pantetheine and Disease-Models--Animal

Previous studies have demonstrated that Galactooligosaccharides (GOS), known as "bifidus factor", has anti-inflammatory effects. Colitis, a kind of colonic inflammatory damage could be induced by different chemicals. The pathogenesis and mechanism of colitis remains unclear, and may be related to intestinal microflora, genetic susceptibility or immune factors. The aim is to explore the effects of GOS on intestinal flora and its anti-inflammatory effects in Dextran Sulfate Sodium (DSS) induced murine colitis and extrapolate the underlying mechanism.. Initially, 5% DSS was used to induced colitis by free access to drinking water for 5-7 days. Then the mice were treated with GOS 1 day after DSS treatment. Colon samples were evaluated grossly using a microscope. The percentage of Treg and Th17 cells was analyzed by flow cytometry. The levels of cytokines secretion and mRNA expression were detected by ELISA and real-time PCR. The level of protein was detected by western blot.. GOS attenuated DSS induced body weight loss and also reduced the increase in disease index caused by DSS. GOS ameliorated DSS induced colonic histological damage. The protective effect of GOS on DSS induced colitis may be partly attributed to intestinal flora regulation and Th17/Treg imbalance. Furthermore, GOS markedly decreased cytokines (IL-6, IL-18, IL-13 and IL-33) secretion and mRNA expression in colon tissues, through inhibiting activation of NF-κB pathways.. GOS could prevent the DSS induced colitis through intestinal flora regulation and reduce the secretion of inflammation related cytokines relying on the NF-κB signaling pathway.

Topics: Animals; Anti-Inflammatory Agents; Blotting, Western; Colitis; Dextran Sulfate; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Gastrointestinal Microbiome; Mice; Mice, Inbred C57BL; NF-kappa B; Oligosaccharides; Pantetheine; Real-Time Polymerase Chain Reaction; Signal Transduction; T-Lymphocytes, Regulatory; Th17 Cells

The low-molecular weight thiol pantethine, known as a hypolipidemic and hypocholesterolemic agent, is the major precursor of co-enzyme A. We have previously shown that pantethine treatment reduces amyloid-β (Aβ)-induced IL-1β release and alleviates pathological metabolic changes in primary astrocyte cultures. These properties of pantethine prompted us to investigate its potential benefits in vivo in the 5XFAD (Tg) mouse model of Alzheimer's disease (AD).1.5-month-old Tg and wild-type (WT) male mice were submitted to intraperitoneal administration of pantethine or saline control solution for 5.5 months. The effects of such treatments were investigated by performing behavioral tests and evaluating astrogliosis, microgliosis, Αβ deposition, and whole genome expression arrays, using RNAs extracted from the mice hippocampi. We observed that long-term pantethine treatment significantly reduced glial reactivity and Αβ deposition, and abrogated behavioral alteration in Tg mice. Moreover, the transcriptomic profiles revealed that after pantethine treatment, the expression of genes differentially expressed in Tg mice, and in particular those known to be related to AD, were significantly alleviated. Most of the genes overexpressed in Tg compared to WT were involved in inflammation, complement activation, and phagocytosis and were found repressed upon pantethine treatment. In contrast, pantethine restored the expression of a significant number of genes involved in the regulation of Αβ processing and synaptic activities, which were downregulated in Tg mice. Altogether, our data support a beneficial role for long-term pantethine treatment in preserving CNS crucial functions altered by Aβ pathogenesis in Tg mice and highlight the potential efficiency of pantethine to alleviate AD pathology.

