Lysosomal TFEB-TRPML1 Axis in Astrocytes Modulates Depressive-like Behaviors.

Lysosomes are important cellular structures for human health as centers for recycling, signaling, metabolism and stress adaptation. However, the potential role of lysosomes in stress-related emotions has long been overlooked. Here, it is found that lysosomal morphology in astrocytes is altered in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social defeat stress. A screen of lysosome-related genes revealed that the expression of the mucolipin 1 gene (Mcoln1; protein: mucolipin TRP channel 1) is decreased in susceptible mice and depressed patients. Astrocyte-specific knockout of mucolipin TRP channel 1 (TRPML1) induced depressive-like behaviors by inhibiting lysosomal exocytosis-mediated adenosine 5'-triphosphate (ATP) release. Furthermore, this stress response of astrocytic lysosomes is mediated by the transcription factor EB (TFEB), and overexpression of TRPML1 rescued depressive-like behaviors induced by astrocyte-specific knockout of TFEB. Collectively, these findings reveal a lysosomal stress-sensing signaling pathway contributing to the development of depression and identify the lysosome as a potential target organelle for antidepressants.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Alleviate Nuclear Pulposus Cells Degeneration Through the miR-145a-5p/USP31/HIF-1α Signaling Pathway.

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes possess therapeutic potential against degenerative diseases. This study aimed to investigate the effects of BMSC-derived exosomes on intervertebral disc degeneration (IVDD) and explore the underlying molecular mechanisms. Through transcriptome sequencing and histological analysis, we observed a significant increase in HIF-1α expression in degenerative nucleus pulposus (NP) tissues. The addition of HIF-1α resulted in elevated expression of inflammatory factors IL-1ß and IL-6, higher levels of matrix-degrading enzyme MMP13, and lower expression of aggrecan in NP cells. Co-culturing with BMSCs diminished the expression of HIF-1α, MMP13, IL-1ß, and IL-6 in degenerative NP cells induced by overload pressure. miRNA chip analysis and PCR validation revealed that miR-145a-5p was the primary miRNA carried by BMSC-derived exosomes. Overexpression of miR-145a-5p was effective in minimizing the expression of HIF-1α, MMP13, IL-1ß, and IL-6 in degenerative NP cells. Luciferase reporter assays confirmed USP31 as the target gene of miR-145a-5p, and the regulation of NP cells by BMSC-derived exosomes via miR-145a-5p was dependent on USP31. In conclusion, BMSC-derived exosomes alleviated IVDD through the miR-145a-5p/USP31/HIF-1α signaling pathway, providing valuable insights into the treatment of IVDD.

Anoikis-related gene signatures predict prognosis of lung adenocarcinoma patients and reveal immune infiltration.

Background: Lung adenocarcinoma (LUAD), a type of lung cancer, is one of the most aggressive and deadly malignancies worldwide. Malignant tumor cells exhibit strong anti-anoikis properties to achieve distant metastasis through the circulatory system. However, more research is needed to understand how anoikis is involved in the progression, metastasis and especially the prognosis of LUAD. Methods: We obtained anoikis-related genes (ARGs) from two websites, Harmonizome and Genecards, and integrated them to select and model the genes associated with LUAD prognosis. In addition, we investigated differences in the immune cell microenvironment and pathways of enrichment analysis between subtypes. We finally constructed a nomogram based on ARGs and used decision curve analysis (DCA) to demonstrate that this model could help clinicians make clinical decisions. Results: Sixty-four differentially expressed genes (DEGs) were found to be associated with survival, and of these, six were chosen to build a prognostic model. The time-dependent receiver operating characteristic (ROC) curves showed that the model had a satisfactory predictive ability. Enrichment analysis and immune microenvironment analysis revealed that the immune status and drug sensitivity of populations at high and low risk were different. We integrated the clinicopathological features of LUAD with the risk score to build the nomogram. The nomogram was shown to be a good predictor of short- and long-term survival in LUAD patients through DCA analysis. Conclusions: This new model based on six ARGs and nomograms in our study could help patients with LUAD develop personalized treatment plans.

Astrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice.

Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients' blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.

