scholarly journals Lessons on the Sigma-1 Receptor in TNBS-Induced Rat Colitis: Modulation of the UCHL-1, IL-6 Pathway

2020 ◽  
Vol 21 (11) ◽  
pp. 4046 ◽  
Author(s):  
Nikoletta Almási ◽  
Szilvia Török ◽  
Szabolcs Dvorácskó ◽  
Csaba Tömböly ◽  
Ákos Csonka ◽  
...  
Keyword(s):  
Radioligand Binding ◽  
Binding Capacity ◽  
Treatment Options ◽  
Experimental Colitis ◽  
Binding Studies ◽  
Trinitrobenzenesulfonic Acid ◽  
Sigma 1 Receptor ◽  
Sigma 1 ◽  
Anti Inflammatory ◽  
Endothelial Nitric Oxide

Inflammatory Bowel Disease (IBD) is an autoimmune ailment of the gastrointestinal (GI) tract, which is characterized by enhanced activation of proinflammatory cytokines. It is suggested that the sigma-1 receptor (σ1R) confers anti-inflammatory effects. As the exact pathogenesis of IBD is still unknown and treatment options are limited, we aimed to investigate the effects of σ1R in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis. To this end, male Wistar–Harlan rats were used to model colitic inflammation through the administration of TNBS. To investigate the effects of σ1R, Fluvoxamine (FLV, σ1R agonist) and BD1063 (σ1R antagonist) were applied via intracolonic administration to the animals once a day for three days. Our radioligand binding studies indicated the existence of σ1Rs as [3H](+)-pentazocine binding sites, and FLV treatment increased the reduced σ1R maximum binding capacity in TNBS-induced colitis. Furthermore, FLV significantly attenuated the colonic damage, the effect of which was abolished by the administration of BD1063. Additionally, FLV potentially increased the expression of ubiquitin C-terminal hydrolase ligase-1 (UCHL-1) and the levels of endothelial nitric oxide synthase (eNOS), and decreased the levels of interleukin-6 (IL-6) and inducible NOS (iNOS) expression. In summary, our study offers evidence for the anti-inflammatory potential of FLV and σ1R in experimental colitis, and our results present a promising approach to the development of new σ1R-targeted treatment options against IBD.

scholarly journals Sigma-1 Receptor Engages an Anti-Inflammatory and Antioxidant Feedback Loop Mediated by Peroxiredoxin in Experimental Colitis

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1081
Author(s):  
Nikoletta Almási ◽  
Szilvia Török ◽  
Zsuzsanna Valkusz ◽  
Máté Tajti ◽  
Ákos Csonka ◽  
...  
Keyword(s):  
Experimental Colitis ◽  
The Body ◽  
Male Rats ◽  
Trinitrobenzenesulfonic Acid ◽  
Simultaneous Treatment ◽  
Sigma 1 Receptor ◽  
Beneficial Effects ◽  
Chronic Inflammatory Condition ◽  
Sigma 1 ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gastrointestinal tract. Since the treatment of IBD is still an unresolved issue, we designed our study to investigate the effect of a novel therapeutic target, sigma-1 receptor (σ1R), considering its ability to activate antioxidant molecules. As a model, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was used to induce colitis in Wistar–Harlan male rats. To test the beneficial effects of σ1R, animals were treated intracolonically (i.c.): (1) separately with an agonist (fluvoxamine (FLV)), (2) with an antagonist of the receptor (BD1063), or (3) as a co-treatment. Our results showed that FLV significantly decreased the severity of inflammation and increased the body weight of the animals. On the contrary, simultaneous treatment of FLV with BD1063 diminished the beneficial effects of FLV. Furthermore, FLV significantly enhanced the levels of glutathione (GSH) and peroxiredoxin 1 (PRDX1) and caused a significant reduction in 3-nitrotyrosine (3-NT) levels, the effects of which were abolished by co-treatment with BD1063. Taken together, our results suggest that the activation of σ1R in TNBS-induced colitis through FLV may be a promising therapeutic strategy, and its protective effect seems to involve the antioxidant pathway system.

