Parathyroid hormone, but not vitamin D, is associated with the metabolic syndrome in morbidly obese women and men: a cross-sectional study

Background

Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of endothelial nitric oxide synthase (eNOS) that is associated with endothelial dysfunction, and is a risk marker for cardiovascular disease, a significant problem in Type 1 diabetes. The aim of the present study was to measure circulating ADMA, and define its association with endothelial dysfunction and endothelial markers in people with Type 1 diabetes with low likelihood of macrovascular disease.

Methods

Sixty-one young people with Type 1 diabetes without macrovascular disease or nephropathy and 62 healthy volunteers underwent brachial artery flow-mediated dilatation (FMD) and assay of plasma ADMA and adhesion molecules.

Results

Age, gender, BMI, lipid profile and renal function were similar in the two groups. People with Type 1 diabetes had impaired FMD compared to healthy controls (5.0 ± 0.4 vs 8.9 ± 0.4%; p < 0.001). Plasma ADMA levels were significantly lower in the people with diabetes compared to healthy controls (0.52 ± 0.12 vs 0.66 ± 0.20 μmol/l, p < 0.001). Plasma ICAM-1, E-selectin and PAI-1 levels were significantly higher in people with diabetes compared to healthy controls (median 201 (IQR 172–226) vs 180 (156–216) μg/l, p = 0.027; 44.2 (32.6–60.9) vs. 33.1 (22.4–51.0) μg/l; p = 0.003 and 70.8 (33.3–85.5) vs 46.3 (23.9–76.8) μg/l, p = 0.035). Plasma ADMA and VCAM-1 levels were positively correlated (r = 0.37, p = 0.003) in people with diabetes. There was no correlation between the plasma ADMA and FMD.

Conclusion

ADMA levels are not associated with endothelial dysfunction in young adults with Type 1 diabetes without microalbuminuria or known macrovascular disease. This suggests that the impaired endothelial function in these individuals is not a result of eNOS inhibition by ADMA.     

Inflammation but not oxidative stress is associated with beta-chemokine levels and prevalence of cardiovascular disease in uraemic patients

Inflammation and oxidative stress (SOX) have been reported in patients with chronic renal failure (CRF), but their influence on β-chemokines levels and cardiovascular disease (CVD) prevalence remains unknown. We assessed β-chemokines, SOX markers and high sensitivity C-reactive protein (hs CRP) as a marker of inflammation in 40 uraemic patients, both with as well as without CVD and 20 controls. Compared with the controls, the patients with CVD showed a significant increase in plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), total peroxide (both p < 0.05), macrophage inflammatory protein 1β (MIP-1β) and hs CRP (both p < 0.01). The values of MCP-1 and hs CRP were more elevated in patients with CVD than without CVD (p < 0.01 and p < 0.05; respectively). Both subgroup of CRF patients were lower of regulated upon activation, normal T cell expressed and secreted (RANTES) levels than in the controls (both p < 0.001). The positive relationships were between hs CRP and presence of CVD, MIP-1β (both p < 0.01) and MCP-1 levels (p < 0.05). SOX markers did not show any significant correlation with β-chemokines, hs CRP and presence of CVD. We documented that increased inflammation but not SOX were associated with significant elevation in plasma β-chemokines levels and CVD prevalence in CRF patients not requiring dialysis.     

Premature aging is associated with higher levels of 8‐oxoguanine and increased DNA damage in the Polg mutator mouse

Mitochondrial dysfunction plays an important role in the aging process. However, the mechanism by which this dysfunction causes aging is not fully understood. The accumulation of mutations in the mitochondrial genome (or “mtDNA”) has been proposed as a contributor. One compelling piece of evidence in support of this hypothesis comes from the Polg ^D257A/D257A mutator mouse (Polg ^mut/mut ). These mice express an error‐prone mitochondrial DNA polymerase that results in the accumulation of mtDNA mutations, accelerated aging, and premature death. In this paper, we have used the Polg ^mut/mut model to investigate whether the age‐related biological effects observed in these mice are triggered by oxidative damage to the DNA that compromises the integrity of the genome. Our results show that mutator mouse has significantly higher levels of 8‐oxoguanine (8‐oxoGua) that are correlated with increased nuclear DNA (nDNA) strand breakage and oxidative nDNA damage, shorter average telomere length, and reduced mtDNA integrity. Based on these results, we propose a model whereby the increased level of reactive oxygen species (ROS) associated with the accumulation of mtDNA mutations in Polg ^mut/mut mice results in higher levels of 8‐oxoGua, which in turn lead to compromised DNA integrity and accelerated aging via increased DNA fragmentation and telomere shortening. These results suggest that mitochondrial play a central role in aging and may guide future research to develop potential therapeutics for mitigating aging process.     