Development and Validation of a Machine Learning Prognostic Model of m5C Related immune Genes in Lung Adenocarcinoma.

BACKGROUND: The aim of this retrospective research was to develop an immune-related genes significantly associated with m5C methylation methylation (m5C-IRGs)-related signature associated with lung adenocarainoma (LUAD). METHODS: We introduced transcriptome data to screen out m5C-IRGs in The Cancer Genome Atlas (TCGA)-LUAD dataset. Subsequently, the m5C-IRGs associated with survival were certificated by Kaplan Meier (K-M) analysis. The univariate Cox, least absolute shrinkage and selection operator (LASSO) regression, and xgboost.surv tool were adopted to build a LUAD prognostic signature. We further conducted gene functional enrichment, immune microenvironment and immunotherapy analysis between 2 risk subgroups. Finally, we verified m5C-IRGs-related prognostic gene expression in transcription level. RESULTS: A total of 76 m5C-IRGs were identified in TCGA-LUAD dataset. Furthermore, 27 m5C-IRGs associated with survival were retained. Then, a m5C-IRGs prognostic signature was build based on the 3 prognostic genes (HLA-DMB, PPIA, and GPI). Independent prognostic analysis suggested that stage and RiskScore could be used as independent prognostic factors. We found that 4104 differentially expressed genes (DEGs) between the 2 risk subgroups were mainly concerned in immune receptor pathways. We found certain distinction in LUAD immune microenvironment between the 2 risk subgroups. Then, immunotherapy analysis and chemotherapeutic drug sensitivity results indicated that the m5C-IRGs-related gene signature might be applied as a therapy predictor. Finally, we found significant higher expression of PPIA and GPI in LUAD group compared to the normal group. CONCLUSIONS: The prognostic signature comprised of HLA-DMB, PPIA, and GPI based on m5C-IRGs was established, which might provide theoretical basis and reference value for the research of LUAD. PUBLIC DATASETS ANALYZED IN THE STUDY: TCGA-LUAD dataset was collected from the TCGA (https://portal.gdc.cancer.gov/) database, GSE31210 (validation set) was retrieved from GEO (https://www.ncbi.nlm.nih.gov/geo/) database.

Head-to-head comparison of 18F-FDG PET/CT and 18F-FDG PET/MRI for lymph node metastasis staging in non-small cell lung cancer: a meta-analysis.

PURPOSE: The current meta-analysis aimed to compare the diagnostic performance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) with 18F-FDG PET/magnetic resonance imaging (MRI) in non-small cell lung cancer (NSCLC) lymph node metastasis staging. METHODS: We searched the PubMed, Web of Science, and Embase databases for relevant articles between November 1992 and September 2022. Studies evaluating the head-to-head comparison of 18F-FDG PET/CT and 18F-FDG PET/MRI for lymph node metastasis in patients with NSCLC were included. The quality of each study was assessed using the Quality Assessment of Diagnostic Performance Studies-2 tool. RESULTS: The analysis includes six studies with a total of 434 patients. The pooled sensitivity of 18F-FDG PET/CT and 18F-FDG PET/MRI was 0.78 [95% confidence interval (CI): 0.59-0.90] and 0.84 (95% CI: 0.68-0.93), and the pooled specificity was 0.87 (95% CI: 0.72-0.94) and 0.87 (95% CI: 0.80-0.92), respectively. The accuracy of 18F-FDG PET/CT and 18F-FDG PET/MRI was 0.81 (95% CI: 0.71-0.90) and 0.84 (95% CI: 0.75-0.92), respectively. When the pre-test probability was set at 50%, the post-test probability for 18F-FDG PET/CT could increase to 85%, and the post-test probability for 18F-FDG PET/MRI could increase to 87%. CONCLUSION: 18F-FDG PET/CT and 18F-FDG PET/MRI have similar diagnostic performance in detecting lymph node metastasis in NSCLC. However, the results of this study were from a small sample study, and further studies with larger sample sizes are needed.

Diagnostic potential of [18F]FDG PET/MRI in non-small cell lung cancer lymph node metastasis: a meta-analysis.

