Distribution of the receptor for advanced glycation end products in the human male reproductive tract: prevalence in men with diabetes mellitus

Mallidis, Con; Agbaje, Ishola; Rogers, Deirdre; Glenn, Josephine V.; McCullough, Stephen; Atkinson, A. B.; Steger, Klaus; Stitt, Alan W.; McClure, Neil

doi:10.1093/humrep/dem156

Cited by 92 publications

(63 citation statements)

References 51 publications

(74 reference statements)

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“…We identified high levels of N 3 -carboxymethyl-lysine (CML), the most prominent advanced glycation end product (AGE; Mallidis et al 2009) and its receptor (RAGE; Mallidis et al 2007) in the testis, epididymis and sperm of diabetic men and mouse models alike (O'Neill et al 2009). As this group of compounds is known to cause cellular dysfunction, oxidative stress and DNA damage in various organs and in a variety of conditions (Vlassara & Palace 2002), we hypothesise that they may also play an equally destructive role in the reproductive tract of diabetics and MetS patients and as such contribute to the sperm nDNA fragmentation seen in these men.…”

Section: Introductionmentioning

confidence: 99%

Spermatogenic and sperm quality differences in an experimental model of metabolic syndrome and hypogonadal hypogonadism

Mallidis¹,

Czerwiec²,

Filippi³

et al. 2011

Reproduction

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The synergistic effect of the co-morbidities that comprise metabolic syndrome (MetS) is increasingly being recognised as an important contributor in the pathology of a broad spectrum of seemingly disparate conditions. However, in terms of male reproductive function, beyond erectile dysfunction, little is known about the influence of this cohort (collectively or separately) on spermatogenesis and sperm quality. The aims of this study were to assess the reproductive tract of a MetS animal model for detrimental changes, to determine whether a group of compounds (advanced glycation end products and their receptor) known to cause cell dysfunction and DNA damage was present and assess whether hypogonadotropic hypogonadism was the main contributing factor for the changes seen. Animals fed a high-fat diet were found to have significantly increased cholesterol, triglycerides, blood glucose, mean arterial pressure and visceral fat levels. Although serum testosterone was decreased, no changes were seen in either testicular or epididymal histology. Immunolocalisation of N 3 -carboxymethyl-lysine and the receptor for advanced glycation end products was found in the testes, epididymides and sperm of the two treated groups of animals; however, ELISA did not show any difference in protein levels. Similarly, assessment of sperm nuclear DNA (nDNA) fragmentation by acridine orange test did not find significant differences in nDNA integrity. We conclude that the minimal effect on spermatogenesis and sperm quality seen in our model is probably due to the moderate increase of blood glucose rather than the hypogonadism.

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Section: Introductionmentioning

confidence: 99%

Spermatogenic and sperm quality differences in an experimental model of metabolic syndrome and hypogonadal hypogonadism

Mallidis¹,

Czerwiec²,

Filippi³

et al. 2011

Reproduction

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“…High levels of RAGE were previously observed in pathological conditions, such as vascular diseases, chronic inflammation, Alzheimer's disease, diabetes, and cancer [Clynes et Yan et al 2009]. RAGE expression was also documented in the seminiferous tubules, interstitial cells [Mallidis et al 2007], and spermatozoa [Karimi et al 2012] of diabetic patients. Engagement of RAGE triggers several signaling molecules, including the transcription factor NF-kB, MAP kinases, and adhesion molecules, that stimulate the inflammatory responses and increase the oxidative stress [Bierhaus et al 2005;Ramasamy et al 2009;Yan et al 2009], with possible alteration of the testicular functions.…”

Section: Discussionmentioning

confidence: 88%

Chronic alcohol administration causes expression of calprotectin and RAGE altering the distribution of zinc ions in mouse testis

Giannessi

Scavuzzo

Giambelluca

et al. 2014

Systems Biology in Reproductive Medicine

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Several studies reported that chronic alcohol consumption alters the intestinal mucosa barrier, and subsequent entrance of endotoxins into the bloodstream. In many tissues endotoxin exposure causes the expression of calprotectin (CP) and the receptor for advanced glycation -end products (RAGE). In this study we investigated whether chronic alcohol administration causes expression of CP and RAGE in mouse testis. The distribution of free and loosely bound Zn 2+ ) in the testicular tissues was also evaluated. Alcohol-induced testicular damage was documented by measuring testosterone blood levels and by light and electron microscope studies. Twenty mice were treated daily for three weeks with 3.0 g/kg of a 25% solution of alcohol. Ten mice were treated in the same period of time with a solution of maltose dextrins, isocaloric to alcohol. Twenty untreated mice were used as controls. Alcohol treated mice showed diffuse expression of CP and RAGE in the interstitial cells. RAGE was found also in the basal compartment of the seminiferous tubules. Depletion of FLB-Zn 2+ was observed in the adluminal compartment of the seminiferous tubules. Expression of CP and RAGE was not found in control mice and maltose dextrin treated mice. Our results indicated novel mechanisms by which alcohol acts in testis. Indeed, CP and RAGE may cause the generation of oxidants and inflammatory mediators, with negative impact on testicular functions. Depletion of FLB-Zn 2+ may contribute to the dysregulation of spermatogenesis.Abbreviations: CP: calprotectin; FLB-Zn 2+ : free and loosely bound Zn

