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Possible participation of advanced glycation end products in the pathogenesis of colorectal cancer in diabetic patients
Abstract
Colorectal cancer is a major public health problem, being the second most common cause of cancer in developed countries. Several epidemiological studies have reported moderately increased risks of colorectal cancer in diabetic patients compared with general population. However, the underlying molecular link between diabetes and colorectal cancer remains to be elucidated. In diabetes mellitus, the formation and accumulation of advanced glycation end products (AGEs) progress. There is a growing body of evidence to show that AGEs-their receptor (RAGE) interactions are involved in the development of atherosclerosis and diabetic microangiopathy. AGEs-RAGE interactions stimulated the growth of human pancreatic cancer cells through the autocrine induction of platelet-derived growth factor-B. Furthermore, we have recently found that AGEs stimulated the growth and migration of cultured human melanoma cells and that anti-RAGE antibodies inhibited tumor formation and lung metastasis of melanoma cell xenografts and subsequently improved survival in athymic mice. These observations let us to hypothesize that AGEs could explain the molecular link between diabetes and colorectal cancer. In this paper, we would like to propose the possible ways of testing our hypotheses. Is elevation of serum AGE levels a risk factor for colorectal cancer in patients with diabetes? Does treatment with metformin, which has a potential effect on the inhibition of glycation reactions in vivo, decrease the risk for colorecetal cancer in diabetic patients? If the answer is yes, is this beneficial effect of metformin superior to that of other anti-diabetic agents with equihypoglycemic properties? Does treatment with pyridoxamine, a post-Amadori inhibitor (so-called Amadorins) of AGE formation, reduce the risk for colorectal cancer as well? Furthermore, are increased levels of AGEs and RAGE in colorectal cancer associated with poor prognosis in patients with diabetes? These clinical studies could clarify whether the AGEs-RAGE interactions serve as a causal link between diabetes and colorectal cancer.
... Stiffening of ECM through glycation and cross-linking promotes tumor progression and invasion through mechanotransduction mechanisms where the exogenous forces induce intracellular signaling to activate ERK, P13 K, Rac and cyclin D1 to encourage the cell cycle progression [157] (Fig. 3). A number of epidemiological studies and meta-analysis indicated a positive link between diabetic conditions and the occurrence of colorectal cancer [216]. Treatment of diabetic cancer patients with hypoglycemic agents such as metformin and thiazolidinediones successfully increased their survival rate [185]. ...
... Hyperglycemia provides a favorable environment to cancer cells by overcoming the ever-increasing demands of cancer cells for nutrients to run its cellular machinery in increased metabolic conditions [37,158]. Importantly, hyperglycemia also accelerates the formation of advanced glycation end products (AGEs) that play a crucial role in the development of a variety of cancers [103,126,157,216]. The supportive roles of inflammation in the genesis of cancer are well-established. ...
... As already discussed, the abnormal conditions of hyperinsulinemia, hyperglycemia and inflammation in diabetes are highly supportive to tumor growth and development. Of particular interest is the observation that the production and release of advanced glycation end products (AGEs) [157,216] and other RAGE ligands (S100 and HMGB1 proteins) is accelerated under hyperglycemic conditions [105,203]. RAGE ligands have shown to induce inflammatory responses and cancer genesis by interacting with RAGE [24,172] (Fig. 1). ...
Abstract
Cancer and diabetes are the two major disorders that affect a large proportion of the world’s population. Results from multiple epidemiological studies have concluded that diabetes and cancer are linked, and diabetic patients live at much higher risks of developing cancer and diabetic complications at the later phase of disease. Inflammation is the central pathway that mediates both diabetic complications as well as cancer. Receptor of advanced glycation end products (RAGE) is a non-specific multi-ligand pattern recognition receptor that induces the inflammatory responses by binding with multiple ligands. RAGE and its ligands are upregulated in diabetes, inflammation and cancer. Advanced glycation end products (AGEs), high mobility group box protein-1 (HMGB1) and S100 proteins are the major RAGE ligands that contribute to these consequences and an increased release of RAGE ligands during diabetic conditions can be a possible mechanism leading to diabetic complications and cancer. Moreover, further release of RAGE ligands from cancer cells can be a possible mechanism behind the worsening of diabetic complications in diabetic cancer patients. Inhibition of RAGE signaling can prevent diabetic complications and cancer in diabetic patients and can be helpful in the management of worsening diabetic complications and cancer in diabetic cancer patients. Curcumin, Quercetin and Withaferin A are known to inhibit multiple molecular pathways that are involved in RAGE signaling. The combined effects of these molecules can be explored to achieve the complete inhibition of RAGE signaling in diabetic patients.
Keywords: RAGE; RAGE ligands; HMGB1; S100 proteins; AGEs; NF-κB; Diabetes; Cancer; Diabetic complications; Inflammation.
... Human studies suggest the involvement of glycer-AGEs in the development of Alzheimer's disease (29), non-alcoholic steatohepatitis (30), vascular inflammation (31) and some rare disorders (32,33). In addition to their potential direct effects, some evidence indicates that glycer-AGEs interact strongly with the receptor for AGEs (RAGE) to cause inflammatory and oxidative responses (28,34)-which are suspected in the development of various cancers, including CRC (35)(36)(37). In view of their apparent direct cytotoxicity, adverse effects on cell function and involvement in inflammatory and oxidative processes, a role for glycer-AGEs in CRC development is plausible, but has yet to be examined in studies on humans. ...
... A role for AGEs in CRC development has been hypothesized (37) but not yet fully explored. This may be due to the complexity of this family of compounds, whose heterogeneous structures are far from being fully understood (51) (carboxymethyl)-lysine (CML) is probably among the most studied and is inferred as an indicator of overall AGEs exposure. ...
Background:
A large proportion of colorectal cancers are thought to be associated with unhealthy dietary and lifestyle exposures, particularly energy excess, obesity, hyperinsulinemia, and hyperglycemia. It has been suggested that these processes stimulate the production of toxic reactive carbonyls from sugars such as glyceraldehyde. Glyceraldehyde contributes to the production of a group of compounds known as glyceraldehyde-derived advanced glycation end-products (glycer-AGEs), which may promote colorectal cancer through their proinflammatory and pro-oxidative properties. The objective of this study nested within a prospective cohort was to explore the association of circulating glycer-AGEs with risk of colorectal cancer.
Methods:
A total of 1,055 colorectal cancer cases (colon n = 659; rectal n = 396) were matchced (1:1) to control subjects. Circulating glycer-AGEs were measured by a competitive ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (95% CI), adjusting for potential confounding factors, including smoking, alcohol, physical activity, body mass index, and diabetes status.
Results:
Elevated glycer-AGEs levels were not associated with colorectal cancer risk (highest vs. lowest quartile, 1.10; 95% CI, 0.82-1.49). Subgroup analyses showed possible divergence by anatomical subsites (OR for colon cancer, 0.83; 95% CI, 0.57-1.22; OR for rectal cancer, 1.90; 95% CI, 1.14-3.19; Pheterogeneity = 0.14).
Conclusions:
In this prospective study, circulating glycer-AGEs were not associated with risk of colon cancer, but showed a positive association with the risk of rectal cancer.
Impact:
Further research is needed to clarify the role of toxic products of carbohydrate metabolism and energy excess in colorectal cancer development.
... However, it is reported that the sRAGE receptor, highly expressed in healthy lung tissues and especially at the site of alveolar epithelium, is significantly downregulated in lung carcinomas [89] and the RAGE expression is reported to be elevated in human pancreatic cells with high metastatic ability and low in tumour cells with low metastatic ability [90] . High RAGE expression is also reported in colonic [91] and prostatic [92] cancers. Little information is, however, available about other types of cancers, including breast cancer, but it has recently been suggested that inhibition of AGE-RAGE interaction might have a potential as a molecular target for both cancer prevention and therapy909192 . ...
... High RAGE expression is also reported in colonic [91] and prostatic [92] cancers. Little information is, however, available about other types of cancers, including breast cancer, but it has recently been suggested that inhibition of AGE-RAGE interaction might have a potential as a molecular target for both cancer prevention and therapy909192 . ...
Chronic diseases are repeatedly associated to accumulation in the body of glycated and lipoxidated proteins and peptides. PubMed reports in excess of 5000 papers plus about 14,000 articles about the related HbA 1c RAGE, a member of the immunoglobulin super-family of cell surface molecules and receptor for advanced glycation end products, functions as a master switch, induces sustained activation of NF-κB, suppresses a series of endogenous auto-regulatory functions and converts long-lasting pro-inflammatory signals into sustained cellular dysfunction and disease. RAGE is activated by high levels of dys-functioning proteins in body fluids and tissues and is strongly associated with chronic diseases from allergy and Alzheimer to rheumatoid arthritis and urogenital disorders. Heat-treatment, irradiation and ionization of foods increase the content in foods of advanced glycated end-products (AGE) and advances lipoxidated end-products (ALE). Some processed foods, much like tobacco smoking are major contributors to accumulation of glycated and lipoxidated molecules in the tissues. Change of life style: avoidance of foods rich in deranged proteins and peptides and increased consumption of antioxidants, especially polyphenols counteracts such a development.
... There is growing body of evidences to show that AGEs and their receptor (RAGE) interactions are involved in the development of human CRC [12,21,27]. It has recently been hypothesized that AGEs could explain the molecular link between diabetes and CRC [27]. ...
... There is growing body of evidences to show that AGEs and their receptor (RAGE) interactions are involved in the development of human CRC [12,21,27]. It has recently been hypothesized that AGEs could explain the molecular link between diabetes and CRC [27]. Elevated glucose concentrations lead to an increase in oxidative stress, to the activation of protein kinase C, to the formation of Amadori products and AGEs, all of which have been hypothesized to play a role in the malignant transformation of colorectal mucosa [12,21]. ...
Fructosamine-3-Kinase (FN3K) is an enzyme phosphorilating fructoselysine (FL) residues on glycated proteins, resulting in the production of protein-bound FL-3-phosphate. The pathological role of the non-enzymatic modification of proteins by reducing sugars has become increasingly evident in various types of disorders, including the cancer. In this study, our aim was to study FN3K enzyme activity, as well as its mRNA in human colorectal cancer (CRC). Thirty consecutive CRC patients undergoing surgery of the colon were enrolled in the study. FN3K enzymatic activity and gene expression were analyzed using a radiometric assay and quantitative RT-PCR, respectively. FN3K is a functionally active enzyme in human colon tissue, without significant differences between normal mucosa and cancer. The mean level of FN3K mRNA was significantly lower in cancer than in the corresponding normal colorectal mucosa The colorectal tumors located on the left side showed lower levels of both enzymatic activity and mRNA FN3K than tumors located in the right side of colon. This paper is the first studying FN3K enzyme activity in human CRC, showing a significant relationship between enzymatic activity, its mRNA and tumor side.
... of the tissue damage and cellular dysfunction associated with hyperglycemia has been attributed to advanced glycation end products (AGEs) created by the nonenzymatic glycation of proteins [64]. While AGE accumulation is a normal part of aging, it occurs at an accelerated rate in diabetes where progressive modifications can lead to irreversible cross-linking, impairing the actions of other molecules [64, 65]. ...
... of the tissue damage and cellular dysfunction associated with hyperglycemia has been attributed to advanced glycation end products (AGEs) created by the nonenzymatic glycation of proteins [64]. While AGE accumulation is a normal part of aging, it occurs at an accelerated rate in diabetes where progressive modifications can lead to irreversible cross-linking, impairing the actions of other molecules [64, 65]. Receptors for AGE (RAGE) mediate many more severe actions and potentiate the cellular response [66]. ...
Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and also one of the most poorly understood. Other health issues that are affecting women with increasing frequency are obesity and diabetes, which are associated with dysglycemia and increased blood glucose. The Warburg Effect describes the ability of fast-growing cancer cells to preferentially metabolize glucose via anaerobic glycolysis rather than oxidative phosphorylation. Recent epidemiological studies have suggested a role for hyperglycemia in the pathogenesis of a number of cancers. If hyperglycemia contributes to tumour growth and progression, then it is intuitive that antihyperglycemic drugs may also have an important antitumour role. Preliminary reports suggest that these drugs not only reduce available plasma glucose, but also have direct effects on cancer cell viability through modification of molecular energy-sensing pathways. This review investigates the effect that hyperglycemia may have on EOC and the potential of antihyperglycemic drugs as therapeutic adjuncts.
... The results showed that MGO promotes tumor growth and metastasis and induces AKT activation through phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin 2 (mTORC2) and Hsp27 regulation, suggesting that MGO is a potential target to tackle EGFR-targeted therapy resistance in colorectal cancer. Yamagishi S et al. discussed the potential molecular link between diabetes and colorectal cancer, proposing several ways to test the hypothesis that advanced glycation end products (AGE) could explain the molecular link between diabetes and colorectal cancer (44). Oxidative stress stands out as a crucial mediator in the intricate interplay between cancer and diabetes. ...
Objective
Despite several observational studies attempting to investigate the potential association between type 1 diabetes mellitus (T1DM) and the risk of digestive cancers, the results remain controversial. The purpose of this study is to examine whether there is a causal relationship between T1DM and the risk of digestive cancers.
Methods
We conducted a Mendelian randomisation (MR) study to systematically investigate the effect of T1DM on six most prevalent types of digestive cancers (oesophageal cancer, stomach cancer, hepatocellular carcinoma, biliary tract cancer, pancreatic cancer, and colorectal cancer). A total of 1,588,872 individuals were enrolled in this analysis, with 372,756 being the highest number for oesophageal cancer and 3,835 being the lowest for pancreatic cancer. Multiple MR methods were performed to evaluate the causal association of T1DM with the risk of six site-specific cancers using genome-wide association study summary data. Sensitivity analyses were also conducted to assess the robustness of the observed associations.
