Complement factor H Y402H polymorphism,plasma concentration and risk of coronary artery disease

Background Inflammation plays an important role in coronary artery disease (CAD). Complement Factor H (CFH) gene has been analyzed in relation to CAD in several studies with conflicting results. The aim of the present study was to investigate the association between the CFH Y402H polymorphism and CAD in Chinese. Methods and results About 336 patients were enrolled, included 166 patients with CAD and 170 controls. The SNP at CFH Y402H was genotyped by ligase detection reaction and plasma levels of CFH were assayed by enzyme-linked immunosorbent assay. Analysis of genotype frequencies did not reveal any significant difference between CAD patients and controls. There were significant differences in the frequencies of C allele and C allele carriers between early-onset CAD and controls. After adjustment of clinical parameters, significant association was identified for CFH Y402H polymorphism, with C allele carriers having a higher risk of early-onset CAD than carriers of TT genotype (odds ratio [OR] 4.66, 95% CI: 1.23–17.62, P = 0.02). There was no difference of plasma CFH levels between CAD group and controls. Conclusions CFH Y402H polymorphism is associated with early-onset CAD in Chinese. Qi Qian and Zhong Chen have contributed equally to this paper.     

Age and metastasis – How age influences metastatic spread in cancer. Colorectal cancer as a model

Metastasis is the major cause of death in cancer patients. Whereas colorectal cancer (CRC) incidence increases with age, metastatic spread seems to decline. Furthermore, the epidemiology of CRC is changing. There is an increase in CRC incidence in the young, presenting at an advanced stage with higher likelihood of synchronous or metachronous metastases, and a decline in CRC incidence and metastatic spread in the oldest-old. Emerging data suggest that age-related changes with regard to tumor biology (e.g. genomic instability), the tumor microenvironment (e.g. inflammaging) and the immune system (e.g. immunosenescence), complemented by interaction between the genome and exposome might contribute to the observed metastatic patterns. As aging is a key prognostic factor, this highlights the need for further studies investigating age-related patterns and underlying mechanisms of tumor growth and dissemination. Eventually, this might allow for better risk stratification, refinement of screening strategies and follow-up care as well as therapies tailored to reflect patient age and that might possibly target responsible biomarkers in a precision medicine approach. This review aims to discuss the influence of aging on metastatic spread in colorectal cancer and elucidate underlying mechanisms responsible for the observed metastatic patterns.     

Regulation of proliferation and apoptosis during development of the preimplantation embryo and the placenta

The preimplantation embryo starts as a single cell, the zygote. The first cell divisions do not lead to volume expansion, but rather to an increasing number of small cells. At the morula stage the first two cell lineages differentiate into the trophoblast and the inner cells mass/embryoblast. During development of the preimplantation embryo, apoptosis occurs only after the onset of the embryonic genome. It has become clear that the development of a healthy child requires not only very high rates of proliferation and differentiation, but also apoptosis, which is a crucial mechanism for morphogenesis and the development of the inner organs. Furthermore, the generation of specific cell types, such as lens cells, erythrocytes, and thrombocytes, depends on the apoptosis pathways. This is also true later in gestation, when the trophoblasts form the placenta and provide the epithelial cover of the villous trees of the placenta. This layer is in direct contact with maternal blood and, as do all epithelia, displays a continuous turnover of cells. Thus, apoptosis is a normal constituent of survival in this layer as well, and changes in the regulation and rate of apoptosis have deleterious effects on the trophoblast and consequently the developing embryo or fetus. Here we present a very brief overview of the importance of apoptosis for the development of the preimplantation embryo and the maintenance of placental trophoblasts. Furthermore, we highlight what happens when regulation of proliferation or apoptosis fails in these systems, and attempt to show that apoptosis is only the consequence of poor embryo or trophoblast development -- not its cause.     

Blood cell lead, calcium, and magnesium levels associated with pregnancy-induced hypertension and preeclampsia

This study compares the red blood cell (Rbc) levels of lead (Pb), calcium (Ca), and magnesium (Mg) in relation to blood pressure in 39 pregnant women in the third trimester of pregnancy. The study population included 20 women with normal pregnancies, 15 with mild hypertension, and 4 with severe hypertension and preeclampsia. The mean±SD for each group was calculated and the difference between the means of the normotensive and the other groups were compared by analysis of variance. Significant differences from normal to the preeclamptic pregnancies were in (1) elevated Rbc Pb (p≤0.001), (2) lower Rbc Ca (p≤0.001), and (3) lower Rbc Mg/Pb ratio (p≤0.0001). Pearson’s rank correlation between blood pressure showed a direct relation to the Rbc Pb level (p≤0.01) and an inverse relation to the Rbc Ca and Mg/Pb ratio (p≤0.004,≤0.007). Apparently, prenatal blood pressure is directly proportional to Rbc Pb content and related or modified by Rbc Ca and Mg.     

