Cholesterol metabolism plays an essential role in cellular functions (including as a component of the plasma membrane, as an energy source, and in hormone production) under normal conditions. Dysregulated cholesterol metabolism causes a wide spectrum of pathological conditions, leading to neuropsychiatric disorders, such as anxiety and depression. In addition, patients with neuropsychiatric disorders also have impaired cholesterol metabolism. Therefore, metabolic disturbances are closely associated with the neuropsychiatric disorders. Although immune disturbance, neuroinflammation, a dysregulated neurotransmitter system, and oxidative stress have been suggested as pathophysiology of neuropsychiatric disorders, dysregulation of cholesterol metabolism is also found in patients with psychiatric diseases. As expected, patients with mental illness appear to be at risk of metabolic disorders, including metabolic syndrome, in which cholesterol influences altered neuronal homeostasis, such as neuronal cell toxicity, neuronal cell death, and neuronal structures and functions, including synaptogenesis, neurogenesis, axonogenesis, and action potential. Therefore, reversing impaired or abnormal cholesterol metabolism may help restore neuronal injury found in mental illness. This review is aimed to discuss the links between cholesterol metabolism impairment and neuropsychiatric disorders and provides insights into neuronal dysfunction due to abnormal cholesterol metabolism in neuropsychiatric disorders.

Postoperative cognitive dysfunction (POCD) occurs immediately after surgery and is characterized by impairment of memory and changes in cognition. POCD can last for several months or years and have adverse effects including delayed hospital stays, diminished function in daily life, and increased complications and mortality. Despite improvements in surgical technique, anesthesia management, and intensive care, many patients suffer from POCD. POCD is one of the important clinical issues in surgical management and understanding its pathophysiology is necessary. In this review, therefore, we have focused on animal models of POCD and measurements of cognitive ability in preclinical studies, and we have suggested novel approaches for prevention/treatment of POCD. In preclinical studies, major abdominal surgery (laparotomy, hepatectomy, and splenectomy), minor abdominal surgery (laparotomy, probe exploration), and tibial fracture surgery, are used as POCD models. In addition, cognitive function is assessed by Morris water maze, passive avoidance task, elevated plus maze, and T maze test. Neuroinflammation, blood-brain barrier dysfunction, beta amyloid deposition, and tau phosphorylation are suggested as pathological mechanisms of POCD in preclinical studies. Based on several studies of these, we suggest erythropoietin, nuclear factor kappa B, interleukin17A, tumor necrosis factor alpha, and nicotinamide adenine dinucleotide phosphate oxidase 2 as candidates for prevention/treatment of POCD. In the preclinical stage, drug development/exploration and research is being carried out to solve cognitive dysfunction after surgery. Ultimately, based on the results of preclinical studies, we expect to overcome POCD.
Anesthesia ; Blood-Brain Barrier ; Cognition ; Critical Care ; Erythropoietin ; Hepatectomy ; Humans ; Length of Stay ; Memory ; Models, Animal ; Mortality ; NADP ; NF-kappa B ; Oxidoreductases ; Phosphorylation ; Plaque, Amyloid ; Tibial Fractures ; Tumor Necrosis Factor-alpha ; Water

Immune system is essential for host homeostasis. Immune cells communicate with each other by binding to receptors or by releasing vesicles including chemokines and cytokines. Under healthy circumstances, immune cell-derived factors are critical for cellular growth, division and function, whereas under conditions such as ageing and inflammatory states, they can aggravate pathologies and cause disease. Cell-derived membranous extracellular vesicles mediate cell-to-cell communication and are implicated in various physiological and pathological processes involving ageing and age-related diseases. Extracellular vesicles are responsible for spreading detrimental factors to the surroundings and the propagation phase of inflammatory diseases. The regulation of extracellular vesicles is a putative target for treatment of inflammatory diseases. Moreover, their features are ideal for developing biomarkers and drug delivery systems modulated by bioengineering in inflammatory diseases. The present review summarizes the current understanding of extracellular vesicles in ageing and inflammatory diseases.

Objective: Hypercholesterolaemia transforms macrophages into lipid-laden foam cells in circulation, which can activate the immune response. Compromised autophagy and inflammatory cytokines are involved in the pathogenesis and progression of metabolic diseases.The aim of this study was to identify the role of autophagy as a modulator of the inflammatory response and cytotoxicity in macrophages under hypercholesterolaemic conditions. Methods: High cholesterol-induced cytokine secretion and alteration of autophagyassociated molecules were confirmed by cytokine array and western blot analysis, respectively. To confirm whether autophagic regulation affects high cholesterol-induced cytokine release and cytotoxicity, protein levels of autophagic molecules, cell viability, and cytotoxicity were measured in cultured macrophages treated autophagy enhancers. Results: Cholesterol treatment increased cytokine secretion, cellular toxicity, and lactate dehydrogenase release in lipopolysaccharide (LPS)-primed macrophages. Concomitantly, altered levels of autophagy-related molecules were detected in LPS-primed macrophages under hypercholesterolaemic conditions. Treatment with autophagy enhancers reversed the secretion of cytokines, abnormally expressed autophagy-associated molecules, and cytotoxicity of LPS-primed macrophages. Conclusion Autophagy enhancers inhibit inflammatory cytokine secretion and reduce cytotoxicity under metabolic disturbances, such as hypercholesterolaemia. Modulation of autophagy may be a novel approach to control the inflammatory response observed in metabolic diseases.

