Vitamin D deficiency could play an important role in the pathogenesis of type 2 diabetes mellitus (T2DM) as it may alter several crucial processes in the development of diabetes and its ...complications, such as pancreatic insulin secretion, peripheral insulin resistance, persistence of systemic "sterile" inflammation and immune activation. Vitamin D may also have an antioxidant effect through the inhibition of free radicals generation. The reported study was designed with eligible consecutively recruited patients with T2DM on standard metformin therapy (n=130), randomized in 1:1 ratio, considered to have undergone Vitamin D supplementation according to the guidelines proposed by the Endocrine Society, or to have continued with metformin only. The potential benefit was monitored through the influence on glycemia level, glycated haemoglobin (HbA1c), insulin resistance index (calculated as homeostatic model assessment; HOMA-IR), Castelli Risk Index I and Tryglicerides/Thiobarbituric acid
reactive substances (TG/TBARS) Index in a 6-month follow up period. Our study indicates that oral daily doses of vitamin D improve HbA1c levels over the 3-month and 6-month period, followed by a significant decrease in advanced oxidation protein products levels over the 3-month period when higher vitamin D doses are given. The effect of vitamin D on HOMA-IR index, malondialdehyde levels and TG/TBARS index was not statistically significant. Further investigation should consider defining the doses of vitamin D in patients with T2DM which may attenuate the oxidative stress risk, the risk of metabolic syndrome and the risk of related cardiovascular events.
Type 2 diabetes mellitus (T2DM) is caused by an interplay of various factors where chronic hyperglycemia and inflammation have central role in its onset and progression. Identifying patient groups ...with increased inflammation in order to provide more personalized approach has become crucial. We hypothesized that grouping patients into clusters according to their clinical characteristics could identify distinct unique profiles that were previously invisible to the clinical eye. A cross-sectional record-based study was performed at the Primary Health Care Center Podgorica, Montenegro, on 424 T2DM patients aged between 30 and 85. Using hierarchical clustering patients were grouped into four distinct clusters based on 12 clinical variables, including glycemic and other relevant metabolic indicators. Inflammation was assessed through neutrophil-to-lymphocyte (NLR) and platelet to lymphocyte ratio (PLR). Cluster 3 which featured the oldest patients with the longest T2DM duration, highest hypertension rate, poor glycemic control and significant GFR impairment had the highest levels of inflammatory markers. Cluster 4 which featured the youngest patients, with the best glycemic control, the highest GFR had the lowest prevalence of coronary disease, but not the lowest levels of inflammatory markers. Identifying these clusters offers physicians opportunity for more personalized T2DM management, potentially mitigating its associated complications.
Dipeptidyl peptidase-4 (DPP-4), glycyl-prolyl-naphthylamidase, is a serine protease that catalyzes the hydrolysis of various proline-containing polypeptides. It is involved in the inactivation of ...glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), having in this way a profound influence on glucose metabolism. During organ damage, stromal and endothelial cells produce a chemokine known as stromal cell-derived factor-1 (SDF-1), a powerful chemoattractant of stem/progenitor cells. SDF-1 binds to a specific α-chemokine receptor (CXCR4) and can be degraded by proteases, including matrix DPP-4/CD26, presented in the circulation, or activated in injured tissues. DPP-4 inhibition has received considerable attention because of its significant therapeutic benefits in the regulation of insulin secretion and tissue insulin sensitivity, the regulation of tumor growth and metastasis, angiogenesis, tissue repair, especially after myocardial infarction, and regulation of endocrine function. Inhibition of circulating proteases appears to maintain the optimal endogenous SDF-1 concentration and may enhance homing of endothelial progenitor cells. In the present article, we present an overview of some basic facts about the role of DPP-4 in glucose homeostasis, the mechanism of its inhibition, and a brief summary of available DPP-4 inhibitors. Furthermore, since protection against the overactivity of proteases is important for restorating cardiac function and repair after myocardial damage, necrosis and apoptosis, we propose that administration of a DPP-4 inhibitor may also be beneficial following myocardial infarction by the prevention of cleavage of stem cell chemoattractant cytokine SDF-1.
