scholarly journals Rare Opportunities for Insights Into Serotonergic Contributions to Brain and Bowel Disorders: Studies of the SERT Ala56 Mouse

2021 ◽  
Vol 15 ◽  
Author(s):  
Samantha E. Stilley ◽  
Randy D. Blakely
Keyword(s):  
Inflammatory Cytokine ◽  
Bowel Function ◽  
Autism Spectrum ◽  
Chromosome 17 ◽  
Compulsive Disorder ◽  
Linkage Marker ◽  
Neurobehavioral Disorders ◽  
P38α Mapk

Altered structure, expression, and regulation of the presynaptic serotonin (5-HT) transporter (SERT) have been associated with multiple neurobehavioral disorders, including mood disorders, obsessive-compulsive disorder (OCD), and autism spectrum disorder (ASD). Opportunities to investigate mechanistic links supporting these associations were spurred with the identification of multiple, rare human SERT coding variants in a study that established a male-specific linkage of ASD to a linkage marker on chromosome 17 which encompassed the location of the SERT gene (SLC6A4). We have explored the most common of these variants, SERT Ala56, in vitro and in vivo. Results support a tonic elevation of 5-HT transport activity in transfected cells and human lymphoblasts by the variant in vitro that leads to an increased 5-HT clearance rate in vivo when studied in the SERT Ala56 mouse model, along with altered sensitivity to SERT regulatory signaling pathways. Importantly, hyperserotonemia, or an elevated whole blood 5-HT, level, was found in SERT Ala56 mice, reproducing a well-replicated trait observed in a significant fraction of ASD subjects. Additionally, we found multiple biochemical, physiological, and behavioral alterations in the SERT Ala56 mice that can be analogized to those observed in ASD and its medical comorbidities. The similarity of the functional impact of the SERT Ala56 variant to the consequences of p38α MAPK activation, ascribed to the induction of a biased conformation of the transporter toward an outward-facing conformation, has resulted in successful efforts to restore normal behavioral and bowel function via pharmacological and genetic p38α MAPK targeting. Moreover, the ability of the inflammatory cytokine IL-1β to enhance SERT activity via a p38α MAPK-dependent pathway suggests that the SERT Ala56 conformation mimics that of a chronic inflammatory state, supporting findings in ASD of elevated inflammatory cytokine levels. In this report, we review studies of the SERT Ala56 variant, discussing opportunities for continued insight into how chronically altered synaptic 5-HT homeostasis can drive reversible, functional perturbations in 5-HT sensitive pathways in the brain and periphery, and how targeting the SERT regulome, particularly through activating pathways such as those involving IL-1β/p38α MAPK, may be of benefit for neurobehavioral disorders, including ASD.

In vivo and in vitro effects of fluoroquinolones on lipopolysaccharide-induced pro-inflammatory cytokine production

2009 ◽  
Vol 15 (3) ◽  
pp. 168-173 ◽  
Author(s):  
Hiromi Ogino ◽  
Miho Fujii ◽  
Mariko Ono ◽  
Kayoko Maezawa ◽  
Junko Kizu ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Inflammatory Cytokine Production ◽  
In Vitro Effects

Abstract 3: Apolipoprotein A-I Inhibits Streptococcal Cell Wall-Induced Arthritis in the Rat in an ABCA1-dependent Manner

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Ben J Wu ◽  
Kwok L Ong ◽  
Sudichhya Shrestha ◽  
Kang Chen ◽  
Philip J Barter ◽  
...  
Keyword(s):  
Cell Wall ◽  
Inflammatory Cytokine ◽  
Density Lipoprotein ◽  
Joint Inflammation ◽  
Chronic Inflammatory Disease ◽  
Dependent Manner ◽  
Tlr2 Expression ◽  
Streptococcal Cell Wall

Introduction. Arthritis is a chronic inflammatory disease characterized by joint inflammation and destruction, reduced high-density lipoprotein (HDL) levels, and increased cardiovascular risk. Objective To determine if apolipoprotein (apo) A-I, the main HDL apolipoprotein, prevents joint inflammation in arthritis. Methods and Results In vivo: Arthritis was induced in female Lewis rats with a single 15 mg/kg intraperitoneal streptococcal cell wall peptidoglycan-polysaccharide (PG-PS) injection and quantified as a combined forepaw and hindpaw inflammation score. Arthritis progressed from an initial, acute phase of joint inflammation during the first 4 days post-PG-PS administration to remission by day 8, followed by chronic joint inflammation up to sacrifice at day 21. Two intravenous infusions of lipid-free apoA-I (8 mg/kg) 24 h pre- and 24 h post-PG-PS injection reduced the acute and chronic joint inflammation by 63±9% at day 3 and by 61±8% at day 21. Infusion of apoA-I at days 7, 9 and 11 post-PG-PS injection reduced the chronic response by 43±11% at day 21. ApoA-I infusions at 24 h prior to and at days 1, 7, 9, 11 post-PG-PS injection reduced joint inflammation by 61±5% at day 3 and by 90±5% at day 21 (p<0.05 for all vs saline infusion). These beneficial effects of apoA-I were accompanied by a reduced inflammatory white blood cell count, reduced pro-inflammatory cytokine levels in synovial fluid, and reduced macrophage accumulation, toll-like receptor 2 (TLR2) and inflammatory cytokine expression in synovial tissue. In vitro: Human monocyte-derived macrophages (HMDMs) were pre-incubated with lipid-free apoA-I, then stimulated with PG-PS (20 μg/mL). Pre-incubation with apoA-I inhibited PG-PS-induced TLR2 and MyD88, a TLR2 adapter protein, expression. Nuclear factor-κB activation and pro-inflammatory cytokine production were also attenuated. These anti-inflammatory effects of apoA-I were abolished in HMDMs transfected with ATP-binding cassette transporter 1 (ABCA1) siRNA. Conclusions These findings establish that apoA-I attenuates PG-PS induced arthritis in the rat. These effects may involve ABCA-1 and inhibition of TLR2 expression and activation.

