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#1 hormoneman

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Posted 03 March 2007 - 09:21 PM

Progression of nephropathy in spontaneous diabetic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation.

Nakamura S, Makita Z, Ishikawa S, Yasumura K, Fujii W, Yanagisawa K, Kawata T, Koike T.

Department of Medicine II, Hokkaido University School of Medicine, Kita-ku, Sapporo, Japan.

Levels of tissue advanced glycation end products (AGEs) that result from nonenzymatic reactions of glucose and proteins are high in both diabetic and aging people. Irreversible AGE formation is based on increases in AGE-derived protein-to-protein cross-linking and is considered to be a factor contributing to the complications of diabetes. A novel inhibitor of advanced glycation, OPB-9195, belongs to a group of thiazolidine derivatives, known as hypoglycemic drugs; however, they do not lower blood glucose levels. We did studies to determine if OPB-9195 would prevent the progression of nephropathy in spontaneous diabetic rats. In vitro inhibitory effects of OPB-9195 on AGE formation and AGE-derived cross-linking were examined by enzyme-linked immunosorbent assay (ELISA) and SDS-PAGE, respectively. Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of NIDDM, were used to evaluate the therapeutic effect of OPB-9195. Light microscopic findings by periodic acid-Schiff (PAS) staining, the extent of AGE accumulation detected by immunohistochemical staining in the kidneys, the levels of serum AGEs by AGE-specific ELISA, and urinary albumin excretion were examined. OPB-9195 effectively inhibited both AGE-derived cross-linking and the formation of AGEs, in a dose-dependent manner in vitro. In addition, the administration of OPB-9195 prevented the progression of glomerular sclerosis and AGE deposition in glomeruli. Elevation of circulating AGE levels and urinary albumin excretion were dramatically prevented in rats, even at 56 weeks of age and with persistent hyperglycemia. We concluded that a novel thiazolidine derivative, OPB-9195, prevented the progression of diabetic glomerular sclerosis in OLETF rats by lowering serum levels of AGEs and attenuating AGE deposition in the glomeruli.

#2 xanadu

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Posted 03 March 2007 - 10:12 PM

It sounds very promising. I'm not going to rush out and try it, even if I could find some but it's nice to know there are things in the pipeline that might turn out to be really great one of these days. Anything that will reduce AGE's without side effects may be very helpful.

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#3 curious_sle

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Posted 04 March 2007 - 12:50 PM

Well, it certainly has been investigated quite a bit to date... I'm cautiously positive about it but we'll see...

J Soc Biol 2001;195(4):391-8
[Antioxidant and anti-AGE therapeutics: evaluation and perspectives]

[Article in French]

Bonnefont-Rousselot D.

Laboratoire de Biochimie Metabolique et Clinique, UFR des Sciences
Pharmaceutiques et Biologiques, 4, avenue de l'Observatoire, 75270
Paris, France.

Diabetic patients exhibit an oxidative stress status, that is an
imbalance between reactive oxygen species and antioxidant defences, in
favour of the first ones. This oxidative stress, together with formation
of advanced glycation endproducts (AGEs), is involved in diabetic
complications. It could thus be of great interest to propose antioxidant
and/or anti-AGE therapeutics as complementary treatment in these
patients. Antioxidants can be classical molecules such as vitamin E,
lipoic acid or N-acetylcysteine. Thus, vitamin E supplementation can
improve insulin efficiency and glycemic equilibrium, as shown by the
decrease of glycaemia, glycated haemoglobin and fructosamine values. In
addition, this kind of supplementation lowers plasma lipid peroxidation
and oxidizability of low density lipoproteins, which is involved in the
atherogenesis process. Moreover, it allows to fight against
complications such as retinopathy. A second category is represented by
molecules able to fight against the effects of glycation end-products
(AGEs). They can act: either by preventing cellular action of AGEs; this
is obtained with soluble receptors of advanced glycation endproducts
(sRAGE); or by inhibiting AGE formation (scavenging of reactive carbonyl
intermediates). Nucleophilic compounds such as pyridoxamine, tenilsetam,
2,3-diaminophenazone, OPB-9195 or aminoguanidine can act in this way.
Aminoguanidine is able to limit the development of the main
diabetes-associated complications in animals. A double-blind clinical
assay has been conducted in type 2 diabetic patients in the United
States and the Canada, in order to determine if aminoguanidine is able
to slow down the progression of diabetes-induced nephropathy. We will
discuss about another guanidic molecule, i.e. metformin, which is also
able to scavenge AGEs, in the last part of this review. A third category
of molecules is constituted by oral antidiabetic molecules exhibiting
antioxidant properties. They are thiazolidinediones (troglitazone) and
sulfonylureas (gliclazide). Troglitazone and gliclazide can thus
decrease LDL oxidizability and monocyte adhesion to endothelial cells,
which is an early step in the atherogenesis process and which is
stimulated by oxidised LDLs. Finally, a prospective way is devoted to
oral antidiabetic drugs exhibiting both antioxidant and anti-AGE
properties. A very used antidiabetic drug of interest is metformin
(dimethylbiguanide), since it can prevent diabetes complications not
only by lowering glycaemia, but also by inhibiting AGE formation and by
stimulating antioxidant defences. The latter therapeutic approach
constitutes a future way in the diabetes area, in order both to obtain a
better glycemic control and a least development of diabetic

