The Effect of Cysteamine Bitartrate on Adiponectin Multimerization in Non-Alcoholic Fatty Liver Disease and Healthy Subjects

Dohil, Ranjan; Meyer, Lauren; Schmeltzer, Susanne; Cabrera, Betty L.; Lavine, Joel E.; Phillips, Susan A.

doi:10.1016/j.jpeds.2012.04.011

Cited by 27 publications

(15 citation statements)

References 30 publications

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“…In a small pilot study in children with nonalcoholic fatty acid liver disease, cysteamine was reported to normalize liver function tests, but liver histology was not available to determine whether hepatic fibrosis was attenuated. 13,14 Although the drug was added to the drinking water in this study and thus the delivered doses are estimated and are much higher than typically administered to humans (typically 30-50 mg/kg per day), the observed peak plasma levels in this study (15-20 mM) were comparable with those observed in cystinotic patients. Due to the short t ½ of cysteamine (94-114 min 28,29 ), "therapeutic" cysteamine levels were only observed overnight while the animals were drinking.…”

Section: Discussionmentioning

confidence: 52%

“…Recent studies suggest that cysteamine may have several other potential therapeutic applications beyond cystinosis, such as neurodegenerative disease, 11 cancer, 12 and nonalcoholic liver disease. 13,14 In this study, we investigated the effects of cysteamine bitartrate therapy in two mouse models of CKD unrelated to cystinosis. The findings provide evidence that cysteamine bitartrate has significant fibrosis-attenuating properties and implicate reduced oxidative stress and attenuated myofibroblast responses as mechanisms.…”

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confidence: 99%

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Cysteamine Modulates Oxidative Stress and Blocks Myofibroblast Activity in CKD

Okamura

Bahrami

Ren

et al. 2014

Journal of the American Society of Nephrology

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Therapy to slow the relentless expansion of interstitial extracellular matrix that leads to renal functional decline in patients with CKD is currently lacking. Because chronic kidney injury increases tissue oxidative stress, we evaluated the antifibrotic efficacy of cysteamine bitartrate, an antioxidant therapy for patients with nephropathic cystinosis, in a mouse model of unilateral ureteral obstruction. Fresh cysteamine (600 mg/kg) was added to drinking water daily beginning on the day of surgery, and outcomes were assessed on days 7, 14, and 21 after surgery. Plasma cysteamine levels showed diurnal variation, with peak levels similar to those observed in patients with cystinosis. In cysteamine-treated mice, fibrosis severity decreased significantly at 14 and 21 days after unilateral ureteral obstruction, and renal oxidized protein levels decreased at each time point, suggesting reduced oxidative stress. Consistent with these results, treatment of cultured macrophages with cysteamine reduced cellular generation of reactive oxygen species. Furthermore, treatment with cysteamine reduced a-smooth muscle actin-positive interstitial myofibroblast proliferation and mRNA levels of extracellular matrix proteins in mice and attenuated myofibroblast differentiation and proliferation in vitro, but did not augment TGF-b signaling. In a study of renal ischemia reperfusion, cysteamine therapy initiated 10 days after injury and continued for 14 days decreased renal fibrosis by 40%. Taken together, these data suggest previously unrecognized antifibrotic actions of cysteamine via TGF-b-independent mechanisms that include oxidative stress reduction and attenuation of the myofibroblast response to kidney injury and support further investigation into the potential benefit of cysteamine therapy in the treatment of CKD.

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Section: Discussionmentioning

confidence: 52%

mentioning

confidence: 99%

Cysteamine Modulates Oxidative Stress and Blocks Myofibroblast Activity in CKD

Okamura

Bahrami

Ren

et al. 2014

Journal of the American Society of Nephrology

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“…32 Morever, clinical trials suggest the efficacy of cysteamine in children suffering from nonalcoholic fatty liver disease. 33 Driven by the excellent safety profile of cysteamine, we investigated whether the oral administration of this compound could rescue CFTR function and improve CF symptoms in vivo. Here we report the therapeutic effect of cysteamine on Cftr F508del mice as well as the capacity of cysteamine to improve CFTR function of ex vivo cultured airway epithelia from CF patients carrying the F508del-CFTR mutation.…”

Section: F508delmentioning

confidence: 99%

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

et al. 2014

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These authors equally contributed to this work.Keywords: cystic fibrosis, CFTR, autophagy, cysteamine, epigallocatechin gallate, sweat chloride Abbreviations: BECN1/Beclin 1, autophagy-related; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CHX, cycloheximide; CSNK2, casein kinase 2; CXCL2, chemokine (C-X-C motif) ligand 2; CXCL8, chemokine (C-X-C motif) ligand 8; EGCG, epigallocatechin gallate; FEV, forced expiratory volume; PM, plasma membrane; RPD, rectal potential difference; SQSTM1, sequestosome 1; TGM2, transglutaminase 2; TNF, tumor necrosis factor.Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in Cftr F508del homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/ TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation.

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“…After cysteamine ingestion, a peak concentration in plasma is reached after approximately one hour. Doses of cysteamine of 15-20 mg/kg lead to a peak plasma concentration of 30-50 μM (Besouw et al 2007, Smolin et al 1988) whereas ingestion of cysteamine together with food decreases the absorption of the drug by approximately 30% (Dohil et al 2012). …”

Section: Caveatsmentioning

confidence: 99%

“…Therefore, the assessment of cellular and plasma levels of therapeutically administered cysteamine is of utmost importance for disease management. Thiol compounds have been detected by a variety of reagents and separation techniques such as HPLC, GC, CE and mass spectrometry between others as it has been published (Bayle et al 2004, Carlucci and Tabucchi 2009, Dohil et al 2012, Kataoka et al 1994, McMenamin et al 2009, Soriano et al 2012). It is uncertain whether cysteamine plasma levels reflect cysteamine tissue levels.…”

Section: Caveatsmentioning

confidence: 99%

Cysteamine revisited: repair of arginine to cysteine mutations

Gallego

Hannibal

Häberle

et al. 2017

J of Inher Metab Disea

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Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides “proof of principle” that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since Arg to Cys changes comprise in general about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.

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The Effect of Cysteamine Bitartrate on Adiponectin Multimerization in Non-Alcoholic Fatty Liver Disease and Healthy Subjects

Cited by 27 publications

References 30 publications

Cysteamine Modulates Oxidative Stress and Blocks Myofibroblast Activity in CKD

Cysteamine Modulates Oxidative Stress and Blocks Myofibroblast Activity in CKD

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

Cysteamine revisited: repair of arginine to cysteine mutations

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