Activities of genes controlling sphingolipid metabolism in human fibroblasts treated with flavonoids

Abstract

Natural flavonoids such as genistein, kaempferol and daidzein were previously found to be able to reduce efficiency of glycosaminoglycan synthesis in cells of patients suffering from mucopolysaccharidoses, inherited metabolic diseases with often brain disease symptoms. This feature was employed to test these compounds as potential drugs for treatment other neuronopathic lysosomal storage disorders, in which errors in sphingolipid metabolism occur. In this report, on the basis of DNA microarray analyses and quantitative real time PCR experiments, we present evidence that these compounds modify expression of genes coding for enzymes required for metabolism of sphingolipids in human dermal fibroblasts (HDFa). Expression of several genes involved in sphingolipid synthesis was impaired by tested flavonoids. Therefore, it is tempting to speculate that they may be considered as potential drugs in treatment of LSD, in which accumulation of sphingolipids, especially glycosphingolipids, occurs. Nevertheless, further studies on more advances models are required to test this hypothesis and to assess a therapeutic potential for flavonoids in this group of metabolic brain diseases.

Abnormal Sphingolipid World in Inflammation Specific for Lysosomal Storage Diseases and Skin Disorders

“…The latest findings of our group allowed us to learn about a putative flavonoid targetome which is responsible for significant molecular processes, such as an impairment of the production and enhancement of degradation of glycosaminoglycans and sphingolipids [ 204 , 205 , 206 ], or cell cycle and DNA replication regulation [ 207 ]. Transcriptomics analyses indicated that selected flavonoids influence the expression of several genes involved in cellular metabolism.…”

“…As these natural compounds can cross the BBB, it was reasonable considering them as potentially valuable in the treatment for neuronopathic forms of LSDs, including sphingolipidoses, in which accumulation of sphingolipids, especially glycosphingolipids, occurs. Indeed, in our studies we showed that flavonoids also have a significant impact on the expression pattern of dozens of genes involved in sphingolipid metabolism [ 205 ]. The transcriptomic analyses showed that the flavonol kaempferol, the isoflavone genistein and a combination of these two agents profiled the activity of the greatest number of genes.…”

The Role of Dimethyl Sulfoxide (DMSO) in Gene Expression Modulation and Glycosaminoglycan Metabolism in Lysosomal Storage Disorders on an Example of Mucopolysaccharidosis

“…The efficiency of this rationale has been observed using the flavonoid genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)-4 H -1-benzopyran-4-one) in Sanfilippo disease, and miglustat (Zavesca ® ) in Gaucher disease [10]. Many investigations have revealed that due to pleiotropic effects, genistein can be used to modulate pivotal mechanisms in human cells, for instance, the cell cycle [11], metabolism of macromolecules [12] or biogenesis and activity of lysosomes [13,14]. Because patients suffering from different types of MPSs have many defects in cellular processes as mentioned above, this isoflavone is considered as a novel therapeutic agent, especially in a combination therapy with an enzyme.…”

Soy isoflavone ameliorated the alterations in circulating adipokines and microRNAs of mice fed a high-fat diet

“…In addition, the putative target genes of these DEMs are associated with the 'sphingolipid signaling pathway' and the 'mTOR signaling pathway' that are known to be involved in the regulation of homeostasis of cell cycle and metabolism. 33,34 Previous studies reported that isoflavones regulate the expression of several genes associated with the biosynthesis and degradation of sphingolipids in human fibroblasts 35 and reduce ceramide levels by inhibiting its biosynthesis in the heart of rats fed a high-fat diet. 36 Here, we observed that consumption of isoflavone at a dose contained in commercial soy protein isolate products reduced obesity-associated complications in high-fat-fed mice.…”