Stem cell therapy has been noted as a novel strategy to various diseases including neurological disorders such as Alzheimer’s disease, Parkinson’s disease, stroke, amyotrophic lateral sclerosis, and Huntington’s disease that have no effective treatment available to date. The adipose-derived stem cells (ASCs), mesenchymal stem cells (MSCs) isolated from adipose tissue, are well known for their pluripotency with the ability to differentiate into various types of cells and immuno-modulatory property. These biological features make ASCs a promising source for regenerative cell therapy in neurological disorders. Here we discuss the recent progress of regenerative therapies in various neurological disorders utilizing ASCs.
The G protein–coupled receptors (GPCRs) form the largest and the most versatile superfamily that share a seven-transmembrane-spanning architecture. GPCR-signaling is involved in vision, taste, olfaction, sympathetic/parasympathetic nervous functions, metabolism, and immune regulation, indicating that GPCRs are extremely important therapeutic targets for various diseases. Cellular dielectric spectroscopy (CDS) is a novel technology that employs a label-free, real-time and cell-based assay approach for the comprehensive pharmacological evaluation of cells that exogenously or endogenously express GPCRs. Among the biosensors that use CDS technology, the CellKeyTM system not only detects the activation of GPCRs but also distinguishes between signals through different subtypes of the Gα protein (Gs, Gi/o, and Gq). In this review, we discuss the traditional assays and then introduce the principles by which the CellKeyTM system evaluates GPCR activation, followed by a perspective on the advantages and future prospects of this system.
A devastating psychiatric disorder, schizophrenia is characterized by three major symptoms, positive and negative symptoms and cognitive deficit. Almost all current therapeutic drugs for schizophrenia have efficacy for positive symptoms, and weak efficacy for negative and cognitive deficit. In particular, social withdrawal, diminished motivation, and anhedonia as the depressive aspects of negative symptoms are resistant to the treatment of antipsychotic drugs. Therefore, there is a need for development of new therapeutic drugs for negative symptoms of schizophrenia, and it is necessary to have comprehensive animal models to understand the neurobiological foundations of their symptoms. In this review, we represent the behavioral phenotypes in available animal models of schizophrenia for drug discovery, focusing on the depressive aspects of negative symptoms. We mention here animal models based on the pathology and epidemiology of schizophrenia, e.g., the pharmacological, neurodevelopmental, genetic, and gene-environment combination models. The animal models of schizophrenia are developed by various approaches and are assessed, but there are few models demonstrating negative symptoms with sensitivities to available therapeutic drugs. The development of comprehensive animal model reflecting negative symptoms and of novel compounds that can remedy them provide certain insight into the neurobiological process of schizophrenia and also point the way to a new therapeutic strategy.
The serotonin 2C receptor subtype (5-HT2C) has a unique profession and continues to provide exciting and critical new information. The 5-HT2C is modulated at the RNA level by several mechanisms, including editing, short variant generation, and small RNAs. Recently, these phenomena, which had been demonstrated individually, were shown to be associated with each other. At present, many reports provide information about the influence of RNA regulation on receptor protein activities and expression, which was thought to be the final functional product. However, complicated behavior at the RNA stage allows us to imagine that the RNA itself has functional roles in the RNA universe. The 5-HT2C RNA may play several roles. This review will outline previous 5-HT2C studies and prospects for future studies.
A natural p300-specific histone acetyltransferase inhibitor, curcumin, may have a therapeutic potential for heart failure. However, a study of curcumin to identify an appropriate dose for heart failure has yet to be performed. Rats were subjected to a left coronary artery ligation. One week later, rats with a moderate severity of myocardial infarction (MI) were randomly assigned to 4 groups receiving the following: a solvent as a control, a low dose of curcumin (0.5 mg∙kg−1∙day−1), a medium dose of curcumin (5 mg∙kg−1∙day−1), or a high dose of curcumin (50 mg∙kg−1∙day−1). Daily oral treatment was continued for 6 weeks. After treatment, left ventricular (LV) fractional shortening was dose-dependently improved in the high-dose (25.2% ± 1.6%, P < 0.001 vs. vehicle) and medium-dose (19.6% ± 2.4%) groups, but not in the low-dose group (15.5% ± 1.4%) compared with the vehicle group (15.1% ± 0.8%). The histological cardiomyocyte diameter and perivascular fibrosis as well as echocardiographic LV posterior wall thickness dose-dependently decreased in the groups receiving high and medium doses. The beneficial effects of oral curcumin on the post-MI LV systolic function are lower at 5 compared to 50 mg∙kg−1∙day−1 and disappear at 0.5 mg∙kg−1∙day−1. To clinically apply curcumin therapy for heart failure patients, a precise, optimal dose-setting study is required.
The present study investigated cis-unsaturated free fatty acid (FFA)-regulated glucose uptake. In the cell-free assay of protein tyrosine phosphatase 1B (PTP1B), cis-unsaturated FFAs such as linoleic, linolenic, and oleic acid significantly suppressed PTP1B activity in a concentration (1 – 100 μM)-dependent manner, with the highest potential for oleic acid. Oleic acid (1 μM) stimulated insulin (0.1 nM)-induced phosphorylation of the insulin receptor at Tyr1185 and increased insulin (0.1 nM)-induced phosphorylation of Akt at Thr308 and Ser473 in differentiated 3T3-L1-GLUT4myc adipocytes. In the föerster resonance energy transfer analysis, oleic acid activated Rac1 in PC-12 cells, which is inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, the 3-phosphoinositide-dependent protein kinase-1 (PDK1) inhibitor BX912, or the Akt inhibitor MK2206. Oleic acid (1 μM) significantly increased insulin (0.1 nM)-stimulated glucose uptake in 3T3-L1-GLUT4myc adipocytes, although oleic acid by itself had no effect on the glucose uptake. Taken together, the results of the present study show that oleic acid enhances insulin receptor signaling through a pathway along an insulin receptor/PI3K/PDK1/Akt/Rac1 axis in association with PTP1B inhibition and facilitates insulin-induced glucose uptake into adipocytes.