PURPOSE: This meta-analysis evaluated the diagnostic accuracy and diagnostic value of [18F]FDG PET/MRI for mediastinal lymph node staging of NSCLC. METHODS: Relevant articles in PubMed, Embase, Web of Science, and the Cochrane Library were searched until January 2023. Research evaluating [18F]FDG PET/MRI for mediastinal lymph node staging of NSCLC was included. Pooled estimates of sensitivity, specificity, PLR, and NLR were calculated by the "Stata" software. RESULTS: Nine researches were included, containing 618 patients. The pooled sensitivity of [18F]FDG PET/MRI for detecting mediastinal lymph node staging of NSCLC was 0.82 (0.70-0.90), and the pooled specificity was 0.88 (0.82-0.93). PLR and NLR were 7.38 (4.73-11.52) and 0.20 (0.11-0.36), respectively. The AUC value of this imaging modality was 0.92 (0.90-0.94). The post-test probability for [18F]FDG PET/MRI might rise to 88% when the pre-test probability was set at 50%. CONCLUSIONS: We considered [18F]FDG PET/MRI as an effective imaging tool with relatively high specificity and sensitivity. It has great potential to be used in the clinical management of patients in NSCLC who are amenable to early surgery. More studies with large sample sizes in the same direction are needed in future to obtain more reliable evidence-based support.

Frequency of metastases within the hypothalamic-pituitary area and the associated high-risk factors in patients with brain metastases.

Objective: Brain radiotherapy often results in impairment of hypothalamic-pituitary (HT-P) function, which in turn causes secretory dysfunction of related hormones. In this paper, the frequency of metastasis in the HT-P area and its high-risk factors in patients with brain metastasis were retrospectively analyzed, and thus provide experimental evidence for protecting HT-P area during whole brain radiotherapy (WBRT). Methods: A retrospective analysis was performed on the data of patients with brain metastasis diagnosed by cranial magnetic resonance imaging (MRI) at the First Hospital of Lanzhou University from 2017 to 2020. The anatomical positions of the hypothalamus and pituitary were delineated, followed by their expansion by 5 mm outwards, respectively, in the three-dimensional direction, and the hypothalamus +5 mm and pituitary +5 mm were obtained as the avoidance area, in which the frequency of brain metastasis was evaluated. Univariate and multivariate logistic regression models were used to analyze the high risk factors of brain metastasis in HT-P area. Results: A total of 3,375 brain metastatic lesions from 411 patients were included in the analysis. The rates of brain metastasis in the hypothalamus +5 mm and pituitary +5 mm in the whole group of cases were 2.9% (12/411) and 1.5% (6/411) respectively; the frequency of lesions was 0.4% (13/3375) and 0.2% (6/3375) respectively. Univariate and multivariate analyses showed that the number of brain metastases (OR = 14.946; 95% CI = 4.071-54.880; p < 0.001), and the occurrence of brain metastasis in the pituitary (OR = 13.331; 95% CI = 1.511-117.620; p = 0.020) were related to brain metastasis in the hypothalamus, and that the only relevant factor for brain metastasis in the pituitary was the occurrence of that in the hypothalamus (OR = 0.069; 95% CI = 0.010-0.461; p = 0.006). There was no correlation between tumor pathological types, the maximum diameter, the total volume of brain metastatic lesions and the risk of brain metastasis in hypothalamus and pituitary. Conclusion: The frequency of brain metastasis in the HT-P area is extremely low. The risk of brain metastases in the hypothalamus is correlated with their number. The larger the number of metastatic lesions, the higher the frequency of brain metastasis. Protection of the HT-P area during WBRT may be unlikely to compromise the tumor recurrence rate for patients with a relatively small number of brain metastases.

Clinical analysis of tubular stapler-assisted nested anastomosis in the prevention of postoperative esophageal cancer complications.

