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Open access

Riying Liang, Meijun Wang, Chang Fu, Hua Liang, Hongrong Deng, Ying Tan, Fen Xu, and Mengyin Cai

Background:

Obesity is associated with the development and progression of chronic kidney disease. Emerging evidence suggests that glucagon-like peptide-1 receptor agonist could reduce renal damage and albuminuria. Sirtuin 1 (SIRT1) was considered as a crucial regulator in metabolism-related kidney disease. Herein, the role of SIRT1 in liraglutide-ameliorated high-fat diet (HFD)-induced kidney injury was illustrated.

Methods:

Male C57BL/6 mice were fed HFD for 20 weeks to induce kidney injury that was then treated with liraglutide for 8 weeks to estimate its protective effect on the kidney. Also, the mechanism of the drug in SV40 MES 13 (SV40) mouse mesangial cells was elucidated.

Results:

Liraglutide treatment ameliorated HFD-induced metabolic disorders, including hyperglycemia, increasing body weight, and insulin resistance. In addition, kidney weight, urine albumin-to-creatinine, and kidney morphological changes such as vacuolated tubules, glomerulomegaly, thickened glomerular basement membrane, and tubulointerstitial fibrosis were also significantly ameliorated. Furthermore, apoptotic cells and apoptosis markers were downregulated in the kidney of liraglutide-treated mice. In addition, the expression of SIRT1 protein was upregulated, whereas thioredoxin-interacting protein (TXNIP), which serves as a mediator of oxidative stress and apoptosis in metabolism disease, was downregulated by liraglutide. In SV40 cells, the effect of liraglutide on reversing the upregulation of cleaved caspase-3 induced by high glucose (30 mM) was hampered when SIRT1 was knocked down; also, the downregulation of TXNIP by liraglutide was blocked.

Conclusions:

Liraglutide might have a beneficial effect on metabolism-related kidney damage by inhibiting apoptosis via activation of SIRT1 and suppression of TXNIP pathway.

Open access

Stan Ursem, Vito Francic, Martin Keppel, Verena Schwetz, Christian Trummer, Marlene Pandis, Felix Aberer, Martin R Grübler, Nicolas D Verheyen, Winfried März, Andreas Tomaschitz, Stefan Pilz, Barbara Obermayer-Pietsch, and Annemieke C Heijboer

Objective

PTH can be oxidised in vivo, rendering it biologically inactive. Non-oxidised PTH (n-oxPTH) may therefore give a better image of the hormonal status of the patient. While vitamin D supplementation decreases total PTH (tPTH) concentration, the effect on n-oxPTH concentration is unexplored. We investigated the effect of vitamin D on n-oxPTH concentration in comparison to tPTH and compared the correlations between parameters of calcium, bone and lipid metabolism with n-oxPTH and tPTH.

Methods

N-oxPTH was measured in 108 vitamin D-insufficient (25(OH)D <75 nmol/L) hypertensive patients, treated with vitamin D (2800 IE daily) or placebo for 8 weeks in the Styrian Vitamin D Hypertension Trial (NCT02136771). We calculated the treatment effect and performed correlation analyses of n-oxPTH and tPTH with parameters of calcium, bone and lipid metabolism and oxidative stress.

Results

After treatment, compared to placebo, 25(OH)D concentrations increased, tPTH decreased by 9% (P < 0.001), n-oxPTH by 7% (P = 0.025) and the ratio of n-oxPTH/tPTH increased (P = 0.027). Changes in phosphate and HDL concentration correlated with changes in n-oxPTH, but not tPTH.

Conclusions

tPTH and n-oxPTH decrease upon vitamin D supplementation. Our study suggests that vitamin D supplementation reduces the oxidation of PTH, as we observed a small but significant increase in the non-oxidised proportion of PTH upon treatment. In addition, we found that changes in phosphate and HDL concentration showed a relationship with changes in n-oxPTH, but not tPTH. This may be explained by the biological activity of n-oxPTH. Further research should be carried out to establish the clinical relevance of n-oxPTH.

Open access

Joanna Klubo-Gwiezdzinska, John Costello Jr, Kirk Jensen, Aneeta Patel, Rok Tkavc, Douglas Van Nostrand, Kenneth D Burman, Leonard Wartofsky, and Vasyl Vasko

Background

Amifostine is a potent scavenger of reactive oxygen species that is used for the salivary gland protection during therapy with radioactive iodine for thyroid cancer. There are no data on the potential effect of amifostine on thyroid cancer cells.

