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Why is PPS Such an Efffective Anti NvCJD Agent Revised

Why is PPS Such an Efffective Anti NvCJD Agent Revised

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Published by Newdeersci
Sulfated polysaccharides (pentosan polysulfates)obtained from algal extracts are potent anti-HIV agents and because of their broad spectrum anti-pathogen activities are suggested to be of continued interest for the treatment of AIDS
Sulfated polysaccharides (pentosan polysulfates)obtained from algal extracts are potent anti-HIV agents and because of their broad spectrum anti-pathogen activities are suggested to be of continued interest for the treatment of AIDS

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05/15/2012

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Why is pentosan polysulphate (PPS) so uniquely highly effective as ananti v-Creutzfeldt Jacob Disease (vCJD) therapeutic agent?Could this property also be of therapeutic value for the treatment of AIDS?
 Note by David Grant Turriff/A. U. 25/4/08*
Summary
 It is suggested that heparin-like drugs (which are well known to be intrinsically well tolerated and have minimal side effects)offer an unique broad spectrum of anti-pathogen actions which include the inhibition of retroviral cellular uptake and replication as well as the inhibition of other AIDS-associated opportunistic infections which suggests that these properties could be of value for use for the long term therapeutic intervention in AIDS.
Heparin-like substances are known to possess potent broad-spectrum anti-pathogen activities includinganti-viral including the kind of anti-retroviral actions which could be of value in treating AIDS victimsfor which the ability of (
e.g 
. the inhibition HIV-1 viral host cell entry and separately inhibition of reverse transcriptase by low molecular weight heparin are likely components of the possible therapeutic benefit of these anionic polysaccharides (
cf. e.g 
. Witrouw & DeClercq; Baba
et al 
.). Howell
et al.
have confirmed that low molecular weight heparin is a promising therapeutic agent for AIDS-relatedmedication formulation. It should also be noted that the heparin-mimetic substances pentosan polysulphates (PPS) are potentanti HIV-1 agents (
e.g 
. Stone
et al 
.) (
cf 
. Grant (1)). It should further be noted that since certain dietaryfactors (
vide infra
) and exogenous heparin (
cf 
. Pinhal
et al 
.) can augment the amounts of endogenousheparin (identified by Engelberg many years ago) which is likely to provide a natural anti-HIV defenceactivity in the bloodstream. This may be further dependent on the redox status of the blood especiallythe presence of nitric oxide and its metabolites which can generate low-molecular-weight-heparin-like-agents
in vivo
and conversely since some dietary factors such as toxic metals and excess fluoride arealso believed to be capable of diminishing this endogenous putative antiviral heparin, an inappropriatediet might be predicted, at least in principle, to negatively affect the progression of AIDS. AIDS-related mortalityseems to be an AIDS-dementia-related phenomenon.
Although research into the cause of AIDS –related dementia associated death is in its infancy, such dementia could, it is thought,arise
inter alia
 
via
Creutzfeldt Jacob-like disease processes which are known to be caused by infectious misfolded prions [
Cf 
.
e.g 
.UCSF; Leblanc
et al 
.].
Bone
et al.
have recently indicated that patients suffering from advanced prion induced encepalopathyapparently can benefit from the direct infusion of PPS into the brain. This finding might suggest that asimilar procedure could also conceivably benefit advanced-stage AIDS patients.It is now proposed that the dual anti-viral and anti-prion activity of PPS arises because this man-madesemi-synthetic sulphated wood-derived xylan [SP54] or marine algal polysaccharide xylans (Grant (1))can mimic animal heparin sulphate (HS) and chondroitin sulphate (ChS) fragments for broad-spectrum(nonspecific immune) tissue protection functions. It should be noted that HS and its derived fragmentscan also bind and regulate the activity of numerous proteinases and growth factors,
e.g 
., during normalwound healing (Bernfield
et al 
.) and a related functions in cancer (
cf.
Zaslaw
et al 
.) as well asconferring anti-pathogen protection by inhibiting viral entry to cells and (and also inhibiting key proteins needed for viral replication and function) and also demonstrate anti-bacterial and anti- protozoan activities (
cf.
Sinnnis
et al 
.;
cf.
also
e.g.
Djanani
et al 
.and
e.g 
. Bjork 
et al.
).HS also provides binding sites for antioxidant enzymes (Adachi
et al 
.)and may also demonstrate (like chitosan (Sipos et al.) and hyaluronan (Merce et al.))the ability to sequester Fenton-hydroxyl radical generating redox metals (Albertini
et al 
.; Grant
et al 
.a).HS is known to create oligosaccharides by both enzymic and inorganic-chemistry determined (Cu,Zn, NO-dependent) routes; these, together with the parent HS polysaccharides, are known to participate inconventional immune system cellular immune surveillance activities as well as protecting cells frommisfolded proteins (the endocytosis of such oligosaccharides evidently can act to remove suchmisfolded prion proteins from cells (
cf., e.g.
Greenwood
et al 
.).However, perhaps the most pertinent tissue protective role of HS and PPS is their ability to inhibit the
in vivo
formation of a wide variety of solid deposits including amyloid fibrils, misfolded prion -derivedfibrils and inorganic crystals and their associated organic proteinaceous/lipid complexes which are possibly the ultimate disease promoting agents
in vivo.
This ability seems to arise from a general chaperone-like activity afforded by these sulphated polysaccharides which seems to derive ultimately from their ability to affect the supramoleulcar structure of water (
e.g 
. by the formation of –SO
4-
-(H
2
O)
n
clusters).
 