Background: Esophageal cancer (EC) is one of the most common malignant tumor types. Surgery is considered the treatment of choice for patients with early- and mid-stage EC. However, because of the traumatic nature of EC surgery and the need for gastrointestinal reconstruction, high rates of postoperative complications such as anastomotic leakage or stenosis, esophageal reflux, and pulmonary infection exist. Its time to explore a novel esophagogastric anastomosis method for McKeown EC surgery to reduce the postoperative complication. Methods: This study recruited a total of 544 patients who underwent McKeown resection for EC between January 2017 and August 2020. The tubular stapler-assisted nested anastomosis was taken as the time node, including 212 patients in the traditional tubular mechanical anastomosis group and 332 patients in the tubular stapler-assisted nested anastomosis group. The 6-month postoperative incidence of anastomotic fistula and anastomotic stenosis was recorded. Anastomosis in McKeown operation for EC and the influence of different anastomosis methods on clinical efficacy were investigated. Results: Compared with traditional mechanical anastomosis, tubular stapler-assisted nested anastomosis had a lower incidence of anastomotic fistula (0% vs. 5.2%), lung infection (3.3% vs. 11.8%), gastroesophageal reflux (6.9% vs. 16.0%), anastomotic stenosis (3.0% vs. 10.4%), neck incision infection (0.9% vs. 7.1%), anastomositis (16.6% vs. 23.6%), and a shorter surgical duration (11.02±1.54 vs. 18.53±3.20 min). Statistical significance was indicated at P<0.05. No significant difference was detected in the incidence of arrhythmia, recurrent laryngeal nerve injury, or chylothorax between the 2 groups. Due to its good effect in McKeown surgery for EC, stapler-assisted nested anastomosis has been widely used in McKeown surgery for EC, and has become a common anastomosis method in our department for McKeown surgery for EC. However, large sample-sized studies and long-term efficacy observation are still needed. Conclusions: The use of tubular stapler-assisted nested anastomosis can significantly reduce the incidence of complications such as anastomotic fistula, anastomotic stricture, gastroesophageal reflux, and pulmonary infection; therefore, it constitutes the preferred technique for cervical anastomosis in McKeown esophagogastrectomy.

Three-dimensional printing template for intraoperative localization of pulmonary nodules in the pleural cavity.

Objectives: Localization of pulmonary nodules is challenging. However, traditional localization methods have high radiation doses and a high risk of complications. We developed a noninvasive 3-dimensional printing navigational template for intraoperative localization. It can reduce puncture-related complications and simplify the localization process. This study will verify the feasibility of this method. Methods: Patients with peripheral pulmonary nodules were included in this study. The computed tomography scan sequences were obtained to design a digital template model, which was then imported into a 3-dimensional printer to produce a physical navigational template. Finally, the navigational template is placed into the patient's pleural cavity for intraoperative localization. The precision of the nodule localization and associated complications were evaluated. Results: Twelve patients were finally included in this study. Intraoperative navigational template localization was used in all patients. The success rate of intraoperative nodule localization was 100%, and the median time of localization was 19.5 minutes (range, 16-23.5 minutes). The deviation median of the navigational template was 2.1 mm (range, 1.1-2.7 mm). Among the included patients, no significant complications occurred during intraoperative localization. Conclusions: The 3-dimensional printing template for intraoperative localization is feasible, will cause no trauma to the patient, and has acceptable accuracy for application in nodules localization. This navigational template greatly simplifies the localization process and may potentially break the dependence of percutaneous localization on computed tomography scanning.

LysM-positive neurons drive Tuberous Sclerosis Complex (TSC)-associated brain lesions.

Mutations of Tsc1 or Tsc2 can lead to excessive activation of mTORC1 and cause Tuberous Sclerosis Complex (TSC), which is an autosomal dominant genetic disease prominently characterized by seizures, mental retardation and multiorgan hamartoma. In TSC, pathological changes in the central nervous system are the leading cause of death and disability. In decades, series of rodent models have been established by mutating Tsc1 or Tsc2 genes in diverse neural cell lineages to investigate the underlying cellular and molecular mechanisms, however, the cellular origin triggering neural pathological changes in TSC is undetermined. In this study, we generated a novel mouse model involving conditional deletion of Tsc1 in lysozyme 2 (Lyz2)-positive cells which replicated several features of brain lesions including epileptic seizures, megalencephaly, highly enlarged pS6-positive neurons and astrogliosis. In addition, we confirmed that bone marrow-derived myeloid cells including microglia with Tsc1 deficiency are not the decisive lineage in the cerebral pathologies in TSC. These histological assays in our murine model indicate an essential contribution of Lyz2-positive neurons to TSC progression. The Lyz2-positive neural population-specific onset of Tsc1 loss in murine postnatal brain might be the key to pathological phenotypes. Our findings thus provided evidences supporting new insights into the role of Lyz2-positive neurons in TSC events.