Topics: Aggression; Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Drug Administration Schedule; Hippocampus; Humans; Male; Mice; Mice, Transgenic; Pantetheine; Phagocytosis; Time Factors

Astrocytes play critical roles in central nervous system homeostasis and support of neuronal function. A better knowledge of their response may both help understand the pathophysiology of Alzheimer's disease (AD) and implement new therapeutic strategies. We used the 5xFAD transgenic mouse model of AD (Tg thereafter) to generate astrocyte cultures and investigate the impact of the genotype on metabolic changes and astrocytes activation. Metabolomic analysis showed that Tg astrocytes exhibited changes in the glycolytic pathway and tricarboxylic acid (TCA) cycle, compared to wild type (WT) cells. Tg astrocytes displayed also a prominent basal inflammatory status, with accentuated reactivity and increased expression of the inflammatory cytokine interleukin-1 beta (IL-1β). Compensatory mechanisms were activated in Tg astrocytes, including: i) the hexose monophosphate shunt with the consequent production of reducing species; ii) the induction of hypoxia inducible factor-1 alpha (HIF-1α), known to protect against amyloid-β (Aβ) toxicity. Such events were associated with the expression by Tg astrocytes of human isoforms of both amyloid precursor protein (APP) and presenilin-1 (PS1). Similar metabolic and inflammatory changes were induced in WT astrocytes by exogenous Aβ peptide. Pantethine, the vitamin B5 precursor, known to be neuroprotective and anti-inflammatory, alleviated the pathological pattern in Tg astrocytes as well as WT astrocytes treated with Aß. In conclusion, our data enlighten the dual pathogenic/protective role of astrocytes in AD pathology and the potential protective role of pantethine.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Astrocytes; Cell Survival; Cells, Cultured; Citric Acid Cycle; Disease Models, Animal; Gene Expression; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interleukin-1beta; Metabolomics; Mice; Mice, Transgenic; Pantetheine; Pentose Phosphate Pathway; Presenilin-1; RNA, Messenger

Coenzyme A is an essential metabolite known for its central role in over one hundred cellular metabolic reactions. In cells, Coenzyme A is synthesized de novo in five enzymatic steps with vitamin B5 as the starting metabolite, phosphorylated by pantothenate kinase. Mutations in the pantothenate kinase 2 gene cause a severe form of neurodegeneration for which no treatment is available. One therapeutic strategy is to generate Coenzyme A precursors downstream of the defective step in the pathway. Here we describe the synthesis, characteristics and in vivo rescue potential of the acetyl-Coenzyme A precursor S-acetyl-4'-phosphopantetheine as a possible treatment for neurodegeneration associated with pantothenate kinase deficiency.

Topics: Animals; Cell Line; Disease Models, Animal; Drosophila; Heredodegenerative Disorders, Nervous System; Humans; Mice; Pantetheine; Phosphotransferases (Alcohol Group Acceptor); Serum; Treatment Outcome

BACKGROUND Migration of leukocytes into airways is the hallmark of allergic asthma. The aim of this study was to target the pathological process using pantethine, a pleiotropic natural compound which has been recently shown to down-regulate chemokine-driven T cell migration. MATERIAL AND METHODS Mice were sensitized to the Leishmania LACK antigen, then treated or not treated with pantethine and exposed to LACK or saline aerosol. After sacrifice of the animals, cells in the bronchoalveolar lavage were analyzed and inflammatory parameters were determined to evaluate inflammation seriousness. RESULTS As compared to untreated animals, pantethine-treated animals displayed a moderated response to the allergen, as documented by decreased infiltration of inflammatory cells (all types), in addition to reduced levels of lung Th2 cytokines and circulating LACK-specific IgE. CONCLUSIONS These data reveal the potential therapeutic importance of pantethine to moderate allergic asthma pathology. The compound has been previously shown to exert a broad range of protective activity in animals and in humans, with few or no adverse effects.

