Vitamin E (α-Tocopherol) Does Not Ameliorate the Toxic Effect of Bisphenol S on the Metabolic Analytes and Pancreas Histoarchitecture of Diabetic Rats.

This study investigated whether the coadministration of vitamin E (VitE) diminishes the harmful effects provoked by plasticizer bisphenol S (BPS) in the serum metabolites related to hepatic and renal metabolism, as well as the endocrine pancreatic function in diabetic male Wistar rats. Rats were divided into five groups (n = 5-6); the first group was healthy rats (Ctrl group). The other four groups were diabetic rats induced with 45 mg/kg bw of streptozotocin: Ctrl-D (diabetic control); VitE-D (100 mg/kg bw/d of VitE); BPS-D (100 mg/kg bw/d of BPS); The animals from the VitE + BPS-D group were administered 100 mg/kg bw/d of VitE + 100 mg/kg bw/d of BPS. All compounds were administered orally for 30 days. Body weight, biochemical assays, urinalysis, glucose tolerance test, pancreas histopathology, proximate chemical analysis in feces, and the activity of antioxidants in rat serum were assessed. The coadministration of VitE + BPS produced weight losses, increases in 14 serum analytes, and degeneration in the pancreas. Therefore, the VitE + BPS coadministration did not have a protective effect versus the harmful impact of BPS or the diabetic metabolic state; on the contrary, it partially aggravated the damage produced by the BPS. VitE is likely to have an additive effect on the toxicity of BPS.

A Systematic Review and Meta-Analysis of the Relationship Between the Severity of Dental Fluorosis and Fluoride Biomarkers in Endemic Areas.

The intake of high concentrations of fluoride, mainly through drinking water, diet and fluoridated dentifrices, produces fluorosis, which in its early stages is manifested as dental fluorosis (DF). To recognize exposure to fluoride in endemic areas and to evaluate the risk of developing health impairment, the WHO has established several biomarkers that are used to determine systemic fluorine (F-) exposure. Thus, the aim of this study was to conduct a systematic review and meta-analysis of the relationship between the severity of DF and fluoride biomarkers in endemic areas. The protocol of this study was previously registered as CRD42021244974. A digital search was carried out in PubMed/Medline, SpringerLink, Scopus, Cochrane and Google Scholar by employing the keywords "urine", "nails", "hair", "plasma", "saliva" and "dental fluorosis" for the original studies with content associated with F- for the biomarkers and DF. The mean difference was established as the effect measure for the meta-analysis. Seven studies fulfilled the eligibility criteria, among which five assessed urine and two employed nails as fluoride biomarkers. A positive significant difference was found between the biomarkers and the severity of DF (0.27, p < 0.001) and individually for each biomarker (urine: 0.14, p = 0.001; nails: 0.88, p < 0.05). The F- concentration in urine and nails is correlated with the severity of DF, with the most evident differences between healthy individuals and those with mild severity. Both biomarkers are adequate to assess this relationship in endemic areas of fluoride and DF.

Environmental Exposure of Arsenic in Groundwater Associated to Carcinogenic Risk in Underweight Children Exposed to Fluorides.

BACKGROUND: The purpose of this study was to determine the concentration of inorganic arsenic (As) in the potable water available to the population to be able to estimate the non-carcinogenic risks for underweight children and the carcinogenic risk for adults exposed to As intake who live in the Mezquital municipality, Durango, Mexico. METHODS: The As content was quantifed in the water supply sources for human use and its intake was estimated in Mezquital population, southern Durango. With the data obtained, the hazard quotient (HQ) was calculated to determine the non-carcinogenic risk to develop chronic systemic effects in underweight children. The Environmental Protection Agency (EPA) reference health values estimating As exposure risk are from 0.0003 mg/kg/day (non-carcinogenic) to 1.5 mg/kg/day (carcinogenic risk). RESULTS: The analyzed waters presented as concentrations that varied from 0.3 to 10.2 µg/L, with a mean of 7.35 µg/L (CI 95% 6.27-8.38). The exposure dose was 0.4 to 1.36, and the HQ was 1.90 to 6.48 mg/kg/day, the estimated carcinogenic risk from adults varied from 1.28 to 4.37E-4, with values of 3.74-4.37E-4 mg/kg/day in central area. CONCLUSIONS: The children are at risk to develop chronic systemic effects due to ingestion of As from water.

High glucose induces mitochondrial p53 phosphorylation by p38 MAPK in pancreatic RINm5F cells.

