Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P56851 (epididymal)
 11,273 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A systematic investigation of potential ligands for the affinity purification of aldehyde reductase (alcohol:NADP+ oxidoreductase, EC 1.1.1.2.) has been carried out. The most suitable nucleotide ligands tested were NADP+ and 2',5'-ADP. Adsorbed enzyme could be eluted with NADPH but not NADH. The chlorotriazinyl dyes Cibacron Blue F3GA and Procion Red HE3B also proved effective as 'affinity' ligands when immobilized to Sepharose 4B. The free dyes and also Blue Dextran (Cibacron Blue F3GA coupled to dextran) were all potent inhibitors of aldehyde reductase. The inhibition by Blue Dextran was shown to be competitive with respect to NADPH (Ki = 1.8 x 10(-7) M). The enzyme was sensitive to inhibition by glutaric acid derivatives, flavonoids and a range of anti-convulsants.
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PMID:Isolation and characterization of rat liver aldehyde reductase. 744 91

Lipoprotein lipase (LPL) is a key regulatory enzyme responsible for the hydrolysis of triglyceride (TG)-rich lipoproteins. The reduction in LPL activity is observed in tumor bearing animals and cancer patients with cachectic symptoms, suggesting an involvement of LPL in inducing cancer cachexia. During a screening program for anti-cachectic agents we found that ponalrestat, an aldose reductase inhibitor, activates LPL activity. Ponalrestat increased the activity of LPL in adipose tissue in mice. The effect of ponalrestat on B16 melanoma-induced cachectic symptoms was next investigated in mice. The decrease in the weight of epididymal fat, carcass and whole body lipid was observed in mice following intraperitoneal inoculation of B16, compared to mice without the tumor inoculation. Treatment with ponalrestat resulted in the attenuation of the decrease in the tissue weight. The increase in the levels of TG and non-esterified fatty acid, and a decrease in the level of glucose in the blood, which was induced by the presence of tumor, were also restored to those of normal mice following ponalrestat treatment. The reduction in locomotor activity in tumor bearing mice was partially restored by the treatment with ponalrestat. Overall, this study demonstrated that ponalrestat, an aldose reductase inhibitor, possesses potent LPL activating activity and that the cachexia induced by B16 melanoma was alleviated by treatment with 'ponalrestat, suggesting that ponalrestat, a LPL activating agent, has a therapeutic potential for the treatment of cancer cachexia.
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PMID:Activation of lipoprotein lipase and inhibition of B16 melanoma-induced cachexia in mice by ponalrestat, an aldose reductase inhibitor. 1022 65

Our recent study has demonstrated that ponalrestat, an aldose reductase inhibitor, activates lipoprotein lipase (LPL) activity in the adipose tissue and alleviates the cachectic symptoms induced by B16 melanoma in mice. In this study, the effect of ponalrestat on cachexia symptoms in nude mice bearing human melanomas G361 and SEKI was investigated because it has been suggested that the suppression of LPL has an important role in cachexia induction by these two melanomas in nude mice. Mice bearing G361 subcutaneously did not gain weight and became cachectic, associated with the tumor growth. Tumor growth was not affected by ponalrestat, nevertheless treatment with ponalrestat resulted in an amelioration of the reduction in the weight of body mass, epididymal fat, gastrocnemius muscle, carcass and whole body lipid induced by the presence of G361. A severe weight loss observed in nude mice bearing SEKI was also partially attenuated by ponalrestat treatment. Overall, this study showed that ponalrestat is effective in the attenuation of the cachectic symptoms induced by human melanomas G361 and SEKI in nude mice, suggesting that ponalrestat has a potential usefulness for the treatment of cancer cachexia.
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PMID:Ponalrestat, an aldose reductase inhibitor, inhibits cachexia syndrome in nude mice bearing human melanomas G361 and SEKI. 1062 59

Our recent study has demonstrated that B16 melanoma-induced cachexia in mice is inhibited by ponalrestat, an aldose reductase inhibitor, which has the ability to activate lipoprotein lipase (LPL) activity both in vitro and in vivo. In this study, the effect of bezafibrate and NO-1886, LPL activators, on B16 melanoma-induced cachectic symptoms was investigated in mice. Treatment with bezafibrate resulted in an attenuation of the decrease in the weight of epididymal fat and whole body lipid observed in mice following intraperitoneal inoculation of B16. The increase in the levels of triglyceride and non-esterified fatty acid, and a decrease in the level of glucose in the blood, which was induced by the presence of tumor, were also restored to that of normal mice after treatment with bezafibrate. The reduction in the weight of epididymal fat and whole body lipid induced by B16 was also ameliorated by NO-1886. Overall, this study demonstrated that cachexia induced by B16 melanoma in mice was alleviated by the LPL activators bezafibrate and NO-1886, suggesting the involvement of the impaired LPL activity in the establishment of cachexia syndrome in mice bearing B16 melanoma.
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PMID:Effect of lipoprotein lipase activators bezafibrate and NO-1886, on B16 melanoma-induced cachexia in mice. 1062 60

