Impact of non-enzymatic glycation in Neurodegenerative diseases: role of natural products in the prevention of its menace.

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Impact of non-enzymatic glycation in Neurodegenerative diseases: role of natural products in the prevention of its menace.

Introduction: -

Glycosylation is the reaction between carbohydrate and other functional group of another molecule. In biology terms glycosylation is the process in which glycans attached to the protein, lipid or other organic molecule in the presence of enzymes. It is one of the forms of post transnational modification. According to their binding nature glycans are divided in five classes.

  1. N-linked glycans specific to nitrogen of asparagines and arginine side chain.
  2. O-linked glycans specific to the hydroxyl oxygen of serine, tyrosine, threonine and hydorxyproline or hydroxylysine side chain.
  3. Phospho glycans attached through the phosphate of phosphor serine.
  4. C-glycans, it is a very rare form of glycosylation. In this type of glycosylation sugar is added to a carbon on a tryptophan side chain.
  5. Glypiation, addition of a GPI acnchor that attached protein to lipids with the help of glycans linkage.
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This glycosylation process is very essential and serves many functions like some protein not folded properly without going under glycosylation process [1].

Glycation (Non Enzymatic Glycosylation): - Glycosylation process is occurs in absence of enzyme reaction, and then this phenomenon is known as glycation or non enzymatic glycosylation. Glycation process occurs inside (endogenous) and outside the body (exogeneous) both. Glycation process complete through a series of complex reactions started from Amadori reaction, Schiff base reactions and Maillard reaction which ultimately gives advanced glycation end product (AGEs)[2] fig.1.

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Sugar added food cooked at high temperature (approx. 120ºC) accelerates exogenous glycation reaction. But slow cooking for the long time also promotes AGEs formation. Some studies also shown that glycation also contribute formation of acrylamide carcinogen during cooking [3]. From the last 50 years to improve food quality food manufacture have added AGEs to food like flavor enhancers and colorants to improve emergence [4].

Glycation and its complication in Diseases: - The researchers discover about the glycation that AGEs are formed after a non-enzymatic reaction sugar and amino group freely present on the protein or deoxyribonucleic acid (DNA). And this process is involved in aging also. DNA glycation of nucleus and cytoplasm formed altered protein product ultimately change the function of protein. Some time it’s generates free radicals causing structural alteration of biomolecule. In diabetic patient due to DNA glycation neo- antigenic epitopes were formed and increased problems in diabetes mellitus [5]. Fructose is prompt glycating agent and necessary component of daily diet. It can modified DNA and generate antibody in the body that can be cause of destruction of b- cells of islets of Langerhans and other problems of diabetes [6]. Many researches shows that hyperglycemia is first step that causes tissue damage in diabetes due to repeated changes in metabolism of glucose, or due to accumulation of advance glycated end product (AGEs) and glycated molecules. Glycation also affects protein like serum albumin, lipoprotein, hemoglobin and insulin and alter their function. AGEs cross linked with extracellular matrix protein and activate their respective RAGEs, resulting in oxidative stress and pro inflammatory signaling caused micro vascular complication, arterial stiffening and endothelium dysfunction [7].

Human serum albumin glycation is also detected in many diseases. And it is ten times more reactive with glucose then HbA1C protein. Human serum protein is present in plasma and it is most abundant protein of plasma. Binding with reducing sugars of plasma it undergoes structural and functional changes and this property make it sensitive for glycation. And due to its in vivo glycation process occurs with plasma glucose it can be used as new disease marker in place of HbA1C for diabetes [8]. The glycation rapidness is also depends on the nature of carbohydrate bind in the process. For example when we compare glucose and ribose together, ribose induces faster glycation than the glucose and gives birth to product similar to amyloid products [9]. In vivo research shows that in healthy person glycated albumin is present in between from 1-10% [10]. But in case of diabetic patient it increased two to three folds when compare to control [11]. Glycated albumin implicated in other disease also like retinopathy, neuropathy, nephropathy and coronary artery diseases [12].

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Glycation and Diabetic problems:-

Glycation complication in Diabetic retinopathy: - Retinopathy is most common complication of diabetes individuals between ages 30 to 70 years [13, 14]. Last stage of retinopathy causes blindness in individuals. In brief this the processes involved in retinopathy are increased blood vessels density, angiogenesis, permeability of retinal capillary increases and thickness increase in capillary basement membrane[13]. Advanced glycated end products play a vital role in the succession of diabetic retinopathy and caused dysfunction and death of retinal cells. The component of AGE- RAGE complex can be hopeful targets for the treatment of diabetic retinopathy [15]. Studies suggest rats have high amount of accumulation of AGEs loss the function of Muller glial cells during diabetic retinopathy [16]. Recent finding revealed that N-(€)-CML, AGEs are modulates developmental steps of nonproliferative retinopathy in type 2 diabetic individuals [17]. Some report shows that AGE contributes increased permeability of retinal endothelial cells. AGEs cross linked with protein and causes vascular stiffness and ECM protein modification leading to decrease pericyte adherence [18]. AGE also induce pericytes death and the signaling pathway involved in this through generation of oxidative stress leading inhibition of protein kinase B/Akt phosphorylation[19].