Expression and secretion of lipocortin 1 in gut inflammation are not regulated by pituitary-adrenal axis

1997 ◽  
Vol 273 (2) ◽  
pp. R623-R629 ◽  
Author(s):  
N. Vergnolle ◽  
C. Comera ◽  
J. More ◽  
M. Alvinerie ◽  
L. Bueno
Keyword(s):  
Culture Medium ◽  
Experimental Colitis ◽  
Myeloperoxidase Activity ◽  
Trinitrobenzenesulfonic Acid ◽  
Gut Inflammation ◽  
Adrenal Axis ◽  
Histological Damage ◽  
Anti Inflammatory ◽  
Pituitary Adrenal Axis

Lipocortin 1 is considered a mediator of the anti-inflammatory actions of glucocorticoids. We have shown that this protein is overexpressed and secreted during an experimental colitis induced by intraluminal injection of trinitrobenzenesulfonic acid (TNBS) in rats. We studied here the in vivo regulation of lipocortin 1 expression and secretion in this model, either by glucocorticoids using adrenalectomized or dexamethasone-treated (3 mg/24 h) animals or by pituitary factors using hypophysectomized animals. Inflammation was evaluated by measuring myeloperoxidase activity and by histological scoring of the damage. Lipocortin 1 was detected by immunoblotting, and its secretion was studied by incubating colonic specimens in-culture medium. In the colon of TNBS-injected animals, cumulative histological damage scores were increased in adrenalectomized and decreased in dexamethasone-treated animals compared with control and hypophysectomized animals. The colons of all TNBS-injected animals (controls, adrenalectomized, dexamethasone treated, hypophysectomized) overexpressed and secreted lipocortin 1. In conclusion, the induction of lipocortin 1 overexpression and secretion during this colitis occurs independently of glucocorticoids or pituitary factors.

scholarly journals Characterization of bovine endothelial nitric oxide synthase as a homodimer with down-regulated uncoupled NADPH oxidase activity: tetrahydrobiopterin binding kinetics and role of haem in dimerization

1997 ◽  
Vol 323 (1) ◽  
pp. 159-165 ◽  
Author(s):  
Barbara M. LIST ◽  
Burkhard KLÖSCH ◽  
Christof VÖLKER ◽  
Antonius C. F. GORREN ◽  
William C. SESSA ◽  
...  
Keyword(s):  
Radioligand Binding ◽  
Specific Binding ◽  
Gel Filtration ◽  
Binding Studies ◽  
Highly Active ◽  
Additional Protein ◽  
Overexpression System ◽  
Oxide Synthase ◽  
Radioligand Binding Studies ◽  
Endothelial Nitric Oxide

The fatty-acylation-deficient bovine endothelial NO synthase (eNOS) mutant (Gly-2 to Ala-2, G2AeNOS) was purified from a baculovirus overexpression system. The purified protein was soluble and highly active (0.2-0.7 μmol of l-citrulline· mg-1·min-1), contained 0.77±0.01 equivalent of haem per subunit, showed a Soret maximum at 396 nm, and exhibited only minor uncoupling of NADPH oxidation in the absence of l-arginine or tetrahydrobiopterin. Radioligand binding studies revealed KD values of 147±24.1 nM and 52±9.2 nM for specific binding of tetrahydrobiopterin in the absence and presence of 0.1 mM l-arginine respectively. The positive co-operative effect of l-arginine was due to a pronounced decrease in the rate of tetrahydrobiopterin dissociation (from 1.6±0.5 to 0.3±0.1 min-1). Low-temperature SDS gel electrophoresis showed that approx. 80% of the protein migrated as haem-containing dimer after preincubation with l-arginine and tetrahydrobiopterin. Gel-filtration chromatography yielded one peak with a Stokes radius of 6.8±0.04 nm, corresponding to a hydrodynamic volume of 1.32×10-24 m3, whereas haem-deficient preparations (approx. 0.3 equivalent per subunit) contained an additional protein species with a hydrodynamic radius of 5.1±0.2 nm and a corresponding volume of 0.55×10-24 m3, suggesting that haem availability regulates eNOS dimerization.

