Patients with Gaucher disease display systemic oxidative stress dependent on therapy status

Kartha, Reena V.; Terluk, Márcia R.; Brown, Roland; Travis, Abigail; Mishra, Usha; Rudser, Kyle; Lau, Heather; Jarnes, Jeanine R.; Weinreb, Neal J.

doi:10.1016/j.ymgmr.2020.100667

Cited by 14 publications

(12 citation statements)

References 34 publications

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“…The CAT gene encodes catalase, a key antioxidant enzyme that protects aerobic cells from reactive oxygen species (ROS). GD patients are primed for oxidative response complications because they are known to have a severe redox imbalance partially caused by alterations in catalase activity [ 44 ]. While plasma from GD patients has elevated catalase enzymatic activity, GD RBCs have significantly lower catalase activity [ 18 , 45 ].…”

Section: Resultsmentioning

confidence: 99%

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

Serfecz

Saadin

Santiago

et al. 2021

IJMS

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Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic GBA1 mutations that reduce the activity of the lysosomal enzyme β-glucocerebrosidase (GCase). GCase catalyzes the conversion of glucosylceramide (GluCer), a ubiquitous glycosphingolipid, to glucose and ceramide. GCase deficiency causes the accumulation of GluCer and its metabolite glucosylsphingosine (GluSph) in a number of tissues and organs. In the immune system, GCase deficiency deregulates signal transduction events, resulting in an inflammatory environment. It is known that the complement system promotes inflammation, and complement inhibitors are currently being considered as a novel therapy for GD; however, the mechanism by which complement drives systemic macrophage-mediated inflammation remains incompletely understood. To help understand the mechanisms involved, we used human GD-induced pluripotent stem cell (iPSC)-derived macrophages. We found that GD macrophages exhibit exacerbated production of inflammatory cytokines via an innate immune response mediated by receptor 1 for complement component C5a (C5aR1). Quantitative RT-PCR and ELISA assays showed that in the presence of recombinant C5a (rC5a), GD macrophages secreted 8–10-fold higher levels of TNF-α compared to rC5a-stimulated control macrophages. PMX53, a C5aR1 blocker, reversed the enhanced GD macrophage TNF-α production, indicating that the observed effect was predominantly C5aR1-mediated. To further analyze the extent of changes induced by rC5a stimulation, we performed gene array analysis of the rC5a-treated macrophage transcriptomes. We found that rC5a-stimulated GD macrophages exhibit increased expression of genes involved in TNF-α inflammatory responses compared to rC5a-stimulated controls. Our results suggest that rC5a-induced inflammation in GD macrophages activates a unique immune response, supporting the potential use of inhibitors of the C5a-C5aR1 receptor axis to mitigate the chronic inflammatory abnormalities associated with GD.

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Section: Resultsmentioning

confidence: 99%

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

Serfecz

Saadin

Santiago

et al. 2021

IJMS

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“…The formation of MDA and the enhancement of MPO activity will accelerate the in ltration of neutrophils in the kidney tissue and promote the progress of in ammation [38] [39]. As effective antioxidants, SOD and GSH-Px are equally important in response to oxidative stress and regulating the redox state of cells [37,[40][41][42]. Studies also showed that Nrf2, an important antioxidant pathway, protect cells from in ammation through regulation of oxidative stress [43].…”

Section: Discussionmentioning

confidence: 99%

The Inhibitory Impact of Schisandrin Against LPS-Induced Acute Kidney Injury in Vitro and in Vivo

Huang

et al. 2021

Preprint

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Schisandrin (Sch) is a main bioactive component of Schisandra sphenanthera Rehd.et Wils. It has been reported that Sch could regulate inflammatory disease. This study evaluated the anti-inflammatory and anti-oxidant effects effect of Sch on lipopolysaccharide (LPS)-induced macrophages activation and acute kidney injury mice. Male Kunming mice were intraperitoneally injected with LPS (15 mg/kg) after administration of Sch (12.5, 25, 50 mg/kg) seven days for developing acute kidney injury vivo model. RAW264.7 macrophages were pretreatment Sch (10, 20, 40 µM) and administrated LPS (1 µg/ml) to create an in vitro injury model. ELISA results found that Sch administration reduced the production of inflammatory factors induced by LPS in kidney tissues and RAW264.7 macrophages. It has been observed that Sch alleviated oxidative stress by reducing the levels of reactive oxygen species, myeloperoxidase and malondialdehyde, and increasing the activity of superoxide dismutase and glutathione peroxidase. Hematoxylin-eosin staining data suggested that Sch administration significantly reduced inflammatory cell infiltration and the kidney tissue damage induced by LPS. The blood urea nitrogen and creatinine levels were also reduced by Sch treatment. In addition, Western blot and immunohistochemical analysis showed that Sch up-regulated the expression of Nrf2 and HO-1, and decreased the expression of p-p38, p-JNK, p-ERK1/2, p-IκBα, p-NF-κBp65 and TLR4. The current research showed that Sch reduced LPS-induced acute kidney injury by inhibiting inflammation and oxidative stress, and provided insights into potential ways to treat AKI.

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“…According to the impairment of central nervous system function, there are three GD types ( Carubbi et al, 2020 ). Gaucher disease type 1 (GD1) was regarded as the mildest form without obvious neurologic involvement at an early stage, but some GD1 patients developed Parkinson disease phenotype at older age ( Kartha et al, 2020 ). Type 2 is the most severe form and appears as an early onset of neurologic disease with an acute course.…”

Section: Introductionmentioning

confidence: 99%

“…Type 2 is the most severe form and appears as an early onset of neurologic disease with an acute course. Type 3 disease is of intermediate severity with a later onset of neurologic symptoms and a more chronic course ( Kartha et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Establishment and Phenotypic Analysis of the Novel Gaucher Disease Mouse Model With the Partially Humanized Gba1 Gene and F213I Mutation

et al. 2022

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Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the GBA1 gene, which produces the glucocerebrosidase (GCase) protein. There are more than 500 mutations reported in GBA1, among which L444P (p.Leu444Pro) and F213I (p.Phe213Ile) are the most common in the Chinese population, while the function of F213I mutation remains elusive. This study aims to establish the GD mouse model of partially humanized Gba1 gene with F213I mutation. In vitro GCase activity assays showed that the product of partially humanized Gba1 gene, in which the mouse exons 5-7 were replace by the corresponding human exons, displayed similar activity with the wild-type mouse Gba1, while the F213I mutation in the humanized Gba1 led to significant decrease in enzyme activity. ES cell targeting was used to establish the mice expressing the partially humanized Gba1-F213I. Gba1F213I/+ mice did not show obviously abnormal phenotypes, but homozygous Gba1F213I/F213I mice died within 24 h after birth, whose epidermal stratum corneum were abnormal from the wild-type. The GCase activity in Gba1F213I/F213I mice greatly decreased. In conclusion, our results showed that the partially humanized GD mouse model with the F213I mutation was developed and homozygous F213I mutation is lethal for newborn mice.

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Patients with Gaucher disease display systemic oxidative stress dependent on therapy status

Cited by 14 publications

References 34 publications

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

The Inhibitory Impact of Schisandrin Against LPS-Induced Acute Kidney Injury in Vitro and in Vivo

Establishment and Phenotypic Analysis of the Novel Gaucher Disease Mouse Model With the Partially Humanized Gba1 Gene and F213I Mutation

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