We conducted a genome-wide association study (GWAS) with replication in 36,180 Chinese individuals and performed further transancestry meta-analyses with data from the Psychiatry Genomics Consortium (PGC2). Approximately 95% of the genome-wide significant (GWS) index alleles (or their proxies) from the PGC2 study were overrepresented in Chinese schizophrenia cases, including ∼50% that achieved nominal significance and ∼75% that continued to be GWS in the transancestry analysis. The Chinese-only analysis identified seven GWS loci; three of these also were GWS in the transancestry analyses, which identified 109 GWS loci, thus yielding a total of 113 GWS loci (30 novel) in at least one of these analyses. We observed improvements in the fine-mapping resolution at many susceptibility loci. Our results provide several lines of evidence supporting candidate genes at many loci and highlight some pathways for further research. Together, our findings provide novel insight into the genetic architecture and biological etiology of schizophrenia.

Prostaglandin E2 is now widely recognized to play critical roles in brain inflammation and injury, although the responsible prostaglandin receptors have not been fully identified. We developed a potent and selective antagonist for the prostaglandin E2 receptor subtype EP2, TG6-10-1, with a sufficient pharmacokinetic profile to be used in vivo. We found that in the mouse pilocarpine model of status epilepticus (SE), systemic administration of TG6-10-1 completely recapitulates the effects of conditional ablation of cyclooxygenase-2 from principal forebrain neurons, namely reduced delayed mortality, accelerated recovery from weight loss, reduced brain inflammation, prevention of blood-brain barrier opening, and neuroprotection in the hippocampus, without modifying seizures acutely. Prolonged SE in humans causes high mortality and morbidity that are associated with brain inflammation and injury, but currently the only effective treatment is to stop the seizures quickly enough with anticonvulsants to prevent brain damage. Our results suggest that the prostaglandin receptor EP2 is critically involved in neuroinflammation and neurodegeneration, and point to EP2 receptor antagonism as an adjunctive therapeutic strategy to treat SE.inflammatory cytokine | electroencephalography | epileptogenesis | gliosis | neuronal injury A s a dominant product of cyclooxygenase-2 (COX-2 or PTGS2) in the brain, prostaglandin E2 (PGE 2 ) is emerging as a crucial mediator of many COX-2-driven pathological events in the central nervous system (CNS) (1). PGE 2 acts on four G protein-coupled receptors named EP1, EP2, EP3, and EP4. Among these, the EP2 receptor is widely expressed in the brain and plays important physiologic functions, such as in neuronal plasticity (2, 3). However, recent studies have identified a possible link between EP2 signaling and secondary neurotoxicity in models of chronic inflammation and neurodegeneration (1,(4)(5)(6). In a rodent model of amyotrophic lateral sclerosis, for example, EP2 receptor knockout mice exhibit improved survival, down-regulation of proinflammatory enzymes, and reduced oxidative stress (6).Prolonged status epilepticus (SE) in humans is associated with brain injury and substantial morbidity. Mortality is high during refractory SE that requires general anesthesia (7,8), and the 30-d mortality is about 35-37% for adults who experience at least 60 min of SE (9). Outcome in humans is dependent upon age, etiology, and SE duration (8-10), and currently the only effective treatment is to stop the seizures quickly enough to prevent brain damage (10). Most deaths from nonrefractory SE occur in the 2-wk period after successful treatment rather than during the seizure episode itself (9), pointing to a delayed but cascading set of responsible events. In mice, prolonged SE induced by pilocarpine causes >25% delayed mortality (11), and is associated with a series of molecular and cellular events in the brain, including neurodegeneration, and selective inflammatory reactions involving reactive microglia and a...