Glucocorticoid Receptor-Dependent Astrocytes Mediate Stress Vulnerability.

BACKGROUND: Major depressive disorder is a devastating psychiatric illness that affects approximately 17% of the population worldwide. Astrocyte dysfunction has been implicated in its pathophysiology. Traumatic experiences and stress contribute to the onset of major depressive disorder, but how astrocytes respond to stress is poorly understood. METHODS: Using Western blotting analysis, we identified that stress vulnerability was associated with reduced astrocytic glucocorticoid receptor (GR) expression in mouse models of depression. We further investigated the functions of astrocytic GRs in regulating depression and the underlying mechanisms by using a combination of behavioral studies, fiber photometry, biochemical experiments, and RNA sequencing methods. RESULTS: GRs in astrocytes were more sensitive to stress than those in neurons. GR absence in astrocytes induced depressive-like behaviors, whereas restoring astrocytic GR expression in the medial prefrontal cortex prevented the depressive-like phenotype. Furthermore, we found that GRs in the medial prefrontal cortex affected astrocytic Ca2+ activity and dynamic ATP (adenosine 5'-triphosphate) release in response to stress. RNA sequencing of astrocytes isolated from GR deletion mice identified the PI3K-Akt (phosphoinositide 3-kinase-Akt) signaling pathway, which was required for astrocytic GR-mediated ATP release. CONCLUSIONS: These findings reveal that astrocytic GRs play an important role in stress response and that reduced astrocytic GR expression in the stressed subject decreases ATP release to mediate stress vulnerability.

Theoretical investigation into the solvent effect on the thermal decomposition of RDX in tetrahydrofuran, acetone, toluene, and benzene.

In order to clarify the solvent effect on the thermal decomposition of explosive, the N-NO2 trigger-bond strengths and ring strains of RDX (cyclotrimethylenetrinitramine) in its H-bonded complexes with solvent molecules (i.e., tetrahydrofuran, acetone, toluene, and benzene), and the activation energies of the intermolecular hydrogen exchanges between the solvent molecules and C3H8O2N4 or CH4O2N2, as the model molecule of RDX, were investigated by the BHandHLYP, B3LYP, MP2(full), and M06-2X methods with the 6-311 + + G(2df,2p) basis set, accompanied by a comparison with the calculations by the integral equation formalism polarized continuum model. The solvent effects ignore the ring strain while strengthening the N-NO2 bond, leading to a possible decreased sensitivity, as is opposite to the experimental results. However, the activation energies are in the order of C3H8O2N4/CH4O2N2∙∙∙acetone < C3H8O2N4/CH4O2N2∙∙∙THF < C3H8O2N4/CH4O2N2∙∙∙toluene < C3H8O2N4/CH4O2N2∙∙∙benzene < C3H8O2N4/CH4O2N2, suggesting that the order of the critical explosion temperatures might be RDX∙∙∙acetone < RDX∙∙∙THF < RDX∙∙∙toluene < RDX∙∙∙benzene < RDX, as is roughly consistent with the experimental results. Therefore, the intermolecular hydrogen exchange with the HONO elimination is a possible mechanism of the solvent effect on the initial thermal decomposition of RDX. The solvent effect on the sensitivity is analyzed by the surface electrostatic potentials.

A rare case of ectopic chest-wall thymoma: a case report.

