Participation of lncRNAs in the development of diabetic complications: Systematic review and meta-analysis. I. Rat.

AIMS: We evaluated the involvement of lncRNAs in the development of pathologies associated with chronic hyperglycaemia in rat models in a model of type 1, type 2 and gestational diabetes. METHODS: Reports were searched in Dialnet, Scielo, HINARI, Springer, ClinicalKey, OTseeker, PubMed and different grey literature databases with any restrictions. Bibliography databases will be searched from their inception to December 2022. RESULTS: Thirty-seven studies met our criteria, and they had the following characteristics: original experimental studies on diabetes, the lncRNAs were extracted or measured from tissues of specific areas and the results were expressed in terms of standard measures by RT-PCR. In most studies, both primary and secondary outcomes were mentioned. On the other hand, we found a total of nine diabetic complications, being retinopathy, nephropathy and neuropathy the most representatives. Additionally, it was found that MALAT1, H19, NEAT1 and TUG1 are the most studied lncRNAs about these complications in rats. On the other hand, the lncRNAs with the highest rate of change were MSTRG.1662 (17.85; 13.78, 21.93), ENSRNOT00000093120_Aox3 (7.13; 5.95, 8.31) and NONRATG013497.2 (-5.55; -7.18, -3.93). CONCLUSIONS: This review found a significant involvement of lncRNAs in the progression of pathologies associated with chronic hyperglycaemia in rat models, and further studies are needed to establish their potential as biomarkers and therapeutic targets for diabetes.

Verbascoside-enriched fraction from Buddleja cordata Kunth ameliorates the effects of diabetic embryopathy in an animal model.

BACKGROUND: The deleterious effects of diabetes mellitus (DM) over development are apparently due to an increase in oxidative stress. Some antioxidants could prevent developmental alterations produced by diabetic state. Extracts of plants of the genus Buddleja are used traditionally for Mexican indigens to ameliorate some diseases. The purpose of this work was to evaluate the effect of the extract of Buddleja cordata over diabetic embryopathy. METHODS: Two experimental approaches were used: an in vivo study and an in vitro model. In the first, rats were treated with streptozotocin, streptozotocin plus methanolic extract of B. cordata, or none. Females were sacrificed at gestational day (GD) 19, and biochemical clinical parameters were measured; also, the fetuses were obtained and morphologically analyzed. In the in vitro model, a verbascoside-enriched fraction (VEF) of the extract was used in whole embryo culture in order to search for the mechanisms for embryoprotection effect over hyperglycemia-induced malformations. RESULTS: In the in vivo experiments, B. cordata extract reduces the frequency and severity of fetal malformations produced by chemically induced diabetes, and additionally partially ameliorates the diabetic condition; in the in vitro model, both severity and frequency of embryo dysmorphogenesis were reduced by the VEF; also, this fraction reduces lipoperoxidation without affecting the activity of the antioxidant enzymes. CONCLUSION: The results suggest that verbascoside of methanolic extract and enriched fraction can directly affect the redox state, and thus, prevents the embryotoxicity mediated by oxidative stress, in embryos of diabetic pregnancy.

Bcl-2 expression in a diabetic embryopathy model in presence of polyamines.

The frequency of congenital malformations is 3-5 times higher in mothers with pregestational diabetes mellitus than in general population. Apparently, this problem is due to change in the expression of apoptotic and antiapoptotic genes induced by the oxidative stress derived from the diabetes/hyperglycemia. One of these genes is Bcl-2, which is associated with the control and inhibition of apoptosis. The purpose of the present work was to study the effect of polyamine addition over expression of Bcl-2 gene in a model of diabetic embryopathy. For this, gestational day 10.5 (GD10.5) rat embryos were incubated at 37°C for 24 h in control medium, medium with high glucose, or medium with high glucose and supplemented with spermidine or spermine. Post-cultured embryos were harvested and observed to obtain morphological scores; some of them were subjected to molecular biology studies: DNA isolation plus conventional PCR or RNA isolation plus RT-PCR; other embryos were fixed with paraformaldehyde and used for immunohistochemical detection of Bcl-2 protein. Although Bcl-2 mRNA was similarly expressed in all rat embryo treatments, Bcl-2 protein was found only in control-incubated embryos. In conclusion, it seems that the inhibition of Bcl-2 gene expression induced by glucose was not reversed by polyamines.

