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Rochín-Hernández, L.S.;  Rochín-Hernández, L.J.;  Flores-Cotera, L.B. Endophytes for Curtailing Advanced Glycation End Products. Encyclopedia. Available online: https://encyclopedia.pub/entry/25416 (accessed on 19 April 2024).
Rochín-Hernández LS,  Rochín-Hernández LJ,  Flores-Cotera LB. Endophytes for Curtailing Advanced Glycation End Products. Encyclopedia. Available at: https://encyclopedia.pub/entry/25416. Accessed April 19, 2024.
Rochín-Hernández, Lory Sthephany, Lory Jhenifer Rochín-Hernández, Luis Bernardo Flores-Cotera. "Endophytes for Curtailing Advanced Glycation End Products" Encyclopedia, https://encyclopedia.pub/entry/25416 (accessed April 19, 2024).
Rochín-Hernández, L.S.,  Rochín-Hernández, L.J., & Flores-Cotera, L.B. (2022, July 21). Endophytes for Curtailing Advanced Glycation End Products. In Encyclopedia. https://encyclopedia.pub/entry/25416
Rochín-Hernández, Lory Sthephany, et al. "Endophytes for Curtailing Advanced Glycation End Products." Encyclopedia. Web. 21 July, 2022.
Endophytes for Curtailing Advanced Glycation End Products
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This entry is adapted from the peer-reviewed paper 10.3390/molecules27144469

Endophytes, microorganisms that live in the internal tissues and organs of plants, are known to produce numerous bioactive compounds, including, at times, some phytochemicals of their host plant. So, endophytes have been quoted as a potential source for discovering bioactive compounds, particularly, of medical interest, including compounds that inhibit the formation or prevent an excessive accumulation of Advanced glycation end products (AGEs). The high levels of AGEs in body tissues are linked with the pathogenesis and development of some non-communicable diseases (NCDs) that are threatening global human health, noticeably: diabetes, neurodegenerative diseases, cancer, and other ailments linked to chronic inflammation and ageing. For that reason, endophytes as a source of compounds able to reduce AGEs could represent a possible treatment alternative for some NCDs.

protein glycation AGEs detoxification

1. Endophytes, an Exceptional Source of Bioactive Compounds

Endophytes comprise mainly fungi and bacteria, but it also includes archaea and protists that live in the internal tissues and organs of plants (leaves, stems, flowers, fruits, seeds, or roots). Some endophytes do not cause apparent signs of disease in their host plants [1]; other may even be beneficial to their host [2], while some could become opportunistic pathogens under particular circumstances [3]. The above depends on the plant and microbial genotype, quorum sensing, co-colonizing microbiota, and environmental conditions [3][4][5]. Endophyte colonization may occur by horizontal transfer through different ways, such as soil-to-root, by phyllosphere (aerial spores) or through vectors (pollinators, arthropods, or sap-feeders), and by vertical or mixed transfer via seeds [6]. Endophyte colonization could involve passive or active mechanisms. In the first one, endophytes get access into a plant tissue through cracks, wounds, or hydathodes. On the other hand, active mechanisms involve the secretion of cell-wall-degrading and other enzymes [3][7]. Once inside the plant, the competent endophytes may spread systematically to reach other different plant tissues, mainly via the xylem vascular system [6].
The diversity and composition of endophytic communities in plants depend on biotic factors such as genotype, developmental stage, and physiology of the host plant. Also, microbial strain type, the endophyte chemotaxis to plant–exudates production, and the presence of other microorganisms could be involved. In addition, abiotic factors such as soil characteristics (pH, moisture, nutrients, presence of pollutants) and environmental conditions (temperature and radiation) could modify the establishment of endophytic communities [3][8][9].
The endophyte–host plant relationship is diverse, complex, and, in many cases, not totally understood. Endophytes could be mutualistic, commensal, and even opportunistic pathogens [3]. In mutualistic endophyte–host plant relationship, the plant offers shelter and nutrients for microorganism survival. In reciprocity, endophytes can promote plant growth, induce a plant defense response, improve the nutrient’s availability, increase resistance to biotic (salinity, drought, heat, and cold) and abiotic stress (caused by phytopathogens or herbivores), and consequently, enhance the plant survival [9][10][11].
Some of the interactions mentioned above take place by eliciting host response or by secondary bioactive metabolites produced by the endophytes [3][10][12]. Thus, endophytes synthesize metabolites that may be useful for the host plant, e.g., antifungals, plant-growth promoters, antibiotics, insecticides, antioxidants, and antiparasitic agents. Moreover, several metabolites synthesized by endophytes have been useful in industrial, agricultural, and medical fields, for example, lytic enzymes, antidiabetics, anti-inflammatory, anticancer, immunosuppressives, antivirals, antiacetylcholinesterase, antimalarial, analgesic and so on [10][13][14]. Additionally, endophytes at times may be able to produce some of the compounds produced by their host plant [14][15]. In summary, the endophytes represent an interesting and environmentally friendly source of potentially valuable bioactive compounds.