Topics: Allergens; Animals; Antigens, Protozoan; Bronchoalveolar Lavage; Cytokines; Disease Models, Animal; Down-Regulation; Female; Inflammation; Leukocytes; Lung; Mice; Mice, Inbred BALB C; Pantetheine; Protozoan Proteins

Endothelial cell (EC) damage in systemic sclerosis (SSc) is reflected by the shedding of microparticles (MPs). The aim of this study was to show that inhibiting MP release using pantethine or by inactivating ATP-binding cassette transporter A1 (ABCA1) ameliorates murine SSc.. First, the effects of pantethine on MP shedding and on basal oxidative and nitrosative stresses in ECs and fibroblasts were determined in vitro. The effects of pantethine were then tested in vivo. SSc was induced in BALB/c mice by daily intradermal injection of HOCl. Mice were simultaneously treated daily with pantethine by oral gavage.. In vitro, pantethine inhibited MP shedding from tumor necrosis factor-stimulated ECs and abrogated MP-induced oxidative and nitrosative stresses in ECs and fibroblasts. Ex vivo, pantethine also restored redox homeostasis in fibroblasts from mice with SSc. In vivo, mice with SSc displayed skin and lung fibrosis associated with increased levels of circulating MPs and markers of oxidative and endothelial stress, which were normalized by administration of pantethine or inactivation of ABCA1.. Pantethine is a well-tolerated molecule that represents a potential treatment of human SSc.

Topics: Administration, Oral; Animals; ATP Binding Cassette Transporter 1; Bleomycin; Cell-Derived Microparticles; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Female; Fibroblasts; Homeostasis; Hypochlorous Acid; In Vitro Techniques; Injections, Intradermal; Mice; Mice, Inbred BALB C; Mice, Knockout; Oxidative Stress; Pantetheine; Scleroderma, Systemic; Treatment Outcome

Pantothenate kinase-associated neurodegeneration (PKAN is a neurodegenerative disease with unresolved pathophysiology. Previously, we observed reduced Coenzyme A levels in a Drosophila model for PKAN. Coenzyme A is required for acetyl-Coenzyme A synthesis and acyl groups from the latter are transferred to lysine residues of proteins, in a reaction regulated by acetyltransferases. The tight balance between acetyltransferases and their antagonistic counterparts histone deacetylases is a well-known determining factor for the acetylation status of proteins. However, the influence of Coenzyme A levels on protein acetylation is unknown. Here we investigate whether decreased levels of the central metabolite Coenzyme A induce alterations in protein acetylation and whether this correlates with specific phenotypes of PKAN models. We show that in various organisms proper Coenzyme A metabolism is required for maintenance of histone- and tubulin acetylation, and decreased acetylation of these proteins is associated with an impaired DNA damage response, decreased locomotor function and decreased survival. Decreased protein acetylation and the concurrent phenotypes are partly rescued by pantethine and HDAC inhibitors, suggesting possible directions for future PKAN therapy development.

Topics: Acetylation; Animals; Coenzyme A; Disease Models, Animal; Drosophila; Histones; Humans; Pantetheine; Pantothenate Kinase-Associated Neurodegeneration; Protein Processing, Post-Translational; Tubulin

Dry-eye syndrome affects millions of individuals and it is essential to develop effective therapeutic agents for the treatment of this complex condition. The goal of this study was to evaluate the effect of apolipoprotein A (ApoA)-1 and its synergistic action with d-pantethine (DP) on corneal epithelial disorders in dry-eye mouse model.. Aqueous tear production of C57BL/6J Jms Slc male mice aged 10 to 12 weeks were inhibited by subcutaneous scopolamine injection and mice were placed in a continuous airflow blower to create desiccating environmental stress. During desiccation, 1 eye of each mouse was treated with ApoA-1 (0.01%, 0.04%, or 0.1%) or ApoA-1 (0.04%) + DP (0.05%, 0.1%, or 0.2%) and the other control eye was instilled with phosphate-buffered saline 4 times daily for 5 days. Phenol red thread test, corneal fluorescein staining (score, 0-4), and measurement of corneal epithelial thickness measurements were performed.. Significant reductions of staining scores and higher corneal epithelial thickness values were observed in both ApoA-1- and ApoA-1 + DP-treated groups compared with untreated dry-eye mouse and phosphate-buffered saline-treated group.. These results suggest that ApoA-1 and DP may be potential therapeutic agents for ocular surface epithelial disorders in patients with dry eye.