Tranexamic acid use is not associated with the risk of melanoma in Danish women: A nested case-control study using Danish health registries

BackgroundRepurposing already approved drugs in a cancer setting has gained increasing interest in recent years. Tranexamic acid is an anti-fibrinolytic drug that has recently been suggested as an anti-cancer drug due to its anti-inflammatory and anti-carcinogenic effects in animal studies. In this study, we aimed to investigate the possible melanoma-preventive role of tranexamic acid in Danish women.MethodIn this nested case-control study, we identified female cases 18–60 years with first-time melanoma during 2000–2015 and age-matched them with 10 female controls. The odds ratio (OR) of melanoma with tranexamic acid ever- or high use (≥ 100,000 mg) was estimated using conditional logistic regression.ResultsA total of 7986 women with incident melanoma were eligible for study inclusion and were matched to 79,860 controls. Most exposed cases and controls were exposed to low cumulative doses of tranexamic acid corresponding to around 5 days of continuous treatment (1000 mg 3 times daily) for the presumed main indication, i.e., menorrhagia.The crude OR associating tranexamic ever use with melanoma was 1.04 (95% CI 0.98–1.11, p = 0.20), and the adjusted OR was 1.03 (0.97–1.10, p = 0.32). We found no dose-response pattern or effect measure modification by age, histologic type, localization, or clinical stage. However, prolonged use with cumulative doses of tranexamic acid (≥ 100,000 mg) was associated with an increased risk of melanoma (adjusted OR 1.23,95 %, CI 0.96–1.56), compared with non-use.ConclusionWe found no association between tranexamic acid use and the risk of melanoma in Danish women. This could be explained by underlying dose- or biological factors, and sporadic use patterns. A higher risk of melanoma was seen among prolonged users which could be due to surveillance bias.     

Free radical-dependent nuclear localization of Bcl-2 in the central nervous system of aged rats is not associated with Bcl-2-mediated protection from apoptosis

We have previously reported that Bcl-2 is up-regulated in the CNS of aged F344 rats as a consequence of oxidative stress. In addition to increased levels of expression, we now report that there is a subcellular redistribution of Bcl-2 in the CNS of aged F344 rats. Using western blotting, we found Bcl-2 predominantly located in the cytosol of young rats. However, in aged rats Bcl-2 was found primarily in the nucleus. This distribution, in the hippocampus and cerebellum, was reversed by treatment with the nitrone spin trap N-tert-butyl-alpha-phenylnitrone (PBN). Paradoxically, PBN treatment in young rats had the opposite effect, changing Bcl-2 from predominantly cytosolic to nuclear. We also detected an increase in Bax in aged hippocampal samples (both nuclear and cytosolic), which was reversed by treatment with PBN. The distribution of Bcl-2 and Bax in the cytosol of aged rats dramatically decreased the Bcl-2/Bax ratio, a probable indicator of neuronal vulnerability, which was restored upon treatment with PBN. In order to assess the effect of nuclear association of Bcl-2 we used PC12 cells stably transfected with a Bcl-2 construct to which we added the nuclear localization sequence of the SV40 large T antigen to the N-terminus which resulted in nuclear targeting of Bcl-2. Measurement of cell death using lactate dehydrogenase assays showed that, contrary to wild-type Bcl-2, Bcl-2 localized to the nucleus was not effective in protecting cells from treatment with 250 microm H2O2. These results suggest that nuclear localization of Bcl-2 observed in the aged CNS may not reflect a protective mechanism against oxidative stress, a major component of age-associated CNS impairments.