With interest waning in the use of cyclooxygenase-2 (COX-2) inhibitors for inflammatory disease, prostaglandin receptors provide alternative targets for the treatment of COX-2-mediated pathological conditions in both the periphery and the central nervous system. Activation of prostaglandin E2 receptor (PGE 2 ) subtype EP2 promotes inflammation and is just beginning to be explored as a therapeutic target. To better understand physiological and pathological functions of the prostaglandin EP2 receptor, we developed a suite of small molecules with a 3-aryl-acrylamide scaffold as selective EP2 antagonists. The 12 most potent compounds displayed competitive antagonism of the human EP2 receptor with K B 2-20 nM in Schild regression analysis and 268-to 4,730-fold selectivity over the prostaglandin EP4 receptor. A brain-permeant compound completely suppressed the up-regulation of COX-2 mRNA in rat cultured microglia by EP2 activation and significantly reduced neuronal injury in hippocampus when administered in mice beginning 1 h after termination of pilocarpine-induced status epilepticus. The salutary actions of this novel group of antagonists raise the possibility that selective block of EP2 signaling via small molecules can be an innovative therapeutic strategy for inflammation-related brain injury.yclooxygenase-2 (COX-2), the inducible isoform of COX, is rapidly up-regulated in damaged tissue, for example in the central nervous system (CNS) after a seizure or cerebral ischemia (1-3). COX-2 induction in CNS overall contributes to inflammation and injury mainly by producing prostanoids (4-7). However, the deleterious cardio-and cerebrovascular side effects from sustained inhibition of COX-2 suggest that some COX-2 downstream prostanoid signaling might be beneficial (8), such that modulation of a specific prostanoid receptor or synthase could be a superior therapeutic strategy compared with generic block of the entire COX-2 cascade. Prostaglandin E2 (PGE 2 ), a dominant enzymatic product of COX-2 in the brain, can activate four Gprotein-coupled receptors (GPCRs): EP1, EP2, EP3, and EP4. Among these, EP2 and EP4 receptors are positively coupled through Gαs to cAMP production (9). In turn, cAMP can initiate multiple downstream events mediated by protein kinase A (PKA) or exchange protein activated by cAMP (Epac) (9).The EP2 receptor is widely expressed in both neurons and glia (3, 10). Neuronal EP2 activation appears to mediate some beneficial effects, such as PKA-dependent neuroprotection in acute models of ischemia and excitotoxicity (3,11,12), early neuroprotection following seizures (13), and promotion of spatial learning (14). Conversely, on the basis of the phenotype of EP2 knockout mice, EP2 activation is thought to promote inflammation and neurotoxicity in animal models of neurodegenerative diseases including Alzheimer's disease (15), Parkinson's disease (16), and amyotrophic lateral sclerosis (10). Glial, especially microglial EP2, is considered to play a major role in brain inflammation associated with chronic ne...

Background-Obesity is a major risk factor for the development of cardiovascular disease. Emerging evidence indicates that leptin, a protein encoded by the obesity gene, is linked with cardiac hypertrophy in obese humans and directly induces cardiomyocyte hypertrophy in vitro. However, the mechanisms by which leptin induces cardiomyocyte hypertrophy are poorly understood. Methods and Results-This study investigated how leptin contributes to cardiomyocyte hypertrophy. Cultured neonatal rat cardiomyocytes were used to evaluate the effects of leptin on hypertrophy. Both endothelin-1 (ET-1) and reactive oxygen species (ROS) levels were elevated in a concentration-dependent manner in cardiomyocytes treated with leptin for 4 hours compared with those cells without leptin treatment. ET-1 stimulated ROS production in a concentrationdependent manner in cardiomyocytes. The augmentation of ROS levels in cardiomyocytes treated with both leptin and ET-1 was reversed by a selective ET A receptor antagonist, ABT-627, and catalase, a hydrogen peroxide-decomposing enzyme. After treatment for 72 hours, leptin or ET-1 concentration-dependently increased total RNA levels, cell surface areas, and protein synthesis in cardiomyocytes, all of which were significantly inhibited by ABT-627 or catalase treatment. Conclusions-These findings indicate that leptin elevates ET-1 and ROS levels, resulting in hypertrophy of cultured neonatal rat cardiac myocytes. The ET-1-ET A -ROS pathway may be involved in cardiomyocyte hypertrophy induced by leptin. ET A receptor antagonists and antioxidant therapy may provide an effective means of ameliorating cardiac dysfunction in obese humans.