Methods

We investigated the effects of the active form of amifostine (WR-1065) on the response of thyroid cancer cells to treatment with DNA-damaging agents. WR-1065 was examined in human thyroid cancer cell lines (FTC133, TPC1, BCPAP and C643) and embryonic fibroblast cells NIH3T3. DNA damage was induced by exposure to H2O2 (0.1 mM), by treatment with the radiomimetic neocarzinostatin (NCS 250 ng/mL) and by γ-radiation (6 Gy). DNA damage, cell viability and apoptosis were examined.

Results

We demonstrated the selective action of WR-1065 (0.1 mM), which prevented oxidative stress–induced DNA damage in fibroblasts, but did not protect thyroid cancer cells from DNA damage and apoptosis documented by caspase-3 and PARP cleavage after exposure to H2O2, NCS and γ-radiation. Prolonged exposure to WR-1065 (0.1 mM for 24 h) was toxic for thyroid cancer cells; this treatment decreased the number of viable cells by 8% in C643 cells, 47% in TPC cells, 92% in BCPAP cells and 82% in FTC 133 cells. The cytotoxic effects of WR-1065 were not associated with induction of apoptosis.

Conclusions

Our data show that amifostine has no protective effect on thyroid cancer cells against DNA-damaging agents in vitro and suggest that amifostine will not attenuate the efficacy of radioiodine treatment in patients with thyroid cancer.

Open access

Angela Köninger, Antonella Iannaccone, Ensar Hajder, Mirjam Frank, Boerge Schmidt, Ekkehard Schleussner, Rainer Kimmig, Alexandra Gellhaus, and Hans Dieplinger

Background

Patients suffering from polycystic ovary syndrome (PCOS) are often insulin resistant and at elevated risk for developing gestational diabetes mellitus (GDM). The aim of this study was to explore afamin, which can be determined preconceptionally to indicate patients who will subsequently develop GDM. Serum concentrations of afamin are altered in conditions of oxidative stress like insulin resistance (IR) and correlate with the gold standard of IR determination, the HOMA index.

Methods

Afamin serum concentrations and the HOMA index were analyzed post hoc in 63 PCOS patients with live births. Patients were treated at Essen University Hospital, Germany, between 2009 and 2018. Mann–Whitney U test, T test, Spearman’s correlation, linear regression models and receiver-operating characteristic (ROC) analyses were performed for statistical analysis.

Results

Patients who developed GDM showed significantly higher HOMA and serum afamin values before their pregnancy (P < 0.001, respectively). ROCs for afamin concentrations showed an area under the curve of 0.78 (95% confidence interval (CI) 0.65–0.90) and of 0.77 (95% CI 0.64–0.89) for the HOMA index. An afamin threshold of 88.6 mg/L distinguished between women who will develop GDM and those who will not with a sensitivity of 79.3% and a specificity of 79.4%. A HOMA index of 2.5 showed a sensitivity of 65.5% and a specificity of 88.2%.

Conclusion

The HOMA index and its surrogate parameter afamin are able to identify pre-pregnant PCOS patients who are at risk to develop GDM. Serum afamin concentrations are independent of fasting status and therefore an easily determinable biomarker.

Open access

Emanuelle Nunes-Souza, Mônica Evelise Silveira, Monalisa Castilho Mendes, Seigo Nagashima, Caroline Busatta Vaz de Paula, Guilherme Guilherme Vieira Cavalcante da Silva, Giovanna Silva Barbosa, Julia Belgrowicz Martins, Lúcia de Noronha, Luana Lenzi, José Renato Sales Barbosa, Rayssa Danilow Fachin Donin, Juliana Ferreira de Moura, Gislaine Custódio, Cleber Machado-Souza, Enzo Lalli, and Bonald Cavalcante de Figueiredo

Objective

Adaptive changes in DHEA and sulfated-DHEA (DHEAS) production from adrenal zona reticularis (ZR) have been observed in normal and pathological conditions. Here we used three different cohorts to assess timing differences in DHEAS blood level changes and characterize the relationship between early blood DHEAS reduction and cell number changes in women ZR.

Materials and methods

DHEAS plasma samples (n = 463) were analyzed in 166 healthy prepubertal girls before pubarche (<9 years) and 324 serum samples from 268 adult females (31.9–83.8 years) without conditions affecting steroidogenesis. Guided by DHEAS blood levels reduction rate, we selected the age range for ZR cell counting using DHEA/DHEAS and phosphatase and tensin homolog (PTEN), tumor suppressor and cell stress marker, immunostaining, and hematoxylin stained nuclei of 14 post-mortem adrenal glands.