Ectopic extrathoracic thymoma is an uncommon clinical entity that has only been described sporadically, and most of them are ectopic hamartomatous thymomas or ectopic cervical thymomas. Here a case of 32-year-old woman with an ectopic thymoma was presented, which was found in right armpit and a postoperative diagnosis of 2018 World Health Organization (WHO) confirmed type B1, modified Masaoka stage I tumor was obtained. The patient had no symptoms of myasthenia or other immune disorders but once misdiagnosed as supernumerary breast. Tumor resection was performed and the tumor was completely removed. To our knowledge, this is a novel report that ectopic thymoma exists on chest wall and type B1 was confirmed according to 2018 WHO histological classification.

Astrocytic Epoxyeicosatrienoic Acid Signaling in the Medial Prefrontal Cortex Modulates Depressive-like Behaviors.

Major depressive disorder is the most common mental illness. Mounting evidence indicates that astrocytes play a crucial role in the pathophysiology of depression; however, the underlying molecular mechanisms remain elusive. Compared with other neuronal cell types, astrocytes are enriched for arachidonic acid metabolism. Herein, we observed brain-region-specific alterations of epoxyeicosatrienoic acid (EET) signaling, which is an arachidonic acid metabolic pathway, in both a mouse model of depression and postmortem samples from patients with depression. The enzymatic activity of soluble epoxide hydrolase (sEH), the key enzyme in EET signaling, was selectively increased in the mPFC of susceptible mice after chronic social defeated stress and was negatively correlated with the social interaction ratio, which is an indicator of depressive-like behavior. The specific deletion of Ephx2 (encode sEH) in adult astrocytes induced resilience to stress, whereas the impaired EET signaling in the mPFC evoked depressive-like behaviors in response to stress. sEH was mainly expressed on lysosomes of astrocytes. Using pharmacological and genetic approaches performed on C57BL/6J background adult male mice, we found that EET signaling modulated astrocytic ATP release in vitro and in vivo Moreover, astrocytic ATP release was required for the antidepressant-like effect of Ephx2 deletion in adult astrocytes. In addition, sEH inhibitors produced rapid antidepressant-like effects in multiple animal models of depression, including chronic social defeated stress and chronic mild stress. Together, our results highlight that EET signaling in astrocytes in the mPFC is essential for behavioral adaptation in response to psychiatric stress.SIGNIFICANCE STATEMENT Astrocytes, the most abundant glial cells of the brain, play a vital role in the pathophysiology of depression. Astrocytes secrete adenosine ATP, which modulates depressive-like behaviors. Notably, astrocytes are enriched for arachidonic acid metabolism. In the present study, we explored the hypothesis that epoxyeicosatrienoic acid signaling, an arachidonic acid metabolic pathway, modulates astrocytic ATP release and the expression of depressive-like behaviors. Our work demonstrated that epoxyeicosatrienoic acid signaling in astrocytes in the mPFC is essential for behavioral homeostatic adaptation in response to stress, and the extent of astrocyte functioning is greater than expected based on earlier reports.

Nicotine inhibits microglial proliferation and is neuroprotective in global ischemia rats.

Ischemic injury in rodent models reliably leads to the activation of microglia, which might play a detrimental role in neuronal survival. Our preliminary studies suggest that nicotine plays a potential role in decreasing the numbers of cultured microglia in vitro. In the present study, we found treatment with nicotine 2, 6, and 12 h after ischemia for 7 days significantly increased the survival of CA1 pyramidal neurons in ischemia/reperfusion rats. This effect was accompanied by a significant reduction in the increase of microglia rather than astrocytes, as well as a significant reduction of enhanced expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1ß) in CA1 induced by ischemia/reperfusion. Nicotine inhibits microglial proliferation in primary cultures with and without the stimulation of granulocyte-macrophage colony-stimulating factor (GM-CSF). Pre-treatment with α-bungarotoxin, a selective α7 nicotinic acetylcholine receptor (α7 nAChR) antagonist, could prevent the inhibitory effects of nicotine on cultured microglial proliferation suggesting that nicotine inhibits the microglial proliferation in an α7 nAChR-dependent fashion. Our results suggest that nicotine inhibits the inflammation mediated by microglia via α7 nAChR and is neuroprotective against ischemic stroke, even when administered 12 h after the insult. α7 nAChR agonists may have uses as anti-ischemic compounds in humans.

Store-operated Ca2+ channels blockers inhibit lipopolysaccharide induced astrocyte activation.