scholarly journals Rationally synthesized coumarin based pyrazolines ameliorate carrageenan induced inflammation through COX-2/pro-inflammatory cytokine inhibition

MedChemComm ◽  
2019 ◽  
Vol 10 (3) ◽  
pp. 421-430 ◽  
Author(s):  
Priyanka Chandel ◽  
Anoop Kumar ◽  
Nishu Singla ◽  
Anshul Kumar ◽  
Gagandeep Singh ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Inhibition ◽  
Cox 2 ◽  
Anti Inflammatory

In the present work, coumarin based pyrazolines (7a–g) have been synthesized and investigated for their in vitro and in vivo anti-inflammatory potential.

scholarly journals Presynaptic dysfunction in CASK-related neurodevelopmental disorders

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Martin Becker ◽  
Francesca Mastropasqua ◽  
Jan Philipp Reising ◽  
Simon Maier ◽  
Mai-Lan Ho ◽  
...  
Keyword(s):  
Induced Pluripotent Stem Cell ◽  
Splice Site Mutation ◽  
Autism Spectrum ◽  
Resonance Spectroscopy ◽  
Limited Information ◽  
Site Mutation ◽  
Mutation Carriers ◽  
Human Neurons

Abstract CASK-related disorders are genetically defined neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK-mutation consequences and neuronal effects using induced pluripotent stem cell-derived neurons from two mutation carriers. One male case with autism spectrum disorder carried a novel splice-site mutation and a female case with intellectual disability carried an intragenic tandem duplication. We show reduction of CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of genes involved in presynaptic development and of CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory–inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in the brain. Our data show that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.

TC11, a Novel Phthalimide Derivative, Directly Binds to NPM1 and Induced Apoptosis of High-Risk Myeloma Cells Via Centrosomal Disruption

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1841-1841
Author(s):  
Saito Sosei ◽  
Kana Yoshikawa ◽  
Noriko Tabata ◽  
Hiroshi Yanagawa ◽  
Tsukasa Oikawa ◽  
...  
Keyword(s):  
High Risk ◽  
Bone Disease ◽  
Chromosomal Abnormalities ◽  
Scid Mice ◽  
Chromosome 17 ◽  
Dependent Manner ◽  
Phthalimide Derivative ◽  
Induced Apoptosis

Abstract Abstract 1841 PURPOSE: Despite recent advances in the treatment of multiple myeloma (MM), patients with high-risk chromosomal changes such as del13q, t(4;14) or del17p revealed significantly shorter survival. In addition, bone disease markedly reduces quality of life of the patients with MM. To overcome these problems, we have designed and screened synthetic phthalimides which significantly inhibited the growth of MM cell lines with high-risk chromosomal abnormalities. The purposes of this study are to explore novel drugs which possess anti-tumor activity against high-risk MM cells and to examine the anti-osteoclastogenic activity and to isolate directly binding molecules. METHODS AND RESULTS: Thirty synthetic phthalimides were screened for anti-proliferative effect on KMS34 cells with t(4;14) and deletion of chromosome 17. A phthalimide derivative, 2-(2,6-diisopropylphenyl)- 5-amino- 1H-isoindole- 1,3- dione (TC11) significantly inhibited growth of KMS34 cells as well as other MM cells lines with high-risk chromosomal abnormalities (IC50 to KMS34 cells= 4μM). TC11 increased annexin V fraction and induced apoptosis in a caspase-dependent manner. In vivo anti-myeloma activity was evaluated using KMS34-bearing lcr/SCID mice by intraperitoneal injection of TC11. Twenty mg/kg of TC11 significantly inhibited growth of TC11-derived tumor cells, and apoptosis of MM cells was observed by histopathological examination. In order to evaluate hematological toxicity of TC11, growth of colony-forming cells was examined. In the presence of 5μM of TC11, formation of CFCs was not suppressed, suggesting low hematopoietic toxicity. In pharmacokinetic study using lcr/SCID mice, the plasma concentrations of TC11 was examined; Cmax=18.1μM, Tmax=1.5hr, T1/2 =4.5hr when 100mg/kg of TC11 was injected, and Cmax=2.1μM Tmax=1.0hr, T1/2 =4.5hr when 20mg/kg was injected. In order to examine efficacy to bone disease, anti-osteoclastogenic activity was examined by adding TC11 to M-CSF/RANK ligand-induced osteoclastogenic culture of mouse bone marrow mononuclear cells. The number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts was reduced in the presence of 1μM of TC11. It was also found that TC11 inhibited bone resorption by pit assay. We also tried to isolate directly binding proteins to TC11 by our unique in vitro selection system using mRNA display, in vitro virus (IVV) method. We identified nucleophosmin 1 (NPM1) as a TC11-binding molecule. Knockdown assay introducing siRNA for NPM1 into HeLa cells induced emergence of the cells with multipolar spindles, suggesting centrosomal disruption during cell division. Since NPM1 gene localizes at chromosome 5q, anti-MDS effect of TC11 was also examined. TC11 also inhibited growth of MDS-L cells (IC50=7μM). CONCLUSION: A novel phthalimide derivative, TC11, has anti-MM activity in vivo and is a potentially effective drug for high-risk MM with bone lesions. TC11 directly binds to NPM1 and induces apoptosis of MM and MDS cells with low toxicity to normal hematopoiesis. Disclosures: No relevant conflicts of interest to declare.

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