Results

We confirmed that overweight girls exhibited higher and earlier DHEAS levels and no difference was found compared with the average European and South American girls with a similar body mass index (BMI). Adrenopause onset threshold (AOT) defined as DHEAS blood levels <2040 nmol/L was identified in >35% of the females >40 years old and associated with significantly reduced ZR cell number (based on PTEN and hematoxylin signals). ZR cell loss may in part account for lower DHEA/DHEAS expression, but most cells remain alive with lower DHEA/DHEAS biosynthesis.

Conclusion

The timely relation between significant reduction of blood DHEAS levels and decreased ZR cell number at the beginning of the 40s suggests that adrenopause is an additional burden for a significant number of middle-aged women, and may become an emergent problem associated with further sex steroids reduction during the menopausal transition.

Open access

Maurício Martins da Silva, Lueni Lopes Felix Xavier, Carlos Frederico Lima Gonçalves, Ana Paula Santos-Silva, Francisca Diana Paiva-Melo, Mariana Lopes de Freitas, Rodrigo Soares Fortunato, Leandro Miranda-Alves, and Andrea Claudia Freitas Ferreira

Bisphenol A (BPA) is the most common monomer in polycarbonate plastics and an endocrine disruptor. Though some effects of BPA on thyroid hormone (TH) synthesis and action have been described, the impact of this compound on thyroid H2O2 generation remains elusive. H2O2 is a reactive oxygen species (ROS), which could have deleterious effect on thyrocytes if in excess. Therefore, herein we aimed at evaluating the effect of BPA exposition both in vivo and in vitro on H2O2 generation in thyrocytes, besides other essential steps for TH synthesis. Female Wistar rats were treated with vehicle (control) or BPA 40 mg/kg BW for 15 days, by gavage. We then evaluated thyroid iodide uptake, mediated by sodium-iodide symporter (NIS), thyroperoxidase (TPO) and dual oxidase (DOUX) activities (H2O2 generation). Hydrogen peroxide generation was increased, while iodide uptake and TPO activity were reduced by BPA exposition. We have also incubated the rat thyroid cell line PCCL3 with 10−9 M BPA and evaluated Nis and Duox mRNA levels, besides H2O2 generation. Similar to that found in vivo, BPA treatment also led to increased H2O2 generation in PCCL3. Nis mRNA levels were reduced and Duox2 mRNA levels were increased in BPA-exposed cells. To evaluate the importance of oxidative stress on BPA-induced Nis reduction, PCCL3 was treated with BPA in association to N-acetylcysteine, an antioxidant, which reversed the effect of BPA on Nis. Our data suggest that BPA increases ROS production in thyrocytes, what could lead to oxidative damage thus possibly predisposing to thyroid disease.

Open access

Jairo Arturo Pinzón-Cortés, Angelina Perna-Chaux, Nicolás Steven Rojas-Villamizar, Angélica Díaz-Basabe, Diana Carolina Polanía-Villanueva, María Fernanda Jácome, Carlos Olimpo Mendivil, Helena Groot, and Valeriano López-Segura

Type 2 diabetes mellitus (T2DM) is characterized by oxidative stress that could lead to chronic micro- and macrovascular complications. We hypothesized that some of the target organ damage is mediated by oxidative alterations in epigenetic mechanisms involving DNA methylation (5mC) and DNA hydroxymethylation (5hmC). We analyzed global DNA methylation and hydroxymethylation in peripheral blood cells in well-controlled and poorly controlled patients with T2DM and compared them with healthy controls. We also analyzed microarrays of DNA methylation and gene expression of other important tissues in the context of diabetes from the GEO database repository and then compared these results with our experimental gene expression data. DNA methylation and, more importantly, DNA hydroxymethylation levels were increased in poorly controlled patients compared to well-controlled and healthy individuals. Both 5mC and 5hmC measurements were correlated with the percentage of glycated hemoglobin, indicating a direct impact of hyperglycemia on changes over the epigenome. The analysis of methylation microarrays was concordant, and 5mC levels were increased in the peripheral blood of T2DM patients. However, the DNA methylation levels were the opposite of those in other tissues, such as the pancreas, adipose tissue and skeletal muscle. We hypothesize that a process of DNA oxidation associated with hyperglycemia may explain the DNA demethylation in which the activity of ten-eleven translocation (TET) proteins is not sufficient to complete the process. High levels of glucose lead to cellular oxidation, which triggers the process of DNA demethylation aided by TET enzymes, resulting in epigenetic dysregulation of the damaged tissues.