Results
We selected 35 single nucleotide polymorphisms associated with T1DM as instrumental variables. Our findings indicate no significant effect of T1DM on the overall risk of oesophageal cancer (OR= 0.99992, 95% CI: 0.99979-1.00006, P= 0.2866), stomach cancer (OR=0.9298,95% CI: 0.92065-1.09466, P= 0.9298), hepatocellular carcinoma (OR= 0.99994,95% CI: 0.99987-1.00001, P= 0.1125), biliary tract cancer (OR=0.97348,95% CI: 0.8079-1.1729, P= 0.7775)), or pancreatic cancer (OR =1.01258, 95% CI: 0.96243-1.06533, P= 0.6294). However, we observed a causal association between T1DM and colorectal cancer (OR=1.000, 95% CI: 1.00045-1.0012, P<0.001), indicating that T1DM increases the risk of colorectal cancer. We also performed sensitivity analyses, which showed no heterogeneity or horizontal pleiotropy. For the reverse MR from T1DM to six digestive cancers, no significant causal relationships were identified.
Conclusions
In this MR study with a large number of digestive cancer cases, we found no evidence to support the causal role of T1DM in the risk of oesophageal cancer, stomach cancer, hepatocellular carcinoma, biliary tract cancer, or pancreatic cancer. However, we found a causal positive association between T1DM and colorectal cancer. Further large-scale prospective studies are necessary to replicate our findings.
... One is through diabetic microangiopathy. This exerts tumor-suppressive effects by rendering the vascular basal membrane less susceptible to cancer cell migration and metastasis (13)(14)(15)(16)(17). Hyperinsulinemia and hyperglycemia can promote tumorigenesis through metabolic remodeling of cancerassociated signaling pathways or by enhancing epithelial-tomesenchymal transition (EMT) (18,19). ...
Background
The consequence of diabetes on lung cancer overall survival (OS) is debated. This retrospective study used two large lung cancer databases to assess comprehensively diabetes effects on lung cancer OS in diverse demographic populations, including health disparity.
Methods
The University of Texas MD Anderson Cancer Center database (32,643 lung cancer cases with 11,973 diabetics) was extracted from electronic health records (EHRs) using natural language processing (NLP). Associations were between diabetes and lung cancer prognostic features [age, sex, race, body mass index (BMI), insurance status, smoking, stage, and histopathology]. Hemoglobin A1C (HgbA1c) and glucose levels assessed glycemic control. Validation was with a Louisiana cohort (17,768 lung cancer cases with 4,746 diabetics) enriched for health disparity cases. Kaplan-Meier analysis, log-rank test, multivariable Cox proportional hazard models, and survival tree analyses were employed.
Results
Lung cancer patients with diabetes exhibited marginally elevated OS or no statistically-significant difference versus non-diabetic patients. When examining OS for two glycemic levels (HgbA1c > 7.0 or glucose > 154 mg/dL versus HgbA1c > 9.0 or glucose > 215 mg/dL), a statistically significant improvement in OS occurred in lung cancers with controlled versus uncontrolled glycemia (P < 0.0001). This improvement spanned gender, age, smoking status, insurance status, stage, race, BMI, histopathology and therapy. Survival tree analysis revealed that obese and morbidly obese patients with controlled glycemia or no known diabetes had higher lung cancer OS than comparison groups.
Conclusion
These findings indicate a need for optimal glycemic control to improve lung cancer OS in diverse populations with diabetes.
... [19] Thus, hyperglycemia may pose direct tumor-enhancing effects as cancer cells strongly rely on the glycolysis process. [20] In addition to the direct effects of insulin and excessive glucose, numerous metabolic abnormalities that occur in conjunction with diabetes mellitus can also result in the development of tumors. Inflammation is viewed as a characteristic of carcinogenesis [21] and is also thought to be a chronic pro-inflammatory condition in type-1 diabetes mellitus. ...
Diabetes is a prevalent metabolic disorder that results in several comorbidities including cancer. Cancer becomes the most severe complication of diabetes patients. Growing evidence proved that impaired glucose homeostasis is an independent risk factor for the occurrence of various types of cancers including liver, pancreatic, gastric (stomach), colorectal, kidney, and breast cancers, and influences cancer prognosis. Diabetes mellitus and cancer have a bidirectional relationship, thus there is a need to look for drugs that can be beneficial in treating both diseases. Therefore, more research is focusing on evaluating the role of antihyperglycemic agents in the treatment of various types of cancers. Metformin, an FDA-approved first-line antihyperglycemic agent can be used as a monotherapy or as an adjuvant to chemotherapeutic agents in the treatment of various types of cancer. However, the exact mechanism of metformin as an anticancer agent is still unknown, the majority of the described putative mechanisms focus on promoting the activity of the AMP-activated protein kinase (AMPK) pathway. This review article thus gives insights into the prognosis of cancer in diabetes patients and aims to explore the possible mechanism of action of metformin in the prevention and treatment of cancer.
... In vitro studies showed that silencing RAGE in human prostate cancer cells caused an inhibition of the proliferation and a decrease in the levels of prostate-specific antigen (PSA) [241]. In other reports, anti-RAGE antibodies inhibited tumour formation and lung metastasis of melanoma cell xenografts and subsequently improved survival in athymic mice [242]. All that evidence suggested that AGEs, via interaction with RAGE, could perform a role in various types of cancer and contribute to tumour development, migration, and metastasis. ...
Ageing is a composite process that involves numerous changes at the cellular, tissue, organ and whole-body levels. These changes result in decreased functioning of the organism and the development of certain conditions, which ultimately lead to an increased risk of death. Advanced glycation end products (AGEs) are a family of compounds with a diverse chemical nature. They are the products of non-enzymatic reactions between reducing sugars and proteins, lipids or nucleic acids and are synthesised in high amounts in both physiological and pathological conditions. Accumulation of these molecules increases the level of damage to tissue/organs structures (immune elements, connective tissue, brain, pancreatic beta cells, nephrons, and muscles), which consequently triggers the development of age-related diseases, such as diabetes mellitus, neurodegeneration, and cardiovascular and kidney disorders. Irrespective of the role of AGEs in the initiation or progression of chronic disorders, a reduction in their levels would certainly provide health benefits. In this review, we provide an overview of the role of AGEs in these areas. Moreover, we provide examples of lifestyle interventions, such as caloric restriction or physical activities, that may modulate AGE formation and accumulation and help to promote healthy ageing.
... AGE adducts have been linked to several diseases due to their interactions with the Receptor for AGEs (RAGE) [24][25][26]. RAGE activation has been reported to be primarily responsible for the pathogenicity associated with AGEs [27,28]. AGE-RAGE interaction has been found to stimulate the growth of human pancreatic cancer cells [29,30]. ...
... Ovarian cancer is metabolically active and boosts its capacity to uptake larger volumes of glucose by upregulating the expression of glucose transporters (116)(117)(118). Chronic hyperglycemia creates DNA damage, cellular dysfunction, and damage to the ovarian epithelium by exposure to produced oxidative stress (i.e., reactive oxygen species) and the effects of glycation (119,120). In hyperglycemic environments, the interaction of advanced glycation end products and their receptors has been demonstrated to enhance tumor cell proliferation or invasiveness (121) by promoting systemic inflammation. ...
The association between insulin resistance (IR) and ovarian neoplasm is little known. The present study attempted to investigate the difference in clinicopathological characteristics, metabolic parameters, and IR prevalence between benign and malignant ovarian neoplasms. The cross‑sectional study involved 52 non‑diabetic women with benign (n=27) and malignant (n=25) diagnoses in a tertiary hospital in Indonesia. Fasting insulin level (FIL), homeostatic model assessment of IR and β‑cell dysfunction (HOMA‑IR and HOMA‑β), fasting IR index (FIRI), and quantitative insulin sensitivity check index (QUICKI) were used as surrogate markers to evaluate IR. Parametric and nonparametric statistical tests were employed to analyze the different parameters between the two groups. Pearson or Spearman's rank test assessed the correlation between markers and clinical variables. Results revealed that patients with benign neoplasms were younger than those with malignant neoplasms (38.63 vs. 47.40 years; P=0.003) and had a higher median body mass index (BMI) than their counterparts (22.98 vs. 18.61 kg/m2; P=0.014). Different characteristics between benign and malignant neoplasm cases were found in menopausal status, ovary side affected, systolic blood pressure, and BMI classes. Endometrial cysts and mucinous carcinoma were the most often diagnosed benign and malignant neoplasms. Malignant neoplasms had a lower median HOMA‑β score than benign neoplasms (49.33 vs. 75.79; P=0.011), indicating more severe β‑cell dysfunction. No significant difference was observed in the prevalence of IR between benign and malignant ovarian neoplasms for the following values of each marker: FIL (25.9% vs. 12.0%), HOMA‑IR (37.0% vs. 28.0%), FIRI (51.9% vs. 48.0%) and QUICKI (81.5% vs. 92.0%). The indicators of FIL, HOMA‑IR, HOMA‑β, FIRI, and QUICKI correlated with each other and confirmed the reliability of these surrogate markers for measuring IR status in ovarian neoplasms. In brief, benign ovarian neoplasms tended to have more IR when compared with malignant ovarian neoplasms. However, this difference was not statistically significant.
... The expression of AGEs receptor (RAGE), which is found to be associated with survival of colon cancer cells [37], is upregulated owing to the higher concentration of AGEs [38]. Thus, enhanced AGEs-RAGE interaction may be the missing link between diabetes and increased risk of CRC [39]. The interaction between RAGE and AGEs induces recruitment and activation of inflammatory cells releasing inflammatory cytokines, which are involved in many cancer-related signal pathways [40]. ...
Several epidemiological studies have identified diabetes as a risk factor for colorectal cancer (CRC). The potential pathophysiological mechanisms of this association include hyperinsulinemia, insulin-like growth factor (IGF) axis, hyperglycemia, inflammation induced by adipose tissue dysfunction, gastrointestinal motility disorder, and impaired immunological surveillance. Several studies have shown that underlying diabetes adversely affects the prognosis of patients with CRC. This review explores the novel anticancer agents targeting IGF-1R and receptor for advanced glycation end products (RAGE), both of which play a vital role in diabetes-induced colorectal tumorigenesis. Inhibitors of IGF-1R and RAGE are expected to become promising therapeutic choices, particularly for CRC patients with diabetes. Furthermore, hypoglycemic therapy is associated with the incidence of CRC. Selection of appropriate hypoglycemic agents, which can reduce the risk of CRC in diabetic patients, is an unmet issue. Therefore, this review mainly summarizes the current studies concerning the connections among diabetes, hypoglycemic therapy, and CRC as well as provides a synthesis of the underlying pathophysiological mechanisms. Our synthesis provides a theoretical basis for rational use of hypoglycemic therapies and early diagnosis and treatment of diabetes-related CRC.
... Therefore, the focus on a single RCS in the absence of a general assessment of the impact of carbonyl stress on cancer limits the understanding and the significance of these interesting data to diabetes and, in general, other carbonyl stress-related conditions that are also widely recognized risk factors for malignancy, such as obesity [44,172], smoking habit [95][96][97], and consumption of high fat and high-temperature-processed food [95,101,173]. This issue may not be purely academic, as several clinical and experimental studies have suggested a role of AGEs in the development and progression of various types of cancers, including breast [174], liver [175,176], colorectal [177], and kidney [178,179]. Most of these and other studies [180] have proposed that the cancer-promoting effect of AGEs is mainly mediated by AGE-RAGE interaction. ...
Both type 2 (T2DM) and type 1 (T1DM) diabetes mellitus confer an increased risk of pancreatic cancer in humans. The magnitude and temporal trajectory of the risk conferred by the two forms of diabetes are similar, suggesting a common mechanism. Carbonyl stress is a hallmark of hyperglycemia and dyslipidemia, which accompanies T2DM, prediabetes, and obesity. Accumulating evidence demonstrates that diabetes promotes pancreatic ductal adenocarcinoma (PDAC) in experimental models of T2DM, a finding recently confirmed in a T1DM model. The carbonyl stress markers advanced glycation end-products (AGEs), the levels of which are increased in diabetes, were shown to markedly accelerate tumor development in a mouse model of Kras-driven PDAC. Consistently, inhibition of AGE formation by trapping their carbonyl precursors (i.e., reactive carbonyl species, RCS) prevented the PDAC-promoting effect of diabetes. Considering the growing attention on carbonyl stress in the onset and progression of several cancers, including breast, lung and colorectal cancer, this review discusses the mechanisms by which glucose and lipid imbalances induce a status of carbonyl stress, the oncogenic pathways activated by AGEs and their precursors RCS, and the potential use of carbonyl-scavenging agents and AGE inhibitors in PDAC prevention and treatment, particularly in high-risk diabetic individuals.
... In vitro, RAGE was found expressed at higher levels in melanoma cells than melanocytes [219]. In two different studies, AGEs were shown to increase melanoma cell proliferation and migration, tumor growth, and metastasis, in a RAGE-dependent manner [219,220]. Recently, Nakamura et al. showed that melanoma growth and the formation of liver metastases could be reduced when using RAGE-targeting DNA aptamers [221]. The decrease in melanoma growth was associated with a decrease in expression levels of RAGE [221]. ...
Despite recent progresses in its treatment, malignant cutaneous melanoma remains a cancer with very poor prognosis. Emerging evidences suggest that the receptor for advance glycation end products (RAGE) plays a key role in melanoma progression through its activation in both cancer and stromal cells. In tumors, RAGE activation is fueled by numerous ligands, S100B and HMGB1 being the most notable, but the role of many other ligands is not well understood and should not be underappreciated. Here, we provide a review of the current role of RAGE in melanoma and conclude that targeting RAGE in melanoma could be an approach to improve the outcomes of melanoma patients.