Publication Types:

* Review
* Review, Tutorial

PMID: 11938556 [PubMed - indexed for MEDLINE]


J Biol Chem 2001 Dec 28;276(52):48967-72 Related Articles, Links
Chelating activity of advanced glycation end-product inhibitors.

Price DL, Rhett PM, Thorpe SR, Baynes JW.

Department of Chemistry and Biochemistry, University of South
Carolina, Columbia, South Carolina 29208, USA.

The advanced glycation end-product (AGE) hypothesis proposes that
accelerated chemical modification of proteins by glucose during
hyperglycemia contributes to the pathogenesis of diabetic complications.
The two most commonly measured AGEs, N(epsilon)-(carboxymethyl)lysine
and pentosidine, are glycoxidation products, formed from glucose by
sequential glycation and autoxidation reactions. Although several
compounds have been developed as AGE inhibitors and are being tested in
animal models of diabetes and in clinical trials, the mechanism of
action of these inhibitors is poorly understood. In general, they are
thought to function as nucleophilic traps for reactive carbonyl
intermediates in the formation of AGEs; however alternative mechanisms
of actions, such as chelation, have not been rigorously examined. To
distinguish between the carbonyl trapping and antioxidant activity of
AGE inhibitors, we have measured the chelating activity of the
inhibitors by determining the concentration required for 50% inhibition
of the rate of copper-catalyzed autoxidation of ascorbic acid in
phosphate buffer. All AGE inhibitors studied were chelators of copper,
as measured by inhibition of metal-catalyzed autoxidation of ascorbate.
Apparent binding constants for copper ranged from approximately 2 mm for
aminoguanidine and pyridoxamine, to 10-100 microm for carnosine,
phenazinediamine, OPB-9195 and tenilsetam. The AGE-breakers,
phenacylthiazolium and phenacyldimethylthiazolium bromide, and their
hydrolysis products, were among the most potent inhibitors of ascorbate
oxidation. We conclude that, at millimolar concentrations of AGE
inhibitors used in many in vitro studies, inhibition of AGE formation
results primarily from the chelating or antioxidant activity of the AGE
inhibitors, rather than their carbonyl trapping activity. Further, at
therapeutic concentrations, the chelating activity of AGE inhibitors and
AGE-breakers may contribute to their inhibition of AGE formation and
protection against development of diabetic complications.

PMID: 11677237 [PubMed - indexed for MEDLINE]


Am J Kidney Dis 2001 Oct;38(4 Suppl 1):S100-6 Related Articles, Links
Advanced glycation end products and the progressive course of renal

Heidland A, Sebekova K, Schinzel R.

Department of Internal Medicine and Physiologische Chemie I,
University of Wurzburg, Germany.

In experimental and human diabetic nephropathy (DN), it has been
shown that advanced glycation end products (AGEs), in particular,
carboxymethyl-lysine and pentosidine, accumulate with malondialdehyde in
glomerular lesions in relation to disease severity and in the presence
of an upregulated receptor for AGE (RAGE) in podocytes. Toxic effects of
AGEs result from structural and functional alterations in plasma and
extracellular matrix (ECM) proteins, in particular, from cross-linking
of proteins and interaction of AGEs with their receptors and/or binding
proteins. In mesangial and endothelial cells, the AGE-RAGE interaction
caused enhanced formation of oxygen radicals with subsequent activation
of nuclear factor-kappaB and release of pro-inflammatory cytokines
(interleukin-6, tumor necrosis factor-alpha), growth factors
(transforming growth factor-beta1 [TGF-beta1], insulin-like growth
factor-1), and adhesion molecules (vascular cell adhesion molecule-1,
intercellular adhesion molecule-1). In tubular cells, incubation with
AGE albumin was followed by stimulation of the mitogen-activating
protein (MAP) kinase pathway and its downstream target, the activating
protien-1 (AP-1) complex, TGF-beta1 overexpression, enhanced protein
kinase C activity, decreased cell proliferation, and impaired protein
degradation rate, in part caused by decreased cathepsin activities. The
pathogenic relevance of AGEs was further verified by in vivo experiments
in euglycemic rats and mice by the parenteral administration of AGE
albumin, leading in the glomeruli to TGF-beta1 overproduction, enhanced
gene expression of ECM proteins, and morphological lesions similar to
those of DN. Evidence for the pathogenic relevance of AGEs in DN also
comes from experimental studies in which the formation and/or action of
AGEs was modulated by aminoguanidine, OPB-9195, pyridoxamine, soluble
RAGEs, serine protease trypsin, and antioxidants, resulting in improved
cell and/or renal function.