The effect of VDR gene polymorphisms and vitamin D level on blood pressure,risk of preeclampsia,gestational age,and body mass index

We investigated the influence of vitamin D receptor (VDR) polymorphisms and vitamin D level on the blood pressure and the risk of preeclampsia. In a case-control study, 200 pregnant women, including 100 individuals with preeclampsia along with 100 healthy pregnant women, were studied for VDR FokI, TaqI, and BmsI polymorphisms and serum 25 (OH)-D level using polymerase chain reaction-restriction fragment length polymorphism method and commercial kit, respectively. The mean level of 25 (OH)-D in preeclamptic patients was significantly lower (16.6 ± 4.2 ng/mL, P < 0.001) compared with controls (19.6 ± 3.8 ng/mL). Among all women, a significantly higher systolic blood pressure and before-pregnancy body mass index and also lower gestational age were observed in the presence of 25 (OH)-D level < 20 ng/mL compared with the 20 to 30 ng/mL. A significantly higher frequency of VDR FokI C allele in preeclamptic patients (83%) than controls (74%) was associated with a 1.72-fold increased risk of preeclampsia. In all the studied individuals, the systolic and diastolic blood pressures were significantly higher in the presence of the FokI CC genotype compared with the TC and TT+TC genotypes. Neither VDR Taq1 nor VDR BmsI was associated with the risk of preeclampsia. The haplotype FokI C, TaqI C and BmsI A (CCA) compared with haplotype CTG increased the risk of preeclampsia by 1.4-fold (P = 0.33). Our study suggests an association between VDR FokI polymorphism and an insufficient serum level of 25 (OH)-D with the risk of preeclampsia and also the influence of insufficient 25 (OH)-D level and VDR FokI polymorphism on maternal factors, including blood pressure.     

Reactions of Peroxynitrite with Uric Acid: Formation of Reactive Intermediates,Alkylated Products and Triuret,and In Vivo Production of Triuret Under Conditions of Oxidative Stress

Hyperuricemia is associated with hypertension, metabolic syndrome, preeclampsia, cardio-vascular disease and renal disease, all conditions associated with oxidative stress. We hypothesized that uric acid, a known antioxidant, might become prooxidative following its reaction with oxidants; and, thereby contribute to the pathogenesis of these diseases. Uric acid and 1,3-¹⁵N₂-uric acid were reacted with peroxynitrite in different buffers and in the presence of alcohols, antioxidants and in human plasma. The reaction products were identified using liquid chromatography-mass spectrometry (LC-MS) analyses. The reactions generate reactive intermediates that yielded triuret as their final product. We also found that the antioxidant, ascorbate, could partially prevent this reaction. Whereas triuret was preferentially generated by the reactions in aqueous buffers, when uric acid or 1,3-¹⁵N₂-uric acid was reacted with peroxynitrite in the presence of alcohols, it yielded alkylated alcohols as the final product. By extension, this reaction can alkylate other biomolecules containing OH groups and others containing labile hydrogens. Triuret was also found to be elevated in the urine of subjects with preeclampsia, a pregnancy-specific hypertensive syndrome that is associated with oxidative stress, whereas very little triuret is produced in normal healthy volunteers. We conclude that under conditions of oxidative stress, uric acid can form reactive intermediates, including potential alkylating species, by reacting with peroxynitrite. These reactive intermediates could possibly explain how uric acid contributes to the pathogenesis of diseases such as the metabolic syndrome and hypertension.     

Oxidation of placental insulin and insulin-like growth factor receptors in mothers with diabetes mellitus or preeclampsia complicated with intrauterine growth restriction

Abstract

Placental insulin receptor (IR) and insulin-like growth factor receptors (IGFRs) are essential for fetal growth. We investigated structural changes of these receptors exposed to increased oxidative stress in mothers diagnosed with diabetes mellitus (DM) or preeclampsia (PE) complicated with intrauterine growth restriction. Increased amount of IR and decreased amounts of IGF1R and IGF2R were found in both pathologies, accompanied by significant elevation in protein carbonyls. When isolated receptors were examined, increased carbonylation of IR and IGF1R in PE placentas was detected, whereas the amounts of carbonylated IR and IGF1R were similar in DM and healthy placentas. Carbonylation status of IGF2R did not change due to pathology, confirming the detrimental role of primary structure and conformation in oxidative susceptibility. Ligand binding was similar in all three groups of samples and did not seem to be affected by receptor oxidation. Since babies delivered by mothers with PE were smaller than the referent population, increased carbonylation of receptors might have affected downstream receptor signaling post-ligand binding.