This may be a related function to why increasing amounts of heparin sulphate and related polysaccharides are needed (putatively to prevent tissue disintegration at higher salinities) by aquaticorganisms exposed to saline habitat waters which demonstrate a strict mathematical relationship between the salinities of these solutions and their tissue contents of HS(Nader 
et al 
.).Evidence that HS is able to act in a servo feedback manner to combat the presence of damaging crystalis that in the kidney Ca-oxalate signals for increased biosynthesis of anti-Ca-oxalate HS (Borges
et al.
);(increased formation of highly sulphated HS molecules which have been demonstrated by
in vitro
experiments to efficiently deactivate Ca-oxalate scale seed crystals (Yamaguchi
et al 
.).Other hints that HS protects cells form crystalline materials which can signal for cell growth in aneoplasia-related scenario is that HS is a potent inhibitor of calcification of CaCO
3
, hydroxyapatite andother related solids (Grant
et al 
. c)(While benign breast cancer is associated with the presence of weddelite microcrystalline formations(Going
et al 
.) when these formations consist of hydroxyapatite-like particles this indicates the presenceof malignant lesions; calcium phosphate particles, it should be noted, can also show mitogen-likeactions
 per se
in
in vitro
cell culture experiments and hydroxyapatite seems to promote mitogenesis andmatrix metalloproteinase expression in human breast cancer cell lines (Morgan
et al 
.). The well-known anti-cancer, anti-metastatic action of pharmaceutical heparin or other non anticoagulantheparin-like molecules can be attributed, at least in part, to the inhibition of MMP-2 activity byheparin/HS (Munesues
et al 
.)HS has similar anti-scale activity to the (man-made) bisphosphonate anti-scale agents which have beenfound useful for the treatment of osteoporosis and other diseases Grant
et al 
. b
cf 
. Russell &Graham),during which procedures an anti-breast cancer side-effect of these drugs was discovered (
cf 
.Fleisch
et al 
.; Sasaki
et al 
.) which has now been attributed to the modulation by the bisphosphonatesdrugs of the activity of metalloproteinases which have been separately associated with tumour metastasis and HS shedding, suggesting that the effect of bisphosphonate treatment is to spare tissue protective HS from excessive depletion arising from tumour-associated augmentation of metalloproteinase secretions.
GAGs have also been reported to occur in association with those Si and Ca containing solids which seem to be key determiningfactors in how excessive ingestion of saccharin promotes cancer in the urinary system of male rats (Cohen
et al 
). These GAGsseemed mainly to consist of ChS (being similar to the GAGs which associated with urinary stones in humans) and perhaps alsoto those GAGs (which now include HS) which have been associated with human amyloid plaques in Alzheimer’s disease and prion diseases.The existence of GAGs associated with such inorganic plaques as well as with protein fibril plaques, arises, it is now suggested,from a failed attempts by the organism to limit the formation of such plaques by the building of a plaque surface GAG-containing barrier.In normal subjects if such fibrils begin to form this activity will be potentially inhibited by sucha surface coverage which neutralizes the potential toxicity of various inorganic surfaces which are ingested or formed in situ in biological tissues.For the optimization of such neutralization activity the organism is required to match the surfaces to be deactivated by anappropriate spaced anionic pattern-GAGs of matched structure which are likely to be needed to bind to the active growth sites attheir surfaces. A ploy which seems to be used by many species is the secretion of mast cell heparin which is a cocktailcontaining a wide variety of HS-like molecules which will likely contain the matching blocking sub-structures needed to matchvarious mineral surfaces.Xylans form plants and algae also contain a similar cocktail which upon further sulphation generate a heparin-like diversity of anionic sites.An elegant demonstration of how GAG analogues (alginates) in marine algae act in this is that the seeded crystallization of BaSO
4
is inhibited in a microstructurally-dependent manner byalginates (seven alginates of different defined gululanate mannuronate blockiness were fractionated from native mixture; thesefractions showed a hierarchy of microstructural-dependent values of the second order rate constant for formation of BaSO
4
crystals)(Grant
et al.
d).
All of the diseases which are known to be associated with and or promoted by plaques of various kindsarise, it is now suggested, from an inappropriate GAG/HS response to the initial generation of plaques by the organism.This could be due to the occurrence of excessive GAG degradation (
e.g.
for HS by free radicaldegradation, by heparanase action as well as by metalloproteinase shedding or NO-dependent routes(the latter is perhaps most characteristic of arthritic diseases) or from failure in the primary HS biosynthetic process to produce the necessary correctly designed of anti-plaque HS or ChS polysaccharides. If HS N-SO
3-
groups are replaced by NH
2
groups the modified HS polysaccharide no
 
