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English to Dutch: Ambroxol and its use in Gaucher disease General field: Science Detailed field: Biology (-tech,-chem,micro-)
Source text - English Ambroxol is an over-the-counter drug that is used as an expellant of excessive mucus in the respiratory tracts, and as an agent against inflammation and pain in the throat due to coughing. Some years ago, ambroxol was suggested to act as an allosteric pharmacological chaperone for lysosomal glucocerebrosidase 1 (GBA1), the enzyme that is dysfunctional in patients with Gaucher disease (GD). A dysfunction in GBA1 activity results in lysosomal storage of glycosylceramide (GlcCer) and its deacylated form glucosylsphingosine (GlcSph). This lysosomal stress and lipid storage also results in the marked increase of protein biomarkers, such as chitotriosidase (CHIT1) and CC chemokine ligand 18 (CCL18), among others. The severity of the phenotype in GD patients depends on the residual activity of GBA1, and can include hepatosplenomegaly, anemia, thrombocytopenia, bone pain, arthritis and even neurological defects, the latter of which is exclusive to neuropathic Type 2/3 GD. Besides ambroxol’s role as a chaperone, ambroxol was also shown to regulate transcription by activating Transcription factor EB (TFEB), which promotes lysosomal biogenesis. The molecular structure of ambroxol additionally allows it to penetrate the blood-brain barrier (BBB). Taken together, ambroxol could be an attractive new treatment strategy against Type 2/3 GD, which is currently only treatable palliatively.
Translation - Dutch Ambroxol is een vrij verkrijgbaar medicijn dat wordt gebruikt tegen overmatig slijm in de luchtwegen, en als middel tegen ontsteking en pijn tijdens het hoesten. Enkele jaren geleden werd gespeculeerd dat ambroxol zou kunnen werken als een allosterische farmacologische chaperonne op lysosomale glucocerebrosidase 1 (GBA1), het enzym dat disfunctioneel is bij patiënten met de ziekte van Gaucher (GD). Een disfunctie in de GBA1-activiteit zorgt voor lysosomale opslag van glycosylceramide (GlcCer) en de gedeacyleerde vorm glucosylsphingosine (GlcSph). Deze lysosomale stress en vetopslag zorgt voor een opmerkelijke toename van eiwitbiomarkers, zoals chitotriosidase (CHIT1) en CC chemokine ligand 18 (CCL18), onder anderen. De ernst van het fenotype bij GD-patiënten hangt af van de resterende activiteit van GBA1. Bij ernstige defecten kan er hepatosplenomegalie, anemie, trombocytopenie, botpijn, artritis en zelfs neurodegeneratie optreden, alhoewel het laatste alleen voorkomt bij neuropathische Type 2/3 GD. Naast de rol van ambroxol als chaperonne werd ook aangetoond dat ambroxol de transcriptie reguleert door Transcription factor EB (TFEB) te activeren, wat de lysosomale biogenese aan zet. De moleculaire structuur van ambroxol maakt het bovendien mogelijk om de bloed-hersenbarrière (BBB) te penetreren. Sammenvattend zou ambroxol een aantrekkelijke nieuwe behandelingsstrategie kunnen zijn tegen Type 2/3 GD; een ziekte die momenteel alleen palliatief behandeld kan worden.
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