497 serves pivotal roles in tumorigenesis, cancer progression, metastasis and chemotherapy resistance in several types of cancer. In the present study, the expression and biological functions of miR­497 host gene (MIR497HG) were investigated in glioma tissue. The expression levels of miR­497 and MIR497HG were measured in glioma, adjacent non­cancerous and normal brain tissue and their association with the prognosis of patients with glioma were analyzed. The biological roles of miR­497 and MIR497HG were investigated in glioma cell lines. In addition, bioinformatics analysis, luciferase reporter assay and functional experiments were performed to identify and validate the downstream targets of miR­497 or MIR497HG. The expression levels of miR­497 and MIR497HG were downregulated in glioma tissue and cell lines compared with those in adjacent non­cancerous and normal brain tissue and normal human cortical neuron cell line. Patients with low miR­497 or MIR497HG expression levels exhibited a poor prognostic outcome. In addition, forced overexpression of miR­497 or MIR497HG significantly inhibited the proliferation and cell cycle progression of glioma cell lines. Furthermore, the results indicated that miR­497 and MIR497HG exerted their biological functions by direct targeting of cyclin E1 and miR­588/tumor suppressor candidate 1. In summary, the data indicated that miR­497 and MIR497HG served as tumor suppressors and may be used as potential therapeutic targets and prognostic biomarkers in glioma.

An incomplete form of anti-ganglioside antibody-positive Miller Fisher syndrome after an Epstein-Barr virus infection: A case report.

RATIONALE: The Miller Fisher syndrome (MFS) is an acute polyradiculoneuritis regarded as an uncommon clinical variant of the Guillain-Barre syndrome (GBS). It is characterized by the clinical triad of ophthalmoplegia, ataxia, and areflexia. The diagnosis of MFS is based on clinical presentation, presence of albuminocytologic dissociation in the cerebrospinal fluid (CSF), and normal brain imaging results. The presence of anti-ganglioside antibodies (GQlb) in the serum is helpful for the diagnosis. A history of upper respiratory tract infection or diarrhea 3 days to 6 weeks before the onset of MFS is common. However, there are some patients with atypical manifestations who are difficult to diagnose. Here, we present an incomplete form of MFS where antibodies against GQ1b were detected in the serum following an Epstein Barr virus (EBV) infection. PATIENT CONCERNS: A 77-year-old Chinese woman was admitted to the hospital with acute diplopia and right blepharoptosis. She had a history of mild upper respiratory tract infection 2 weeks ago. In 1 week, the symptoms rapidly progressed into bilateral ophthalmoplegia and hyporeflexia of the limbs without ataxia. CSF analysis on the third day after onset was normal, without albuminocytologic dissociation. EBV immunoglobulin G (IgG) antibodies were detected in the CSF. GQ1b and GD1b IgG antibodies were positive in the serum and negative in the CSF. No responsible lesion was found on brain imaging examination. DIAGNOSES: In accordance with the progressive bilateral ophthalmoplegia and hyporeflexia, the history of upper respiratory tract infection, the detection of EBV and GQ1b antibodies, and the negative brain imaging examination, the diagnosis of MFS was confirmed. INTERVENTIONS: The patient was administered intravenous immunoglobulin for 5 days. OUTCOMES: She had a favorable outcome after treatment. At the 6-week follow-up, bilateral ocular movement limitation and tendon reflexes had recovered. LESSONS: The diagnosis of MFS can be challenging, especially when encountered with incomplete symptoms and normal CSF results. Attention should be paid to the presence of anti-GQ1b IgG antibodies when the clinical manifestations are incomplete. Furthermore, EBV primary infection could be associated with MFS and considered a potential causative agent.

The Cannabinoid WIN 55,212-2 Reduces Delayed Neurologic Sequelae After Carbon Monoxide Poisoning by Promoting Microglial M2 Polarization Through ST2 Signaling.