Pancreatic ß-cell death in type 2 diabetes has been related to p53 subcellular localisation and phosphorylation. However, the mechanisms by which p53 is phosphorylated and its activation in response to oxidative stress remain poorly understood. Therefore, the aim of this study was to investigate mitochondrial p53 phosphorylation, its subcellular localisation and its relationship with apoptotic induction in RINm5F cells cultured under high glucose conditions. Our results show that p53 phosphorylation in the mitochondrial fraction was greater at ser392 than at ser15. This increased phosphorylation correlated with an increase in reactive oxygen species, a decrease in the Bcl-2/Bax ratio, a release of cytochrome c and an increase in the rate of apoptosis. We also observed a decline in ERK 1/2 phosphorylation over time, which is an indicator of cell proliferation. To identify the kinase responsible for phosphorylating p53, p38 mitogen-activated protein kinase (MAPK) activation was analysed. We found that high glucose induced an increase in p38 MAPK phosphorylation in the mitochondria after 24-72 h. Moreover, the phosphorylation of p53 (ser392) by p38 MAPK in mitochondria was confirmed by colocalisation studies with confocal microscopy. The addition of a specific p38 MAPK inhibitor (SB203580) to the culture medium during high glucose treatment blocked p53 mobilisation to the mitochondria and phosphorylation; thus, the release of cytochrome c and the apoptosis rate in RINm5F cells decreased. These results suggest that mitochondrial p53 phosphorylation by p38 MAPK plays an important role in RINm5F cell death under high glucose conditions.

O-GlcNAc-selective-N-acetyl-beta-D-glucosaminidase activity and mRNA expression in muscle is related to glucosamine-induced insulin resistance.

Glucosamine (GlcN)-induced insulin resistance is associated with an increase in O-linked-N-acetylglucosaminylated modified proteins (O-GlcNAcylated proteins). The role played by O-GlcNAc-selective-N-acetyl-beta-D-glucosaminidase (O-GlcNAcase), which removes O-N-acetyl-glucosamine residues from O-GlcNAcylated proteins, has not yet been demonstrated. We investigated whether GlcN-induced whole-body insulin resistance is related to tissue O-GlcNAcase activity and mRNA expression. GlcN (30 mumol/kg/min) or physiological saline (control) was intravenously infused into Sprague-Dawley rats for 2 h. After GlcN treatment, rats were subjected to the following: intravenous glucose tolerance test, insulin tolerance test or removal of the liver, muscle and pancreas. GlcN was found to provoke hyperglycemia compared to control (8.6 +/- 0.41 vs. 4.82 +/- 0.17 mM, p < 0.001). The insulin resistance index (HOMA-IR) increased (15.76 +/- 1.47 vs. 10.14 +/- 1.41, p < 0.001) and the beta-cell function index (HOMA-beta) diminished (182.69 +/- 22.37 vs. 592.01 +/- 103, p < 0.001). Liver glucose concentration was higher in the GlcN group than in the control group (0.37 +/- 0.04 vs. 0.24 +/- 0.038 mmol/g dry weight, p < 0.001). Insulin release index (insulin/glucose) was less in the GlcN group than in the control (2.2 +/- 0.1 vs. 8 +/- 0.8 at 120 min, p < 0.001). In the GlcN group, muscle O-GlcNAcase activity diminished (0.28 +/- 0.019 vs. 0.36 +/- 0.018 nmol of p-nitrophenyl/mg protein/min, p < 0.001), and K(m) increased (1.51 +/- 0.11 vs. 1.12 +/- 0.1 mM, p < 0.001) compared to the control. In the GlcN group, O-GlcNAcase activity/mRNA expression was altered (0.6 +/- 0.07 vs. 1 +/- 0.09 of control, p < 0.05). In conclusion, O-GlcNAcase activity is posttranslationally inhibited during GlcN-induced insulin resistance.

Changes in the glucose-6-phosphate dehydrogenase activity in granulosa cells during follicular atresia in ewes.

Apoptosis of granulosa cells during follicular atresia is preceded by oxidative stress, partly due to a drop in the antioxidant glutathione (GSH). Under oxidative stress, GSH regeneration is dependent on the adequate supply of NADPH by glucose-6-phosphate dehydrogenase (G6PD). In this study, we analyzed the changes of G6PD, GSH, and oxidative stress of granulosa cells and follicular liquid and its association with apoptosis during atresia of small (4-6 mm) and large (>6 mm) sheep antral follicles. G6PD activity was found to be higher in granulosa cells of healthy small rather than large follicles, with similar GSH concentration in both cases. During atresia, increased apoptosis and protein oxidation, as well as a drop in GSH levels, were observed in follicles of both sizes. Furthermore, the activity of G6PD decreased in atretic small follicles, but not in large ones. GSH decreased and protein oxidation increased in follicular fluid. This was dependent on the degree of atresia, whereas the changes in G6PD activity were based on the type of follicle. The higher G6PD activity in the small follicles could be related to granulosa cell proliferation, follicular growth, and a lower sensitivity to oxidative stress when compared with large follicles. The results also indicate that GSH concentration in atretic follicles depends on other factors in addition to G6PD, such as de novo synthesis or activity of other NADPH-producing enzymes. Finally, lower G6PD activity in large follicles indicating a higher susceptibility to oxidative stress associated to apoptosis progression in follicle atresia.

Mechanism of granulosa cell death during follicular atresia depends on follicular size.