2. Advanced Glycation End Products

AGEs are a heterogeneous group of molecules whose formation usually involves non-enzymatic reactions of reducing sugars with proteins through the Maillard reaction [2]. Initially, the carbonyl group of a reducing sugar reacts with amino groups of proteins, preferentially those of lysine or arginine, to form Schiff bases [16][17]. Rearrangements of the Schiff bases lead to the formation of more stable compounds known as Amadori products (ketoamines) [16][17]. Subsequently, the Amadori products via oxidation, deprotonation, and fragmentation reactions form dicarbonyl compounds in the propagation phase [16]. Methylglyoxal and other α-dicarbonyl compounds are the primary AGEs precursors. These precursors may also originate from sugar autoxidation, lipid peroxidation, amino acid breakdown, and acetone metabolism. Polyol pathway, glycolysis, and fructolysis are metabolic pathways that may contribute to the triose phosphate pool and consequently to the methylglyoxal formation [18][19][20]. Ultimately, reactions of cyclization, isomerization, retro-aldol cleavage, hydrolytic and oxidative α-cleavage, and β-cleavage may generate a great variety of AGEs in the final phase of AGEs formation [2][19].
Depending on the chemical structure and ability to emit fluorescence, AGEs can be classified as fluorescent and cross-linked, (e.g., pentosidine, crossline, and vesperlysine), fluorescent and non-cross-linked, (e.g., argpyrimidine), non-fluorescent and cross-linked, (e.g., glyoxal-lysine dimer, methylglyoxal-lysine dimer, glyoxal-derived imidazolium cross-link, methylglyoxal-derived imidazolium cross-link and so on), and non-fluorescent, non-cross-linked adducts, (e.g., carboxymethyl-lysine, carboxyethyl-lysine, pyrraline, and imidazolones) [21]. The cellular formation of AGEs is common under physiological conditions. However, it may undesirably increase under conditions of hyperglycemia, hyperlipidemia, oxidative stress, and inflammation, all of which are common in diabetes, chronic diseases, and ageing [22]. In addition to the endogenous formation of AGEs, exogenous sources such as dietary AGEs (dAGEs) may be consumed as fried or processed foods [23]. Furthermore, AGEs may be inhaled from tobacco smoke, which contributes to the AGEs circulating in the body [24]. Increased rates of AGEs production or accumulation may have pernicious health consequences because AGEs could prompt the formation of covalent cross-links between proteins to form aggregates or may alter the conformation, activity, or function of proteins, as well as their removal by proteolytic means [14][25]. Moreover, AGEs often trigger intracellular signaling processes through their attachment to AGEs receptors (RAGE), so they may cause oxidative stress, inflammatory responses, immune dysfunction, and DNA damage [26][27]. The interactions cited above may explain, at least in part, why AGEs have been linked to a wide range of diseases (Figure1), such as diabetes and its complications (retinopathy, cataract, neuropathy, nephropathy, atherosclerosis, and heart diseases) [28][29][30], neurodegenerative diseases (Alzheimer’s, Parkinson’s, and Huntington’s diseases)[31] and other ailments related to chronic inflammation and ageing (rheumatoid arthritis, lupus erythematosus, psoriasis, chronic lower limb ischemia and so on [32][33][34][35]. 
Figure 1. Diseases linked to high levels of AGEs accumulation. The excessive formation or accumulation of AGEs and their interaction with RAGEs contribute to the pathogenesis and development of diabetic complications, different kinds of cancer, and neurodegenerative and inflammatory diseases. Created with BioRender.com.

2.2. Reducing AGEs Accumulation as a Potential Treatment Strategy for Some NCDs

The high incidence and prevalence of NCDs emphasize the importance of finding more effective treatment alternatives. It has been proposed that the inhibition of formation or accumulation of AGEs may help to delay or prevent the progression of some non-communicable diseases [27][36][37]. In order to reduce the exogenous AGEs intake, it is often recommended to consume fresh vegetables, fruits, and whole grains, as well as restrict sugary, processed, or fried foods, and cook meals at low temperatures with high humidity. Similarly, having a healthy diet and lifestyle, including exercise and not smoking, are important for the prevention or management of most, if not all, NCDs [38].
Cells possess their own AGEs detoxification systems, e.g., glyoxalase. However, under pathogenic conditions or with ageing, they often become insufficient to keep optimal physiological conditions. Therefore, compounds that inhibit the formation or prevent an excessive accumulation of AGES may represent a potential strategy to retard the onset of detrimental health effects resulting from undue AGEs accumulation and, by doing so, may delay the development of NCDs [36][37].
Due to the rather complex AGEs formation process, several mechanisms exist by which a given compound may operate for this purpose. Herein,  “antiAGEs compounds” was referred as those that may reduce the harmful consequences of AGEs accumulation by at least one of the action mechanisms enlisted below (Figure 2):
  • Blocking the carbonyl groups of reducing sugars or stabilizing the protein structure to inhibit the Maillard reaction or the formation of Schiff bases and Amadori products;
  • Scavenging of free radicals and chelating metal ions. Consequently, fewer reactive carbonyl groups and fewer radical-based reactions occur;
  • Blocking or breaking the AGEs cross-links to lessen protein aggregation;
  • Disrupting the AGEs–RAGE interaction, thus preventing inflammatory process and oxidative stress;
  • Some indirect mechanisms may be stimulating the glyoxalase system and other dicarbonyl detoxification systems to reduce the available AGEs precursors. Inhibition of polyol pathway enzymes (aldose reductase and sorbitol dehydrogenase) to reduce fructose intake and hypoglycemic activity to reduce sugar availability and so on. [37][39].
Figure 2. The mechanisms of action of antiAGEs compounds. The antiAGEs compounds could restrict in different ways, shown with a red cross, the undue accumulation, and consequent harmful effects of AGEs. These compounds may block sugar attachment to proteins, scavenge free radicals, chelate ions, trap reactive dicarbonyl species, break AGEs cross-links, or block the AGEs–RAGEs interaction. Hyperglycemic control and inhibition of aldose reductase or sorbitol dehydrogenase may decrease the reducing sugars available and, therefore, the formation of AGEs. Created with Biorender.com.

