Pantethine Prevents Murine Systemic Sclerosis Through the Inhibition of Microparticle Shedding

Kavian, Niloufar; Marut, Wioleta; Servettaz, Amélie; Nicco, Carole; Chéreau, Christiane; Lemaréchal, Hervé; Guilpain, Philippe; Chimini, Giovanna; Galland, Franck; Weill, Bernard; Naquet, Philippe; Batteux, Frédéric

doi:10.1002/art.39121

Cited by 34 publications

(32 citation statements)

References 34 publications

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“…Pantethine is a dietary low-molecular-weight thiol, precursor of vitamin B5, known to reduce metabolic dysfunctions [31–34], decrease inflammation and mediate immune responses [35,36]. In our study we showed that pantethine moderated metabolic dysfunctions and astrocyte reactivity linked to AD-like pathogenesis, suggesting that the compound could help maintain homeostasis and function of the AD brain.…”

Section: Introductionsupporting

confidence: 54%

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Gijsel-Bonnello¹,

Baranger²,

Benech³

et al. 2017

PLoS ONE

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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.

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Section: Introductionsupporting

confidence: 54%

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Gijsel-Bonnello¹,

Baranger²,

Benech³

et al. 2017

PLoS ONE

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“…Consistent with a disrupted endothelial homeostasis [9], we confirmed that EMP release is increased in patients with SSc. The EMPs can promote or aggravate pre-existing vascular dysfunction in cardiovascular diseases [4] and have been shown to be deleterious via the induction of an oxidative burst in a murine model of SSc [47]. In the present study, EMP levels were not associated with disease severity.…”

Section: Discussionmentioning

confidence: 40%

Increased serum levels of fractalkine and mobilisation of CD34+CD45− endothelial progenitor cells in systemic sclerosis

et al. 2017

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BackgroundThe disruption of endothelial homeostasis is a major determinant in the pathogenesis of systemic sclerosis (SSc) and is reflected by soluble and cellular markers of activation, injury and repair. We aimed to provide a combined assessment of endothelial markers to delineate specific profiles associated with SSc disease and its severity.MethodsWe conducted an observational, single-centre study comprising 45 patients with SSc and 41 healthy control subjects. Flow cytometry was used to quantify circulating endothelial microparticles (EMPs) and CD34+ progenitor cell subsets. Colony-forming unit-endothelial cells (CFU-ECs) were counted by culture assay. Circulating endothelial cells were enumerated using anti-CD146-based immunomagnetic separation. Blood levels of endothelin-1, vascular endothelial growth factor (VEGF) and soluble fractalkine (s-Fractalkine) were evaluated by enzyme-linked immunosorbent assay. Disease-associated markers were identified using univariate, correlation and multivariate analyses.ResultsEnhanced numbers of EMPs, CFU-ECs and non-haematopoietic CD34+CD45− endothelial progenitor cells (EPCs) were observed in patients with SSc. Patients with SSc also displayed higher serum levels of VEGF, endothelin-1 and s-Fractalkine. s-Fractalkine levels positively correlated with CD34+CD45− EPC numbers. EMPs, s-Fractalkine and endothelin-1 were independent factors associated with SSc. Patients with high CD34+CD45− EPC numbers had lower forced vital capacity values. Elevated s-Fractalkine levels were associated with disease severity, a higher frequency of pulmonary fibrosis and altered carbon monoxide diffusion.ConclusionsThis study identifies the mobilisation of CD34+CD45− EPCs and high levels of s-Fractalkine as specific features of SSc-associated vascular activation and disease severity. This signature may provide novel insights linking endothelial inflammation and defective repair processes in the pathogenesis of SSc.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1271-7) contains supplementary material, which is available to authorized users.

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“…d -pantethine has been shown to reduce vesicle formation in mice infected with malaria compared to that of non-pantethine treated mice [27,28]. As it inhibits MV release, it so prevents systemic sclerosis in mice, as does knocking out the ABCA1 gene [29]. The most effective inhibitor in this study, Cl-amidine, affects peptidylarginine deiminase activation, which causes post-translational protein deimination.…”

Section: Discussionmentioning

confidence: 99%

Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition of Exosome and Microvesicle Release and Enhanced Efficacy of Cancer Chemotherapy

Kosgodage

Trindade

Thompson

et al. 2017

IJMS

124

164

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Microvesicle (MV) release from tumour cells influences drug retention, contributing to cancer drug resistance. Strategically regulating MV release may increase drug retention within cancer cells and allow for lower doses of chemotherapeutic drugs. The contribution of exosomes to drug retention still remains unknown. Potential exosome and MV (EMV) biogenesis inhibitors, tested on human prostate cancer (PC3) cells for their capacity to inhibit EMV release, were also tested on PC3 and MCF-7 (breast cancer) cells for improving chemotherapy. Agents inhibiting EMV release most significantly, whilst maintaining cell viability, were chloramidine (Cl-amidine; 50 µM) and bisindolylmaleimide-I (10 µM). Apoptosis mediated by the chemotherapy drug 5-fluorouracil (5-FU) was significantly enhanced in PC3 cells in the presence of both these EMV inhibitors, resulting in a 62% (Cl-amidine + 5-FU) and 59% (bisindolylmaleimide-I + 5-FU) decrease in numbers of viable PC3 cells compared to 5-FU alone after 24 h. For MCF-7 cells, there were similar increased reductions of viable cells compared to 5-FU treatment alone ranging from 67% (Cl-amidine + 5-FU) to 58% (bisindolylmaleimide-I + 5-FU). Using combinatory treatment, the two EMV inhibitors further reduced the number of viable cancer cells tested. Neither inhibitor affected cell viability. Combining selected EMV inhibitors may pose as a novel strategy to enhance the efficacy of chemotherapeutic drug-mediated apoptosis.

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Pantethine Prevents Murine Systemic Sclerosis Through the Inhibition of Microparticle Shedding

Cited by 34 publications

References 34 publications

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Increased serum levels of fractalkine and mobilisation of CD34+CD45− endothelial progenitor cells in systemic sclerosis

Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition of Exosome and Microvesicle Release and Enhanced Efficacy of Cancer Chemotherapy

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