scholarly journals Intestinal anti-inflammatory effects of RGD-functionalized silk fibroin nanoparticles in trinitrobenzenesulfonic acid-induced experimental colitis in rats

2016 ◽  
Vol Volume 11 ◽  
pp. 5945-5958 ◽  
Author(s):  
Alba Rodriguez-Nogales ◽  
Francesca Algieri ◽  
Laura De Matteis ◽  
A. Abel Lozano-Perez ◽  
Jose Garrido-Mesa ◽  
...  
Keyword(s):  
Silk Fibroin ◽  
Experimental Colitis ◽  
Trinitrobenzenesulfonic Acid ◽  
Silk Fibroin Nanoparticles ◽  
Anti Inflammatory

Characterization of oxytocin receptors in rat adenohypophysis using a radioiodinated receptor antagonist peptide

1989 ◽  
Vol 122 (2) ◽  
pp. 465-470 ◽  
Author(s):  
S. E. Chadio ◽  
F. A. Antoni
Keyword(s):  
Receptor Antagonist ◽  
Radioligand Binding ◽  
Specific Activity ◽  
Dissociation Constants ◽  
Binding Capacity ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Binding Studies ◽  
Single Class ◽  
Oxytocin Receptors

ABSTRACT Oxytocin may function as a hypothalamic releasing hormone for prolactin and ACTH secretion in the rat. In the present study we have investigated the properties of putative oxytocin receptors in the rat adenohypophysis by radioligand-binding assay. A novel oxytocin receptor antagonist [1-(β-mercapto-β,β-cyclopentamethylene propionic acid),2-(ortho-methyl)-Tyr2-Thr4-Orn8-Tyr9-NH2]-vasotocin (OTA) was radioiodinated by the iodogen method to a specific activity of 0·6 nCi/fmol. The radioiodinated derivative 125I-labelled OTA (125I-OTA) was reacted with membrane suspensions prepared from the uterus or adenohypophysis of female rats which were (a) ovariectomized for 7 days, (b) ovariectomized and treated with 5 μg oestradiol-17β 48 h before death or (c) implanted with a piece of silicone elastomer tubing containing 50 mg diethylstilboestrol (DES) 5 days before death. In uterine as well as the pituitary membrane suspensions, the radioligand was bound reversibly and with high affinity (dissociation constants 0·2 ± 0·1 and 0·1±0·01 nmol/l respectively; means + s.e.m., n=3) to a single class of sites with limited binding capacity, which varied with the type of pretreatment. Oestradiol-17β increased the binding capacity fivefold in the uterus in ovariectomized rats, but only very low specific radioligand binding was found in pituitary preparations from the same animals. Treatment with DES markedly increased the number of receptors in both the uterus and the adenohypophysis. Studies with several agonist and antagonist analogues revealed no difference in the ligand specificity of the uterine and adenohypophysial sites binding 125I-OTA, indicating that they are the same species of receptor. Furthermore, ligand-binding studies, carried out with tritiated vasopressin as tracer in pituitary membrane preparations, showed that OTA is not bound by pituitary vasopressin receptors at concentrations below 1 μmol/l. In summary, 125I-OTA is a highly specific radioligand suitable for the analysis of pituitary oxytocin receptors. The low number of oxytocin receptors in the adenohypophysis of rats treated with oestradiol-17β suggests that the prolactin-stimulating action of oxytocin is mediated by highly efficient transmembrane signalling. Journal of Endocrinology (1989) 122, 465–470

scholarly journals Investigation of H2S Donor Treatment on Neutrophil Extracellular Traps in Experimental Colitis

2021 ◽  
Vol 22 (23) ◽  
pp. 12729
Author(s):  
Szilvia Török ◽  
Nikoletta Almási ◽  
Zsuzsanna Valkusz ◽  
Anikó Pósa ◽  
Csaba Varga ◽  
...  
Keyword(s):  
High Mobility ◽  
Experimental Colitis ◽  
Neutrophil Extracellular Traps ◽  
Treated Group ◽  
Arginine Deiminase ◽  
Male Rats ◽  
Trinitrobenzenesulfonic Acid ◽  
Extracellular Traps ◽  
Bowel Diseases ◽  
Anti Inflammatory