2.3. Synthetic AntiAGEs Compounds

Synthetic antiAGEs compounds include aminoguanidine, N-phenacylthiazolium bromide (PTB), tenilsetam, pyridoxamine, pentoxifylline, benfotiamine, LR-90, alagebrium chloride (ALT-711), edaravone, TM2002, pioglitazone and metformin [36]. The two last compounds are widely used for diabetes treatment. Edaravone has been used to treat amyotrophic lateral sclerosis [40], whereas pentoxifylline is used to improve blood flow in patients with blood circulation problems. However, most of the other antiAGEs compounds have failed in human clinical trials due to severe side effects or deficient effectiveness [36]. For that reason, natural antiAGEs compounds are being studied as a potentially safer and environmentally friendly alternative.
Newman and Cragg [41] wrote: “Natural products still hold out the best options for finding novel agents/active templates, which, when worked on in conjunction with synthetic chemists and biologists, offer the potential to discover novel structures that can lead to effective agents in a variety of human diseases”.
Several natural antiAGEs compounds have been found and identified as plant metabolites, including polyphenols, polysaccharides, terpenoids, vitamins, alkaloids, and peptides [25][42][43][44][45][46][47]. In contrast, there are scarce reports about antiAGEs compounds synthesized by endophytes, despite the fact that in some cases, these organisms have the capacity to generate the same or similar bioactive compounds as their host [14][48].

3. Plant antiAGEs Compounds Have Also Been Reported in Endophytes

Endophytes are a rich source of a wide variety of chemical compounds such as alkaloids, phenols, tannins, amino acids, carbohydrates, saponins, terpenes, flavonoids, and sterols [49]. Various metabolites and crude extracts of endophytes have shown antioxidant activity, which is known to inhibit the formation of AGEs [50][51]. Gutiérrez-García et al. [52] explored the antiAGEs compounds produced by endophytes from Piper auritum. They found that 2,4-diacetylphloroglucinol (DAPG) and congeners such as 5-hydroxyferulic acid synthesized by endophytic Pseudomonas strains inhibit, in vitro, the formation of Amadori products and fluorescent-AGEs.

Natural antiAGEs compounds have been studied and found primarily in plants. However, some of these plant-derived antiAGEs compounds have also been reported as metabolites synthesized by endophytes [53][54][44][55]. Some of this compounds are protocatechuic acid [56][57], gallic acid [58][59][60][61], coumaric acid [60][61], caffeic acid [58][60][61][62][63][64][65], ferulic acid [56][58][61][62], rosmarinic acid [58][61][66], and chlorogenic acid [60][61][63], apigenin and derivatives such as vitexin and isovitexin [58][61][64][67][68][69], kaempferol and derivatives [65][70][71], luteolin [58][61][72], quercetin and derivatives [61][62][64][65][72], catechin [58], daidzein [73], genistein [64][73], icariin [58], rutin and derivatives [58][61][65], resveratrol,  [74][75][76][77][78], tyrosol [79][80][81][82], ellagic acid [60][65], and 2,4-diacetyl-phloroglucinol [52], ginsenosides (Rb, Rd, Rg) [83][84][85], tanshinones [86], and stigmasterol [87], emodin [88][89][90], umbelliferone [60],  hypericin [90] and matrine [91]. 
Additionally, endophytes may be useful to elicit the production of bioactive phytochemicals by plants and induce the production of novel ones. However, some outstanding challenges still limit the discovery and commercial use of these microorganisms as sources of antiAGEs compounds and other bioactive compounds. The use of new technologies in biotechnological platforms and the advancement of omic sciences will help in the understanding of endophytes and their complex interactions with other organisms. This new knowledge will allow endophytes to be harnessed as a safe, sustainable, economical, and profitable option for developing new antiAGEs and other pharmaceutical compounds. The above could be a significant aid for the treatment and control of at least some prevalent non-communicable diseases that threaten global health.

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Subjects: Biotechnology & Applied Microbiology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Lory Sthephany Rochín-Hernández
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Lory Jhenifer Rochín-Hernández
,
Luis Bernardo Flores-Cotera
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Update Date: 22 Jul 2022
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