Delayed neurologic sequelae (DNS) are among the most serious complications of carbon monoxide (CO) poisoning caused partly by elevated neuroinflammation. WIN 55,212-2, a non-selective agonist of cannabinoid receptors, has been demonstrated to have anti-inflammatory properties in various brain disorders. The anti-inflammatory action of WIN 55,212-2 is potentially associated with driving microglial M2 polarization. ST2 signaling is important in regulating inflammatory responses and microglial polarization. Therefore, we aimed to investigate the neuroprotective effect of WIN 55,212-2 on DNS after CO poisoning and elucidate its relationship with ST2-mediated microglial M2 polarization. The behavioral tests showed that treatment with WIN 55,212-2 significantly ameliorates the cognitive impairment induced by CO poisoning. This behavioral improvement was accompanied by reduced neuron loss, decreased production of pro-inflammatory cytokines, and a limited number of microglia in the hippocampus. Moreover, WIN 55,212-2 elevated the protein expression of IL-33 (the ligand of ST2) and ST2, increased the ratio of CD206-positive (M2 phenotype) and ST2-positive microglia, and augmented production of M2 microglia-associated cytokines in the hippocampus of CO-exposed rats. Furthermore, we observed that the WIN 55,212-2-mediated increases in ST2 protein expression, CD206-positive and ST2-positive microglia, and microglia-associated cytokines were blocked by the cannabinoid receptor 2 (CB2R) antagonist AM630 but not by the cannabinoid receptor 1 (CB1R) antagonist AM251. In contrast, the WIN 55,212-2-induced upregulation of the IL-33 protein expression was inhibited by AM251 but not by AM630. Altogether, these findings reveal cannabinoid receptors as promising therapeutic agents for CO poisoning and identify ST2 signaling-related microglial M2 polarization as a new mechanism of cannabinoid-induced neuroprotection.

MicroRNA-144 represses gliomas progression and elevates susceptibility to Temozolomide by targeting CAV2 and FGF7.

Malignant gliomas are the most common tumor in central nervous system with poor prognosis. Due to the limitation of histological classification in earlier diagnosis and individualized medicine, it is necessary to combine the molecular signatures and the pathological characteristics of gliomas. Lots of microRNAs presented abnormal expression in gliomas and modulated gliomas development. Exploration the miRNAs profile is helpful for the diagnosis, therapy and prognosis of gliomas. It has been demonstrated that miR-144 plays important roles in solid tumors. However, the detail mechanisms remained unrevealed. In this study, we have demonstrated the level of miR-144 decreased in glioma tissues from patients, especially in gliomas with higher grades. MiR-144 was also validated have lower expression in glioma cell lines compared with cortical neuron cell by using qRT-PCR. The in vitro functional experiment indicated miR-144 improved gliomas progression through repressing proliferation, sensitizing to chemotherapeutics and inhibiting metastasis. We further identified fibroblast growth factor 7 (FGF7) and Caveolin 2 (CAV2) were target genes of miR-144 by luciferase reporter assay and western blotting. The mechanisms study suggested forced FGF7 expression elevated Akt activation and decreased reactive oxygen species (ROS) generation. The MTT and cell cycle assay indicated miR-144 suppressed glioma cells proliferation through modulating FGF mediated Akt signaling pathway. Meanwhile, miR-144 promoted Temozolomide (TMZ) induced apoptosis in glioma cells via increasing ROS production by using FACS. On the other hand, CAV2, as another target of miR-144, accelerated glioma cells migration and invasion via promoting glioma cells EMT progress. Retrieved expression of FGF7 or CAV2 rescued the proliferation and migration function mediated by miR-144. Furthermore, the in vivo experiments in PDX models displayed the anti-tumor function of miR-144, which could be retrieved by overexpression of FGF7 and CAV2. Taken together, these findings indicated miR-144 acted as a potential target against gliomas progression and uncovered a novel regulatory mechanism, which may provide a new therapeutic strategy and prognostic indicator for gliomas.

[Expression of peroxisome proliferator-activated receptor gamma in hippocampus neurons in rats after oxygen deprivation/oxygen supply in vitro].

OBJECTIVE: To observe the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in hippocampus neurons in rats after different time of neuron oxygen deprivation/oxygen supply, and to investigate the role of PPARgamma in neuron ischemia reperfusion injury. METHODS: One day old newborn SD rats were chosen. Primary cultured hippocampus neurons were used to establish neuron ischemic reperfusion model in vitro by oxygen and glucose depriving 15 minutes and supplying again, and then the neuron structure was observed by transmission electron microscope of JEM-200EX. The expression of PPARgamma mRNA and protein were detected by RT-PCR and Western blot, respectively. RESULTS: Neuron structure was damaged after neuron oxygen deprivation/oxygen supply. There was no significant difference between 0 h oxygen supply group and the control group. The expression of PPARgamma was decreased both at mRNA and protein level after 6 h of oxygen supply. The difference between 6 h oxygen supply group and the control group was significant (P<0.01), which decreased with the length of reperfusion and the lowest was at 48 h after the reperfusion. The difference among the different reperfusion groups and the control group was significant (P<0.01). CONCLUSION: PPARgamma may participate in the pathological damage course of neuron ischemical reperfusion injury, and may become a new intervention target of treatment for ischemic cerebrovascular disease.