Biphasic effect of alpha-linolenic acid on glucose-induced dysmorphogenesis and lipoperoxidation in whole rat embryo in culture.

Type 1 diabetes mellitus complicated with pregnancy, know as diabetic embryopathy, is the cause of neonatal malformations and low for gestational age neonates. With the use of the whole-embryo culture system, it has been demonstrated that high glucose causes embryo dysmorphogenesis, and that oxidative stress appears to be the main mechanism. In recent years, beneficial effect of omega-3 fatty acids has been demonstrated in various diabetic models, and in diabetic complications. Since diabetic embryopathy is mediated probably through membrane lipoperoxidation, This study was designed to find if omega-3 fatty acids could ameliorate the effect of high glucose over the dysmorphogenesis of whole rat embryo in culture. Postimplantational rat embryos were cultured in hyperglycemic media, with addition of alpha-linolenic acid, and morphologic and morphometric parameters were registered. Also, lipoperoxidation and fatty acids composition were measured in cultured embryos. Growth of embryos cultured in presence of glucose was very affected, whereas lipoperoxidation was increased, and it was found that Triton X-100 causes similar results than glucose. Addition of low micromolar doses of alpha-linolenic acid overcome the effect of high glucose or Triton X-100, but higher doses does not ameliorates the effects of the carbohydrate or the detergent. Paradoxically, there are not significant changes in fatty acids composition, although the U/S fatty acids ratio shows an increasing tendency by high glucose and a normalizing tendency by omega-3 fatty acids. In conclusion, glucose and Triton X-100 induces in vitro dysmorphogenesis in post-implantational rat embryos associated with increased lipoperoxidation; and this nocive effect could be ameliorated by low micromolar doses of ALA.

[Antiteratogenic capacity of resveratrol in streptozotocin-induced diabetes in rats]. / Capacidad antiteratogénica del resveratrol en diabetes inducida por estreptozotocina en ratas.

OBJECTIVES: To evaluate the anti-hyperglycemic and anti-teratogenic capacity of resveratrol in streptozotocin-induced diabetic rats. MATERIAL AND METHODS: Experimental study. There were three groups, of five rats each; two groups were treated with a single dose of 50 mg/Kg of streptozotocin (STZ), in citrate buffer, at the 4th day of gestation, and the third group was considered the control, and were administered with citrate buffer only. One of the two STZ induced groups was administered with 100 mg/Kg resveratrol the days 8th to 12th, when neurulation occurs. Fetuses were obtained the 19th gestational day, and were subjected to morphologic analysis; and in fetal liver the activities of scavenging enzymes catalase, superoxide dismutase and gluthathione peroxidase were measured. RESULTS: Resveratrol can decrease the teratogenic effect of STZ-induced diabetes, and scavenging activities were beneficed by the administration of this antioxidant. CONCLUSION: Resveratrol shown embryoprotective properties mediated by amelioration of oxidative stress produced by maternal hyperglycemia.

Capacidad antiteratogénica del resveratrol en diabetes inducida por estreptozotocina en ratas / Antiteratogenic capacity of resveratrol in streptozotocin-induced diabetes in rats

Evaluar la capacidad antihiperglucémica y antiteratogénica del resveratrol en ratas inducidas a diabetes por estreptozotocina. Materiales y métodos. Estudio de tipo experimental. Se tuvieron tres grupos, de cinco ratas Wistar preñadas cada uno, dos de los cuales fueron tratados el cuarto día de gestación con una dosis de estreptozotocina de 50 mg/kg, disuelta en tampón de citratos, y el otro fue considerado como control, y solo se le administró el tampón de citratos. A uno de los grupos inducidos con estreptozotocina se le administró resveratrol a dosis de 100 mg/kg durante los días 8 al 12 de gestación, cuando sucede la neurulación. Los fetos se obtuvieron el día 19 de gestación y se les realizó un análisis morfológico, y en el hígado fetal se determinó la actividad de las enzimas depuradoras de especies reactivas catalasa, superóxido dismutasa y glutatión peroxidasa. Resultados. La administración de resveratrol (DM+R) revierte los parámetros a valores similares a los del grupo control. Las actividades de catalasa y de glutatión peroxidasa, se vieron incrementadas en el grupo tratado con resveratrol con respecto al grupo diabético, en cuanto a la frecuencia de malformaciones en el grupo control y en el grupo tratado con resveratrol no presentaron malformaciones, mientras que en las ratas con diabetes inducida, se encontró una elevada frecuencia de malformaciones. Conclusiones. El resveratrol muestra propiedades antiteratogénicas a través de la disminución del estrés oxidativo que se presenta a causa de la hiperglucemia materna...