Publication Types:

* Review
* Review, Tutorial

PMID: 11576932 [PubMed - indexed for MEDLINE]

#4 curious_sle

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Posted 04 March 2007 - 12:54 PM

J Biol Chem. 2004 May 7;279(19):19816-23. Epub 2004 Mar 05.

Advanced glycation end products increase collagen-specific chaperone
protein in mouse diabetic nephropathy.

Ohashi S, Abe H, Takahashi T, Yamamoto Y, Takeuchi M, Arai H, Nagata
K, Kita T, Okamoto H, Yamamoto H, Doi T.

Department of Clinical Biology and Medicine, Course of Biological
Medicine, School of Medicine, The University of Tokushima, 3-18-15
Kuramoto-cho, Tokushima 770-8503, Japan.

Advanced glycation end products (AGEs) appear to contribute to the
diabetic complications. This study reports the inhibitory effect of
OPB-9195 (OPB), an inhibitor of AGEs formation, and the role of a
collagen-specific molecular chaperone, a 47-kDa heat shock protein
(HSP47) in diabetic nephropathy. Transgenic mice carrying nitric-oxide
synthase cDNA fused with insulin promoter (iNOSTg) leads to diabetes
mellitus. The iNOSTg mice at 6 months of age represented diffuse
glomerulosclerosis, and the expression of HSP47 was markedly increased
in the mesangial area in parallel with increased expression of types I
and IV collagens. OPB treatment ameliorated glomerulosclerosis in the
iNOSTg mice associated with the decreased expression of HSP47 and
types I and IV collagens. The expression of transforming growth
factor-beta (TGF-beta) was increased in glomeruli of iNOSTg mice and
decreased after treatment with OPB. To confirm these mechanisms,
cultured mesangial cells were stimulated with AGEs. AGEs significantly
increased the expression of HSP47, type IV collagen, and TGF-beta
mRNA. Neutralizing antibody for TGF-beta inhibited the overexpression
of both HSP47 and type IV collagen in vitro. In conclusion, AGEs
increase the expression of HSP47 in association with collagens, both
in vivo and in vitro. The processes may be mediated by TGF-beta.

PMID: 15004023 [PubMed - indexed for MEDLINE]


I think tintinet can say much more on it if I am not entirely mistaken :-)

#5 tintinet

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Posted 05 March 2007 - 01:58 PM

Not on this particular one, sorry! As you note, it's been around a while,

Diabetes 1997 Diabetes 1997May;46(5):895-9

and has apparent sponsorship by major pharma, yet I've not seen any
human use studies or indications thereof. So many from which to choose!

For now, I 'm sticking with benfotiamine, carnosine, pyridoxamine, as well
as other strategies aimed to minimize AGE formation(not to mention AGE-breakers.)

Edited by tintinet, 05 March 2007 - 02:21 PM.

#6 maxwatt

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Posted 05 March 2007 - 04:44 PM

5-aminosalicylic acid is said to be an age breaker in a patent I've read, I think for Torrent Pharmaceuticals. It is available as a prescription drug, as Mesalamine, Pentasa, Asacol, used to tread inflammatory bowel disease. Its been fairly well studied as to safety.

You could get an off-label prescription, or order online. There are side-effects to look out for.

#7 hormoneman

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Posted 05 March 2007 - 11:32 PM

Is it possible to obtain any OBP-9195??

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#8 Logic

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Posted 08 November 2015 - 10:16 AM

5-aminosalicylic acid is said to be an age breaker in a patent I've read, I think for Torrent Pharmaceuticals. It is available as a prescription drug, as Mesalamine, Pentasa, Asacol, used to tread inflammatory bowel disease. Its been fairly well studied as to safety.

You could get an off-label prescription, or order online. There are side-effects to look out for.


The patent's abstract:


Advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of a variety of debilitating diseases such as diabetes, atherosclerosis, Alzheimer's and rheumatoid arthritis, as well as in the normal aging process. Five compounds are here reported to be active in breaking AGE-protein cross-links. These compounds are

  • L-bis-[4-(4-chlorobenzamido-phenoxyisobutyryl)cystine] (LR20);
  • 4-(3,5-dichlorophenylureido)phenoxyisobutyryl-1-amido-cyclohexane-1-carboxylic acid (LR23);
  • methylene bis [4,4'-(2-chlorophenylureido-phenoxyisobutyric acid)] (LR90);
  • 5-aminosalicylic acid (5-ASA);
  • and metformin.

These compounds may be used to reverse the debilitating effects of those diseases in which AGEs are formed.



The references in this patent may be worth following up on and perhaps these substances are worthy of their own thread when one considers that effect of AGEs on TGF-β1, Telomerase etc Maxwatt.


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