Effects of flavonoids on glycosaminoglycan synthesis: implications for substrate reduction therapy in Sanfilippo disease and other mucopolysaccharidoses

Sanfilippo disease (mucopolysaccharidosis type III, MPS III) is a severe metabolic disorder caused by accumulation of heparan sulfate (HS), one of glycosaminoglycans (GAGs), due to a genetic defect resulting in a deficiency of GAG hydrolysis. This disorder is characterized as the most severe neurological form of MPS, revealing rapid deterioration of brain functions. Among therapeutic approaches for MPS III, one of the most promising appears to be the substrate reduction therapy (SRT). Genistein (5, 7-dihydroxy-3- (4-hydroxyphenyl)-4H-1-benzopyran-4-one) is an isoflavone that has been used in SRT for MPS III. In this report, we tested effects of other flavonoids (apigenin, daidzein, kaempferol and naringenin) on GAG synthesis. Their cytotoxicity and anti-proliferation features were also tested. We found that daidzein and kaempferol inhibited GAG synthesis significantly. Moreover, these compounds were able to reduce lysosomal storage in MPS IIIA fibroblasts. Interestingly, although genistein is believed to inhibit GAG synthesis by blocking the tyrosine kinase activity of the epidermal growth factor receptor, we found that effects of other flavonoids were not due to this mechanism. In fact, combinations of various flavonoids resulted in significantly more effective inhibition of GAG synthesis than the use of any of these compounds alone. These results, together with results published recently by others, suggest that combination of flavonoids can be considered as a method for improvement of efficiency of SRT for MPS III

The rise of dentine hypersensitivity and tooth wear in an ageing population

Our understanding of the aetiology of dentine hypersensitivity (DH) has changed dramatically over the past few decades. It is no longer an enigma, but other problems exist. The prevalence of DH in the world and in particular in the UK is increasing, predominately due to increases in tooth wear and the erosive dietary intake in the younger population. DH is increasingly reported in all age groups and is shown to provide clinical indication of an active erosive tooth wear. As the population ages and possibly retain teeth for longer, the likelihood of tooth wear and DH could increase. This paper describes the prevalence, aetiology, diagnosis and management of DH in relation to tooth wear, which work together through a surface phenomenon. The aim is to raise awareness of the conditions and to help inform a prevention strategy in an ageing population, which starts from younger age groups to reduce disease into older age

Platelet rich plasma and dentine effect on sheep dental pulp cells regeneration/revitalization ability (in vitro)

Background: Platelet rich plasma (PRP) has been proposed as a scaffold for pulp regeneration/revitalization instead of a blood clot. The aim of the following in vitro study was to evaluate the effect of PRP scaffold on proliferation, migration and differentiation of cultured ovine (sheep) dental pulp cells (ODPC) in the presence of dentine. Methods: PRP was prepared by centrifuging blood at 140 g for 12 min. ODPC were cultured on PRP or platelet poor plasma (PPP) scaffolds with and without dentine discs. Cell proliferation, migration and differentiation rates were assessed. Results: ODPC cultured on PRP scaffold showed significantly greater proliferation rates, migration and mineralization compared with cells on PPP or without a scaffold. Dentine discs reduced the proliferation and mineralization potential of the cells. Conclusions: A PRP scaffold has a positive effect on the proliferation, migration and differentiation of ODPC; however, dentine discs have an adverse effect on the activity of ODPC.M Altaii, X Kaidonis, S Koblar, P Cathro, L Richard

N-butyldeoxynojirimycin treatment restores the innate fear response and improves learning in mucopolysaccharidosis IIIA mice

Available online 13 April 2016Abstract not availableXenia Kaidonis, Sharon Byers, Enzo Ranieri, Peter Sharp, Janice Fletcher, Ainslie Derrick-Robert

Lentiviral-mediated gene therapy results in sustained expression of beta-Glucuronidase for up to 12 Months in the Gus mps/mps and up to 18 Months in the Gus tm(L175F)Sly mouse models of mucopolysaccharidosis type VII

A number of mucopolysaccharidosis type VII (MPS VII) mouse models with different levels of residual enzyme activity have been created replicating the range of clinical phenotypes observed in human MPS VII patients. In this study, a lentivirus encoding murine β-glucuronidase was administered intravenously at birth to both the severe (Gus(mps/mps) strain) and attenuated (Gus(tm(L175F)Sly) strain) mouse models of MPS VII. Circulating enzyme levels were normalized in the Gus(mps/mps) mice and were 3.5-fold higher than normal in the Gus(tm(L175F)Sly) mouse 12 and 18 months after administration. Tissue β-glucuronidase activity increased over untreated levels in all tissues evaluated in both strains at 12 months, and the elevated level was maintained in Gus(tm(L175F)Sly) tissues at 18 months. These elevated enzyme levels reduced glycosaminoglycan storage in the liver, spleen, kidney, and heart in both models. Bone mineral volume decreased toward normal in both models after 12 months of therapy and after 18 months in the Gus(tm(L175F)Sly) mouse. Open-field exploration was improved in 18-month-old treated Gus(tm(L175F)Sly) mice, while spatial learning improved in both 12- and 18-month-old treated Gus(tm(L175F)Sly) mice. Overall, neonatal administration of lentiviral gene therapy resulted in sustained enzyme expression for up to 18 months in murine models of MPS VII. Significant improvements in biochemistry and enzymology as well as functional improvement of bone and behavior deficits in the Gus(tm(L175F)Sly) model were observed. Therapy significantly increased the lifespan of Gus(mps/mps) mice, with 12 months being the longest reported lentiviral treatment for this strain. It is important to assess the long-term outcome on enzyme levels and effect on pathology for lentiviral gene therapy to be a potential therapy for MPS patients.Ainslie L.K. Derrick-Roberts, Carmen E. Pyragius, Xenia M. Kaidonis, Matilda R. Jackson, Donald S. Anson, and Sharon Byer

Characterization of p75 neurotrophin receptor expression in human dental pulp stem cells

Abstract not availableWenru Pan, Karlea L. Kremer, Xenia Kaidonis, Victoria E. Ludlow, Mary-Louise Rogers, Jianling Xie, Christopher G. Proud, Simon A. Kobla

Comparative regenerative mechanisms across different mammalian tissues

Stimulating regeneration of complex tissues and organs after injury to effect complete structural and functional repair, is an attractive therapeutic option that would revolutionize clinical medicine. Compared to many metazoan phyla that show extraordinary regenerative capacity, which in some instances persists throughout life, regeneration in mammalians, particularly humans, is limited or absent. Here we consider recent insights in the elucidation of molecular mechanisms of regeneration that have come from studies of tissue homeostasis and injury repair in mammalian tissues that span the spectrum from little or no self-renewal, to those showing active cell turnover throughout life. These studies highlight the diversity of factors that constrain regeneration, including immune responses, extracellular matrix composition, age, injury type, physiological adaptation, and angiogenic and neurogenic capacity. Despite these constraints, much progress has been made in elucidating key molecular mechanisms that may provide therapeutic targets for the development of future regenerative therapies, as well as previously unidentified developmental paradigms and windows-of-opportunity for improved regenerative repair