longer binds Ca
2+
(Liang
et al 
.
cf 
. Long & Williamson; Hamakaki
et al 
.) and changes from an anti- plaque-forming agent into a plaque formation promoter.Defective anti-plaque polysaccharide scenarios could arise from some dietary insufficiency of cofactorsknown to promote or diminish correct GAG/HS biosynthesis (as have been established by cell culturestudies). These include the inorganic ions Ca
2+
[Takeuchi
et al.
]Mg
2+
[Jaya & Kurup] and Mn
2+
[Kalea
et al 
.] and a variety of organic dietary factors: e.g. retinoic acid[Zhang
et al 
.] and ascorbate [Edward & Oliver] with boost the biosynthesis of more highly sulphatedHS molecules; various HS-diminishing effects are known to be produced by the effects of excessiveconcentrations of blood glucose in diabetic subjects (Moreno
et al 
.) the presence of excessive amountsinappropriate structured dietary (including) oxidised lipids, and the effects of certain ions (
e.g 
. Cd
2+
[Cardenas
et al 
] and Pb
2+
[Fujiwara & Kaji] or excessive amounts of F
-
[Pawalowska-Goral
et al 
.]).Bacterial endotoxin also inhibits HS biosynthesis (Colburn
et al 
.); (cf. also Chang
et al 
.; Paka
et al.
;Pinhal
et al.
; Sivaram
et al 
.). Perturbation of Ca
2+
signalling by Ba
2+
may alter HS biosynthesis insuch a manner as to induce disease processes (
cf 
. Purdey).Insufficiency of inorganic sulphate, is another putative dietary defect; a related effect is a defectivesulphate transporter which requires the presence of a thyroid factor and Vitamin D where insufficiencyof Vitamin D/UV light radiation of tissue could promote those disease processes which are normallyinhibited by HS.The
in vitro
demonstration by anti-plaque (anti-scale) anti crystal promoting seed function of HS-likeagents suggests HS and heparin are the most effective anti-CaCO
3
(calcite) inhibitors (de-N-sulphatedheparin is however ineffective inhibitor indeed is a promoter of calcification-those pathologicalconditions which promote excess de-N-sulphonation of HS could therefore change the HS system from being anti-plaque protective to being a pro-plaque, disease-promoting agent).This scenario which has been apparently evidenced (Bursima
et al 
.) to occur Alzheimer’s disease andmay be the ultimate origin of the GAG-associated plaque forming process. This suggests that thisdisease, like prion diseases may arise
via
error induction in HS processing which prevents theformation of appropriate anti-plaque polysaccharides which are necessary tissue protection agentswhich are essential for the effective functioning of organs.It should be noted that the different classes of GAGs show a hierarchy of anti-CaCO
3
(calcite)activities; for this purpose hyaluronan is not effective, ChSs is moderately effective but DeS and KeSand de-N-sulphonated heparin actually promote crystal growth and scale formation.The occurrence of (supersaturated amounts of) CO
2
in plasma (Grant et al., b, c) points to a likely primary role of initial formation of CaCO
3
for later deposition of Ca
3
(PO3)
4
/hydroxyapatite scale on such primary solid seed motes for the formation of hydroxyapatite-type scale,
e.g 
. at blood vessel walls.Arterial GAGs extracted (Murata
et al 
.) from atherosclerotic arterial surfaces of the brain (from acohort of human subjects of widely different ages) showed a linear diminution of HS content occurredwith increasing age. These findings also showed that such HS diminution was accompanied by anincrease with increased age of other GAGs which promote the formation of Ca-plaque].[A similar finding been reported by Feyzi
et al 
. has but explained by the age-dependent alteration inHS microstructure toward a pro-arteriosclerosis protein binding mode; these results, it can besuggested, also can be explained by the inorganic calcification hypothesis outlined above].The hypothesis that the chemical nature of the extracellular mixed sulphated polysaccharides is the keydeterminants of the formation of pathological arterial plaques (a phenomenon which is believed to theunderlying reason for the anti-atherosclerosis and anti cancer effects of such endogenous heparin (
cf.
Engelberg) has recently been confirmed by NMR studies (Reid
et al 
. reported that phosphate salt plaque was coated with similar anionic polysaccharides which occur at growing bone and dentine theformation of which being indicated to be polysaccharide regulated).The above scenario could ultimately be dependent by the effect of these GAGs on water activity/structure effects (
cf 
Grant
et al 
. e).

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