Glycation in Diabetic cataract: - Loss of transparency of eye lens is a primary step of cataract development and AGEs play a key role in this process [20]. Reports revealed that in diabetic individuals progression of cataract is high [21]. In diabetic individual’s cataract protein of lens gets glycated and which ultimately leading to blindness [22]. Some research reports suggested that AGEs cause vision impairment by accumulation in the eye lens and induce severe changes in structural protein. Finally leads to protein aggregation in lens and these high molecular weight aggregates that spread out light and hamper vision [23]. Few reports revealed that AGEs, by changing surface charge of protein lead to affect protein-water and protein- protein interaction and finally decreased the transparence property of eye lens [24, 25]. In diabetes patient glucose level increased in aqueous humor and induces glycation of protein. This process resulting superoxide radical’s generation and AGEs productions. In another research binding of AGEs with RAGE present on the epithelium of the lens elevated O2- and H2O2 levels [26]. All these report demonstrated that protein glycation altered protein structure leading to change in amino acid involved in cataract development.

Glycation in Diabetics neuropathy: - Diabetic neuropathy affecting both peripheral and autonomic nerves. It is also cause diarrhea, constipation and urinary incontinence. Studies have suggested that AGE-RAGE play key role in the pathogenesis of diabetic neuropathy [27]. It has already shown in previous research that glycolaldehyde (one type of precursor of AGEs) at physiological concentration low down the viability of rat Schwann cells.

Natural products for neurodegenerative disease: -

Discovery of new drug from the natural products were in use from the Vedic period. More than 80% drug molecules are natural product or inspired by natural compound. The past studies show that the use of plant and other natural product derived drugs in the treatment of various diseases like cardiovascular diseases, cancer and neurological condition.

Alzheimer’s disease is the most common form of dementia. It is a chronic neurodegenerative disease. The common symptoms of this disease are short term memory loss. And when the disease became advance symptoms included disorientation, loss of motivation and problem with language. The cause of AD is not well understood, some hypothesis were proposed to explain the AD development.

Natural products are the best source for the discovery of new drugs, which were in use even from the Vedic period. It is well established that 80% drug molecules are natural products or natural compound inspired1. The investigation of natural products as a source of novel human therapeutics reached its peak in the western pharmaceutical industry during 1970-1980, which resulted in a pharmaceutical landscape heavily influenced by non synthetic molecules2. The past history of use of plants and other natural product-derived drugs in the treatment of many major afflictions like cancer, cardiovascular diseases and neurological conditions augurs well for their future utilization in this regard. Traditional Indian System of Medicine has a very long term history of usage in a number of disease, disorders, but lacks recorded safety and efficacy data3. Ayurvedic Indian and Chinese systems are great traditional systems that have relatively organized database, and more exhaustive description of botanical material that is available and can be tested using modern scientific methods. Both systems of medicine thus have an important role in bio prospecting of new medicines2. Recently, it has been suggested that drug discovery should not always be limited to discovery of a single molecule and the current belief is that rationally designed poly herbal formulation could also be investigated as an alternative in multi target therapeutics and prophylaxis. Development of standardized, safe and effective herbal formulation with proven scientific evidence can also provide an economical alternative in several diseases areas3

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The most common early symptom is difficulty in remembering recent events (short term memory loss).[1]As the disease advances, symptoms can include:problems with language,disorientation(including easily getting lost),mood swings, loss ofmotivation, not managingself care, andbehavioural issues.[2][1]

Alzheimer’s disease (AD) is aneurodegenerative disorderand the most common form of dementia, affecting more than 5.4 million people in the USA. Although the cause of AD is not well understood, the cholinergic, amyloid and tau hypotheses were proposed to explain its development. Drug discovery for AD based on the cholinergic and amyloid theories have not been effective. In this article we summarize tau-basednatural productsas AD therapeutics from a variety of biological sources, including the anti-amyloid agent curcumin, isolated from turmeric, the microtubule stabilizer paclitaxel, from the Pacific YewTaxus brevifolia, and the Streptomyces-derived Hsp90 inhibitor, geldanamycin.

Impact of non-enzymatic glycation in Neurodegenerative diseases: role of natural products in the prevention of its menace.

Or

The effect of natural products on glycation involved in Neurodegenerative disorder

Or

Role of glycation in various neurodegenerative diseases and use of natural product against neurodegenerative diseases: a therapeutic approach

Or

The effect of different compounds isolated from natural resources on the neurodegenerative diseases and glycation.

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