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“…6 Hyperglycemia in DM increases the RAGE expression which leads to the activation of ROS generation and causes sperm oxidative damage. 5 Furthermore, the increase of RAGE expression stimulates ROS generation and apoptosis signaling pathway such as MAPKs, RAC-1, PI3kinase, JAK/STAT, and NFkB. 7 ROS causes leakage citokrom C from mitochondria activating the mitochondrial pathway through the activation of caspase 9.…”

Section: Discussionmentioning

confidence: 99%

“…The RAGE expression was evaluated using immunohistochemistry method as conducted by Mallidis et al 5 with modification. Briefly, antigen unmasking was performed by incubating the sperm smears slides with a 50% trypsin : 50% vercene solution for 2 minutes.…”

Section: Immunohistochemical Analysis Of Rage Expressionmentioning

confidence: 99%

“…Hyperglycemia increases the expression of receptor for glycosilation advanced end products (RAGE) that is responsible for the activation of ROS generation and sperm apoptosis signal. 5 The increase of RAGE expression in DM compared to basal state is stimulated by the increase of advanced glycosilation end products (AGE) as a result of non-enzymatic glycosylation of glucose that occurs due to hyperglycemia. 6 The binding of AGE to RAGE increases the formation of ROS, nitrit oxide (NO), and ceramides as well as mitogen-activated protein kinases (MAPKs) such as JNK and p38 that can paticipate in apoptosis through induction of proapoptotic transcription factors forkhead box 1 (FOXO1) and caspase-3.…”

Section: Introductionmentioning

confidence: 99%

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Expression of receptor advanced glycosilation end product (RAGE) and active caspase-3 of the streptozotocin-induced chronic diabetes mellitus Sprague Dawley rats’ sperm with soybean (Glycin max) powder suspension treatment

2013

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Diabetes mellitus (DM) affects all the process of spermatogenesis. Chronic hyperglycemia in DM increases the expression of receptor for advanced glycosilation end products (RAGE) that is responsible for the activation of signal production of reactive oxygen species (ROS) and caspase 3. Active caspase 3 plays an important role in cell apoptosis. Soybean (Glycin max) is reported to have antihyperglycemic and antiadvanced glycosilation end products (antiAGE) and antioxidants activities. The aim of this study was to evaluate the effect of soybean powder suspension on the expression of RAGE and active caspase 3 of diabetic rats' sperm. This was an experimental study with post test only control group design using 30 male Sprague Dawley rats, aged 11-12 weeks old and weighed 200-250g. The rats were divided into five groups with six rats in each group. Group 1 was non diabetic rats and Group 2 was diabetic rats that were given aquadest. Group 3-5 were diabetic rats that were given a soybean powder suspension at dose of 400; 800 and 1600 mg/kg body weight (BW)/day, respectively. Diabetic rats were made by induction of a single intraperitoneal injection of streptozotocin (STZ) at a dose of 60 mg/kg BW. Soybean powder suspension was ingested for four weeks after 14 days STZ induction. Blood glucose levels were monitored before and three days after STZ induction and four weeks after suspension ingestion. The expression of RAGE and active caspase-3 were analyzed using immunohistochemistry method four weeks after suspension ingestion. The results showed that soybean powder suspension ingestion significantly decreased blood glucose level of diabetic rats toward normality (p<0.05). However, the expression of RAGE and active caspase-3 in diabetic rats' sperm were not significantly lower than those after suspension ingestion. In conclusion, soybean powder suspension does not significantly affect the expression of RAGE and active caspase-3 in diabetic rats' sperm. ABSTRAKDiabetes melitus (DM) mempengaruhi semua proses spermatogenesis. Hiperglikemia kronis pada DM meningkatkan ekspresi receptor for advanced glycosilation end products (RAGE) yang bertanggung jawab terhadap aktivasi sinyal produksi reactive oxygen species (ROS) dan caspase-3. Caspase-3 aktif berperan penting pada apoptosis sel. Kedelai (Glycin max) dilaporkan memiliki aktivitas antihiperglikemia, antiadvanced glycosilation end products (antiAGE) dan antioksidan. Tujuan penelitian ini adalah mengevaluasi efek suspensi bubuk kedelai terhadap ekspresi RAGE 2 J Med Sci, Volume 45, No. 1, March 2013: 1-11 dan caspase-3 aktif pada sperma tikus diabetes. Penelitian ini merupakan penelitian eksperimental dengan rancangan post test only control group menggunakan 30 ekor tikus jantan Sprague Dawley, umur 11-12 minggu dan berat 200-250 g. Tikus dibagi menjadi lima kelompok dengan masing-masing kelompok 6 ekor. Kelompok 1, tikus tidak DM dan Kelompok 2, tikus DM yang diberi akuades. Kelompok 3-5, tikus diabetes yang diberi suspensi bubuk kedelai dengan dosis berturut-...

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Distribution of the receptor for advanced glycation end products in the human male reproductive tract: prevalence in men with diabetes mellitus

Abstract: The presence of RAGE implies that it may play a central role in sperm nDNA damage particularly in diabetic men where the levels are elevated.

Cited by 92 publications

References 51 publications

Spermatogenic and sperm quality differences in an experimental model of metabolic syndrome and hypogonadal hypogonadism

Spermatogenic and sperm quality differences in an experimental model of metabolic syndrome and hypogonadal hypogonadism

Chronic alcohol administration causes expression of calprotectin and RAGE altering the distribution of zinc ions in mouse testis

Expression of receptor advanced glycosilation end product (RAGE) and active caspase-3 of the streptozotocin-induced chronic diabetes mellitus Sprague Dawley rats’ sperm with soybean (Glycin max) powder suspension treatment

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