Inflammatory bowel diseases (IBD) are chronic, immune-mediated disorders, which affect the gastrointestinal tract with intermittent ulceration. It is increasingly clear that neutrophil extracellular traps (NETs) seem to have a role in IBD; however, the associated pathogenesis is still not known. Furthermore, several conventional therapies are available against IBD, although these might have side effects. Our current study aimed to investigate the effects of hydrogen sulfide (H2S) treatment on NETs formation and on the expression of inflammatory mediators in experimental rat colitis. To model IBD, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was administered intracolonically (i.c.) to Wistar–Harlan male rats. Animals were treated (2 times/day) with H2S donor Lawesson’s reagent per os. Our results showed that H2S treatment significantly decreased the extent of colonic lesions. Furthermore, the expression of members of NETs formation: peptidyl arginine deiminase 4 (PAD4), citrullinated histone H3 (citH3), myeloperoxidase (MPO) and inflammatory regulators, such as nuclear transcription factor-kappa B (NF-κB) and high-mobility group box 1 (HMGB1) were reduced in H2S treated group compared to TNBS. Additionally, H2S donor administration elevated the expression of ubiquitin C-terminal hydroxylase L1 (UCHL-1), a potential anti-inflammatory mediator. Taken together, our results showed that H2S may exert anti-inflammatory effect through the inhibition of NETs formation, which suggests a new therapeutic approach against IBD.

Novel Radioligands for Sigma‐1 Receptor Binding Studies

2008 ◽  
Vol 22 (S2) ◽  
pp. 628-628
Author(s):  
james A Fishback ◽  
Christophe Mesangeau ◽  
Sanju Narayanan ◽  
Christopher R McCurdy ◽  
Rae R Matsumoto
Keyword(s):  
Receptor Binding ◽  
Binding Studies ◽  
Sigma 1 Receptor ◽  
Sigma 1

Pridopidine in the treatment of Huntington’s disease

2020 ◽  
Vol 31 (4) ◽  
pp. 441-451 ◽  
Author(s):  
Magdalena Jabłońska ◽  
Klaudyna Grzelakowska ◽  
Bartłomiej Wiśniewski ◽  
Ewelina Mazur ◽  
Kamil Leis ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuroprotective Effect ◽  
Treatment Options ◽  
D2 Receptor ◽  
Cognitive Disorders ◽  
Symptomatic Treatment ◽  
Sigma 1 Receptor ◽  
Conduction Disorders ◽  
Sigma 1

AbstractHuntington’s disease (HD) is a highly common inherited monogenic neurodegenerative disease, and the gene responsible for its development is located in the 4p16.3 chromosome. The product of that gene mutation is an abnormal huntingtin (Htt) protein that disrupts the neural conduction, thus leading to motor and cognitive disorders. The disease progresses to irreversible changes in the central nervous system (CNS). Although only a few drugs are available to symptomatic treatment, ‘dopamine stabilizers’ (as represented by the pridopidine) may be the new treatment options. The underlying causes of HD are dopaminergic conduction disorders. Initially, the disease is hyperkinetic (chorea) until it eventually reaches the hypokinetic phase. Studies confirmed a correlation between the amount of dopamine in the CNS and the stage of the disease. Pridopidine has the capacity to be a dopamine buffer, which could increase or decrease the dopamine content depending on the disease phase. A research carried out on animal models demonstrated the protective effect of pridopidine on nerve cells thanks to its ability to alter the cortical glutamatergic signaling through the N-methyl-D-aspartate (NMDA) receptors. Studies on dopamine stabilizers also reported that pridopidine has a 100-fold greater affinity for the sigma-1 receptor than for the D2 receptor. Disturbances in the activity of sigma-1 receptors occur in neurodegenerative diseases, including HD. Their interaction with pridopidine results in the neuroprotective effect, which is manifested as an increase in the plasticity of synaptic neurons and prevention of their atrophy within the striatum. To determine the effectiveness of pridopidine in the treatment of HD, large multicenter randomized studies such as HART, MermaiHD, and PRIDE-HD were carried out.

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