To evaluate the anti-hyperglycemic and anti-teratogenic capacity of resveratrol in streptozotocin-induced diabetic rats. Material and methods. Experimental study. There were three groups, of five rats each; two groups were treated with a single dose of 50 mg/Kg of streptozotocin (STZ), in citrate buffer, at the 4th day of gestation, and the third group was considered the control, and were administered with citrate buffer only. One of the two STZ induced groups was administered with 100 mg/Kg resveratrol the days 8th to 12th, when neurulation occurs. Fetuses were obtained the 19th gestational day, and were subjected to morphologic analysis; and in fetal liver the activities of scavenging enzymes catalase, superoxide dismutase and gluthathione peroxidase were measured. Results. Resveratrol can decrease the teratogenic effect of STZ-induced diabetes, and scavenging activities were beneficed by the administration of this antioxidant. Conclusion. Resveratrol shown embryoprotective properties mediated by amelioration of oxidative stress produced by maternal hyperglycemia...

Change in lipoperoxidation but not in scavenging enzymes activity during polyamine embryoprotection in rat embryo cultured in hyperglycemic media.

DM1 complicated with pregnancy is the cause of neonatal malformations and low-for-gestational-age neonates. With the use of the whole-embryo culture system, it has been demonstrated that high glucose causes embryo dysmorphogenesis. Previously, our group has found that spermidine or spermine addition reverts almost fully the severity and frequency of dysmorphogenesis, whereas the effect of arginine and putrescine it is only partial. A hypothesis for polyamine mechanism is the amelioration of oxidative stress caused by high glucose. The purpose of this work was to evaluate the effect of polyamines over the activity of scavenging enzymes and lipoperoxidation in whole-embryo rat in culture. Post-implantation (gestational day 10.5) rat embryos were cultured for 24 h in normal medium or hyperglycemic medium, alone or supplemented with L-arginine or polyamine. Embryos were recovered and visualized, and morphologic parameters were registered. Cultured embryos were homogenized, and superoxide dismutase and glutathione-reductase activities, as well as lipoperoxidation, were measured. The activity of superoxide dismutase and glutathione peroxidase were not affected by the treatment, but lipoperoxidation was increased in embryos cultured in hyperglycemic medium; spermidine or spermine supplementation restore lipoperoxidation to near-normal values, and putrescine and L-arginine reverts only partially the glucose effect. Taken together, these results pointed out that spermidine and spermine embryoprotection could be mediated by direct antioxidant activity. However, further studies are needed to support this hypothesis.

Polyamines protect rat embryo in vitro from high glucose-induced developmental delay and dysmorphogenesis.

BACKGROUND: Pregnancy in mammals with diabetes mellitus results in low birth weight, malformations, and intrauterine death. Parenteral application of natural polyamines or their precursor, L-arginine, to diabetic pregnant rats partially prevents the alterations of development caused by diabetes mellitus. This experiment has been designed to understand if this preventive action also occurs in rat whole embryo in culture. MATERIALS AND METHODS: Rat embryos of gestational day 10 were cultured for 24 h in normal medium, high glucose medium, or high glucose medium supplemented with polyamines or L-arginine, and furthermore embryo growth and development were evaluated. RESULTS: L-arginine and putrescine partially prevents the dysmorphogenic effects of high glucose, whereas spermidine and spermine prevent these effects almost completely. CONCLUSIONS: Polyamines directly protect the embryo from the toxic effect of high glucose concentration on growth and development, although the mechanism remains to be elucidated.