Changes in granulosa cell lysosomal and mitochondrial functions in relation to follicular size and to the stage of atresia were studied by fluorescent emission spectra and intensity using flow cytometry. Antral follicles were grouped by size in two groups: small, 3-6 mm and large, >6mm in diameter, and classified into three stages of atresia: non-atretic, initially atretic and advanced atretic. Differences in Rhodamine 123 (Rh123) and Acridine Orange (AO) fluorescent intensity indicated that changes in mitochondrial function are the primary mechanism of granulosa cell death in atretic follicles 3-6 mm in diameter, while its role in granulosa cell death in >6 mm atretic follicles seemed to be less important. However, modifications in lysosomal function (shown by a decrease in fluorometric intensity of AO incubated granulosa cells) were mainly associated with cell death in large atretic follicles. Our results support the hypothesis that the pathway of granulosa cell death during follicular atresia depends on the state of energy metabolism or on the production of hypoxic conditions related to follicular size. Changes in mitochondrial membrane potential and production of permeability transition pores were the main changes found in small follicles, while lysosomal function destabilization seemed to be the major cause of granulosa cell death during atresia in large follicles.

Asymmetric calmodulin distribution in the hypothalamus: role of sexual differentiation in the rat.

The Ca2+/calmodulin (CaM) system plays important roles both in hypothalamic sexual differentiation and in the progesterone-induced facilitation of lordosis behavior in the adult rat. We recently showed sex-dependent differences in rat hypothalamic CaM levels, both in newborn and in adult animals. Here, we evaluated the presence of left-right hypothalamic asymmetries in CaM concentration in male and female rats, as well as the changes induced on these parameters by neonatal (1 h after birth) subcutaneous administration of tamoxifen (200 microg/rat) or testosterone (30 microg/rat). CaM was measured by RIA in each half of the hypothalamus (at 2, 6, 12, and 24 h and at 90 days after birth) in both control and treated animals. In untreated young rats (2-24 h after birth), CaM concentration was significantly higher in the right half of the hypothalamus of males, whereas in females, it was higher in the hypothalamic left half. Treatment of females with testosterone or tamoxifen to males, consistently reversed these results. In the hypothalamus of treated animals, we found higher CaM levels in the left half of males, as well as in the right half of females. In control adult females, CaM concentration was also higher in the left half of the hypothalamus, as it was in the right half of adult males. However, this asymmetry was lost after neonatal hormone manipulation. These results reinforce the role of CaM in the development of sex-related hypothalamic functions.

La apoptosis y su importancia biomédica / Apoptosis and its biomedical importance

En este trabajo, revisaremos las características morfológicas y las fases en que se ha dividido a la apoptosis, así como la importancia de su presencia en algunas enfermedades.La apoptosis y la necrosis son dos mecanismos mediante los cuales puede ocurrir muerte celular. La apoptosis constituye una medida fisiológica de remoción celular, bajo control genético, que se caracteriza por colapso celular, condensación de la cromatina y fragmentación del ácido desoxirribonucleico (ADN). Las células apoptóticas son rápidamente fagocitadas por células vecinas o macrófagos, previniendo así una reacción inflamatoria. La apoptosis se ha propuesto como un evento crítico para mantener la homeostasis tisular que asegura el estado de salud de los organismos.La necrosis implica la ruptura de la membrana e hipoxia, lo que conduce a la disminución en las concentraciones de adenosin trifosfato (ATP), colapso metabólico, edematización y disolución de la célula originando un proceso inflamatorio.

Inhibidores del sistema calcio-Calmodulina y diferenciación sexual hipotalámica en la rata. Parámetros bioquímicos / Inhibitors of calcium-calmoduline system and hypothalamic sexual diferentiation: Biochemical parameters

Se estudió el efecto de la administración perinatal de algunos fármacos psicotrópicos (haloperidol, penfluridol, trifluoperazina, pimocida y verapamil) sobre algunos parámetros morfológicos y bioquímicos del hipotálamo, en ratas machos y en hembras androgenizadas por la administración de propionato de testosterona a las 72 horas de vida extrauterina. El verapamil indujo el crecimiento hipotalámico tanto en machos como en hembras androgenizadas. Todos los fármacos disminuyeron el peso testicular, siendo más eficaces el haloperidol (1.50 ñ 0.49 g) y la pimocida (2.00 ñ 0.11 g). En las hembras neonatas, la testosterona disminuyó el desarrollo ovárico (46.3 ñ 4.5 vs 23.1 ñ 2.7 mg). El haloperidol y la pimocida revirtieron parcialmente dicho efecto mientras que el verapamil fue ineficaz. Las concentraciones de proteínas, DNA y RNA fueron mayores en el hipotálamo de la hembra adulta, tanto normal como tratada, que en el macho (fig. 1). La testosterona disminuyó las concentraciones de las tres macromoléculas al nivel encontrado en los machos; todos los fármacos utilizados revirtieron este efecto. En los machos, todos los tratamientos mostraron tendencia a elevar la concentración de proteínas, DNA y RNA a los niveles encontrados en la hembra adulta; la trifluoperazina, el verapamil y el penfluridol fueron los más eficaces, la pimocida sólo elevó las protéinas y el haloperidol únicamente elevó el DNA