The Effects of Intelectin-1 on Antioxidant and Angiogenesis in HUVECs Exposed to Oxygen Glucose Deprivation.

Objective: Ischemic stroke leads to cellular death and tissue damage by depriving the areas of glucose and oxygen supplies. The effective treatment of stroke remains a challenge for modern medicine. This study used an oxygen-glucose deprivation (OGD) model of human umbilical vein endothelial cells (HUVECs) to mimic ischemic injuries and explored the role and mechanism of intelectin-1. Methods: Intelectin-1 was transduced into the HUVECs using a lentiviral vector. The PI3K/Akt signaling was examined in intelectin-induced eNOS phosphorylation. The PI3K inhibitor LY294002 was dealed in HUVECs. Results: Our results demonstrated an increase in capillary density, decrease in apoptotic cells, and increase in HIF-1α protein expression following intelectin-1 treatment. Real-time PCR and Western blotting revealed the increased intelectin-1 expression alongside eNOS and Akt phosphorylation with enhanced bcl-2 expression under OGD. Capillary density decreased significantly after LY294002 treatment. Conclusion: These results suggest intelectin-1 promotes angiogenesis, inhibits oxidative stress and reduces apoptosis by stimulating the Akt-eNOS signaling pathway in response to ischemia in vitro.

Silencing lncRNA FOXD2-AS1 inhibits proliferation, migration, invasion and drug resistance of drug-resistant glioma cells and promotes their apoptosis via microRNA-98-5p/CPEB4 axis.

OBJECTIVE: This study was conducted to elucidate the long non-coding RNA FOXD2-AS1 (lncRNA FOXD2-AS1) expression in glioma and its mechanism on the biological features of glioma cells and the drug resistance of temozolomide (TMZ). RESULTS: Highly expressed FOXD2-AS1 was found in glioma. There was more powerful chemotherapeutic resistance of TMZ resistant cell lines than that of the parent cell lines. Silence of FOXD2-AS1 suppressed proliferation and drug resistance and promoted apoptosis of drug-resistant glioma cells. Overexpressed FOXD2-AS1 presented an opposite trend. FOXD2-AS1 could be used as a competing endogenous RNA to adsorb miR-98-5p, thereby up-regulating CPEB4. CONCLUSION: Our study suggests that down-regulated FOXD2-AS1 repressed invasion, proliferation, migration and drug resistance of drug-resistant glioma cells while stimulating their apoptosis via increasing miR-98-5p and inhibiting CPEB4 expression. METHODS: FOXD2-AS1, microRNA-98-5p (miR-98-5p) and cytoplasmic polyadenylation element binding (CPEB4) expression in glioma tissues were tested. Expression of E-cadherin, N-cadherin and Vimentin in glioma cells were explored. A series of assays were conducted to detect the function of FOXD2-AS1 in migration, proliferation, apoptosis, and invasion of glioma cells. Changes in drug-resistance of cells under TMZ treatment were examined, and tumor formation in nude mice was performed to test the changes of drug resistance in vivo.

Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice.

Mesenchymal stem cell-derived exosomes (MSC-Exo) have robust anti-inflammatory effects in the treatment of neurological diseases such as epilepsy, stroke, or traumatic brain injury. While astrocytes are thought to be mediators of these effects, their precise role remains poorly understood. To address this issue, we investigated the putative therapeutic effects and mechanism of MSC-Exo on inflammation-induced alterations in astrocytes. Methods: Lipopolysaccharide (LPS)-stimulated hippocampal astrocytes in primary culture were treated with MSC-Exo, which were also administered in pilocarpine-induced status epilepticus (SE) mice. Exosomal integration, reactive astrogliosis, inflammatory responses, calcium signaling, and mitochondrial membrane potentials (MMP) were monitored. To experimentally probe the molecular mechanism of MSC-Exo actions on the inflammation-induced astrocytic activation, we inhibited the nuclear factor erythroid-derived 2, like 2 (Nrf2, a key mediator in neuroinflammation and oxidative stress) by sgRNA (in vitro) or ML385 (Nrf2 inhibitor) in vivo. Results: MSC-Exo were incorporated into hippocampal astrocytes as well as attenuated reactive astrogliosis and inflammatory responses in vitro and in vivo. Also, MSC-Exo ameliorated LPS-induced aberrant calcium signaling and mitochondrial dysfunction in culture, and SE-induced learning and memory impairments in mice. Furthermore, the putative therapeutic effects of MSC-Exo on inflammation-induced astrocytic activation (e.g., reduced reactive astrogliosis, NF-κB deactivation) were weakened by Nrf2 inhibition. Conclusions: Our results show that MSC-Exo ameliorate inflammation-induced astrocyte alterations and that the Nrf2-NF-κB signaling pathway is involved in regulating astrocyte activation in mice. These data suggest the promising potential of MSC-Exo as a nanotherapeutic agent for the treatment of neurological diseases with hippocampal astrocyte alterations.