Neural stem cells (NSCs) have been suggested as a groundbreaking solution for stroke patients because they have the potential for self-renewal and differentiation into neurons. The differentiation of NSCs into neurons is integral for increasing the therapeutic efficiency of NSCs during inflammation. Apoptosis signal-regulating kinase 1 (ASK1) is preferentially activated by oxidative stress and inflammation, which is the fundamental pathology of brain damage in stroke. ASK1 may be involved in the early inflammation response after stroke and may be related to the differentiation of NSCs because of the relationship between ASK1 and the p38 mitogen-activated protein kinase pathway. Therefore, we investigated whether ASK1 is linked to the differentiation of NSCs under the context of inflammation. On the basis of the results of a microarray analysis, we performed the following experiments: western blot analysis to confirm ASK1, DCX, MAP2, phospho-p38 expression; fluorescence-activated cell sorting assay to estimate cell death; and immunocytochemistry to visualize and confirm the differentiation of cells in brain tissue. Neurosphere size and cell survival were highly maintained in ASK1-suppressed, lipopolysaccharide (LPS)-treated brains compared with only LPS-treated brains. The number of positive cells for MAP2, a neuronal marker, was lower in the ASK1-suppressed group than in the control group. According to our microarray data, phospho-p38 expression was inversely linked to ASK1 suppression, and our immunohistochemistry data showed that slight upregulation of ASK1 by LPS promoted the differentiation of endogenous, neuronal stem cells into neurons, but highly increased ASK1 levels after cerebral ischemic damage led to high levels of cell death. We conclude that ASK1 is regulated in response to the early inflammation phase and regulates the differentiation of NSCs after inflammatory-inducing events, such as ischemic stroke.
Animals ; Cell Death ; Infarction, Middle Cerebral Artery/*metabolism ; Lipopolysaccharides/pharmacology ; MAP Kinase Kinase Kinase 5/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Microtubule-Associated Proteins/genetics/metabolism ; Neural Stem Cells/cytology/drug effects/*metabolism ; *Neurogenesis ; Neuropeptides/genetics/metabolism ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism

Macroautophagy/autophagy is a conserved degradation system that engulfs intracytoplasmic contents, including aggregated proteins and organelles, which is crucial for cellular homeostasis. During aging, cellular factors suggested as the cause of aging have been reported to be associated with progressively compromised autophagy. Dysfunctional autophagy may contribute to age-related diseases, such as neurodegenerative disease, cancer, and metabolic syndrome, in the elderly. Therefore, restoration of impaired autophagy to normal may help to prevent age-related disease and extend lifespan and longevity. Therefore, this review aims to provide an overview of the mechanisms of autophagy underlying cellular aging and the consequent disease. Understanding the mechanisms of autophagy may provide potential information to aid therapeutic interventions in age-related diseases.
Aged ; Aging ; Autophagy ; Cell Aging ; DNA Damage ; Homeostasis ; Humans ; Longevity ; Neurodegenerative Diseases ; Organelles ; Oxidative Stress ; Telomere Shortening

The interleukin-1 receptor antagonist (IL-1RA) is a potential stroke treatment candidate. Intranasal delivery is a novel method thereby a therapeutic protein can be penetrated into the brain parenchyma by bypassing the blood-brain barrier. Thus, this study tested whether intranasal IL-1RA can provide neuroprotection and brain penetration in transient cerebral ischemia. In male Sprague-Dawley rats, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 1 h. The rats simultaneously received 50 mg/kg human IL-1RA through the intranasal (IN group) or intraperitoneal route (IP group). The other rats were given 0.5 mL/kg normal saline (EC group). Neurobehavioral function, infarct size, and the concentration of the administered human IL-1RA in the brain tissue were assessed. In addition, the cellular distribution of intranasal IL-1RA in the brain and its effect on proinflammatory cytokines expression were evaluated. Intranasal IL-1RA improved neurological deficit and reduced infarct size until 7 days after MCAO (p<0.05). The concentrations of the human IL-1RA in the brain tissue 24 h after MCAO were significantly greater in the IN group than in the IP group (p<0.05). The human IL-1RA was confirmed to be co-localized with neuron and microglia. Furthermore, the IN group had lower expression of interleukin-1β and tumor necrosis factor-α at 6 h after MCAO than the EC group (p<0.05). These results suggest that intranasal IL-1RA can reach the brain parenchyma more efficiently and provide superior neuroprotection in the transient focal cerebral ischemia.
Administration, Intranasal* ; Animals ; Blood-Brain Barrier ; Brain ; Brain Ischemia* ; Cytokines ; Humans ; Infarction, Middle Cerebral Artery ; Interleukin 1 Receptor Antagonist Protein ; Interleukin-1* ; Ischemic Attack, Transient ; Male ; Methods ; Microglia ; Models, Animal* ; Necrosis ; Neurons ; Neuroprotection ; Rats* ; Rats, Sprague-Dawley ; Stroke