... Nevertheless, there was a missing link in related signaling pathways. Yamagishi et al. hypothesized that RAGE and enhanced serum AGEs were the bridge between associated diseases and increase the risk of colorectal cancer in patients with diabetes (201). Upregulated RAGE and its ligands have been indicated in different inflammatory conditions, including IBD, diabetes, and cancer (54). ...
Receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein taken in diverse chronic inflammatory conditions. RAGE behaves as a pattern recognition receptor, which binds and is engaged in the cellular response to a variety of damage-associated molecular pattern molecules, as well as HMGB1, S100 proteins, and AGEs (advanced glycation end-products). The RAGE activation turns out to a formation of numerous intracellular signaling mechanisms, resulting in the progression and prolongation of colorectal carcinoma (CRC). The RAGE expression correlates well with the survival of colon cancer cells. RAGE is involved in the tumorigenesis, which increases and develops well in the stressed tumor microenvironment. In this review, we summarized downstream signaling cascade activated by the multiligand activation of RAGE, as well as RAGE ligands and their sources, clinical studies, and tumor markers related to RAGE particularly in the inflammatory tumor microenvironment in CRC. Furthermore, the role of RAGE signaling pathway in CRC patients with diabetic mellitus is investigated. RAGE has been reported to drive assorted signaling pathways, including activator protein 1, nuclear factor-κB, signal transducer and activator of transcription 3, SMAD family member 4 (Smad4), mitogen-activated protein kinases, mammalian target of rapamycin, phosphoinositide 3-kinases, reticular activating system, Wnt/β-catenin pathway, and Glycogen synthase kinase 3β, and even microRNAs.
... carcinogenic mutations. [13][14][15] Insulin resistance, which precedes the development of hyperglycemia, can also favor the development of cancer through the effects of insulin and insulin-like growth factors on cell proliferation and apoptosis. 16,17 Finally, disturbances of glucose metabolism can induce adverse changes in natural killer (NK) cells and NK-T cells which play an important role in defending against cancer. ...
... The name RAGE derives from its ability to bind advanced glycation end-products (AGEs). Although a role for these major RAGE ligands has been tentatively proposed to explain the increased risk of various cancers (including PaC) in diabetic and obese individuals [18], surprisingly, their role in pancreatic carcinogenesis has never been investigated [19]. AGEs comprise a heterogeneous group of compounds [20] that accumulate in tissues of ageing individuals and, at an accelerated rate, in diabetic and obese subjects, owing to mechanisms including increased carbohydrate and lipid substrate availability, oxidative and non-oxidative conditions favouring the glycation process, and impaired detoxification [21]. ...
Diabetes is an established risk factor for pancreatic cancer (PaC), together with obesity, Western diet and tobacco smoking. The common mechanistic link might be the accumulation of advanced glycation endproducts (AGEs), which characterizes all the above disease conditions and unhealthy habits. Surprisingly, however, the role of AGEs in PaC has not been examined yet, despite the evidence of a tumor-promoting role of RAGE, the receptor for AGEs. Here, we tested the hypothesis that AGEs promote PaC through RAGE activation. To this end, we investigated the effects of the AGE Nε-carboxymethyllysine (CML) in human pancreatic ductal adenocarcinoma (PDA) cell lines and in a mouse model of Kras-driven PaC interbred with a bioluminescent model of proliferation. Tumor growth was monitored in vivo by bioluminescence imaging and confirmed by histology. CML promoted PDA cell growth and RAGE expression, in a concentration- and time-dependent manner, and activated downstream tumorigenic signaling pathways. These effects were counteracted by RAGE antagonist peptide (RAP). Exogenous AGE administration to PaC-prone mice induced RAGE upregulation in pancreatic intraepithelial neoplasias (PanINs) and markedly accelerated progression to invasive PaC. At 11 weeks of age (6 weeks of CML treatment), PaC was observed in 8/11 (72.7%) CML-treated versus 1/11 (9.1%) vehicle-treated (Ctr) mice. RAP delayed PanIN development in Ctr mice but failed to prevent PaC promotion in CML-treated mice, likely due to competition with soluble RAGE for binding to AGEs and/or compensatory upregulation of the RAGE homolog CD166/ALCAM, which also favored tumor spread. These findings indicate that AGEs modulate the development and progression of PaC through receptor-mediated mechanisms and might be responsible for the additional risk conferred by diabetes and other conditions characterized by increased AGE accumulation. Finally, our data suggest that an AGE reduction strategy, instead of RAGE inhibition, might be suitable for risk management and prevention of PaC.
... Although this hyperglycemia-induced glycation is a non-specific reaction, proteins undergo this modification more frequently than other macromolecules, with substantial functional and structural consequences [7][8][9][10][11]. Different clinical studies have reported the role of AGEs in the pathogenesis of various types of cancers in patients with diabetes mellitus, including colorectal [12], kidney [13], and liver cancer [14]. Lately, a growing body of evidence has suggested the direct consequences of diabetes-related hyperglycemia and hyperinsulinemia as AGEs can increase the development and progression of breast cancer [15][16][17]. ...
Diabetes mellitus potentiates the risk of breast cancer. We have previously described the pro-tumorigenic effects of advanced glycation endproducts (AGEs) on estrogen receptor (ER)-negative MDA-MB-231 breast cancer cell line mediated through the receptor for AGEs (RAGE). However, a predominant association between women with ER-positive breast cancer and type 2 diabetes mellitus has been reported. Therefore, we have investigated the biological impacts of AGEs on ER-positive human breast cancer cell line MCF-7 using in vitro cell-based assays including cell count, migration, and invasion assays. Western blot, FACS analyses and quantitative real time-PCR were also performed. We found that AGEs at 50-100 μg/mL increased MCF-7 cell proliferation and cell migration associated with an enhancement of pro-matrix metalloproteinase (MMP)-9 activity, without affecting their poor invasiveness. However, 200 μg/mL AGEs inhibited MCF-7 cell proliferation through induction of apoptosis indicated by caspase-3 cleavage detected using Western blotting. A phospho-protein array analysis revealed that AGEs mainly induce the phosphorylation of extracellular-signal regulated kinase (ERK)1/2 and cAMP response element binding protein-1 (CREB1), both signaling molecules considered as key regulators of AGEs pro-tumorigenic effects. We also showed that AGEs up-regulate RAGE and ER expression at the protein and transcript levels in MCF-7 cells, in a RAGE-dependent manner after blockade of AGEs/RAGE interaction using neutralizing anti-RAGE antibody. Throughout the study, BSA had no effect on cellular processes. These findings pave the way for future studies investigating whether the exposure of AGEs-treated ER-positive breast cancer cells to estrogen could lead to a potentiation of the breast cancer development and progression.
... Human studies have suggested the involvement of TAGE in the onset of vascular inflammation [30], NASH [50], AD [80], and some rare disorders [81,82]. In addition to their potential direct effects, some evidence indicates that TAGE interact strongly with RAGE to cause inflammatory and oxidative responses, which have been implicated in the onset of various cancers [83][84][85]. ...
Advanced glycation end-products (AGEs) generated with aging or in the presence of diabetes mellitus, particularly AGEs derived from the glucose/fructose metabolism intermediate glyceraldehyde (Glycer-AGEs; termed toxic AGEs (TAGE)), were recently shown to be closely involved in the onset/progression of diabetic vascular complications via the receptor for AGEs (RAGE). TAGE also contribute to various diseases, such as cardiovascular disease; nonalcoholic steatohepatitis; cancer; Alzheimer’s disease, and; infertility. This suggests the necessity of minimizing the influence of the TAGE-RAGE axis in order to prevent the onset/progression of lifestyle-related diseases (LSRD) and establish therapeutic strategies. Changes in serum TAGE levels are closely associated with LSRD related to overeating, a lack of exercise, or excessive ingestion of sugars/dietary AGEs. We also showed that serum TAGE levels, but not those of hemoglobin A1c, glucose-derived AGEs, or Nε-(carboxymethyl)lysine, have potential as a biomarker for predicting the progression of atherosclerosis and future cardiovascular events. We herein introduce the usefulness of serum TAGE levels as a biomarker for the prevention/early diagnosis of LSRD and the evaluation of the efficacy of treatments; we discuss whether dietary AGE/sugar intake restrictions reduce the generation/accumulation of TAGE, thereby preventing the onset/progression of LSRD.
... Advanced glycation end products (AGE), generally recognized as products of multiple complications from various diseases including diabetes, have been considered as possible human carcinogens (Yamagishi et al. 2005 ) . During the authors' studies on chemical carcinogens and chemopreventive agents of natural origin (Kapadia et al. 1997(Kapadia et al. , 1998Tokuda and Iida 2006 ) , human albumin and glucose natural mixture (HAGE) was identi fi ed as a possible human carcinogen with signi fi cant experimental tumor-initiating potency in the two-stage mouse skin tumor model described above. ...
Currently, there is considerable interest in the anticancer effects of red beetroot (Beta vulgaris L.) pigment extract, which is used worldwide as red food color E162 and as a natural colorant in cosmetics and drugs. Of particular significance is its broad spectrum of multi-organ antitumor activity demonstrable in laboratory animal models. Further, this nontoxic plant extract, when used in combination with potent anticancer drugs such as doxorubicin (Adriamycin), has the potential to act synergistically and mitigate treatment-related drug toxicity. Betanin, the betacyanin constituent primarily responsible for red beet color, is an antioxidant with an exceptionally high free radical-scavenging activity and is a modulator of oxidative stress. Research focused on anticancer activities of beetroot extract, in animal models, has unraveled their potential benefits as chemopreventive and chemotherapeutic agents, although further progress is needed on the identification and elucidation of anticancer mechanism(s) of individual active constituent(s) in additional well-designed experimental models and clinical trials, as discussed in this chapter.
... Both in vitro experimental cell culture and in vivo animal models respectively revealed the involvement of RAGE in complication of pancreatic cancer. This fact was incident in two pivotal and independent studies where AGE-RAGE interaction was found to stimulate the growth of human pancreatic cancer cells through the autocrine induction of platelet-derived growth factor-B [29,30]. In a recent study Kang et al. linked for the first time, the HMGB1-RAGE pathway with changes in bioenergetics. ...
... Its dimer configuration, on the other hand, is dominant in cancer cells and has low affinity for its natural substrate (phosphoenolpyruvate acid), resulting in intracellular accumulation of glycosylation products. Finally multiple studies confirm that excessive accumulation of advanced glycosylation end products in non-malignant cells leads to activation of inflammatory metabolic pathways, resulting in unstable gene mutations and activation of protooncogenes [48][49][50][51][52]. The presence of advanced glycosylation end products also results in activation of specific cell membrane receptors resulting in autocrine activation of inflammatory pathways, including paracrine mobilization of inflammatory cells, such as macrophages and neutrophils [53][54][55][56]. ...
The incidence of cancer is increased in patients with diabetes mellitus. Numerous epidemiological studies confirm this phenomenon, specifically with malignancies of the pancreas, liver, bile ducts, uterus, kidney, breast in postmenopausal women, colon, bladder and aggressive forms of prostate cancer. Disruption of homeostatic glucose metabolism may play a significant role in malignant cellular transformation and disease progression. Additionally, recent advances in molecular and biochemical technology allow for deeper understanding of the pathophysiology of disrupted glucose-insulin axis pathways in diabetics at the subcellular level. These technological advances may provide answers as to how malignant cellular transformation occurs and identify potential treatment targets.
... Some mechanisms have been hypothesized to understand why the impaired fasting glucose concentration is a risk factor for many cancers. An excess level of glucose can lead to accumulation of glycation end-products in the cells that causes the degenerative changes in cell metabolism leading to the carcinogenic mutation [7][8][9]. Moreover high glucose concentration can better sustain the intensive proliferation of typical cancer cells [10,11]. ...
Oncogenic K-Ras represents the most common molecular change in human lung adenocarcinomas, the major histologic subtype of non-small cell lung cancer (NSCLC). The presence of K-Ras mutation is associated with a poor prognosis, but no effective treatment strategies are available for K-Ras -mutant NSCLC. Epidemiological studies report higher lung cancer mortality rates in patients with type 2 diabetes. Here, we use a mouse model of K-Ras-mediated lung cancer on a background of chronic hyperglycemia to determine whether elevated circulating glycemic levels could influence oncogenic K-Ras-mediated tumor development. Inducible oncogenic K-Ras mouse model was treated with subtoxic doses of streptozotocin (STZ) to induce chronic hyperglycemia. We observed increased tumor mass and higher grade of malignancy in STZ treated diabetic mice analyzed at 4, 12 and 24 weeks, suggesting that oncogenic K-Ras increased lung tumorigenesis in hyperglycemic condition. This promoting effect is achieved by expansion of tumor-initiating lung bronchio-alveolar stem cells (BASCs) in bronchio-alveolar duct junction, indicating a role of hyperglycemia in the activity of K-Ras-transformed putative lung stem cells. Notably, after oncogene K-Ras activation, BASCs show upregulation of the glucose transporter (Glut1/Slc2a1), considered as an important player of the active control of tumor cell metabolism by oncogenic K-Ras. Our novel findings suggest that anti-hyperglycemic drugs, such as metformin, may act as therapeutic agent to restrict lung neoplasia promotion and progression.
... Other studies have shown that AGEs are increased in diseases such as atherosclerosis [38], osteoporosis [39] and diabetes [40], which are common comorbidities in patients with COPD. The cardiovascular complications in diabetes are postulated to be due to the high levels of AGEs in the circulation [40]. ...