Ischemic reperfusion kidney injury (IRKI) is a complex pathophysiological event, which is the most common cause of the acute kidney injury. The key characteristic of IRKI is a reduction in glomerular ...filtration rate, which implies an underlying impairment in hemodynamic regulation. In recent decades, convincing evidence illuminated the molecular and pathological events in the acute kidney injury, revealing the role of ischemia/reperfusion, oxidative stress, apoptosis, inflammation, fibrosis and changes in gene expression which activate different signaling pathways. The cascade of inflammation events is a key mediator of IRKI, which includes the inflammation process, complement activation and mobilization of innate immunity. Oxidative stress represents the increased presence of various free radicals that cannot be buffered by the antioxidant capacity which comprises of enzymatic and non-enzymatic components. Renal tissue injury during ischemia/reperfusion comes as a result of membrane lipids peroxidation, oxidative damage of proteins and DNA and results in apoptosis and necrosis. It is evident from many studies that augmentation of the antioxidant defense mechanisms has a protective role on kidney tissue. In recent years, the importance of heat-shock proteins and MicroRNAs in the pathogenesis of IRKI has been revealed and there are promising indications that in future they could serve as diagnostic biomarkers or therapeutic targets. Striking changes in global gene expression were shown, providing a great potential for fundamental understanding and clinical management of IRKI. The clinical outcome among patients with kidney transplantation will have the furthermost advance from the better understanding of the underlying molecular pathology of IRKI.
Soluble suppressor of tumorigenicity 2 (sST2), galectin-3, growth differentiation factor (GDF)-15 and syndecan-1 represent biomarkers of cardiac remodeling, involved in heart failure (HF) ...progression. We hypothesize that their plasma concentrations, together with brain natriuretic peptide (BNP), are different in HF stratified by ejection fraction (EF), demonstrating correlations with echocardiographic parameters that indicate left ventricular (LV) hypertrophy; LV mass index (LVMI) and posterior wall and septum diameters. HF patients (n = 77) were classified according to EF: reduced EF < 40% (HFrEF), mid-range EF = 40-49% (HFmrEF), preserved EF > 50% (HFpEF). We found that plasma concentrations of four cardiac remodeling biomarkers were highest in HFrEF and lowest in HFpEF, p < 0.001. In HFpEF, remodeling biomarkers independently correlated with LVMI: sST2 (p = 0. 002), galectin-3 (p < 0.001), GDF-15 (p = 0.011), and syndecan-1 (p = 0.006), whereas galectin-3 correlated after multivariable adjustments (p = 0.001). Independent correlates of septum and posterior wall diameters, in HFpEF, were sST2 (p = 0.019; p = 0.026), galectin-3 (p = 0.011; p = 0.009), GDF-15 (p = 0.007; p = 0.001), and syndecan-1 (p = 0.005; p = 0.002). In HFrEF, only sST2, adjusted, correlated with LVMI (p = 0.010), whereas BNP correlated with LVMI (p = 0.002) and EF (p = 0.001). GDF-15 correlated with diastolic dysfunction in HFpEF (p = 0.046) and HFrEF (p = 0.024). Cardiac remodeling biomarkers are potential circulating indicators of LV hypertrophy in HFpEF, which may ensure timely recognition of disease progression among high-risk patients.
Aristolochic acid nephropathy is a progressive exposome‐induced disease characterized by tubular atrophy and fibrosis culminating in end‐stage renal disease and malignancies. The molecular mechanisms ...of the energy crisis as a putative cause of fibrosis have not yet been elucidated. In light of the fact that aristolochic acid forms DNA and RNA adducts by covalent binding of aristolochic acid metabolites to exocyclic amino groups of (deoxy)adenosine and (deoxy)guanosine, we hypothesize here that similar aristolochic acid adducts may exist with other purine‐containing molecules. We also provide new insights into the aristolochic acid‐induced energy crisis and presumably a link between already known mechanisms. In addition, an overview of potential targets in fibrosis treatment is provided, which is followed by recommendations on possible preventive measures that could be taken to at least postpone or partially alleviate aristolochic acid nephropathy.
The prototypic sensors for the induction of innate and adaptive immune responses are the Toll-like receptors (TLRs). Unusually high expression of TLRs in prostate carcinoma (PC), associated with less ...differentiated, more aggressive and more propagating forms of PC, changed the previous paradigm about the role of TLRs strictly in immune defense system. Our data reveal an entirely novel role of nucleic acids-sensing Toll-like receptors (NA-TLRs) in functional adaptation of malignant cells for supply and digestion of surrounding metabolic substrates from dead cells as specific mechanism of cancer cells survival, by corresponding ligands accelerated degradation and purine/pyrimidine salvage pathway. The spectrophotometric measurement protocols used for the determination of the activity of RNases and DNase II have been optimized in our laboratory as well as the enzyme-linked immunosorbent method for the determination of NF-κB p65 in prostate tissue samples. The protocols used to determine Dicer RNase, AGO2, TARBP2 and PIWIL4 were based on enzyme-linked immunosorbent assay. The amount of pre-existing acid-soluble oligonucleotides was measured and expressed as coefficient of absorbance. The activities of acid DNase II and RNase T2, and the activities of nucleases cleaving TLR3, TLR7/8 and TLR9 ligands (Poly I:C, poly U and unmethylated CpG), increased several times in PC, compared to the corresponding tumor adjacent and control tissue, exerting very high sensitivity and specificity of above 90%. Consequently higher levels of hypoxanthine and NF-κB p65 were reported in PC, whereas the opposite results were observed for miRNA biogenesis enzyme (Dicer RNase), miRNA processing protein (TARB2), miRNA-induced silencing complex protein (Argonaute-AGO) and PIWI-interacting RNAs silence transposon. Considering the crucial role of
nucleotides as
carriers, subunits of nucleic acids and nucleotide cofactors, future explorations will be aimed to design novel anti-cancer immune strategies based on a specific acid endolysosomal nuclease inhibition.
