Levels of Soluble Advanced Glycation End Product-Receptors and Other Soluble Serum Markers as Indicators of Diabetic Neuropathy in the Foot

El‐Mesallamy, Hala O.; Hamdy, Nadia M.; Ezzat, Omnia; Reda, Ahmed

doi:10.2310/jim.0b013e318231db64

Cited by 43 publications

(34 citation statements)

References 37 publications

(42 reference statements)

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“…Various studies have shown that AGE-RAGE axis is involved in the development of diabetic complications such as diabetic nephropathy, retinopathy, neuropathy, and cardiomyopathy [24,25,26,27]. Furthermore, in vivo studies have also shown the role of AGE-RAGE in myocardial ischemia reperfusion injury in diabetic rats [8].…”

Section: Discussionmentioning

confidence: 99%

Molecular Pathways Involved in the Amelioration of Myocardial Injury in Diabetic Rats by Kaempferol

Suchal

Malik

Khan

et al. 2017

IJMS

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There is growing evidence that chronic hyperglycemia leads to the formation of advanced glycation end products (AGEs) which exerts its effect via interaction with the receptor for advanced glycation end products (RAGE). AGE-RAGE activation results in oxidative stress and inflammation. It is well known that this mechanism is involved in the pathogenesis of cardiovascular disease in diabetes. Kaempferol, a dietary flavonoid, is known to possess antioxidant, anti-apoptotic, and anti-inflammatory activities. However, little is known about the effect of kaempferol on myocardial ischemia-reperfusion (IR) injury in diabetic rats. Diabetes was induced in male albino Wistar rats using streptozotocin (70 mg/kg; i.p.), and rats with glucose level >250 mg/dL were considered as diabetic. Diabetic rats were treated with vehicle (2 mL/kg; i.p.) and kaempferol (20 mg/kg; i.p.) daily for a period of 28 days and on the 28th day, ischemia was produced by one-stage ligation of the left anterior descending coronary artery for 45 min followed by reperfusion for 60 min. After completion of surgery, rats were sacrificed and the heart tissue was processed for biochemical, morphological, and molecular studies. Kaempferol pretreatment significantly reduced hyperglycemia, maintained hemodynamic function, suppressed AGE-RAGE axis activation, normalized oxidative stress, and preserved morphological alterations. In addition, there was decreased level of inflammatory markers (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and NF-κB), inhibition of active c-Jun N-terminal kinase (JNK) and p38 proteins, and activation of Extracellular signal regulated kinase 1/2 (ERK1/2) a prosurvival kinase. Furthermore, it also attenuated apoptosis by reducing the expression of pro-apoptotic proteins (Bax and Caspase-3), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells, and increasing the level of anti-apoptotic protein (Bcl-2). In conclusion, kaempferol attenuated myocardial ischemia-reperfusion injury in diabetic rats by reducing AGE-RAGE/ mitogen activated protein kinase (MAPK) induced oxidative stress and inflammation.

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Section: Discussionmentioning

confidence: 99%

Molecular Pathways Involved in the Amelioration of Myocardial Injury in Diabetic Rats by Kaempferol

Suchal

Malik

Khan

et al. 2017

IJMS

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“…Long-term hyperglycemia causes metabolic disorders due to activation of additional polyol glucose metabolism pathway with increased accumulation of toxic sorbitol in cells of nervous tissue lading to vascular damage (11,12). Furthermore, neuropathy in diabetes is correlated with neurovascular damage not only resulting from metabolic defects, but caused by other risk factors such as hypertension, dyslipidemia, obesity and cigarette smoking (12)(13)(14). Persistent hyperglycemia leads to epithelial cell dysfunction, which results in a decrease of pro-angiogenic signalling and production of nitric oxide (NO) (13).…”

Section: Molecular Basis Of Diabetic Foot Ulcersmentioning

confidence: 98%

“…Persistent hyperglycemia leads to epithelial cell dysfunction, which results in a decrease of pro-angiogenic signalling and production of nitric oxide (NO) (13). NO additionally causes relaxation of smooth muscle, and its absence decreases vasodilatation effectively leading to limb/nerve ischemia (12,14). The neuropathy and poor local blood flow added with the impaired immune function of diabetic patients due to defects in leukocyte functions in hyperglycaemia, results in an inadequate inflammatory response at the site of concern (11, 12).…”