Chronic obstructive pulmonary disease (COPD) is associated with systemic inflammation and oxidative stress. These conditions may lead to the formation of advanced glycation end-products (AGEs).
In this study we investigated in 88 COPD patients and 55 control subjects (80% ex-smokers) the association of the plasma protein-bound AGEs N ϵ -(carboxymethyl)lysine (CML), pentosidine, N ϵ -(carboxyethyl)lysine (CEL), and AGE accumulation in skin by skin autofluorescence (AFR), with lung function.
Mean± sd plasma CML was decreased (COPD 61.6±15.6 nmol·mmol ⁻¹ lysine, never-smokers 80.7±19.8 nmol·mmol ⁻¹ lysine and ex-smokers 82.9±19.3 nmol·mmol ⁻¹ lysine) and CEL (COPD 39.1±10.9 nmol·mmol ⁻¹ lysine, never-smokers 30.4±5.0 nmol·mmol ⁻¹ lysine and ex-smokers 27.7±6.4 nmol·mmol ⁻¹ lysine) and AFR (COPD 3.33±0.67 arbitrary units (AU), never-smokers 2.24±0.45 AU and ex-smokers 2.31±0.47 AU) were increased in COPD patients compared to controls. Disease state was inversely associated with CML, and linearly associated with CEL and AFR. Performing regression analyses in the total group, CEL and AFR showed a negative association and CML a positive association with lung function, even after correction for potential confounders.
In conclusion, CEL and AFR were negatively and CML was positively associated with disease state. In the total group only the AGEs showed an association with forced expiratory volume in 1 s. Our data suggest that AGEs are involved in the pathophysiology of COPD, although their exact role remains to be determined.
... Animal model hyperglycemia was shown to be involved in metastatic processes [177], and liver tumors tend to be significantly larger in high glucose environment which was independent of hyperinsulinemia [178]. Enhanced formation of advanced glycation end products (AGE) was documented as a growth promoter for melanoma, pancreatic and possibly colon cancer in animal models [179]. Hyperglycemia may exert a direct tumor promoting effect, since cancer cells rely strongly on glycolysis [180]. ...
Diabetes and cancer represent two complex, diverse, chronic, and potentially fatal diseases. Cancer is the second leading cause of death, while diabetes is the seventh leading cause of death with the latter still likely underreported. There is a growing body of evidence published in recent years that suggest substantial increase in cancer incidence in diabetic patients. The worldwide prevalence of diabetes was estimated to rise from 171 million in 2000 to 366 million in 2030. About 26.9% of all people over 65 have diabetes and 60% have cancer. Overall, 8-18% of cancer patients have diabetes. In the context of epidemiology, the burden of both diseases, small association between diabetes and cancer will be clinically relevant and should translate into significant consequences for future health care solutions. This paper summarizes most of the epidemiological association studies between diabetes and cancer including studies relating to the general all-site increase of malignancies in diabetes and elevated organ-specific cancer rate in diabetes as comorbidity. Additionally, we have discussed the possible pathophysiological mechanisms that likely may be involved in promoting carcinogenesis in diabetes and the potential of different antidiabetic therapies to influence cancer incidence.
... A panoply of studies have focused on the factors involved in the pathogenesis of diabetic complications and most seeking effective therapies [27,28]. However, the exact cellular or molecular basis of these complications has not yet been fully elucidated [29]. ...
Background
Many indigenous plants of Mascarene Islands have been used in folkloric medicine to manage diabetes but few species have received scientific attention. Selected traditional medicinal plants (Antidesma madagascariense Lam. -Euphorbiaceae (AM), Erythroxylum macrocarpum O.E.Schulz -Erythroxylaceae (EM), Pittosporum senacia Putterl -Pittosporaceae (PS), Faujasiopsis flexuosa Lam. C.Jeffrey -Asteraceae (FF), Momordica charantia Linn -Cucurbitaceae (MC) and Ocimum tenuiflorum L -Lamiaceae (OT) were evaluated for their antioxidant, antiglycation and cytotoxic potential in vitro.
Methods
Graded concentrations (1.25-100 μg/mL) of the crude methanolic and water extracts and fractions (dichloromethane, ethyl-acetate, n-butanol and water) were evaluated for abilities to scavenge 2,2-diphenyl-2-picrylhydrazyl hydrate (DPPH), nitric oxide (NO), superoxide (SO) radicals and to inhibit lipoxygenase and formation of advanced glycation endproduct (AGE) in vitro. The MTT (3-(4, 5-dimethylthazol-2-yl)-2,5-diphenyl tetrazonium bromide) cytotoxicity test was performed on 3T3 cell line.
Results
Only IC50 for DPPH, SO, NO and lipoxygenase for AM, FF and OT crude extracts and fractions were comparable to ascorbic acid and quercetin activity. Crude aqueous extracts of AM and FF showed IC50 of 4.08 and 3.89 μg/mL respectively for lipoxygenase which was significantly lower (p < 0.05) than quercetin (10.86 ± 0.68 μg/mL). The three crude aqueous extracts of these plants and their n-butanol fractions also showed antiglycation activities (p < 0.05) comparable to aminoguanidine. Increasing concentrations (250-2000 μg/mL) of the six crude extracts (Methanol and water) and their fractions did not inhibit mitochondrial respiration as measured by MTT cytotoxicity assay.
Conclusion
AM, FF and OT crude extracts and fractions have potent antioxidant and antiglycation properties with no apparent cytotoxicity and might have prophylactic and therapeutic potentials in the management of diabetes and related complications. Our study tends to validate the traditional use of these medicinal herbs and food plants as complementary and alternative medicines.
... Many reports have suggested the involvement of AGEs in diabetic vascular complications [17,18,20,27,28,[31][32][33]35,37], and other age-related disorders such as inflammatory disease [11,115], atherosclerosis [89,[116][117][118], cancer [39,[119][120][121][122], and AD [10,103,104,[123][124][125][126][127][128]. Since AGE and RAGE levels are upregulated in the brains of diabetic patients with AD [124,129,130], the enhanced AGEs-RAGE axis could partly account for the clinical link between DM and AD. ...
Recent clinical evidence has suggested diabetes mellitus as one of the risk factors for the development and progression of Alzheimer's disease (AD). Continuous hyperglycemia is a causative factor for diabetic vascular complications, and it enhances the generation of advanced glycation end-products (AGEs), thereby being involved in the pathogenesis of AD as well. Moreover, there is a growing body of evidence to show that the interaction of glyceraldehyde-derived AGEs (Glycer-AGE), which is a predominant structure of toxic AGEs (TAGE), with a receptor for AGEs elicits oxidative stress generation in numerous types of cells, all of which could contribute to the pathological changes of diabetic vascular complications and AD. Indeed, we have recently found that Glycer-AGE induces apoptotic cell death in cultured cortical neuronal cells. We also found that the neurotoxic effect of diabetic serum on neuronal cells was blocked by a neutralizing antibody raised against the Glycer-AGE epitope. Moreover, in human AD brain, Glycer-AGE is distributed in the cytosol of neurons in the hippocampus. These results suggest that Glycer-AGE is involved in the pathogenesis of AD. In this review, we discuss the pathophysiological role for AGEs in the development and progression of diabetic vascular complications and AD, especially focusing on TAGE.
... 42 Recent studies have demonstrated that glyceraldehyde-derived and glycolaldehyde-derived AGEs have a pyridinium moiety, [118][119][120] suggesting that a specific and common chemical scaffold may be responsible for the cytotoxicity of TAGE. TAGE stimulate the growth and migration of cancer cells, 30,121 and they may also cause other neurodegenerative disease (Figure 4). Pathophysiological and structural studies of TAGE will give us valuable information regarding the development of age-related diseases and their prevention. ...
Several epidemiological studies have reported moderately increased risks of Alzheimer's disease (AD) in diabetic patients compared with general population. In diabetes mellitus, the formation and accumulation of advanced glycation end products (AGEs) progress more rapidly. Recent understanding of this process has confirmed that interactions between AGEs and their receptor (RAGE) may play a role in the pathogenesis of diabetic complications and AD. The authors have recently found that glyceraldehyde-derived AGEs (AGE-2), which is predominantly the structure of toxic AGEs (TAGE), show significant toxicity on cortical neuronal cells and that the neurotoxic effect of diabetic serum is completely blocked by neutralizing antibody against the AGE-2 epitope. Moreover, in human AD brains, AGE-2 is distributed in the cytosol of neurons in the hippocampus and parahippocampal gyrus. These results suggest that TAGE is involved in the pathogenesis of AD as well as other age-related diseases. In this review, the authors discuss the molecular mechanisms of AD, especially focusing on TAGE-RAGE system.
... However, it is reported that the sRAGE receptor, highly expressed in healthy lung tissues and especially at the site of alveolar epithelium, is significantly down-regulated in lung carcinomas, 83 and the RAGE expression is reported to be elevated in human pancreatic cells with high metastatic ability and decreased in tumor cells with low metastatic ability. 84 High RAGE expression is also reported in colonic 85 and prostatic 86 cancers. Little information is available about other types of cancers, including breast cancer, but it has recently been suggested that inhibition of AGE-RAGE interaction might have a potential as a molecular target for both cancer prevention and therapy. ...
High levels of glycated and lipoxidated proteins and peptides in the body are repeatedly associated with chronic diseases. These molecules are strongly associated with activation of a specific receptor called RAGE and a long-lasting exaggerated level of inflammation in the body.
PubMed reports over 5000 papers plus >13,500 articles about the related HbA(1c), most of them published in the past 5 years. Most of the available abstracts have been read and approximately 800 full papers have been studied.
RAGE, a member of the immunoglobulin superfamily of cell surface molecules and receptor for advanced glycation end products, known since 1992, functions as a master switch, induces sustained activation of nuclear factor kappaB (NFkappaB), suppresses a series of endogenous autoregulatory functions, and converts long-lasting proinflammatory signals into sustained cellular dysfunction and disease. Its activation is associated with high levels of dysfunctioning proteins in body fluids and tissues, and is strongly associated with a series of diseases from allergy and Alzheimers to rheumatoid arthritis and urogenital disorders. Heat treatment, irradiation, and ionization of foods increase the content of dysfunctioning molecules.
More than half of the studies are performed in diabetes and chronic renal diseases; there are few studies in other diseases. Most of our knowledge is based on animal studies and in vitro studies. These effects are worth further exploration both experimentally and clinically. An avoidance of foods rich in deranged proteins and peptides, and the consumption of antioxidants, especially polyphenols, seem to counteract such a development.
... In addition, during diabetes, advanced products of glycosylation are generated that are also found in senile plaques [31]. These products potentially lead to Aβ glycation, enhancing its aggregation, as observed in AD [32]. ...
Glycosylation and Glycation in Health and Diseases provides a comprehensive exploration of the essential biochemical processes, their implications in physiology, and their role in disease progression. This book is divided into two key sections: the first focuses on glycosylation, an enzymatic process essential for cellular function, while the second covers glycation, a nonenzymatic reaction linked to aging and chronic diseases. It covers congenital glycosylation disorders, the biology of advanced glycation end products (AGEs), and the critical role of the receptor for AGEs (RAGE) in inflammatory, neurological, cardiovascular, and cancer-related conditions. A valuable resource for students, researchers, and industry professionals, this book highlights the significance of glycobiology in drug discovery, diagnostics, and therapeutic innovations. Key Features: - Covers fundamental and advanced concepts of glycosylation and glycation. - Discusses the role of glycans in cellular function and disease pathology. - Explores AGE-RAGE interactions in cardiovascular, pulmonary, and neurological disorders. - Highlights applications in biopharmaceuticals, diagnostics, and vaccine development.
Methylglyoxal (MG) is a highly reactive α-dicarbonyl compound which reacts with proteins to form advanced glycation end products (AGEs). MG-induced AGE (MAGE) formation is particularly significant in diabetic condition. In the current study, we have undertaken a time-dependant characterization of MG-modified myoglobin following incubation of the heme protein with the α-dicarbonyl compound for different time periods. Interestingly, mass spectrometric studies indicated modifications at two specific lysine residues, Lys-87 and Lys-133. The AGE adducts identified at Lys-87 were carboxymethyllysine and carboxyethyllysine, while those detected at Lys-133 included pyrraline-carboxymethyllysine and carboxyethyllysine, respectively. Far-UV CD studies revealed a decrease in the native α-helical content of the heme protein gradually with increasing time of MG incubation. In addition, MG modification was found to induce changes in tertiary structure as well as surface hydrophobicity of the heme protein. MG-derived AGE adducts thus appear to alter the structure of Mb considerably. Considering the increased level of MG in diabetic condition, the current study appears physiologically relevant in terms of understanding AGE-mediated protein modification and subsequent structural changes.
Protein glycation is a post-translational modification of proteins which is thought to be the root cause of different complications, particularly in diabetes mellitus and age-related disorders. The reactive α-dicarbonyl compound, glyoxal, increases in diabetic condition and reacts with proteins to form advanced glycation end products (AGEs) following Maillard-like reaction. In the current study, the effect of glyoxal on the monomeric protein myoglobin has been investigated following incubation for a period of 30 days. Long-term incubation with glyoxal induced alteration of secondary structure of the heme protein from α-helix to β-sheet resulting in aggregation of the protein. The aggregates were found to exhibit amyloidal features with amorphous morphology as evident from subsequent biophysical spectroscopic and microscopic studies. Finally, mass spectrometric studies revealed glyoxal-induced modification of Lys-96, Lys-118, Lys-145, Arg-31 and Arg-139 residues of myoglobin to AGE adducts. The AGEs detected and identified were carboxymethyllysine (Lys-96), pyrrolidone-carboxymethyllysine (Lys-96, Lys-118 and Lys-145), arginine-derived hydroimidazolone (Arg-31) and the cross-linking adduct pentosidine (Lys-145 and Arg-139). Thus glyoxal-derived AGE adducts appear to induce structural constrain and subsequent aggregation of the heme protein. Considering the increased level of glyoxal in diabetes and the significance of AGE-mediated protein modification, the present study appears clinically relevant in understanding AGE-induced protein modification and subsequent conformational disorders.
