Abstract Background and aims Several epidemiological studies highlighted the association between folate and B-vitamins low intake and cardiovascular diseases (CVD) risk. Contrasting results were ...reported on the relationship between folate intake and DNA-methylation. Folate and B-vitamins may modulate DNA-methylation of specific enzymes which are included in the One-Carbon Metabolism (OCM) and in the homocysteine (Hcy) pathways. The aim of the study was to evaluate whether DNA-methylation profiles of OCM and Hcy genes could modulate the myocardial infarction (MI) risk conferred by a low B-vitamins intake. Methods and results Study sample (206 MI cases and 206 matched controls) is a case-control study nested in the prospective EPIC cohort. Methylation levels of 33 candidate genes where extracted by the whole epigenome analysis (Illumina-HumanMethylation450K-BeadChip). We identified three differentially methylated regions in males (TCN2 promoter, CBS 5′UTR, AMT gene-body) and two in females (PON1 gene-body, CBS 5′UTR), each of them characterized by an increased methylation in cases. Functional in silico analysis suggested a decreased expression in cases. A Recursively Partitioned Mixture Model cluster algorithm identified distinct methylation profiles associated to different MI risk: high-risk vs. low-risk methylation profile groups, OR = 3.49, p = 1.87 × 10−4 and OR = 3.94, p = 0.0317 in males and females respectively (multivariate logistic regression adjusted for classical CVD risk factors). Moreover, a general inverse relationship between B-vitamins intake and DNA-methylation of the candidate genes was observed. Conclusions Our findings support the hypothesis that DNA-methylation patterns in specific regions of OCM and Hcy pathways genes may modulate the CVD risk conferred by folate and B-vitamins low intake.
The objective of this study was to characterize the temporal behavior of contaminant mass discharge, and the relationship between reductions in contaminant mass discharge and reductions in ...contaminant mass, for a very heterogeneous, highly contaminated source-zone field site. Trichloroethene is the primary contaminant of concern, and several lines of evidence indicate the presence of organic liquid in the subsurface. The site is undergoing groundwater extraction for source control, and contaminant mass discharge has been monitored since system startup. The results show a significant reduction in contaminant mass discharge with time, decreasing from approximately 1 to 0.15kg/d over five years. Two methods were used to estimate the mass of contaminant present in the source area at the initiation of the remediation project. One was based on a comparison of two sets of core data, collected 3.5years apart, which suggests that a significant (~80%) reduction in aggregate sediment-phase TCE concentrations occurred between sampling events. The second method was based on fitting the temporal contaminant mass discharge data with a simple exponential source-depletion function. Relatively similar estimates, 784 and 993kg, respectively, were obtained with the two methods. These data were used to characterize the relationship between reductions in contaminant mass discharge (CMDR) and reductions in contaminant mass (MR). The observed curvilinear relationship exhibits a reduction in contaminant mass discharge essentially immediately upon the initiation of mass reduction. This behavior is consistent with a system wherein significant quantities of mass are present in hydraulically poorly accessible domains for which mass removal is influenced by rate-limited mass transfer. The results obtained from the present study are compared to those obtained from other field studies to evaluate the impact of system properties and conditions on mass-discharge and mass-removal behavior. The results indicate that factors such as domain scale, hydraulic-gradient status (induced or natural), and flushing-solution composition had insignificant impact on the CMDR–MR profiles and thus on underlying mass-removal behavior. Conversely, source-zone age, through its impact on contaminant distribution and accessibility, was implicated as a critical factor influencing the nature of the CMDR–MR relationship.
•Temporal contaminant mass discharge (CMD) was measured for a DNAPL source zone.•The relationship between reductions in CMD and reductions in mass was characterized.•The results were compared to data processed for other field sites.•Source-zone age was indicated as a significant mediator of observed behavior.
Cyclic nitroxides (RNO•) mimic the activity of superoxide dismutase (SOD) and demonstrate antioxidant properties in numerous in vitro and in vivo models. Their broad antioxidant activity may involve ...the participation of their reduced and oxidized forms, that is, hydroxylamine (RNO-H) and oxoammonium cation (RNO+). To examine this possibility we studied the reactions of RNO• and RNO+ with HO2 •/O2 •- and with several reductants by pulse radiolysis and rapid-mixing stopped-flow techniques. The oxoammonium cations were generated by electrochemical and radiolytic oxidation of 2,2,6,6-tetramethylpiperidinoxyl (TPO) and 3-carbamoyl-2,2,5,5-tetramethylpyrrolidinoxyl (3-CP). The rate constant for the reaction of RNO• with HO2 • to form RNO+ was determined to be (1.2 ± 0.1) × 108 for TPO and (1.3 ± 0.1) × 106 M-1 s-1 for 3-CP. The kinetics results demonstrate that the reaction of RNO• with HO2 • proceeds via an inner-sphere electron-transfer mechanism. The rate constant for the reaction of RNO• with O2 •- is lower than 1 × 103 M-1 s-1. The rate constant for the reaction of RNO+ with O2 •- was determined to be (3.4 ± 0.2) × 109 for TPO+ and (5.0 ± 0.2) × 109 M-1 s-1 for 3-CP+. Hence, both nitroxides catalyze the dismutation of superoxide through the RNO•/RNO+ redox couple, and the dependence of the catalytic rate constant, k cat, on pH displayed a bell-shaped curve having a maximum around pH 4. The oxoammonium cation oxidized ferrocyanide and HO2 - by a one-electron transfer, whereas the oxidation of methanol, formate, and NADH proceeded through a two-electron-transfer reaction. The redox potential of RNO•/RNO+ couple was calculated to be 0.75 and 0.89 V for 3-CP and TPO, respectively. The elucidated mechanism provides a clearer insight into the biological antioxidant properties of cyclic nitroxides that should permit design of even more effective antioxidants.