Our recent study has demonstrated that ponalrestat, an aldose reductase inhibitor, activates lipoprotein lipase activity and alleviates B16 melanoma-induced cachexia in mice. In this study, the effect of ponalrestat on murine adenocarcinoma colon26-induced cachexia was investigated in mice. Mice bearing colon26 subcutaneously lost weight and became cachectic, associated with the tumor growth. Although tumor growth was slightly stimulated when tumor bearing mice were treated with ponalrestat: nevertheless, the drug attenuated the reduction in the weight of body mass, epididymal fat, gastrocnemius muscle and carcass induced by colon26, as well as significantly prolonged the survival of the colon26 bearing mice. Ponalrestat inhibited the production of interleukin-1 (IL-1) from human monocytes stimulated by Lipopolysaccharide (LPS) in vitro, and also suppressed LPS-induced increase of IL-1 in the blood in mice. Overall, this study showed that ponalrestat suppresses IL-1 production both in vitro and in vivo, and inhibits the cachectic symptoms induced by colon26 adenocarcinoma in mice, suggesting that ponalrestat has a therapeutic potential for the treatment of cancer cachexia.
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PMID:Ponalrestat, an aldose reductase inhibitor, inhibits cachexia syndrome induced by colon26 adenocarcinoma in mice. 1062 61

During the epididymal transit, mammalian spermatozoa acquire new surface proteins necessary for male gamete function. We have previously shown that membranous vesicles, called epididymosomes, interact with spermatozoa allowing the transfer of some proteins to sperm surface within the epididymal lumen. The protein composition of those vesicles has been investigated to document the mechanisms of protein transfer from epididymosomes to spermatozoa. Electrophoretic analysis revealed that protein composition is different from the epididymal soluble compartment as well as from similar vesicles present in the semen. Protein association with epididymosome is very strong as revealed by resistance to extraction with detergent. Matrix-assisted laser desorption ionization time-of-flight as well as immunodetection techniques have been used to identify some proteins associated to epididymosomes and spermatozoa. An aldose reductase known for its 20alpha-hydroxysteroid dehydrogenase activity and the cytokine (macrophage migration inhibitory factor) have been identified. These two proteins have been immunolocalized in principal cells of the epididymal epithelium, a more intense signal being detected in the distal epididymal segment as well as in the vas deferens. Database search revealed that these two proteins are characterized by the lack of a signal peptide. These results are discussed with regard to a possible apocrine mode of secretion of these proteins acquired by spermatozoa during the epididymal transit.
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PMID:Aldose reductase and macrophage migration inhibitory factor are associated with epididymosomes and spermatozoa in the bovine epididymis. 1282 72

During the epididymal transit, male gametes acquire new surface proteins necessary for their fertilizing ability. We have previously shown that membranous vesicles, called epididymosomes, interact with sperm surface within the epididymal fluid allowing transfer of some proteins to different subcellular compartments of spermatozoa. We previously showed that one of the major proteins associated with epididymosomes was an aldose reductase (gene: AKR1B5) and confirmed that aldose reductase is located in the epithelial cells bordering the intraluminal compartment of the epididymis. The present study shows that cytosolic aldose reductase activity was maximal in the proximal and middle segments of the epididymis and decreased in the distal epididymis. Western and Northern blot analysis confirmed the distribution pattern of aldose reductase and of the encoding mRNA. The optimal pH of epididymal aldose reductase was 6.0-6.5 when glucose was used as a substrate; this corresponds to the pH of the intraluminal epididymal fluid. In order to evaluate the possible involvement of sorbitol in sperm physiology, Western blot of tissue homogenates were probed with an anti-sorbitol dehydrogenase antibody. The amount of enzyme immunodetected was higher in the proximal and distal segments of the epididymis when compared to the amount detectable in the middle segment of the epididymis. Sorbitol dehydrogenase activity as well as the level of the encoding mRNA showed the same pattern of distribution. Furthermore, immunohistological studies using the anti-sorbitol dehydrogenase revealed that this enzyme was synthesized by the epididymal epithelial cells bordering the intraluminal compartment. Knowing the importance of sorbitol and fructose in sperm metabolism, we hypothesized that the polyol pathway is involved in the modulation of sperm motility within the epididymis.
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PMID:Polyol pathway along the bovine epididymis. 1545 14