Collagen and elastin are the most abundant structural proteins in animals and play an integral biological and structural role in the extracellular matrix. The biosynthesis and maturation of collagen and elastin occurs via multi-step intracellular and extracellular processes including the formation of several covalent crosslinks to stabilise their structure, confer thermal stability and provide biochemical properties to tissues. There are two major groups of crosslinks based on their formation pathways, enzymatic and non-enzymatic. The biosynthesis of enzymatic crosslinks starts with the enzymatic oxidation of lysine or hydroxylysine residues into aldehydes. These aldehdyes undergo a series of spontaneous condensation reactions with lysine, hydroxylysine or other aldehdye residues to form immature covalent crosslinks which are further matured via poorly understood mechanisms into multivalent crosslinks. While enzymatic crosslinks make up the majority of protein-protein crosslinks, the non-enzymatic unselective glycation of lysine residues via the Maillard reaction results in the formation of Advanced Glycation Endproducts (AGEs). These latter biosynthesis pathways are not fully understood as they are produced by a series of oxidative reactions between carbohydrates and collagen via Amadori rearrangements. Both covalent crosslinks and AGEs appear to correlate with several diseases such as skin and bone disorders, cancer metastasis, diabetes, Alzheimer's and cardiovascular diseases. Although several crosslinks are isolated, purified and described in collagen and elastin, only a few of them are chemically synthesized. Chemical synthesis plays an essential and important role in research providing pure crosslinks as reference materials and enabling the discovery of compounds to understand the biosynthesis of crosslinks and their properties. Synthetic crosslinks are crucial to verify the structures of collagen and elastin crosslinks where only a handful of structures have been determined by NMR spectroscopy and many other structures have only been predicted using mass spectrometry. This makes crosslinks and AGEs an interesting target for organic synthesis to produce sufficient quantities of material to enable studies on their biological significance and determine their absolute stereochemistry. The biological and chemical synthesis of both enzy-matic and non-enzymatic crosslinks are extensively described in this review. Collagen Collagen is integral for the structure of the extracellular matrix (ECM) and therefore vital for living organisms like mammals. 1 Collagen is expressed throughout all organs and tissues making it the main component of connective tissues in the body. 2 In vertebrates, up to 28 different types of collagen are known, most of them interact with other ECM proteins to form supramolecular network architecture which play a vital part in cell adhesion, migration and proliferation as well as providing strength. 3 The most common type is the fibrillar type I collagen (Col-I) contributing about 90% of total collagen content in the body. Col-I has an average size of 3000 amino acid residues and is involved in the formation of the structural network of tissues including skin, tendons, bones, cornea and the vascular system. 4 There are significant differences between the amino acid number and sequence, structure, and the role of different col-lagen types, however all share a common feature of at least one triple helical domain. 5 This domain is formed by three helical polyproline type II (PP-II) chains tightly packed into a right-handed triple helix which consists of a characteristic repeating amino acid motif (X AA-Y AA-Gly)n. Glycine occupies every third position in the sequence which fit into the centre of the triple helix, therefore larger residues are not tolerated. Even minor
BACKGROUND
Braised chicken is one of the well‐known traditional processed meat products in China. However, reports are scarce with respect to the formation of Nɛ‐carboxymethyllysine (CML) and Nɛ‐carboxyethyllysine (CEL) during chicken braising. Furthermore, braising for a long time and using high‐temperature process will result in water loss. However, the relationship between water loss and advanced glycation end products (AGEs) kinetics is limited. The present study aimed to investigate the relationship between water loss and kinetics of free and protein‐bound CML and CEL in braised chicken under different braising conditions (60–100 °C for 5–60 min).
RESULTS
Levels of free and protein‐bound CML and CEL were found to increase with heating time and temperature. The correlation coefficient (r²) was largest at zero‐order reaction (free CML: r² = 0.908–0.954, protein‐bound CML: r² = 0.901–0.958, free CEL: r² = 0.952–0.973, protein‐bound CEL: r² = 0.959–0.965). The activation energy was 44.158 ± 3.638 kJ mol⁻¹ for free CML, 40.041 ± 3.438 kJ mol⁻¹ for protein‐bound CML, 40.971 ± 0.334 kJ mol⁻¹ for free CEL and 40.247 ± 0.553 kJ mol⁻¹ for protein‐bound CEL. Furthermore, with the increase of braising time and temperature, the drip loss and cooking loss also became aggravated. A significant positive correlation between water loss and AGEs levels during braising was observed by Pearson's correlation analysis (P < 0.05).
CONCLUSION
We conclude that the levels of free and protein‐bound CML and CEL during braising were different, although they all met zero‐order reaction kinetics. Water loss was probably one of the main reasons for the formation of AGEs during chicken braising. © 2020 Society of Chemical Industry
Advanced glycation end products (AGEs) are a family of compounds of diverse chemical nature that are the products of nonenzymatic reactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs bind to one or more of their multiple receptors (RAGE) found on a variety of cell types and elicit an array of biologic responses. In this review, we have summarized the data on the nature of AGEs and issues associated with their measurements, their receptors, and changes in their expression under different physiologic and disease states. Last, we have used this information to prescribe lifestyle choices to modulate AGE-RAGE cycle for better health.
It is well established that the risk of colorectal cancer (CRC) is significantly increased in diabetic patients. As one of main forms of the advanced glycation end products (AGEs) that accumulate in vivo, glucose-derived AGEs play an important role in the pathogenesis of diabetic complications and may contribute to CRC progression. However, to date, both the contribution of glucose-derived AGEs to the course of CRC and the underlying mechanism are unclear. In the present study, the concentration of glucose-derived AGEs in the serum and tumor tissue of patients with CRC increased. A clinical data analysis demonstrated that the expression of the receptor for AGEs (RAGE), Specificity Protein 1 (Sp1), and matrix metallopeptidase -2 (MMP2) was significantly higher in cancerous tissues compared with non-tumor tissue in Chinese Han patients with CRC and that RAGE expression was closely associated with lymph node metastasis and TNM stage. Furthermore, in vivo and in vitro experiments showed that AGEs promoted invasion and migration of colorectal cancer, and the AGEs treatment increased the expression of RAGE, Sp1, and MMP2 in a dose-dependent manner. A RAGE blocking antibody and an Sp1-specific siRNA attenuated the AGE-induced effects. Moreover, the AGEs treatment increased the phosphorylation of ERK, and reducing the phosphorylation level of ERK by MEK1/2 inhibitor decreased the expression of Sp1. In conclusion, glucose-derived AGEs promote the invasion and metastasis of CRC partially through the RAGE/ERK/SP1/MMP2 cascade. These findings may provide an explanation for the poor prognoses of colorectal cancer in diabetic patients.
Le diabète est une maladie associée à une perturbation du métabolisme glucidique et représentent un problème de santé publique majeur. L'importante majorité des patients présente un diabète de type 2.Les complications les plus courantes sont vasculaires. Chez le diabétique, l'angiogenèse est défectueuse et paradoxale. La microangiopathie qui survient lors du diabète modifie le microenvironnement de la moelle osseuse et entraine egalement des problemes de cicatrisation alors qu'une angiogenèse exacerbé est responsable de pathologie telle que la rétinopathie ou la néphropathie diabétique.Les cellules souches mésenchymateuses (CSMs) sont connues pour leur potentiel de différenciation et de libération de facteurs paracrins, qui sont impliqués dans la régénération tissulaire. Les mécanismes qui associent le microenvironnement et les fonctions des CSMs dans un contexte diabétique restent actuellement méconnus. Le diabète peut modifier les caractéristiques des CSMs et le microenvironnement diabétique peut influencer la fonctionnalité de CSMs transplantées tout autant que leurs effets autocrins et/ou paracrins sur les cellules environnantes. L'étude du potentiel de CSMs diabétiques et du microenvironnement diabétique sur de CSMs pourrait alors avoir d'importantes implications cliniques. L'objectif primaire de cette étude est de caractériser l'impact du diabète sur la fonctionnalité et le potentiel angiogènique de CSMs à l'aide du modèle de rat dit Zucker Diabetic Fatty (ZDF) qui développe spontanément le diabète de type 2 et les complications vasculaire qui l'accompagne.
Epidemiological evidence suggests that people with diabetes have a significantly increased risk of developing various cancers. The aim of the study was to assess the frequency of various cancers in diabetic patients admitted in the National Institute of Diabetes Nutrition and Metabolic Diseases “Prof. N.C. Paulescu” between 01.01.2011 and 01.09.2014.
: The study analyzed a total of 24.104 admissions, corresponding to a total of 13.960 patients. A total of 520 hospitalizations with a diagnosis of cancer and diabetes were indentified. Finally, 298 patients meeting the inclusion and exclusion criteria were included in the study. For these patients, personal history, clinical and laboratory data were assessed.
The prevalence of cancer in hospitalized diabetic patients was 2.13%. The most frequent types of cancer (number of cases) were: breast - 63 patients, colorectal - 45 patients, pancreatic - 37 patients, lung - 31 patients and prostate - 20 patients.
Our data showed that the most common form of cancer associated with diabetes was breast cancer (21%), followed by colorectal cancer (15.10%) and pancreatic cancer (12.42%). Further prospective studies are needed in the long term on larger study groups to evaluate the incidence and prevalence of various forms of cancer in the diabetic population.
Chronic diseases (CD) represent the main cause of mortality in developed countries. The increase in the prevalence of of CD is associated with changes in lifestyle habits, including those related to the consumption of processed foodstuffs. In these foods advanced glycation end products (AGE) and advanced lipoperoxydation products (ALE) are formed as a consequence of the reactivity of proteins, carbohydrates, lipid and other components. The aim of the present review is to offer a perspective of how AGE and ALE affect the physiology and development of CD. Continous intake of AGE and ALE contributes to the exccesive accumulation of these products into body tissues, which in turn negatively influence the innate immune system, inflammatory responses, and resistance to diseases. This is achieved by direct interaction of AGE and ALE with specific cell AGE receptors (RAGE) that have a key role as master switches regulating the development of CD. Long-life molecules, namely collagen and myelin, and low-turnover tissues, e.g. connective, bone and neural tissues, are the main targets of AGE and ALE. In these tissues, AGE and ALE lead to the synthesis of insoluble compounds that severely alter cellular functionality. It has been reported associations of AGE and ALE with allergic and autoimmune diseases, Alzheimer disease and other degenerative disorders, catarats, atherosclerosis, cancer, and diabetes mellitus type 2, as well as a number of endocrine, gastrointestinal, skeleton-muscle, and urogenital alterations. Controlling all those pathologies would need further dietary recommendations aiming to limit the intake of processed foods rich in AGE and ALE, as well as to reduce the formation of those products by improving technological processes applicable to foods.
Advanced glycation end products (AGE) accumulate in human tissue proteins during aging, particularly under hyperglycemia conditions. AGEs induce oxidative stress and inflammation via the receptor for AGEs (RAGE) and soluble RAGE (sRAGE) can neutralize the effects mediated by RAGE-ligand engagement.
We examined the association between N(ε)-(carboxymethyl)lysine (CML), a prominent AGE, and sRAGE and colorectal cancer risk in a prospective case-cohort study nested within a cancer prevention trial among 29,133 Finnish male smokers. Among study subjects who were alive without cancer 5 years after baseline (1985-1988), we identified 483 incident colorectal cancer cases and randomly sampled 485 subcohort participants as the comparison group with the follow-up to April 2006. Baseline serum levels of CML-AGE, sRAGE, glucose and insulin were determined. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI.
Comparing highest with lowest quintile of sRAGE, the RR for incident colorectal cancer was 0.65 (95% CI, 0.39-1.07; P(trend) = 0.03), adjusting for age, years of smoking, body mass index, and CML-AGE. Further adjustment for serum glucose strengthened the association (RR = 0.52; 95% CI, 0.30-0.89; P(trend) = 0.009). Highest quintile of CML-AGE was not associated with an increased risk of colorectal cancer (multivariate RR = 1.20; 95% CI, 0.64-2.26).
Higher prediagnostic levels of serum sRAGE were associated with lower risk of colorectal cancer in male smokers.
This is the first epidemiologic study to implicate the receptor for AGEs in colorectal cancer development.
Diabetes and cancer are diseases which take the size of an epidemic spread across the globe. Those diseases are influenced by many factors, both genetic and environmental. Precise knowledge of the complex relationships and interactions between these two conditions is of great importance for their prevention and treatment. Many epidemiological studies have shown that certain types of cancer, especially gastrointestinal cancers (pancreas, liver, colon) and also the urinary and reproductive system cancers in women are more common in patients with diabetes or related metabolic disorders. There are also studies showing the inverse relationship between diabetes and cancer, or the lack of it, but they are less numerous and relate mainly to prostate cancer or squamous cell carcinoma of the esophagus. Epidemiological studies, however, do not say anything about the mechanisms of these dependencies. For this purpose, molecular research is needed on the metabolism of cells (including tumor cells) and on metabolic dysfunctions that arise due to changes in the cell environment taking place in the sick, as well as in the intensely treated human organism.