[Voxel-based analysis of cerebral blood flow changes in Parkinson disease using arterial spin labeling technique].

OBJECTIVE: To explore the imaging biomarker for early diagnosis and disease course monitoring of Parkinson disease (PD) in arterial spin labeling (ASL) technique. METHODS: Between July, 2014 and May, 2017, 23 patients with PD underwent magnetic resonance imaging (MRI) and ASL examinations in our hospital, including 13 in the early stage and 10 in advanced stages. Voxel-based analysis (VBA) was used to observe the regional cerebral blood flow (rCBF) characteristics in PD patients in different stages and three-dimensional continuous arterial spin labeling (3D CASL) was used to analyze the mean cerebral blood flow (mCBF). RESULTS: No significant difference was found in mCBF among PD patients in the early stage, patients in advanced stages and normal control subjects (P=0.30). Compared with the normal control group, the patients with early-stage PD had decreased rCBF in resting state mainly in the right superior occipital gyrus and the right superior frontal gyrus as revealed by VBA (P < 0.001); the patients with advanced PD showed decreased rCBF mainly in the left precentral gyrus and the postcentral gyrus (P < 0.001). The patients with advanced PD exhibited lowered rCBF in the right substantia nigra and the bilateral corpus callosum as compared with the early-stage patients (P < 0.001). CONCLUSIONS: VBA of ASL reveals rCBF alterations in association with the disease progression in PD patients, suggesting that this technique might provide assistance in identification of potential markers for early PD diagnosis and for monitoring the disease course.

miR-183-96-182 clusters alleviated ox-LDL-induced vascular endothelial cell apoptosis in vitro by targeting FOXO1.

OBJECTIVE: To investigate the role of FOXO1 and miR-183-96-182 clusters in ox-LDL induced endothelial cell apoptosis. METHODS: FOXO1 overexpression (OE) and knockdown (KD) as well as AKT1 OE in human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs) were achieved by lentiviral transduction. Upregulation of miR-183-5p, miR-182-5p or miR-96-5p was mimicked by agomir treatment. FOXO1 gene transcription was monitored by FOXO1 promotor reporter assay. Cell apoptosis in culture was monitored by TiterTACS in situ detection. Regulation of FOXO1 gene expression by an miRNA targeting mechanism was monitored by AGO2-RNA immunoprecipitation assay. RESULTS: FOXO1 mRNA and protein expression levels in ox-LDL treated HUVECs or HAECs were significantly upregulated due to transcriptional and miRNA targeting mechanisms. MiR-183-5p, miR-182-5p and miR-96-5p expression levels in HUVECs or HAECs were significantly reduced by ox-LDL treatment, the overexpression of which by agomir treatment partially reduced the FOXO1 mRNA/protein expression levels and cell apoptosis which was upregulated by ox-LDL treatment. FOXO1 overexpression antagonized the effect of the agomir treatment indicated above. MiR-183-5p, miR-182-5p and miR-96-5p agomir treatment partially rescued the FOXO1 pSer256/total FOXO1 protein ratio and the AKT1 pSer473 level that were reduced by ox-LDL treatment in the HUVECs or HAECs. AKT1 overexpression significantly reduced FOXO1 protein expression, increased miR-182-5p and miR-183-5p expression, and partially alleviated ox-LDL induced HUVEC or HAEC apoptosis in an miR-183-5p and miR-182-5p-dependent manner. CONCLUSION: miR-183-96-182 clusters could partially alleviate ox-LDL-induced apoptosis in HUVECs or HAECs by targeting FOXO1.