Even tough differentiated spermatozoa are unable of transcriptional or translational activity; the sperm surface undergoes major modifications in macromolecules composition during the transit along the male reproductive tract. This is the result of sequential, well orchestrated interactions between the male reproductive tract secretions and the transiting male gamete. This is particularly true when spermatozoa transit along the epididymis. The epididymis is a long convoluted tubules in which the spermatozoa leaving the testis have to transit. The unraveled epididymal tubule can be as long as 80 m in stallion, and the transit time of spermatozoa is of 3-12 days depending on the species. The epididymis is usually divided in three segments: the caput (proximal part), the corpus, and cauda. While the cauda epididymides acts as a sperm reservoir, the caput and corpus are responsible for sperm maturation. This means that, under androgen control, the epididymal epithelium secretes proteins that will interact sequentially with sperm surface. Some of the sperm proteins acquired during maturation along the excurrent duct behave as integral membrane proteins. In fact, some epididymal originating proteins are glycosylphosphatidylinositol (GPI)-anchored to the sperm plasma membrane. Our laboratory has shown that some of these proteins are secreted in an apocrine manner by the epididymal epithelium and are associated to exosomes, called epididymosomes. Epididymosomes are rich in sphingomyelin and are characterized by a high cholesterol/phospholipids ratio. Many proteins are associated to epididymosomes, some of which are selectively transferred to spermatozoa during the epididymal transit. We have identified some of these exosomes associated proteins transferred to the maturing spermatozoa. These include two enzymes involved in the polyol pathway: an aldose reductase and a sorbitol dehydrogenase. A cytokine named MIF (macrophage migration inhibitory factor) is another protein associated to exosomes who is transferred to spermatozoa during the epididymal transit. We hypothesized that both the polyol pathway and MIF secreted in an apocrine fashion by the epididymal epithelium modulate sperm motility during the transit along the male reproductive tract. Finally, P25b, belonging to a family of sperm surface proteins (P26h/P34H) necessary for the binding to the surface of the egg, is also acquired through the interaction between epididymosomes and the male gamete. In vitro studies have defined the conditions of protein transfer when epididymal spermatozoa are co-incubated with epididymosomes. The transfer of selected proteins to specific membrane domains of spermatozoa is saturable, temperature and pH-dependent, being optimal at pH 6.5. The presence of zinc in the incubation medium, but not of calcium neither magnesium, significantly increases the efficiency of protein transfer. These results show that exosomes play a role in sperm epididymal maturation which is an essential event to produce male gametes with optimal fertilizing ability.
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PMID:Role of exosomes in sperm maturation during the transit along the male reproductive tract. 1589 44

Two enzymes are involved in the polyol pathway: an aldose reductase that reduces glucose in sorbitol followed by its oxidation in fructose by sorbitol dehydrogenase. It has been previously shown that both enzymes are presented in the bovine epididymis, where they are associated with membranous vesicles called epididymosomes. Based on the distribution of these enzymes, it has been hypothesized that the polyol pathway can modulate sperm motility during the epididymal transit. In the present study, polyol pathway was investigated in semen and along the epididymis in humans in order to determine if sperm maturation can be associated with this sugar pathway. Western blot analysis shows that both aldose reductase and sorbitol dehydrogenase are associated with ejaculated spermatozoa and prostasomes in humans. These enzymes are also associated with epididymosomes collected during surgical vasectomy reversal. Western blot, Northern blot, and reverse transcription-polymerase chain reaction analysis show that aldose reductase and sorbitol dehydrogenase are expressed at the transcriptional and translational levels along the human epididymis. Unlike what occurs in the bovine model, distribution of these enzymes is rather uniform along the human excurrent duct. Immunohistological studies together with Western blot analysis performed on epididymosomes preparations indicate that the polyol pathway enzymes are secreted by the epididymal epithelium. These results indicate that the polyol pathway plays a role in human sperm physiology.
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PMID:Polyol pathway in human epididymis and semen. 1627 69

Concentrations of D-glucose, D-fructose and D-sorbitol were quantified in porcine epididymal fluid by spectrofluorimetric assays and aldose reductase (AR) and sorbitol dehydrogenase (SDH) were located immunohistochemically in the epididymal epithelium. Glucose and fructose concentrations were low (<1 mM) and decreased in the cauda whereas sorbitol concentration (4-7 mM) was rather uniform along the duct. AR was luminally located on microvilli in the caput and corpus with less presence distally and was present in the lumen. SDH was present apically and basally in epithelial cells throughout the epididymis and in the lumen. The observations are consistent with diffusion of circulating glucose into the lumen, its conversion via AR to sorbitol which accumulates in the lumen and the action of SDH on sorbitol to produce fructose. Sperm metabolism of glucose and fructose may explain their lower concentrations in the cauda and sorbitol could be a metabolic substrate or osmolyte required for volume regulation.
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PMID:Study of the polyol pathway in the porcine epididymis. 1659 33


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