Receptor for advanced glycation end products (RAGE) is expressed in a range of cell types such as endothelial cells, smooth muscle cells, mesangial cells, mononuclear phagocytes and certain neurons. It is a multi-ligand receptor and a member of the immunoglobulin superfamily of cell surface molecules. Its repertoire of ligands includes advanced glycation end products (AGEs), amyloid fibrils, amphoterin and S100/calgranulins. This variety of ligands allows RAGE to be implicated in a wide spectrum of pathological conditions such as diabetes and its complications, Alzheimer's disease, cancer and inflammation. Additionally, genetic polymorphisms in the RAGE gene may have impact on the functional activity of the receptor. It becomes obvious that RAGE pathway is a complicated one and the question of whether blockade of RAGE is a feasible and safe strategy for the prevention/treatment of chronic diseases is gradually gaining the attention of the pharmaceutical community. In this review the biology of RAGE and the triggered signaling cascades involved in health and disease will be presented. Additionally, its potential as an attractive pharmacotherapeutic target will be explored by pointing out the pharmacotherapeutic agents that have been developed for RAGE blockade.
The receptor for advanced glycation end-products (RAGE) takes part in the pathogenesis of many diseases, including diabetes mellitus and cancer. AGE-precursors are detoxified by glyoxalase (GLO). sRAGE, soluble RAGE, is an inhibitor of pathological effects mediated via RAGE. The aim was to study sRAGE and polymorphisms of RAGE (AGER) and GLO genes in patients with pancreas cancer (PC).
The studied group consisted of 51 patients with PC (34 with impaired glucose tolerance-IGT, 17 without IGT), 34 type 2 DM and 154 controls. For genetic analysis, the number of patients was increased to 170. Serum sRAGE was measured by ELISA and all polymorphisms (RAGE -429T/C, -374T/A, 2184A/G, Gly82Ser and GLO A419C) were determined by PCR-RFLP and confirmed by sequencing.
Soluble RAGE is decreased in patients with PC compared to patients with DM and controls (975+/-532 vs. 1416+/-868 vs. 1723+/-643pg/mL, p<0.001). Patients with PC and IGT have lower sRAGE levels compared to patients with PC without IGT (886+/-470 vs. 1153+/-616pg/mL, p<0.05). No relationship of sRAGE to the stage was found. We did not show any difference in allelic and genotype frequencies in all RAGE and GLO polymorphisms among the studied groups.
This is the first study demonstrating decreased sRAGE in patients with pancreas cancer. Its levels are even lower than in diabetics and are lowest in patients with PC and IGT. Our study supports the role of glucose metabolism disorder in cancerogenesis. Further studies are clearly warranted, especially with respect to potential preventive and therapeutic implications.
In end-stage renal disease (ESRD) there is not only excessive morbidity and mortality due to cardiovascular disease but also an enhanced occurrence of various types of cancer. Both are characterized by oxidative stress and inflammation as two of the central underlying causes of the disease states. In cancer, genomic damage has been demonstrated to be of high pathogenetic relevance. DNA lesions may induce mutations of oncogenes and tumor-suppressor genes which, in the long-run, may lead to malignancies if mutagenicity is not mitigated by repair mechanisms. A high incidence of genomic damage in ESRD patients has been validated by various biomarkers of DNA lesions. We reviewed the mechanisms of DNA damage, focusing in particular on the role of advanced glycation end products (AGEs) which accumulate markedly in renal insufficiency. Considering the in vitro and in vivo findings to date, one has to assume a significant role of AGEs in DNA damage and the potential development of cancer.
Alzheimer's disease (AD) is the most common cause of dementia in developed countries. AD is characterized pathologically by the presence of senile plaques and neurofibrillary tangles (NFTs), the major constituents of which are amyloid beta protein (A beta) and tau protein, respectively. Based on the disease pathology, numerous blood and cerebrospinal fluid (CSF) tests have been proposed for early detection of AD. However, there is no definite clinical method to determine in which patients with mild cognitive impairment will progress to AD with dementia. Therefore, to develop a novel promising biomarker for early diagnosis of AD is urgently needed. Several epidemiological studies have reported moderately increased risks for AD in diabetic patients compared with general population. In diabetes mellitus, the formation and accumulation of advanced glycation end-products (AGEs), senescent macroprotein derivatives, progress more rapidly. In addition, recent understanding of this process has confirmed that AGEs-their receptor (RAGE) interactions may play a role in the pathogenesis of neurodegenerative disorders including AD. In human AD brains, AGEs are distributed in the cytosol of neurons in the hippocampus and para-hippocampal gyrus. In this paper, we discuss the pathophysiological role for toxic AGEs (TAGE) in AD. We further review here the possibility that serum or cerebrospinal fluid levels of TAGE could become a promising biomarker for early detection of AD.
Chronic diseases (CD) represent the main cause of mortality in developed countries. The increase in the prevalence of of CD is associated with changes in lifestyle habits, including those related to the consumption of processed foodstuffs. In these foods advanced glycation end products (AGE) and advanced lipoperoxydation products (ALE) are formed as a consequence of the reactivity of proteins, carbohydrates, lipid and other components. The aim of the present review is to offer a perspective of how AGE and ALE affect the physiology and development of CD. Continous intake of AGE and ALE contributes to the exccesive accumulation of these products into body tissues, which in turn negatively influence the innate immune system, inflammatory responses, and resistance to diseases. This is achieved by direct interaction of AGE and ALE with specific cell AGE receptors (RAGE) that have a key role as master switches regulating the development of CD. Long-life molecules, namely collagen and myelin, and low-turnover tissues, e.g. connective, bone and neural tissues, are the main targets of AGE and ALE. In these tissues, AGE and ALE lead to the synthesis of insoluble compounds that severely alter cellular functionality. It has been reported associations of AGE and ALE with allergic and autoimmune diseases, Alzheimer disease and other degenerative disorders, catarats, atherosclerosis, cancer, and diabetes mellitus type 2, as well as a number of endocrine, gastrointestinal, skeleton-muscle, and urogenital alterations. Controlling all those pathologies would need further dietary recommendations aiming to limit the intake of processed foods rich in AGE and ALE, as well as to reduce the formation of those products by improving technological processes applicable to foods.
Patients with Type 2 diabetes mellitus may be at increased colorectal adenoma and cancer risk. Moreover, chronic insulin therapy may increase the risk of colorectal cancer among patients with Type 2 diabetes mellitus. We investigated to determine whether insulin therapy might increase the risk of colorectal adenoma among clinically confirmed patients with Type 2 diabetes mellitus.
We conducted a retrospective study among patients with Type 2 diabetes mellitus who underwent total colonoscopy between January 2003 and July 2006 at Hallym University Sacred Heart Hospital. Among them (n = 325), patients with histologically confirmed colorectal adenomas (n = 100) and the same number of controls matched by age and sex were selected and analyzed.
Adenoma cases showed significantly higher rate of chronic insulin therapy (more than 1 year) than controls (P = 0.018). In multivariate regression analysis, patients who received chronic insulin therapy had three times the risk of colorectal adenoma compared with patients who received no insulin (odds ratio, 3; 95 percent confidence interval, 1.1-8.9; P = 0.04).
Chronic insulin therapy was associated with increased colorectal adenoma risk among Type 2 diabetes mellitus patients. This result may provide a need for more intensive colorectal cancer screening program in patients with Type 2 diabetes mellitus, especially those who receive chronic insulin therapy.
Spontaneous non-enzymatic reaction of protein amino groups with glucose and other reducing sugars, known as glycation or Maillard reaction, has long been considered irreversible and inevitably followed by slow conversion of fructosamines and advanced glycation end products. Instead, recent identification of fructosamine 3 kinase (FN3K) has unveiled that fructosamines can be physiologically repaired, so that the FN3K enzyme could be considered a new form of protein repair.
Thirty-one consecutive patients with colorectal cancer were enrolled in the study. FN3K gene expression was determined using quantitative RT-PCR.
The mean level of FN3K gene expression was significantly lower in cancer tissue than in the corresponding normal colorectal mucosa, and FN3K gene was under-expressed most particularly in the tumours located on the left side of the colon.
Low mRNA levels of this enzyme in colon cancer tissue with respect to normal surrounding mucosa suggests that neoplastic cells have lost a protective enzymatic system. Reduced FN3K gene expression may be important in the pathogenesis and progression of colorectal cancer.
Delayed stool transit and other gastrointestinal abnormalities are commonly observed in persons with diabetes mellitus and
are also known to be associated with colorectal cancer. Previous studies of the contribution of diabetes to colorectal cancer
incidence and mortality have been limited by small sample sizes and failure to adjust for covariates. With more than 1 million
respondents, the 1959-1972 Cancer Prevention Study provided a unique opportunity to explore whether persons with diabetes
(n = 15,487) were more likely to develop colorectal cancer during a 13–year follow-up period than were persons without diabetes
(n = 850,946). After adjustment for colorectal cancer risk factors, such as race, educational level, body mass index, smoking,
alcohol use, dietary intake, aspirin use, physical activity, and family history of colorectal cancer, the incidence density
ratio comparing colorectal cancer in those with diabetes and those without diabetes was 1.30 (95% confidence interval 1.03–1.65)
for men and 1.16 (95% confidence interval 0.87-1.53) for women. However, diabetes was not associated with greater case fatality.
Future studies should explore the possibility of a cancer-promoting gastrointestinal milieu, including delayed stool transit
and elevated fecal bile acid concentrations, associated with hyperglycemia and diabetic neuropathy. Am J Epidemiol 1998; 147:816–25.
This is the first part of a bipartite review that summarizes the rising knowledge on the molecular mechanisms underlying the action of advanced glycation endproducts (AGEs) and their contribution to diabetic complications and vascular disease. While the first part presented here focusses on AGE formation, the second part will describe the AGE-protein/receptor interactions and their role in mediating AGE-dependent intracellular signalling.
Nonenzymatic glycation, in which reducing sugars are covalently attached to free amino groups and ultimately form AGEs, has been found to occur during normal aging and at accelerated rate in diabetes mellitus. Oxidation, accompanying glycation in vivo, further supports chemical modifications. AGE formation and protein crosslinking are irreversible processes that alter the structural and functional properties of proteins, lipid components and nucleic acids. AGE modifications do not only change the physicochemical properties of the afflicted molecules, but also induce cellular signalling, activation of transcription factors and subsequent gene expression in vitro and in vivo.
AGEs elicit a wide range of cell-mediated responses that might contribute to the pathogenesis of diabetic complications, vascular and renal disease and Alzheimer's disease. Substances that inhibit AGE formation, reduce oxidative stress or destroy already formed crosslinks may limit the progression of disease and may offer new tools for therapeutic interventions in the therapy of AGEs mediated disease.
Several thrombogenic abnormalities are associated with diabetes. To investigate the underlying molecular mechanisms, we examined the effects of advanced glycation endproducts (AGE), non-enzymatically glycated protein derivatives, on the production of prostacyclin (PGI2), an anti-thrombogenic prostanoid, and of plasminogen activator inhibitor-1 (PAI-1), a fast-acting serine protease inhibitor of fibrinolysis, in human microvascular endothelial cells (EC). Firstly, AGE-bovine serum albumin (BSA) but not non-glycated BSA, was found to considerably decrease the production of PGI2 to about two-thirds of the control value. Secondly, quantitative reverse transcription-polymerase chain reaction showed that AGE-BSA increased the EC levels of mRNA coding for PAI-1, this being associated with a concomitant increase in the immunoreactive PAI-1 contents and the anti-fibrinolytic activity. Thirdly, the effects of AGE on PGI2 and PAI-1 syntheses in EC were found to be mediated by a receptor for AGE (RAGE) because antisense DNA against RAGE mRNA could reverse the AGE effects. Further, it was found that AGE decreased the intracellular cyclic AMP concentrations in EC and that cyclic AMP agonists such as dibutyryl cyclic AMP, forskolin and PGI2 analogue reduced the AGE-stimulated PAI-1 production, suggesting the involvement of cyclic AMP in the AGE-signalling pathway. The results thus suggest that AGE have the ability to cause platelet aggregation and fibrin stabilization, resulting in a predisposition to thrombogenesis and thereby contributing to the development and progression of diabetic vascular complications.
Methylglyoxal (MG) is a reactive alpha-dicarbonyl that is thought to contribute to diabetic complications either as a direct toxin or as a precursor for advanced glycation end products. It is produced primarily from triose phosphates and is detoxified to D-lactate (DL) by the glyoxalase pathway. Because guanidino compounds can block dicarbonyl groups, we have investigated the effects of the diamino biguanide compound metformin and of hyperglycemia on MG and its detoxification products in type 2 diabetes. MG and DL were measured by high-performance liquid chromatography in plasma from 57 subjects with type 2 diabetes. Of these subjects, 27 were treated with diet, sulfonylureas, or insulin (nonmetformin), and 30 were treated with metformin; 28 normal control subjects were also studied. Glycemic control was determined by HbA1c. MG was significantly elevated in diabetic subjects versus the normal control subjects (189.3 +/- 38.7 vs. 123.0 +/- 37 nmol/l, P = 0.0001). MG levels were significantly reduced by high-dosage (1,500-2,500 mg/day) metformin (158.4 +/- 44.2 nmol/l) compared with nonmetformin (189.3 +/- 38.7 nmol/l, P = 0.03) or low-dosage (< or = 1,000 mg/day) metformin (210.98 +/- 51.0 nmol/l, P = 0.001), even though the groups had similar glycemic control. Conversely, DL levels were significantly elevated in both the low- and high-dosage metformin groups relative to the nonmetformin group (13.8 +/- 7.7 and 13.4 +/- 4.6 vs. 10.4 +/- 3.9 micromol/l, P = 0.03 and 0.06, respectively). MG correlated with rising HbA1c levels (R = 0.4, P = 0.03, slope = 13.2) in the nonmetformin subjects but showed no increase with worsening glycemic control in the high-dosage metformin group (R = 0.0004, P = 0.99, slope = 0.02). In conclusion, MG is elevated in diabetes and relates to glycemic control. Metformin reduces MG in a dose-dependent fashion and minimizes the effect of worsening glycemic control on MG levels. To the extent that elevated MG levels lead to their development, metformin treatment may protect against diabetic complications by mechanisms independent of its antihyperglycemic effect.
