Pyrofosfaatti, PPi

uutiset Tiede, sitaatti:

" Harvinainen parantumaton sairaus tukki Markku Laitisen valtimot ja vei näön – lääkärin nerokkaan oivalluksen ansiosta tautiin kehitetään nyt lääkettä

Markku Laitisen sairastama PXE-sairaus on diagnosoitu Suomessa vain 28 ihmisellä. Tähän ihoon, silmiin ja verisuoniin vaikuttavaan salakavalasti etenevään sairauteen ei ole olemassa hoitoa. Kunnes Tampereella Taysissa työskentelevä lääkäri Pasi Nevalainen keksi, että sairautta voidaan hoitaa elintarvikkeissa lisäaineena käytettävällä pyrofosfaatilla."

 http://www.socialstyrelsen.se/rarediseases/pseudoxanthomaelasticum#anchor_3

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022264/

Tässä on tärkeä karta PXE asiasta. 

Muistiin 19.3. 2019 

Sitaatti linkistä 2. 

"Background

Pseudoxanthoma elasticum (PXE) is characterized by skin (papular lesions), ocular (subretinal neovascularisation) and cardiovascular manifestations (peripheral artery disease), due to mineralization and fragmentation of elastic fibres in the extracellular matrix (ECM). Caused by mutations in the ABCC6 gene, the mechanisms underlying this disease remain unknown. The knowledge on the molecular background of soft tissue mineralization largely comes from insights in vascular calcification, with involvement of the osteoinductive Transforming Growth Factor beta (TGFβ) family (TGFβ1-3 and Bone Morphogenetic Proteins [BMP]), together with ectonucleotides (ENPP1), Wnt signalling and a variety of local and systemic calcification inhibitors. In this study, we have investigated the relevance of the signalling pathways described in vascular soft tissue mineralization in the PXE knock-out mouse model and in PXE patients.
Methods

The role of the pro-osteogenic pathways  

BMP2-SMADs-RUNX2, 

TGFβ-SMAD2/3 and 

Wnt-MSX2,

 apoptosis and ER stress was evaluated using immunohistochemistry, mRNA expression profiling and immune-co-staining in dermal tissues and fibroblast cultures of PXE patients and the eyes and whiskers of the PXE knock-out mouse. Apoptosis was further evaluated by TUNEL staining and siRNA mediated gene knockdown. ALPL activity in PXE fibroblasts was studied using ALPL stains.

 Results

We demonstrate the upregulation of the BMP2-SMADs-RUNX2 and TGFβ-2-SMAD2/3 pathway, co-localizing with the mineralization sites, and the involvement of MSX2-canonical Wnt signalling. Further, we show that apoptosis is also involved in PXE with activation of Caspases and BCL-2. 

 In contrast to vascular calcification, neither the other BMPs and TGFβs nor endoplasmic reticulum stress pathways seem to be perturbed in PXE.

Conclusions 

Our study shows that we cannot simply extrapolate knowledge on cell signalling in vascular soft tissue calcification to a multisystem ectopic mineralisation disease as PXE. 

Contrary, we demonstrate a specific set of perturbed signalling pathways in PXE patients and the knock-out mouse model. Based on our findings and previously reported data, we propose a preliminary cell model of ECM calcification in PXE. Keywords: Pseudoxanthoma elasticum, Ectopic mineralization, Elastic fibres, Osteogenic signalling pathway, BMP2-SMADs-RUNX2, TGFβ signalling, Canonical Wnt pathway, Apoptosis, Endoplasmic reticulum stress.

ABC- geeneistä

ABCC6 (MRP alaperhettä)
 https://www.ncbi.nlm.nih.gov/gene/4363
Also known as ARA; PXE; MLP1; MRP6; PXE1; URG7; ABC34; GACI2; MOATE; MOAT-E; EST349056
Summary The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). The encoded protein, a member of the MRP subfamily, is involved in multi-drug resistance. Mutations in this gene cause pseudoxanthoma elasticum. Alternatively spliced transcript variants that encode different proteins have been described for this gene. [provided by RefSeq, Jul 2008] Expression Biased expression in liver (RPKM 16.7), kidney (RPKM 9.5) and 9 other tissues See more Orthologsmouse all

URG: BACKGROUND INFORMATION: Up-regulated Gene clone 7 (URG7) is an ER resident protein, whose expression is up-regulated in the presence of hepatitis B virus X antigen (HBxAg) during HBV infection. In virus-infected hepatocytes, URG7 shows an anti-apoptotic activity due to the PI3K/AKT signalling activation, does not seem to have tumorigenic properties, but it appears to promote the development and progression of fibrosis. However, the molecular mechanisms underlying URG7 activity remain largely unknown. To shed light on URG7 activity, we first analysed its interactome in HepG2 transfected cells: this analysis suggests that URG7 could have a role in affecting protein synthesis, folding and promoting proteins degradation. Moreover, keeping into account its subcellular localisation in the ER and that several viral infections give rise to ER stress, a panel of experiments was performed to evaluate a putative role of URG7 in ER stress. Our main results demonstrate that in ER-stressed cells URG7 is able to modulate the expression of Unfolded Protein Response (UPR) markers towards survival outcomes, up-regulating GRP78 protein and down-regulating the pro-apoptotic protein CHOP. Furthermore, URG7 reduces the ER stress by decreasing the amount of unfolded proteins, by increasing both the total protein ubiquitination and the AKT activation and reducing Caspase 3 activation. CONCLUSIONS: All together these data suggest that URG7 plays a pivotal role as a reliever of ER stress-induced apoptosis. SIGNIFICANCE: This is the first characterisation of URG7 activity under ER stress conditions. The results presented here will help to hypothesise new strategies to counteract the antiapoptotic activity of URG7 in the context of the viral infection.