Background:Cancer stem cells (CSCs) paradigm suggests that CSCs might have important clinical implications in cancer therapy. Previously, we reported that accumulation efficiency of CSCs is different post low- and high-LET irradiation in 48 h.Methods:Cancer stem cells and non-stem cancer cells (NSCCs) were sorted and functionally identified through a variety of assays such as antigen profiles and sphere formation. Inter-conversion between CSCs and NSCCs were in situ visualised. Cancer stem cells proportions were assayed over multiple generations under normal and irradiation surroundings. Supplement and inhibition of TGF-β1, as well as immunofluorescence assay of E-cadherin and Vimentin, were performed.Results:Surface antigen markers of CSCs and NSCCs exist in an intrinsic homoeostasis state with spontaneous and in situ visualisable inter-conversions, irrespective of prior radiations. Supplement with TGF-β1 accelerates the equilibrium, whereas inhibition of TGF-β signalling disturbs the equilibrium and significantly decreases CSC proportion. Epithelial mesenchymal transition (EMT) might be activated during the process.Conclusion:Our results indicate that the intrinsic inter-conversion and dynamic equilibrium between CSCs and NSCCs exist under normal and irradiation surroundings, and TGF-β might have important roles in the equilibrium through activating EMT.

As a prominent inflammatory effector of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) mediates brain inflammation and injury in many chronic central nervous system (CNS) conditions including seizures and epilepsy, largely through its receptor subtype EP2. However, EP2 receptor activation might also be neuroprotective in models of excitotoxicity and ischemia. These seemingly incongruent observations expose the delicacy of immune and inflammatory signaling in the brain, thus the therapeutic window for quelling neuroinflammation might vary with injury type and target molecule. Here, we identify a therapeutic window for EP2 antagonism to reduce delayed mortality and functional morbidity after status epilepticus (SE) in mice. Importantly, treatment must be delayed relative to SE onset to be effective, a finding that could be explained by the time-course of COX-2 induction after SE and compound pharmacokinetics. A large number of inflammatory mediators were upregulated in hippocampus after SE with COX-2 and IL-1β temporally leading many others. Thus, EP2 antagonism represents a novel anti-inflammatory strategy to treat SE with a tightly-regulated therapeutic window.

Background: Microglial activation contributes strongly to brain inflammation. Results: The modulation of microglial cyclooxygenase-2, iNOS, and cytokine production by EP2 (PTGER2) activation is not blocked by a protein kinase A antagonist but is mimicked by an Epac agonist. Conclusion: Epac signaling pathways prominently contribute to the modulation of microglial activation by EP2. Significance: EP2 and Epac represent potential immunomodulatory targets during brain inflammation.

ObjectiveAutophagy is activated in ischemic heart diseases, but its dynamics and functional roles remain unclear and controversial. In this study, we investigated the dynamics and role of autophagy and the mechanism(s), if any, during postinfarction cardiac remodeling.Methods and resultsAcute myocardial infarction (AMI) was induced by ligating left anterior descending (LAD) coronary artery. Autophagy was found to be induced sharply 12–24 hours after surgery by testing LC3 modification and Electron microscopy. P62 degradation in the infarct border zone was increased from day 0.5 to day 3, and however, decreased from day 5 until day 21 after LAD ligation. These results indicated that autophagy was induced in the acute phase of AMI, and however, impaired in the latter phase of AMI. To investigate the significance of the impaired autophagy in the latter phase of AMI, we treated the mice with Rapamycin (an autophagy enhancer, 2.0 mg/kg/day) or 3-methyladenine (3MA, an autophagy inhibitor, 15 mg/kg/day) one day after LAD ligation until the end of experiment. The results showed that Rapamycin attenuated, while 3MA exacerbated, postinfarction cardiac remodeling and dysfunction respectively. In addition, Rapamycin protected the H9C2 cells against oxygen glucose deprivation in vitro. Specifically, we found that Rapamycin attenuated NFκB activation after LAD ligation. And the inflammatory response in the acute stage of AMI was significantly restrained with Rapamycin treatment. In vitro, inhibition of NFκB restored autophagy in a negative reflex.ConclusionSustained myocardial ischemia impairs cardiomyocyte autophagy, which is an essential mechanism that protects against adverse cardiac remodeling. Augmenting autophagy could be a therapeutic strategy for acute myocardial infarction.