Maillard or browning reactions lead to formation of advanced glycation end products (AGEs) on protein and contribute to the increase in chemical modification of proteins during aging and in diabetes. AGE inhibitors such as aminoguanidine and pyridoxamine (PM) have proven effective in animal model and clinical studies as inhibitors of AGE formation and development of diabetic complications. We report here that PM also inhibits the chemical modification of proteins during lipid peroxidation (lipoxidation) reactions in vitro, and we show that it traps reactive intermediates formed during lipid peroxidation. In reactions of arachidonate with the model protein RNase, PM prevented modification of lysine residues and formation of the advanced lipoxidation end products (ALEs) N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, malondialdehyde-lysine, and 4-hydroxynonenal-lysine. PM also inhibited lysine modification and formation of ALEs during copper-catalyzed oxidation of low density lipoprotein. Hexanoic acid amide and nonanedioic acid monoamide derivatives of PM were identified as major products formed during oxidation of linoleic acid in the presence of PM. We propose a mechanism for formation of these products from the 9- and 13-oxo-decadienoic acid intermediates formed during peroxidation of linoleic acid. PM, as a potent inhibitor of both AGE and ALE formation, may prove useful for limiting the increased chemical modification of tissue proteins and associated pathology in aging and chronic diseases, including both diabetes and atherosclerosis.
Hyperinsulinaemia and hyperglycaemia are two possible risk factors for colorectal cancer, which constitutes the third leading cause of cancer death in Western countries. Molecular evidence as well as animal models provide support for these associations: Insulin has been shown to be an important growth factor for colonic carcinoma cells, and both insulin and insulin-like growth factor-1 receptors have been detected in colon cancer tissue. The insulin-signal transduction pathway is involved in the regulation of gene expression and apoptosis. The role of hyperglycaemia in carcinogenesis could include pathways via luminal factors (related to fecal bile acid concentrations, stool bulk, and prolonged transit time) or circulatory factors (via glucose as the only energy source for neoplastic cells). This review summarizes the epidemiologic literature with respect to hyperinsulinaemia and hyperglycaemia as risk factors for colorectal cancer, and aims to integrate the biological and epidemiological evidence. Epidemiologic findings to date indicate a slightly increased risk of colorectal cancer for diabetic patients; however, there are some inconsistencies. Possible explanations for these inconsistencies include inadequate information about patients' diabetic disease and treatment states. We suggest that future studies should take medical history, staging and treatment for hyperinsulinaemia and hyperglycaemia into account to further our understanding of the role of hyperglycaemia and hyperinsulinaemia in colorectal carcinogenesis.
Variation in colorectal cancer rates between countries and within ethnic groups upon migration and/or Westernization suggests a role for some aspects of Western lifestyle in the etiology of this disease. We conducted a population-based case-control study in the multiethnic population of Hawaii to evaluate associations between colorectal cancer and a number of characteristics of the Western lifestyle (high caloric intake, physical inactivity, obesity, smoking, and drinking) and some of their associated diseases. We interviewed in person 698 male and 494 female United States-born or immigrant Japanese, Caucasian, Filipino, Hawaiian, and Chinese patients diagnosed in 1987-1991 with colorectal cancer and 1192 population controls matched on age, sex, and ethnicity. Conditional logistic regression was used to estimate odds ratios adjusting for dietary and nondietary risk factors. Place of birth and duration of residence in the United States were unrelated to colorectal cancer risk. Energy intake (independent of the calorie source) and body mass index were directly associated with risk, and lifetime recreational physical activity was inversely associated with risk. The associations with these factors were independent of each other, additive (on the logistic scale) and stronger in men. When individuals were cross-categorized in relation to the medians of these variables, those with the higher energy intake and body mass index and lower physical activity were at the highest risk (for males, OR, 3.0; 95% confidence interval, 1.8-5.0, and for females, OR, 1.7; 95% confidence interval, 1.0-3.2). Smoking in the distant, as well as recent, past and alcohol use were directly associated with colorectal cancer in both sexes. Individuals with a history of diabetes or frequent constipation were at increased risk for this cancer, whereas past diagnosis of hypercholesterolemia was inversely associated with risk. The findings were consistent between sexes, among ethnic groups, and across stages at diagnosis, making bias an unlikely explanation. These results confirm the data from immigrant studies that suggest that the increase in colorectal cancer risk experienced by Asian immigrants to the United States occurred in the first generation because we found no difference in risk between the immigrants themselves and subsequent generations. They also agree with recent findings that suggest that high energy intake, large body mass, and physical inactivity independently increase risk of this disease and that a nutritional imbalance, similar to the one involved in diabetes, may lead to colorectal cancer.
The possibility that diabetes is associated with an elevated risk of cancer mortality has been discussed for many years. Recently, Levine et al. (Am J Epidemiol, 1990; 131:254-62) approached this issue by relating post-load plasma glucose concentration to cancer mortality. For men, there appeared to be a positive association between post-load glucose and mortality from cancer for all sites combined and for some specific sites. However, that analysis was based on only 298 cancer deaths among 11,521 men followed for 12 years. The current authors explored this issue in a cohort of 18,274 male civil servants, among whom there were 1,282 cancer deaths over 18-20 years of follow-up. There was no association between post-load glucose and cancer mortality, except for pancreatic cancer. A role for asymptomatic hyperglycemia in the etiology of cancer is not supported by the results of the present study.
The proliferation rate of malignant cells in vivo is one of the important factors which affect the formation of tumor metastasis. A highly metastatic variant of mouse colon adenocarcinoma 26 (NL-17) grew more rapidly than a low-metastatic variant (NL-44) both in vitro and in vivo. The effect of growth factors on the proliferation of NL-17 and NL-44 cells was examined in serum-free medium. Among growth factors examined, human insulin and insulin-like growth factor 1 (IGF-1), which were produced by gene engineering techniques, stimulated the growth of metastatic NL-17 and NL-44 cells as determined by thymidine incorporation and cell counts. DNA synthesis and cell proliferation of the high-metastatic NL-17 was stimulated to a greater extent by insulin and IGF-1 than those of the low-metastatic NL-44. These findings suggest that circulating growth factors could enhance the formation of tumor metastasis. Scatchard analysis of [125I]IGF-1 binding to NL-17 and NL-44 showed that each cell line had an almost equal number of IGF-1 receptors (1.37 x 10(5)/cell and 1.26 x 10(5)/cell, respectively), which had similar dissociation constants (8.94 x 10(-10) M and 9.54 x 10(-10) M, respectively). Since the number and affinity of IGF-1 receptors are equivalent between low- and high-metastatic cells, the intracellular events which result in the cell growth after binding of IGF-1 may differ between NL-17 and NL-44 cells.
Butyric acid has two contrasting functional roles. As a product of fermentation within the human colon, it serves as the most important energy source for normal colorectal epithelium. It also promotes the differentiation of cultured malignant cells. A switch from aerobic to anaerobic metabolism accompanies neoplastic transformation in the colorectum. The separate functional roles for n-butyrate may reflect the different metabolic activities of normal and neoplastic tissues. Relatively low intracolonic levels of n-butyrate are associated with a low fibre diet. Deficiency of n-butyrate, coupled to the increased energy requirements of neoplastic tissues, may promote the switch to anaerobic metabolism. The presence of naturally occurring differentiating agents, such as n-butyrate, may modify the patterns of growth and differentiation of gastrointestinal tumours.
Subsequent cancer incidence was determined in the population-based incidence cohort of Rochester, Minnesota, residents diagnosed with diabetes mellitus between 1945 and 1969. The relative risk of having cancer, excluding cervical and non-melanoma skin cancers, was not significantly increased following the diagnosis of diabetes mellitus. The potential biases of increased medical surveillance among diabetics and exacerbation of subclinical diabetes by occult malignancy did not appear to be important except in the case of subsequent pancreatic cancer.
The association of refined sugars and colorectal cancers and polyps in three recent case-control studies led us to investigate
the effects of sucrose, fructose and glucose on colonic epithelial proliferation and sensitivity to carcinogenesis. CF1 and
C57BL/6J mice were used; proliferation was assessed as vincristine-accumulated mitotic figures per crypt section; sensitivity
to carcinogenesis was assessed as the number of aberrant crypt foci (ACF) per colon observed following the colon carcinogen,
azoxymethane (AOM, 3 mg/kg and 5 mg/kg). Oral gavages of sucrose and fructose in CF1 mice (10 g/kg) increased colonic proliferation
16 h later (2.8±0.6 and 4.1±0.7 (mean±SEM) accumulated mitotic figures/crypt section), compared with glucose and water (1.0+0.2
and 0.4±0.1). Sucrose and fructose given 14 h prior to the AOM (5 mg/kg) increased the sensitivity of the colon to carcinogenesis
(18.4±1.5 and 13.1±1.8 ACF/colon), compared with glucose and water (11.4±2.0 and 8.6±1.1). Similar results were observed with
C57BL/6J mice. We conclude that dietary sucrose and fructose may represent risk factors for colorectal cancer through a direct
effect of the sugars on colonic epithelial proliferation.
The molecular basis for the clinical association between diabetes mellitus and pancreatic cancer was investigated, using Mia PaCa-2 human pancreatic cancer cells in culture. Advanced glycation endproducts (AGE) prepared with bovine serum albumin and glucose were found to stimulate Mia PaCa-2 cell synthesis of DNA in a dose-dependent manner and also to significantly increase the number of viable cells. Evidence that platelet-derived growth factor-B (PDGF-B) mediates this growth promotion was obtained; AGE upregulated the level of PDGF-B mRNA, and antibodies against PDGF-BB completely neutralized the AGE-induced DNA synthesis. Antisense oligodeoxyribonucleotides complementary to mRNA encoding a receptor for AGE were found to reverse both the PDGF-B upregulation and the AGE-induced DNA synthesis. These results thus indicate that AGE ligand-receptor interactions could play an active part in the progression of pancreatic cancer through the induction of autocrine PDGF-B.
Variation in colorectal cancer rates between countries and within ethnic groups upon migration and/or Westernization suggests a role for some aspects of Western lifestyle in the etiology of this disease. We conducted a population-based case-control study in the multiethnic population of Hawaii to evaluate associations between colorectal cancer and a number of characteristics of the Western lifestyle (high caloric intake, physical inactivity, obesity, smoking, and drinking) and some of their associated diseases. We interviewed in person 698 male and 494 female United States-born or immigrant Japanese, Caucasian, Filipino, Hawaiian, and Chinese patients diagnosed in 1987-1991 with colorectal cancer and 1192 population controls matched on age, sex, and ethnicity. Conditional logistic regression was used to estimate odds ratios adjusting for dietary and nondietary risk factors. Place of birth and duration of residence in the United States were unrelated to colorectal cancer risk. Energy intake (independent of the calorie source) and body mass index were directly associated with risk, and lifetime recreational physical activity was inversely associated with risk. The associations with these factors were independent of each other, additive (on the logistic scale) and stronger in men. When individuals were cross-categorized in relation to the medians of these variables, those with the higher energy intake and body mass index and lower physical activity were at the highest risk (for males, OR, 3.0; 95% confidence interval, 1.8-5.0, and for females, OR, 1.7; 95% confidence interval, 1.0-3.2). Smoking in the distant, as well as recent, past and alcohol use were directly associated with colorectal cancer in both sexes. Individuals with a history of diabetes or frequent constipation were at increased risk for this cancer, whereas past diagnosis of hypercholesterolemia was inversely associated with risk. The findings were consistent between sexes, among ethnic groups, and across stages at diagnosis, making bias an unlikely explanation. These results confirm the data from immigrant studies that suggest that the increase in colorectal cancer risk experienced by Asian immigrants to the United States occurred in the first generation because we found no difference in risk between the immigrants themselves and subsequent generations. They also agree with recent findings that suggest that high energy intake, large body mass, and physical inactivity independently increase risk of this disease and that a nutritional imbalance, similar to the one involved in diabetes, may lead to colorectal cancer.
The epidemiology and molecular biology of colorectal cancer are reviewed with a view to understanding their interrelationship. Risk factors for colorectal neoplasia include a positive family history, meat consumption, smoking, and alcohol consumption. Important inverse associations exist with vegetables, nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and physical activity. There are several molecular pathways to colorectal cancer, especially the APC (adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor; a transcriptional activator) pathway and the pathway involving abnormalities of DNA mismatch repair. These are important, both in inherited syndromes (familial adenomatous polyposis [FAP] and hereditary nonpolyposis colorectal cancer [HNPCC], respectively) and in sporadic cancers. Other less well defined pathways exist. Expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. The roles of several of the environmental exposures in the molecular pathways either are established (e.g., inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and tobacco smoke as sources of specific blood-borne carcinogens; vegetables as a source of folate, antioxidants, and inducers of detoxifying enzymes). The roles of other factors (e.g., physical activity) remain obscure even when the epidemiology is quite consistent. There is also evidence that some metabolic pathways, e.g., those involving folate and heterocyclic amines, may be modified by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some evidence that the general host metabolic state can provide a milieu that enhances or reduces the likelihood of cancer progression. Understanding the roles of environmental exposures and host susceptibilities in molecular pathways has implications for screening, treatment, surveillance, and prevention.
To study the occurrence of cancer amongst patients with diabetes mellitus (DM).
Population based cohort study.
Denmark.