BACKGROUND: Use of universal leukoreduction for prevention of leukocyte associated transfusion reactions is common practice in many countries. This study was conducted in order to evaluate the performance of a newly developed leukoreduction filter for red blood cells (RBCs), the RF300 (Kolon Industries, Inc, Gumi, Korea). METHODS: Filtration time, RBC recovery, residual leukocyte count, and leukocyte removal rate were evaluated. To assess the quality of RBCs after filtration, percent hemolysis was monitored for a period of 21 days. Performance of the RF300 (N=78) was compared with that of the Bio-R O2 plus (Fresenius, Hamburg, Germany), the Pall Purecell RC (Pall Co., Washington, USA), and the Sepacell R-500N (Asahi, Tokyo, Japan). RESULTS: The shortest filtration time was observed using the RF300 (P<0.05). Using the RF300, recovery of RBC was 96.5%, which was higher than that of two filters (P<0.05). Mean residual leukocyte count was 0.26x10(6)/unit, with a leukocyte removal rate of 3 log. Using the RF300, mean percent hemolysis was 0.32% at day 21, which was comparable with that of two filters, but lower than that of one filter (P<0.05). CONCLUSION: The RF300 meets all established quality requirements for conduct of safe and effective leukoreduction of RBCs.
Blood Group Incompatibility ; Collodion ; Erythrocytes ; Filtration ; Hemolysis ; Leukocyte Count ; Leukocytes ; Tokyo ; Washington

P450 CYP2D6 enzyme(debrisoquine hydroxylase) is known to metabolize many neuroleptics and some genetic polymorphisms in the CYP2D6 gene were reported to be associated with tardive dyskinesia(TD). We investigeted the association of two genetic polymorphisms in the CYP2D6 gene, CYP2D6*4 and CYP2D6*10, with TD in Korean schizophrenic subjects. Subjects consisted of 71 Korean schizophrenics and TD was evaluated using the Abnormal Involuntary Movement Scale(AIMS). There were no statistically significant differences in the demographic variables of age, male to female percentage and the current antipsychotic(CPZ equivalent) dose between the grup with TD and the group without TD. But the duration of antipsychotic drug exposure was siginificantly higher in the group without TD(p=0.000, by independent t-test). The mean AIMS score in the group with TD was 11.2+/-6.6(S.D.). Genotypings ofr the presence of CYP2D6*4 and CYP2D6*10 wee done using PCR amplifications and endonuclease digestions. There were no statistically significant genotypic and alleleic associations between TD and CYP2D6*4(by chi-square tests), and between TD and CYP2D6*10(by chi-square tests). These results indicate that the CYP2D6*4 and CYP2D6*10 polymorphisms have no significant roles in the causation of TD.
Antipsychotic Agents ; Asian Continental Ancestry Group ; Cytochrome P-450 CYP2D6 ; Dyskinesias ; Female ; Humans ; Male ; Movement Disorders* ; Polymerase Chain Reaction ; Polymorphism, Genetic

BACKGROUND: Respiratory mucosa defects result in airway obstruction and infection, requiring subsequent functionalrecovery of the respiratory epithelium. Because site-specific extracellular matrix (ECM) facilitates restoration of organfunction by promoting cellular migration and engraftment, previous studies considered decellularized trachea an idealECM; however, incomplete cell removal from cartilage and mucosal-architecture destruction are frequently reported. Here,we developed a decellularization protocol and applied it to the respiratory mucosa of separated porcine tracheas. METHODS: The trachea was divided into groups according to decellularization protocol: native mucosa, freezing–thawing (FT), FT followed by the use of Perasafe-based chemical agents before mucosal separation (wFTP), after mucosalseparation (mFTP), and followed by DNase decellularization (mFTD). Decellularization efficacy was evaluated by DNAquantification and hematoxylin and eosin staining, and ECM content of the scaffold was evaluated by histologic analysisand glycosaminoglycan and collagen assays. Biocompatibility was assessed by cell-viability assay and in vivotransplantation. RESULTS: The mFTP mucosa showed low antigenicity and maintained the ECM to form a proper microstructure.Additionally, tonsil-derived stem cells remained viable when cultured with or seeded onto mFTP mucosa, and the in vivohost response showed a constructive pattern following implantation of the mFTP scaffolds. CONCLUSION These results demonstrated that xenogenic acellular respiratory mucosa matrix displayed suitable biocompatibilityas a scaffold material for respiratory mucosa engineering.