Pancreatic cancer (PC) is a common cause of cancer-related death, due to difficulties in detecting early-stage disease, to its aggressive behaviour, and to poor response to systemic therapy. ...Therefore, developing strategies for early diagnosis of resectable PC is critical for improving survival. Diabetes mellitus is another major public health problem worldwide. Furthermore, diabetes can represent both a risk factor and a consequence of PC: nowadays, the relationship between these two diseases is considered a high priority for research. New-onset diabetes can be an early manifestation of PC, especially in a thin adult without a family history of diabetes. However, even if targeted screening for patients at higher risk of PC could be a promising approach, this is not recommended in asymptomatic adults with new-onset diabetes, due to the much higher incidence of hyperglycaemia than PC and to the lack of a safe and affordable PC screening test. Prompted by a well-established and productive multidisciplinary cooperation, the Italian Association of Medical Oncology (AIOM), the Italian Medical Diabetologists Association (AMD), the Italian Society of Endocrinology (SIE), and the Italian Society of Pharmacology (SIF) here review available evidence on the mechanisms linking diabetes and PC, addressing the feasibility of screening for early PC in patients with diabetes, and sharing a set of update statements with the aim of providing a state-of-the-art overview and a decision aid tool for daily clinical practice.
•The incidence of PC is increasing and its prognosis is very poor; therefore, early detection is fundamental.•New-onset diabetes may be an early manifestation of PC, often disappearing after its resection.•Screening for PC is not currently recommended among people with new-onset diabetes, due to its high incidence.•Thin subjects >50 years old at the time of diabetes onset, with sudden weight loss and severe hyperglycaemia are at higher risk.•Currently some clinical models are promising for stratifying cancer risk in people with new-onset diabetes.
The primary objective of this study was to investigate whether the presence of comorbidities was associated with a lower health-related quality of life (HRQOL) in elderly patients with chronic ...myeloid leukemia (CML). A sample of 174 CML patients aged 60 years or above was analyzed. HRQOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). A number of pre-selected sociodemographic and disease-related factors were considered as potential confounding factors for the association between comorbidity and HRQOL. Mean age of the 174 patients analyzed was 70 years (range 60–87 years) and 55 % were male. Overall, 111 patients (64 %) reported at least one comorbidity. Analysis stratified by age group category showed a greater proportion of patients with comorbidities in the older sub-group population (≥70 years) compared to younger patients (60 to 69 years). Differences in HRQOL outcomes between patients with no comorbidity at all and those with two or more comorbid conditions were at least twice the magnitude of a clinically meaningful difference in all the physical and mental health scales of the SF-36. In multivariate analysis, after adjusting for key confounding factors, the following scales were significantly lower in those with comorbidity: general health (
p
< 0.001), bodily pain (
p
< 0.001), physical functioning (
p
= 0.002), and vitality (
p
= 0.002). Assessing comorbidity in elderly patients with CML is important to facilitate identification of those most in need of HRQOL improvements.
Propolis, a natural product derived from plant resins collected by honeybees, has been used for thousands of years in traditional medicine all over the world. The composition of the propolis depends ...upon the vegetation of the area from where it was collected and on the bee species.
In this study, we investigated the antioxidant activity of a propolis sample, provided by NATURANDES-CHILE, collected in a temperate region of central Chile. In addition, this natural compound was tested for its antiproliferative capacity on KB (human mouth epidermoid carcinoma cells), Caco-2 (colon adenocarcinoma cells) and DU-145 (androgen-insensitive prostate cancer cells) human tumor cell lines. Results showed that this Chilean propolis sample exhibits interesting biological properties, correlated with its chemical composition and expressed by its capacity to scavenge free radicals and to inhibit tumor cell growth.
We studied the role of the matrix metalloproteinase gelatinase B (gelB; MMP-9) in epithelial regeneration using the gelB-deficient mouse. We report the novel finding that, in contrast to other MMPs ...expressed at the front of the advancing epithelial sheet in wounds of cornea, skin, or trachea, gelB acts to inhibit the rate of wound closure. We determined this to be due to control of cell replication, a novel capacity for MMPs not previously described. We also found that gelB delays the inflammatory response. Acceleration of these processes in gelB-deficient mice is correlated with a delay in signal transduction through Smad2, a transcription factor that inhibits cell proliferation, and in accumulation of epithelial-associated interleukin-1α, a cytokine that inhibits Smad2 signaling and promotes the inflammatory response. GelB-deficient mice also reveal defects in remodeling of extracellular matrix at the epithelial basement membrane zone, in particular, failure to effectively remove the fibrin(ogen) provisional matrix. We conclude that gelB coordinates and effects multiple events involved in the process of epithelial regeneration.
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