Two cohorts of patients with DM were identified. One cohort comprised 1659 conscripts diagnosed with type I DM before the age of 20 years. Another cohort comprised 1499 men and women with insulin treated DM identified by means of medical prescriptions on 1 July 1973. Both cohorts were followed until the end of 1992.
The relative risk of cancer in the two cohorts was estimated as the ratio of observed to expected number of cancers in the cohort (SIR).
No unusual risk of cancer was observed amongst the conscripts (SIR 0.9, n = 13) or amongst patients with onset of DM before the age of 30 years in the prescription cohort (SIR 0.9, n = 32). Amongst those aged 30 years or more at DM onset in the prescription cohort, the overall risk of cancer did not depart from normal (SIR 1.0, n = 103), however, pancreatic cancer occurred in excess both immediately (< 1 year) (SIR 190, n = 1), and during 1-9 years after DM onset (SIR 9.0, n = 4). Similarly, the risk of non-Hodgkin's lymphoma was increased significantly (SIR 3.3, n = 6), all cases occurring more than 10 years after DM onset.
Our data suggest that there is no unusual risk of cancer associated with type I DM. Type II DM may be the first symptom of pancreatic cancer and may be associated with an increased risk of non-Hodgkin's lymphoma.
Diabetes mellitus begins as a disorder of glucose metabolism that progressively compromises the function of virtually every organ system as the secondary complications inexorably develop. The quality of life for patients with diabetes is diminished by the consequences of these complications. Accelerated and aggressive atherosclerosis is the greatest cause of morbidity and mortality with diabetes, emphasizing the importance of determining underlying mechanisms. This review highlights the role of the multiligand receptor for advanced glycation endproducts (RAGE) and two of its ligands, advanced glycation endproducts (AGEs) and S100/calgranulins, in the pathogenesis of atherosclerosis associated with diabetes. The results of the studies reviewed herein suggest that RAGE is a potential therapeutic target for macrovascular disease in diabetes.
Insulin and insulin-like growth factor (IGF) axes are major determinants of proliferation and apoptosis and thus may influence carcinogenesis. In various animal models, modulation of insulin and IGF-1 levels through various means, including direct infusion, energy excess or restriction, genetically induced obesity, dietary quality including fatty acid and sucrose content, inhibition of normal insulin secretion and pharmacologic inhibition of IGF-1, influences colonic carcinogenesis. Human evidence also associates high levels of insulin and IGF-1 with increased risk of colon cancer. Clinical conditions associated with high levels of insulin (noninsulin-dependent diabetes mellitus and hypertriglyceridemia) and IGF-1 (acromegaly) are related to increased risk of colon cancer, and increased circulating concentrations of insulin and IGF-1 are related to a higher risk of colonic neoplasia. Determinants and markers of hyperinsulinemia (physical inactivity, high body mass index, central adiposity) and high IGF-1 levels (tall stature) are also related to higher risk. Many studies indicate that dietary patterns that stimulate insulin resistance or secretion, including high consumption of sucrose, various sources of starch, a high glycemic index and high saturated fatty acid intake, are associated with a higher risk of colon cancer. Although additional environmental and genetic factors affect colon cancer, the incidence of this malignancy was invariably low before the technological advances that rendered sedentary lifestyles and obesity common, and increased availability of highly processed carbohydrates and saturated fatty acids. Efforts to counter these patterns are likely to have the most potential to reduce colon cancer incidence, as well as cardiovascular disease and diabetes mellitus.
RAGE (receptor for advanced glycation end products) is a multiligand cell surface molecule of the immunoglobulin superfamily. It was originally described as a receptor for protein adducts formed by glycoxidation (AGEs) that accumulate in diseases such as diabetes and renal failure. Performing RT-PCR and Western blot analysis we intended to determine RAGE expression in the human colon adenocarcinoma cell line Caco-2. Moreover, Caco-2 cells were incubated in the presence of AGEs. Since RAGE ligation triggers the p21(ras) signal transduction pathway the activation state of p44/42 (ERK1/2) MAP kinases was determined. Here we demonstrate for the first time that Caco-2 cells express RAGE and that administration of the food-derived casein-linked AGE N(epsilon)-(carboxymethyl)lysine (Cas-CML) results in Caco-2 p44/42 (ERK1/2) MAP kinase activation.
Pigment epithelium-derived factor (PEDF) has recently been shown to be the most potent inhibitor of angiogenesis in the mammalian eye, suggesting that loss of PEDF is involved in the pathogenesis of proliferative diabetic retinopathy. However, a protective role for PEDF in pericyte loss in early diabetic retinopathy remains to be elucidated. In this study, we investigated whether PEDF proteins could protect against advanced glycation end product (AGE)-induced injury in retinal pericytes. Ligand blot analysis revealed that pericytes possessed a membrane protein with binding affinity for PEDF. PEDF proteins were found to significantly inhibit AGE-induced reactive oxygen species (ROS) generation and the subsequent decrease in DNA synthesis and apoptotic cell death in pericytes. Further, PEDF proteins completely restored the down-regulation of bcl-2 gene expression in AGE-exposed pericytes. The results demonstrated that PEDF proteins protected cultured pericytes from AGE-induced cytotoxicity through its anti-oxidative properties. Our present study suggests that substitution of PEDF proteins may be a promising strategy in treatment of patients with early diabetic retinopathy.
To determine the influence of diabetes mellitus on long-term outcomes and treatment-related toxicity among patients with curatively resected colon cancer.
This study was a cohort study within a large, randomized adjuvant chemotherapy trial of 3,759 patients with high-risk stage II and stage III colon cancer treated between 1988 and 1992 throughout the United States. In the cohort, 287 patients were identified as having diabetes mellitus. With a median follow-up of 9.4 years, we analyzed differences in overall survival (OS) and colon cancer recurrence as well as treatment-related toxicity between patients with diabetes and those without diabetes.
At 5 years, patients with diabetes mellitus, compared with patients without diabetes, experienced a significantly worse disease-free survival (DFS; 48% diabetics v 59% nondiabetics; P <.0001), OS (57% v 66%; P <.0001), and recurrence-free survival (RFS; 56% v 64%, P =.012). Median survival was 6.0 years and 11.3 years for diabetics and nondiabetics, respectively. Compared with patients without a history of diabetes, those with diabetes had a 42% increased risk of death from any cause (P <.0001) and 21% increased risk for recurrence (P =.05) after adjustment for other predictors of colon cancer outcome. Treatment-related toxicities were similar between the two groups, although patients with diabetes experienced an increase in treatment-related diarrhea.
Patients with diabetes mellitus and high-risk stage II and stage III colon cancer experienced a significantly higher rate of overall mortality and cancer recurrence, even after adjustment for other predictors of colon cancer outcome. These results underscore the need for further research to understand the mechanism that underlies this relation.
The insulin resistance-colon cancer hypothesis, stating that insulin resistance may be associated with the development of colorectal cancer, represents a significant advance in colon cancer, as it emphasizes the potential for this cancer to become a modifiable disease. The fact that the incidence of insulin resistance has been increasing in the United States and much of the rest of the Western world where colon cancer remains the second leading cause of cancer death makes the exploration of the interrelationship of these conditions a subject of high priority. Here, we review the salient features of insulin resistance, defined as impaired biological response to the action of insulin. Recent epidemiological studies, evaluating potential associations between colon cancer risk and diabetes mellitus, dietary intake and metabolic factors, and IGF levels in several clinical settings, provide strong support of the insulin resistance-colon cancer hypothesis (without establishing causality). Mechanistically, insulin resistance has been associated with hyperinsulinemia, increased levels of growth factors including IGF-1, and alterations in NF-kappaB and peroxisome proliferator-activated receptor signaling, which may promote colon cancer through their effects on colonocyte kinetics. It is a reasonable expectation that in the not too distant future, critical interventions to the already mapped molecular sequence of events, which link two apparently disparate entities, combined with lifestyle changes could abrogate the development of colon cancer.
Diabetic vascular complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Chronic hyperglycemia is essentially involved in the pathogenesis of diabetic micro- and macrovascular complications via various metabolic derangements. In this review, we discuss the molecular mechanisms of diabetic retinopathy and nephropathy, especially focusing on advanced glycation end products (AGEs) and their receptor (RAGE) system. Several types of AGE inhibitors and their therapeutic implications in diseases, including diabetic microangiopathy, will be discussed in the next review article.
The advanced stage of the glycation process (one of the post-translational modifications of proteins) leads to the formation of advanced glycation end-products (AGEs) and plays an important role in the pathogenesis of angiopathy in diabetic patients, and in Alzheimer's disease (AD). Recently we have provided direct immunochemical evidence for the existence of six distinct AGEs structures, designated AGEs-1 to -6, within the AGEs-modified proteins and peptides that circulate in the serum of diabetic patients. We found for the first time that glyceraldehyde-derived AGEs (AGE-2), which comprise main structure of TAGE (toxic AGEs), in the serum of diabetic patients have diverse biological activities on vascular wall cells and cortical neurons. These results suggest a causal role for AGE-2 in the pathogenesis of diabetic complications and AD in vivo. In AD brains, AGE-2 epitope was mainly present in the cytosol of neurons in the hippocampus and para-hipocampal gyrus. We propose three pathways for the in vivo formation of AGE-2 precursor, glyceraldehyde, by: (i) glycolytic pathway, (ii) polyol pathway, and (iii) fructose metabolic pathway. Glyceraldehyde can be transported or can leak passively across the plasma membrane. It can react non-enzymatically with proteins to lead to accelerated formation of AGE-2 at both intracellular and extracellular region.
The advanced stage of the glycation process (one of the post-translational modifications of proteins) leads to the formation of advanced glycation end-products (AGEs) and plays an important role in the pathogenesis of angiopathy in diabetic patients, in aging, and in neurodegenerative diseases. However, it is still not clear which AGEs subtypes play a pathogenetic role and which of several AGEs receptor mediate AGEs effects on cells. We have provided direct immunochemical evidence for the existence of six distinct AGEs structures (AGEs-1 to -6) within the AGEs-modified proteins and peptides that circulate in the serum of diabetic patients. Recently we demonstrated for the first time that glyceraldehyde-derived AGEs (AGEs-2) and glycolaldehyde-derived AGEs (AGE-3) have diverse biological activities on vascular wall cells, mesangial cells, Schwann cells, malignant melanoma cells and cortical neurons. We also demonstrated for the first time that acetaldehyde (AA)-derived AGEs (AA-AGE) have cytotoxic activity on cortical neurons and the AA-AGE epitope was detected in human brain of alcoholics. These results indicate that of the various types of AGEs structures that can form in vivo, the toxic AGEs (TAGE) structures (AGEs 2, 3, and AA-AGE), but not non-toxic AGEs (N-carboxymethyllysine, pentosidine, pyrraline etc.) are likely to play an important role in the pathophysiological processes associated with AGEs formation.
Advanced glycation end products (AGEs), the senescent macroprotein derivatives that form in increased amounts in diabetes, have been implicated in the pathogenesis of diabetic vascular complications. Indeed, AGEs elicit oxidative stress generation in vascular wall cells through an interaction with their receptor (RAGE), thus playing an important role in vascular inflammation and altered gene expression of growth factors and cytokines. We have previously shown that nifedipine, one of the most popular dihydropyridine-based calcium antagonists, blocked tumor necrosis factor-alpha-induced monocyte chemoattractant protein-1 expression in endothelial cells (ECs) through its antioxidative properties. However, the effects of nifedipine on AGE-exposed ECs remain to be elucidated. In this study we investigated whether nifedipine could inhibit the AGE-induced reactive oxygen species (ROS) generation and subsequent RAGE gene expression in human umbilical vein endothelial cells (HUVEC). Nifedipine completely inhibited AGE-induced ROS generation in HUVEC. Furthermore, nifedipine was found to prevent up-regulation of RAGE mRNA levels in AGE-exposed HUVEC. These results demonstrate that nifedipine can inhibit RAGE overexpression in AGE-exposed ECs by suppressing ROS generation. Our present study suggests that nifedipine may have therapeutic potential in the treatment of patients with AGE-related disorders such as diabetic vascular complications.
Advanced glycation end products (AGE), nonenzymatically glycated protein derivatives, have been implicated in the development and progression of diabetic angiopathies, including skin dermopathy. Nevertheless, the involvement of AGE in the development and progression of melanoma has not been fully elucidated. In this study we investigated the expression levels of their receptor for AGE (RAGE) in human melanoma and subsequently studied the effects of AGE on melanoma growth and migration. First, RAGE was detected in the cytoplasm of human melanoma cells (G361 and A375). Among the different types of AGE, glyceraldehyde- and glycolaldehyde-derived AGE significantly stimulated the growth and migration of human melanoma cells. Furthermore, tumor formation of melanoma cell xenografts in athymic mice was prevented by treatment with anti-RAGE neutralizing antibodies. In tumor-bearing mice, survival rates were prolonged, and spontaneous pulmonary metastases were inhibited by treatment using anti-RAGE neutralizing antibodies. In addition, all AGE were present in beds of human melanoma tumor, whereas they were barely detected in normal skin. These results suggest that AGE might be involved in the growth and invasion of melanoma through interactions with RAGE and represent promising candidates for assessing the future therapeutic potential of this therapy in treating patients with melanoma.
There is a growing body of evidence that advanced glycation end product-receptor(AGE-RAGE) interaction elicits oxidative stress generation, thus indicating that it is involved in the pathogenesis of diabetic retinopathy. Inhibition of AGE formation or blockade of the downstream RAGE signaling is a promising therapeutic strategy for treatment of patients with diabetic retinopathy.
Pigment epithelium-derived factor protects cultured retinal pericytes from advanced glycation end product-induced injury through its antioxidative properties
- Yamagishi
Colorectal cancer: molecules and populations
- Potter