The destruction of calcium homeostasis is an important factor leading to neurological diseases. Store-operated Ca(2+) (SOC) channels are essential for Ca(2+) homeostasis in many cell types. However, whether SOC channels are involved in astrocyte activation induced by lipopolysaccharide (LPS) still remains unknown. In this study, we used LPS as an exogenous stimulation to investigate the role of SOC channels in astrocyte activation. Using calcium imaging technology, we first found that SOC channels blockers, 1-[h-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole (SKF-96365) and 2-aminoethyldiphenyl borate (2-APB), inhibited LPS induced [Ca(2+)]i increase, which prompted us to speculate that SOC channels may be involved in LPS induced astrocyte activation. Further experiments confirmed our speculation shown as SOC channels blockers inhibited LPS induced astrocyte activation characterized as cell proliferation by MTS and BrdU assay, raise in glial fibrillary acidic protein expression by immunofluorescence and Western Blot and secretion of interleukin 6 (IL-6) and interleukin 1ß (IL-1ß) by ELISA. So, our studies showed that SOC channels are involved in LPS-induced astrocyte activation.

Astrocyte-derived ATP modulates depressive-like behaviors.

Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the world's population; however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a Gq G protein-coupled receptor only in astrocytes to enable selective activation of astrocytic Ca(2+) signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD.

Astrocytic adenosine 5'-triphosphate release regulates the proliferation of neural stem cells in the adult hippocampus.

Astrocytes are key components of the niche for neural stem cells (NSCs) in the adult hippocampus and play a vital role in regulating NSC proliferation and differentiation. However, the exact molecular mechanisms by which astrocytes modulate NSC proliferation have not been identified. Here, we identified adenosine 5'-triphosphate (ATP) as a proliferative factor required for astrocyte-mediated proliferation of NSCs in the adult hippocampus. Our results indicate that ATP is necessary and sufficient for astrocytes to promote NSC proliferation in vitro. The lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficient ATP release from astrocytes. This deficiency led to a dysfunction in NSC proliferation that could be rescued via the administration of exogenous ATP. Moreover, P2Y1-mediated purinergic signaling is involved in the astrocyte promotion of NSC proliferation. As adult hippocampal neurogenesis is potentially involved in major mood disorder, our results might offer mechanistic insights into this disease.

Prognosis of percutaneous coronary intervention and coronary artery bypass grafts for ostial right coronary lesions in propensity-matched individuals.

OBJECTIVE: Our aim was to evaluate the relative safety and efficacy of percutaneous coronary intervention (PCI) with drug-eluting stents (DES) versus coronary artery bypass grafts (CABG) for the treatment of ostial right coronary stenosis (ORCS) lesions. METHODS: Three hundred fifty-nine cases of ORCS lesion were treated via CABG (n = 232) or PCI (n = 127) procedures. Propensity scores for undergoing the CABG procedure were estimated and used to match 105 pairs of patients between the two groups. Kaplan-Meier major adverse cardiac and cerebrovascular events (MACCE)-free curves were constructed to compare long-term MACCE-free survival between the two groups. RESULTS: For the 105 propensity-matched pairs, patients were more likely to undergo repeat revascularization with CABG in the PCI group than in the CABG group during the first 30 days (4 cases vs. 0 case, P= 0.043, χ(2) = 4.08) and the 1-year follow-up (5 cases vs. 0 case, P= 0.02, χ(2) = 5.17). With a mean follow-up of 12.04 ± 6.47 months and a total of 210.67 patient-years, the freedom from MACCE in the CABG group was significantly higher than that in the PCI group (Log rank test, χ(2) = 4.48, P= 0.03). There were no significant differences in the rates of death, myocardial infarction, nonfatal stroke, death/myocardium infarction/stroke, or repeated PCI between the two groups during the first 30 days and during the 1-year follow-up period. CONCLUSION: For OCRS lesions, CABG provided greater protection than PCI procedure in terms of freedom from MACCE, mainly due to the reduced number of repeated revascularization procedures. CABG should be considered as first-choice revascularization strategy for ORCS lesions.