Section: Molecular Basis Of Diabetic Foot Ulcersmentioning

confidence: 99%

Genetic and molecular basis of diabetic foot ulcers: Clinical review

Jhamb

Vangaveti

Malabu

2016

Journal of Tissue Viability

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“…Several studies focused on diabetics, though not all [177], likewise find that ADMA is a negative prognostic factor for cardiovascular health [154,178,179,180,181,182]. Moreover, a number of case-control studies have reported higher ADMA levels in diabetics afflicted with nephropathy retinopathy, or neuropathy [183,184,185,186,187,188,189,190]. Higher ADMA also was found in diabetics with vertebral fractures, likely reflecting a role for eNOS in bone health [191,192].…”

Section: Citrulline Can Counter the Adverse Impact Of Adma And Argmentioning

confidence: 99%

Supplementation with Phycocyanobilin, Citrulline, Taurine, and Supranutritional Doses of Folic Acid and Biotin—Potential for Preventing or Slowing the Progression of Diabetic Complications

McCarty

2017

Healthcare

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Oxidative stress, the resulting uncoupling of endothelial nitric oxide synthase (eNOS), and loss of nitric oxide (NO) bioactivity, are key mediators of the vascular and microvascular complications of diabetes. Much of this oxidative stress arises from up-regulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Phycocyanobilin (PhyCB), the light-harvesting chromophore in edible cyanobacteria such as spirulina, is a biliverdin derivative that shares the ability of free bilirubin to inhibit certain isoforms of NADPH oxidase. Epidemiological studies reveal that diabetics with relatively elevated serum bilirubin are less likely to develop coronary disease or microvascular complications; this may reflect the ability of bilirubin to ward off these complications via inhibition of NADPH oxidase. Oral PhyCB may likewise have potential in this regard, and has been shown to protect diabetic mice from glomerulosclerosis. With respect to oxidant-mediated uncoupling of eNOS, high-dose folate can help to reverse this by modulating the oxidation status of the eNOS cofactor tetrahydrobiopterin (BH4). Oxidation of BH4 yields dihydrobiopterin (BH2), which competes with BH4 for binding to eNOS and promotes its uncoupling. The reduced intracellular metabolites of folate have versatile oxidant-scavenging activity that can prevent oxidation of BH4; concurrently, these metabolites promote induction of dihydrofolate reductase, which functions to reconvert BH2 to BH4, and hence alleviate the uncoupling of eNOS. The arginine metabolite asymmetric dimethylarginine (ADMA), typically elevated in diabetics, also uncouples eNOS by competitively inhibiting binding of arginine to eNOS; this effect is exacerbated by the increased expression of arginase that accompanies diabetes. These effects can be countered via supplementation with citrulline, which efficiently enhances tissue levels of arginine. With respect to the loss of NO bioactivity that contributes to diabetic complications, high dose biotin has the potential to “pinch hit” for diminished NO by direct activation of soluble guanylate cyclase (sGC). High-dose biotin also may aid glycemic control via modulatory effects on enzyme induction in hepatocytes and pancreatic beta cells. Taurine, which suppresses diabetic complications in rodents, has the potential to reverse the inactivating impact of oxidative stress on sGC by boosting synthesis of hydrogen sulfide. Hence, it is proposed that concurrent administration of PhyCB, citrulline, taurine, and supranutritional doses of folate and biotin may have considerable potential for prevention and control of diabetic complications. Such a regimen could also be complemented with antioxidants such as lipoic acid, N-acetylcysteine, and melatonin—that boost cellular expression of antioxidant enzymes and glutathione—as well as astaxanthin, zinc, and glycine. The development of appropriate functional foods might make it feasible for patients to use complex nutraceutical regimens of the sort suggested here.

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Levels of Soluble Advanced Glycation End Product-Receptors and Other Soluble Serum Markers as Indicators of Diabetic Neuropathy in the Foot

Abstract: Soluble forms of the receptor for advanced glycation end product could be an endogenous protection factor against occurrence of DF, hence may be of therapeutic value in the treatment of DF.

Cited by 43 publications

References 37 publications

Molecular Pathways Involved in the Amelioration of Myocardial Injury in Diabetic Rats by Kaempferol

Molecular Pathways Involved in the Amelioration of Myocardial Injury in Diabetic Rats by Kaempferol

Genetic and molecular basis of diabetic foot ulcers: Clinical review

Supplementation with Phycocyanobilin, Citrulline, Taurine, and Supranutritional Doses of Folic Acid and Biotin—Potential for Preventing or Slowing the Progression of Diabetic Complications

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