Renal fibrosis is mainly characterized by activation and proliferation of interstitial fibroblasts and by excessive synthesis and accumulation of extracellular matrix (ECM) components, including fibronectin (FN) and collagen. This study investigated the effects of curcumin on proliferation of renal interstitial fibroblasts and their underlying mechanisms in vivo and in vitro. ECM components were visualized by Sirius red and immunohistochemistry staining and quantified by western blot analysis in mice with unilateral ureteral obstruction (UUO). Duplex staining for proliferating cell nuclear antigen and α-smooth muscle actin (α-SMA), as well as MTT and flow cytometry assays, were performed to measure fibroblast proliferation. Protein expression of phosphorylated Smad2/3 (p-Smad2/3) and peroxisome proliferator-activated receptor-γ (PPAR-γ) were assessed by western blotting. Curcumin treatment decreased the accumulation of type I collagen and FN in the kidney of animals with UUO. Activation of rat renal interstitial fibroblasts (NRK-49F) was induced by TGF-β1. Curcumin treatment inhibited fibroblast proliferation and the cell cycle was arrested in the G1 phase. Curcumin treatment upregulated the expression of PPAR-γ and downregulated the expression of p-Smad2/3. These results suggest that curcumin treatment ameliorates renal fibrosis by reducing fibroblast proliferation and ECM accumulation mediated by PPAR-γ and Smad-dependent TGF-β1 signaling.
We investigated the anesthetic effects of propofol on the electrocardiogram (ECG) in mice. We also compared the effects of isoflurane (2%) inhalation anesthesia, intraperitoneal propofol (50 or 100 mg/kg), and pentobarbital (50 mg/kg) on ECG in mice. Isoflurane inhalation and pentobarbital anesthesia were both associated with an acceptable heart rate (HR) range (ca. 450 – 500 bpm). In contrast, high-dose propofol anesthesia significantly decreased the HR. Importantly, propofol anesthesia led to significantly reduced responses to propranolol, a β-blocker, suggesting that it affects sympathetic tonus and is not suitable for the evaluation of cardiovascular or sympathetic function. Propofol also reduced the response to atropine, indicative of suppression of mouse parasympathetic nerve activity. Our data suggest that propofol anesthesia should not be the first choice for cardiovascular analysis in mice.
The anti-inflammatory and anti-hepatotoxic effects of Ampelopsis brevipedunculata (A.bre) have been well known in folk medicine. An ethanol-extract of A.bre has been reported to inhibit carbon tetrachloric acid induced hepatic injury, suggesting that extracted components from A.bre could potentially treat inflammatory disease. To test this hypothesis, in this study, we extracted polysaccharide components from leaves of A.bre and investigated the anti-inflammatory effects in PMA stimulated THP-1 cells. THP-1 cells activated by PMA in the presence or absence of A.bre demonstrated that a water-extract of A.bre inhibited the expression of pro-inflammatory cytokine IL-1β and chemokine CCL-5 in a dose-dependent manner. In addition, A.bre suppressed production of cyclooxygenase (COX)-2 in THP-1 cells activated by PMA. Moreover, A.bre markedly down-regulated the expression of p-JNK1/3, whereas it did not inhibit production of the phosphorylated form of p38 and extracellular signal–regulated kinase in THP-1 cells treated by PMA. Particularly, A.bre inhibited the translocation of transcription factor NF-κB from the cytosol into the nucleus in PMA-stimulated THP-1 cells. Collectively, our data showed that water-extracted A.bre inhibited the protein kinase C–JNKs/NF-κB signaling pathways, resulting in the suppression of IL-1β, CCL-5, and COX-2 expression. This study suggests that water extracted A.bre may be a therapeutic agent against inflammatory disease.
The effects of anesthetics on the transmission and processing of sensory information within the thalamocortical pathway and the underlying mechanism are not fully understood. Using the extracellular recording technique, we investigated the changes of spontaneous and stimulation-evoked activities within and between the ventral posteromedial nucleus (VPM) and primary somatosensory cortex barrel field (S1BF) of the rat in vivo during propofol anesthesia. Spontaneous local field potentials, whiskers deflection–elicited somatosensory evoked potentials, and multi-unit activities in VPM/S1BF were assessed at different depths of propofol anesthesia. In VPM and S1BF, powers of spontaneous and stimulation-evoked activities, coupled with stimulation-evoked multi-unit, were decreased with increasing of propofol anesthesia. Cortical onset latency increased during intermediate/deep level propofol anesthesia, whereas thalamic onset latencies were not changed even at different depths of anesthesia. In addition, spontaneous and whisker deflectionevoked alpha oscillations were observed during propofol anesthesia, which is similar to sleep spindles, These data suggest that propofol affects processing of sensory information by 1) attenuating respective neuronal activities in VPM and S1BF, 2) delaying the ascending signal transmission from VPM to S1BF, and 3) inducing a natural-sleep type of anesthesia.
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