Open access

Emmanuel K Fai, Cheryl Anderson, and Victor Ferreros

The purpose of this quantitative study was to investigate the extent to which patient attitudes and intentions predict adherence to the use of oral antihyperglycemic regimens in African Americans. This cross-sectional study of 115 participants used correlation analysis to establish relationships among patient attitudes, intentions and adherence. Data analyses showed significant correlations between the variables. Multiple regression analysis was used to establish predictions between the variables. A prediction model containing attitudes, subjective norms and perceived behavioral control (PBC) explained 37% of the variance to behavioral intention. Intentions accounted for 8.5% of the variance to adherence. Attitudes predicted behavioral intentions. The findings support the theory of planned behavior model and identify important correlations between attitudes, intentions and behaviors. In addition, the results underscore the need for promoting positive attitudes and positive intentions in effective adherence to the use of oral antihyperglycemic regimens. Achieving adequate adherence through behavioral counseling can effect positive social change by reducing the mortality and morbidity that are associated with inadequate adherence to the use of oral diabetic agents.

Open access

Caroline Nguyen, Elisabeth Celestin, Delphine Chambolle, Agnès Linglart, Martin Biosse Duplan, Catherine Chaussain, and Lisa Friedlander

Introduction. X-linked hypophosphatemia (XLH) is a rare, hereditary, and lifelong phosphate wasting disorder characterized by rickets in childhood and impaired teeth mineralization. In the oral cavity, spontaneous abscesses can often occur without any clinical signs of alteration of the causal tooth. The objective of our study was to evaluate the oral care pathway and the oral health-related quality of life (OHRQoL) of patients followed in an expert oral medicine department located within a Parisian hospital and working in close collaboration with an endocrinology department expert in this pathology. Methods. This study employed a qualitative descriptive design including semi-structured interviews using guiding themes. Results. Twenty-one patients were included in the study. The topics brought up exceeded the initial objectives as the patients mostly addressed the alteration of their oral health-related and general quality of life; a very chaotic oral health care pathway with oral health professionals not aware of their pathology; consequences on their social, professional, and school integration. Patients declared the importance of having a multidisciplinary team around them, including medical and dental professionals. Conclusions. The variety of manifestations in patients with XLH necessitates a high coordination of multidisciplinary patient care to optimize quality of life and reduce disease burden. Oral health care pathways are very chaotic for patients who have difficulty finding professionals with sufficient knowledge of the disease. OHRQoL is therefore diminished. This situation improves when patients enter a coordinated care network.

Open access

Enora Le Roux, Florence Menesguen, Isabelle Tejedor, Marc Popelier, Marine Halbron, Pauline Faucher, Sabine Malivoir, Graziella Pinto, Juliane Léger, Stephane Hatem, Michel Polak, Christine Poitou, and Philippe Touraine

Objective

The transition from paediatric to adult medicine involves risks of poor patient outcomes and of significant losses of patients to follow up. The research aimed to analyse the implementation in an initial cohort of patients of a new programme of transition to adult care based on a case management approach.

Design

A longitudinal study of the case management approach to transition, initiated in a university hospital in France in September 2016.

Methods

Patients with the endocrine or metabolic disease diagnosed during childhood and transferred to adult care were included. The transition programme includes three steps based on case management: liaising with paediatric services, personalising care pathways, and liaising with structures outside the hospital (general practitioners, agencies in the educational and social sector).

Results

The cohort included 500 patients, with malignant brain tumour (n = 56 (11%)), obesity (n = 55 (11%)), type 1 diabetes (n = 54 (11%)), or other disease (n = 335 (67%)). Their median age at transfer was 19, and the sex ratio was 0.5. At median 21 months of follow-up, 439 (88%) had a regular follow-up in or outside the hospital, 47 (9%) had irregular follow-up (absence at the last appointment or no appointment scheduled within the time recommended), 4 had stopped care on doctor’s advice, 4 had died, 3 had moved, and 3 had refused care. The programme involved 9615 case management actions; 7% of patients required more than 50 actions. Patients requiring most support were usually those affected by a rare genetic form of obesity.

Conclusions

Case managers successfully addressed the complex needs of patients. Over time, the cohort will provide unprecedented long-term outcome results for patients with various conditions who experienced this form of transition.