Purpose: The aim of the study was to evaluate the intensity of oxidative stress in the brain of animals chronically exposed to mobile phones and potential protective effects of melatonin in reducing ...oxidative stress and brain injury. Materials and methods: Experiments were performed on Wistar rats exposed to microwave radiation during 20, 40 and 60 days. Four groups were formed: I group (control)- animals treated by saline, intraperitoneally (i.p.) applied daily during follow up, II group (Mel)- rats treated daily with melatonin (2 mg kg-1 body weight i.p.), III group (MWs)- microwave exposed rats, IV group (MWs＋Mel)- MWs exposed rats treated with melatonin (2 mg kg-1 body weight i.p.). The microwave radiation was produced by a mobile test phone (SAR＝0.043-0.135 W/kg). Results: A significant increase in the brain tissue malondialdehyde (MDA) and carbonyl group concentration was registered during exposure. Decreased activity of catalase (CAT) and increased activity of xanthine oxidase (XO) remained after 40 and 60 days of exposure to mobile phones. Melatonin treatment significantly prevented the increase in the MDA content and XO activity in the brain tissue after 40 days of exposure while it was unable to prevent the decrease of CAT activity and increase of carbonyl group contents. Conclusion: We demonstrated two important findings; that mobile phones caused oxidative damage biochemically by increasing the levels of MDA, carbonyl groups, XO activity and decreasing CAT activity; and that treatment with the melatonin significantly prevented oxidative damage in the brain.
Given the fact that the studies that examined oxidative stress in relation to obesity that included late adolescents are scarce and show inconclusive results we aimed to investigate a wide spectrum ...of nitro-oxidative stress biomarkers i.e., malondialdehyde (MDA), xanthine oxidase (XO), xanthine oxidoreductase (XOD), xanthine dehydrogenase (XDH), advanced oxidation protein products (AOPP) and nitric oxide products (NOx), as well as an antioxidative enzyme, i.e., catalase (CAT) in relation with obesity in the cohort of adolescent girls ages between 16 and 19 years old.
A total of 59 teenage girls were included in this cross-sectional study. Binary logistic regression analysis was performed to examine possible associations between biochemical and nitro-oxidative stress markers and body mass index (BMI).
There were not significant differences between oxidative stress markers between normal weight and overweight/obese girls (i.e., AOPP, XOD, XO, XDH) and CAT, except for MDA (p<0.001) and NOx (p=0.010) concentrations which were significantly higher in overweight/obese adolescent girls. Positive associations were evident between BMI and high sensitivity C-reactive protein (hsCRP) (OR=2.495), BMI and uric acid (OR=1.024) and BMI and MDA (OR=1.062). Multivariable binary regression analysis demonstrated significant independent associations of BMI and hsCRP (OR=2.150) and BMI and MDA (OR=1.105). Even 76.3% of the variation in BMI could be explained with this Model.
Inflammation (as measured with hsCRP) and oxidative stress (as determined with MDA) independently correlated with BMI in teenage girls.
Purpose
The pathophysiological mechanism of the relationship between xanthine oxidase (XO) activity and obesity has not been completely elucidated. Since inflammation and oxidative stress are ...regarded as key determinants of enlarged adipose tissue, we aimed to investigate the association between oxidative stress (as measured with XO activity), inflammation as measured with high-sensitivity C-reactive protein (hsCRP) and obesity as measured with body mass index (BMI). In addition, we wanted to examine whether hsCRP itself plays an independent role in XO activity increase or it is only mediated through obesity.
Methods
A total of 118 overweight/obese volunteers (mean age 54.76 ± 15.13 years) were included in the current cross-sectional study. Anthropometric, biochemical parameters, and blood pressure were obtained.
Results
Significant differences between age, BMI, waist circumference, concentrations of uric acid and hsCRP, as well as xanthine dehydrogenase (XDH) activities were evident among XO tertile groups. Multiple linear regression analysis revealed that BMI (beta = 0.241,
p
= 0.012) and XDH (beta = − 0.489,
p
< 0.001) are the independent predictors of XO activity (
R
2
-adjusted = 0.333), whereas hsCRP lost its independent role in XO activity prediction.
Conclusion
Obesity (as determined with increased BMI) is an independent predictor of high XO activity in overweight/obese population.
Level of Evidence
Level V: cross-sectional descriptive study.
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