Sodium phenyl butyrate downregulates endothelin‐1 expression in cultured human endothelial cells: Relevance to sickle‐cell disease

Odièvre, Marie‐Hélène; Brun, Marion; Krishnamoorthy, Rajagopal; Lapouméroulie, Claudine; Élion, Jacques

doi:10.1002/ajh.20709

Cited by 13 publications

(8 citation statements)

References 22 publications

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“…4-PBA is an orally administrated short-chain fatty acid used regularly in treatment of urea cycle disorders [31]. 4-PBA has been shown, both in vitro and in vivo, to promote trafficking of mutant proteins [33,43,93,175,213,215,216,240,261,283,284], as well as to prevent protein aggregation [49], induce differentiation and maturation of malignant cells [6,134,247], influence lipid metabolism [121] and promote protein synthesis [3, 53,54], all with great impact on different types of diseases. The most well studied effect of 4-PBA is in restoring the cystic fibrosis conductance channel to the plasma membrane [213,290] and it has already been tested with some degree of success in human patients with cystic fibrosis [240,289].…”

Section: Resultsmentioning

confidence: 99%

Nephrin is involved in podocyte maturation but not survival during glomerular development

Doné

Takemoto

et al. 2008

Kidney International

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Nephrin, a major component of the glomerular slit diaphragm (SD), is both a structural protein as well as a signaling molecule influencing foot process (FP) formation and maintenance of podocyte integrity. Analyses of near-term embryonic kidneys showed normal cellular viability and no apoptosis in glomeruli from nephrin knockout mice. Moreover, expression and location of other SD or glomerular basement membrane components were similar in wild-type and mutant mice as was the location and levels of most podocyte-specific proteins. Transcriptional profiling showed that the lack of nephrin had minor impact on the expression of genes for FPs and SD proteins. Claudin 3, a tight-junction protein normally absent in glomeruli, was upregulated threefold in the knockout mice, suggesting a role of nephrin in claudin 3 gene expression within the glomeruli. Our results suggest that nephrin is expressed late in the process of podocyte differentiation and is a locus for the formation of SD and FP maintenance and physical integrity in vivo. Nephrin does not seem to have a primary role in cell survival but has a small impact on gene regulation during glomerular development.

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Section: Resultsmentioning

confidence: 99%

Nephrin is involved in podocyte maturation but not survival during glomerular development

Doné

Takemoto

et al. 2008

Kidney International

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“…Increased circulating ET-1 levels have been demonstrated clinically in sickle cell patients during vasoocclusive episodes 122–126. Hydroxyurea is used in the treatment of painful vasoocclusive episodes, and it has been shown to downregulate ET-1 gene expression in endothelial cells 127,128. Children with SCD treated with hydroxyurea have been shown to have levels of circulating ET-1 that were two times lower than those of untreated SCD children or controls 129.…”

Section: Specific Diseasesmentioning

confidence: 99%

Evidence for the endothelin system as an emerging therapeutic target for the treatment of chronic pain

Smith¹,

Haymond²,

Smith³

et al. 2014

JPR

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Many people worldwide suffer from pain and a portion of these sufferers are diagnosed with a chronic pain condition. The management of chronic pain continues to be a challenge, and despite taking prescribed medication for pain, patients continue to have pain of moderate severity. Current pain therapies are often inadequate, with side effects that limit medication adherence. There is a need to identify novel therapeutic targets for the management of chronic pain. One potential candidate for the treatment of chronic pain is therapies aimed at modulating the vasoactive peptide endothelin-1. In addition to vasoactive properties, endothelin-1 has been implicated in pain transmission in both humans and animal models of nociception. Endothelin-1 directly activates nociceptors and potentiates the effect of other algogens, including capsaicin, formalin, and arachidonic acid. In addition, endothelin-1 has been shown to be involved in inflammatory pain, cancer pain, neuropathic pain, diabetic neuropathy, and pain associated with sickle cell disease. Therefore, endothelin-1 may prove a novel therapeutic target for the relief of many types of chronic pain.

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“…4PBA is a known inhibitor of histone deacetylase (HDAC) that could also affect gene expression (Daosukho et al, 2007). 4PBA is FDA-approved and is licensed for the treatment of urea cycle disorders (Iannitti and Palmieri, 2011), sickle cell disease (Odievre et al, 2007), and thalassemia (Collins et al, 1995). Amelogenesis imperfecta (AI) is an inherited disorder of enamel development with an incidence as high as 1 in 700 live births (Backman and Holm, 1986).…”

Section: Introductionmentioning

confidence: 99%

4-phenylbutyrate Mitigates Fluoride-Induced Cytotoxicity in ALC Cells

et al. 2017

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Chronic fluoride over-exposure during pre-eruptive enamel development can cause dental fluorosis. Severe dental fluorosis is characterized by porous, soft enamel that is vulnerable to erosion and decay. The prevalence of dental fluorosis among the population in the USA, India and China is increasing. Other than avoiding excessive intake, treatments to prevent dental fluorosis remain unknown. We previously reported that high-dose fluoride induces endoplasmic reticulum (ER) stress and oxidative stress in ameloblasts. Cell stress induces gene repression, mitochondrial damage and apoptosis. An aromatic fatty acid, 4-phenylbutyrate (4PBA) is a chemical chaperone that interacts with misfolded proteins to prevent ER stress. We hypothesized that 4PBA ameliorates fluoride-induced ER stress in ameloblasts. To determine whether 4PBA protects ameloblasts from fluoride toxicity, we analyzed gene expression of Tgf-β1, Bcl2/Bax ratio and cytochrome-c release in vitro. In vivo, we measured fluorosis levels, enamel hardness and fluoride concentration. Fluoride treated Ameloblast-lineage cells (ALC) had decreased Tgf-β1 expression and this was reversed by 4PBA treatment. The anti-apoptotic Blc2/Bax ratio was significantly increased in ALC cells treated with fluoride/4PBA compared to fluoride treatment alone. Fluoride treatment induced cytochrome-c release from mitochondria into the cytosol and this was inhibited by 4PBA treatment. These results suggest that 4PBA mitigates fluoride-induced gene suppression, apoptosis and mitochondrial damage in vitro. In vivo, C57BL/6J mice were provided fluoridated water for six weeks with either fluoride free control-chow or 4PBA-containing chow (7 g/kg 4PBA). With few exceptions, enamel microhardness, fluorosis levels, and fluoride concentrations of bone and urine did not differ significantly between fluoride treated animals fed with control-chow or 4PBA-chow. Although 4PBA mitigated high-dose fluoride toxicity in vitro, a diet rich in 4PBA did not attenuate dental fluorosis in rodents. Perhaps, not enough intact 4PBA reaches the rodent ameloblasts necessary to reverse the effects of fluoride toxicity. Further studies will be required to optimize protocols for 4PBA administration in vivo in order to evaluate the effect of 4PBA on dental fluorosis.

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Sodium phenyl butyrate downregulates endothelin‐1 expression in cultured human endothelial cells: Relevance to sickle‐cell disease

Cited by 13 publications

References 22 publications

Nephrin is involved in podocyte maturation but not survival during glomerular development

Nephrin is involved in podocyte maturation but not survival during glomerular development

Evidence for the endothelin system as an emerging therapeutic target for the treatment of chronic pain

4-phenylbutyrate Mitigates Fluoride-Induced Cytotoxicity in ALC Cells

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