Topics: Administration, Topical; Animals; Apolipoprotein A-I; Corneal Diseases; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Dry Eye Syndromes; Epithelium, Corneal; Male; Mice; Mice, Inbred C57BL; Ophthalmic Solutions; Pantetheine; Pilot Projects; Treatment Outcome

Few studies have examined the impact of long-term treatments or exposures on the development of cataract in maturity-onset animal models. We studied the effect of treatment with D-pantethine and exposure to ultraviolet-B (UVB) radiation on the development of lenticular opacity in the Emory mouse.. A total of 164 Emory mice were randomized by litter at weaning to exposure to UVB light at 12 mJ/cm(2) for 6 hr/day (UV) or usual room light (A), and within litter, were further randomized to bi-weekly intra-peritoneal injections of 0.8 g/kg pantethine (T) or no treatment (C). Retro illumination lens photos were taken at 2, 4, 6, 8, and 10 months after weaning, and graded in masked fashion. The animals were sacrificed at 10 months and the lenses analyzed for total pantethine and total cysteamine.. Lens pantethine and cysteamine levels were significantly (P < 0.001) higher for the T as compared to C litters. Mean cataract grade increased monotonically over time for all four groups. Unadjusted mean grade for the AT group at 8 (1.32) and 10 (1.86) months appeared lower than for the other groups (AC: 2.17, 2.39; UVC: 1.77, 2.40; UVT: 1.88, 2.37). However, the mean grade for the pantethine-treated litters did not differ significantly from the untreated litters except at 2 months (when untreated litters had significantly lower grades), when adjusting for UV treatment, gender and litter effect. No significant difference in cataract score existed between UV-exposed and ambient litters. Mortality was higher among pantethine-treated (hazard ratio = 1.8, p = 0.05) and UV-exposed animals (hazard ratio = 1.8, p = 0. 03) than among the untreated and unexposed litters.. Significantly increased lens levels of pantethine are achieved with long-term intra-peritoneal dosing. The impact of pantethine on the progression of lenticular opacity in the Emory mouse is less than has been reported in other models. This level of chronic UVB exposure appeared to have no effect on the development of cataract in this model.

Topics: Animals; Cataract; Cysteamine; Disease Models, Animal; Disease Progression; Female; Lens, Crystalline; Male; Mice; Mice, Inbred Strains; Pantetheine; Ultraviolet Rays

To characterize the time period during cataract formation in which administration of pantethine inhibits lens cell opacification in the selenite model for cataract.. Pantethine was administered to neonatal rat pups at selected time points from -0.5 to 17 hours with respect to injection of selenite at time = 0. The injection dose of pantethine was 820 mg/kg (1.5 mmol/kg) diluted in water at 410 mg/ml concentration. The injection dose of selenite was 3.28 mg/kg (19 mumol/kg) diluted in saline at 1.8 mg/ml concentration. Opacification was observed using a slit lamp microscope at selected time points over a 14-day period. Cataracts were staged using a classification of opacity from 0 (normal) to 6 (mature).. The effect of pantethine was characterized by three different time periods: administration -0.5 to 6 hours with respect to selenite injection provided highly significant protection, P < 0.001; administration 8 hours after selenite provided significant protection, P < 0.005; administration 10 to 17 hours after selenite was not protective.. The metabolite pantethine inhibited lens opacification during cataract formation in the selenite model. Even when pantethine was injected several hours after the administration of selenite, opacification was inhibited. Advanced stages of opacification were unresponsive to the administration of pantethine. The inhibitory effect of pantethine was statistically significant when administered during the earliest stage of opacification in the selenite model for cataract.

Topics: Animals; Animals, Newborn; Cataract; Disease Models, Animal; Female; Injections, Subcutaneous; Lens, Crystalline; Male; Pantetheine; Rats; Rats, Sprague-Dawley; Sodium Selenite; Time Factors

Topics: Animals; Clofibrate; Disease Models, Animal; Hyperlipidemias; Hypolipidemic Agents; Lipoproteins, HDL; Male; Pantetheine; Rats; Sulfhydryl Compounds