Toxic metal exposures from infant diets: Risk prevention strategies for caregivers and health care professionals.

Concerns are growing regarding the presence of toxic elements such as arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) in the ingredients and prepared foods for infants and young children. There are few clear, evidence-based, guidelines on the maximum tolerable limits of toxicants in foods and little understanding of toxicant exposure or adverse health effects attributable to dietary exposure. Caregivers are faced with the burden of making decisions about which foods to select, how often to feed them to their children, and what foods to limit. This article reviews the current literature and existing recommendations on dietary exposure to toxic elements in children under 2 years of age, and their health effects in early childhood-focusing on growth, neurodevelopment, and immune function. The article also outlines best practices for healthcare providers to address the concerns of toxic element exposure through the diet in young children. Several foods consistently appear in the literature as potential sources of toxic element exposure. Contaminated drinking and cooking water, including water used to prepare infant formula, could also be a major exposure source. In the absence of stronger evidence on effects of dietary modification, exclusive breastfeeding until six months of age, followed by a diverse diet are some strategies to reduce dietary toxic element exposure while ensuring an adequate and balanced nutrient intake. Healthcare providers can support families by sharing information and encouraging blood Pb testing, the only element for which such testing is currently recommended.

Metabolome-Wide Association Study of Primary Open Angle Glaucoma.

PURPOSE: To determine if primary open-angle glaucoma (POAG) patients can be differentiated from controls based on metabolic characteristics. METHODS: We used ultra-high resolution mass spectrometry with C18 liquid chromatography for metabolomic analysis on frozen plasma samples from 72 POAG patients and 72 controls. Metabolome-wide Spearman correlation was performed to select differentially expressed metabolites (DEM) correlated with POAG. We corrected P values for multiple testing using Benjamini and Hochberg false discovery rate (FDR). Hierarchical cluster analysis (HCA) was used to depict the relationship between participants and DEM. Differentially expressed metabolites were matched to the METLIN metabolomics database; both DEM and metabolites significantly correlating with DEM were analyzed using MetaboAnalyst to identify metabolic pathways altered in POAG. RESULTS: Of the 2440 m/z (mass/charge) features recovered after filtering, 41 differed between POAG cases and controls at FDR = 0.05. Hierarchical cluster analysis revealed these DEM to associate into eight clusters; three of these clusters contained the majority of the DEM and included palmitoylcarnitine, hydroxyergocalciferol, and high-resolution METLIN matches to sphingolipids, other vitamin D-related metabolites, and terpenes. MetaboAnalyst also indicated likely alteration in steroid biosynthesis pathways. CONCLUSIONS: Global ultrahigh resolution metabolomics emphasized the importance of altered lipid metabolism in POAG. The results suggest specific metabolic processes, such as those involving palmitoylcarnitine, sphingolipids, vitamin D-related compounds, and steroid precursors, may contribute to POAG status and merit more detailed study with targeted methods.

Mitochondrial haplogroups are associated with severity of diabetic retinopathy.

PURPOSE: To determine if specific mitochondrial haplogroups associate with nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). METHODS: Deidentified medical records for Caucasian patients with diabetic retinopathy (DR; 153 NPDR and 138 PDR) were obtained from BioVU, Vanderbilt University's electronic, deidentified DNA databank. An independent cohort of Caucasian patients with DR (44 NPDR and 57 PDR) from the Vanderbilt Eye Institute (VEI) was used for validation. We tested for an association between mitochondrial haplogroups and PDR among patients with DR. RESULTS: In the BioVU cohort, PDR frequency among Caucasian DR patients differed significantly by mitochondrial haplogroup (P = 0.027). Replication in the VEI cohort confirmed this association (P = 0.0064). In the combined cohort, patients from the common haplogroup H were more likely to have PDR (odds ratio [OR] = 2.0 [95% confidence interval (CI) = 1.3-3.0], P = 0.0012), while patients from haplogroup Uk were less likely to have PDR (OR = 0.5 [95% CI = 0.3-0.8], P = 0.0049). In logistic regression analyses, the addition of diabetes duration, hemoglobin A1c (HgbA1c) levels, and hypertension had no effect on the associations of haplogroups H and Uk with PDR. CONCLUSIONS: In this study, DR patients from mitochondrial haplogroup H were more likely to have PDR, while DR patients from haplogroup Uk were less likely to have PDR. The association was independent of the major clinical variables affecting PDR. The mitochondrial haplogroups were as strong a risk factor for PDR as were elevated HgbA1c levels.

Survivin and escaping in therapy-induced cellular senescence.

Therapy-induced accelerated cellular senescence (ACS) is a reversible tumor response to chemotherapy that is likely detrimental to the overall therapeutic efficacy of cancer treatment. To further understand the mechanism by which cancer cells can escape the sustained cell cycle arrest in ACS, we established a tissue culture model, in which the p53-null NCI-H1299 cells can be induced into senescence by an abbreviated exposure to a chemotherapeutic agent. Previously, we have reported that senescent cells overexpress Cdc2/Cdk1 when they bypassed the prolonged arrest and their viability is dependent on Cdc2/Cdk1 kinase activity. In our study, we show that human survivin is the immediate downstream effector of the Cdc2/Cdk1 mediated survival signal. Survivin cooperates with Cdc2/Cdk1 to inhibit apoptosis following chemotherapy and promote senescence escape. Using HIV-1 TAT peptides to disrupt survivin phosphorylation by Cdc2/Cdk1, we also found that phosphorylated survivin is necessary both for the escape of senescent cells and for maintenance of subsequent viability after bypassing senescence. These results further propose survivin as an important determinant of senescence reversibility and as a putative molecular target to enforce cell death in ACS.

Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers.

Accelerated cellular senescence (ACS) has been described for tumor cells treated with chemotherapy and radiation. Following exposure to genotoxins, tumor cells undergo terminal growth arrest and adopt morphologic and marker features suggestive of cellular senescence. ACS is elicited by a variety of chemotherapeutic agents in the p53-null, p16-deficient human non-small cell H1299 carcinoma cells. After 10 to 21 days, infrequent ACS cells (1 in 10(6)) can bypass replicative arrest and reenter cell cycle. These cells express senescence markers and resemble the parental cells in their transcription profile. We show that these escaped H1299 cells overexpress the cyclin-dependent kinase Cdc2/Cdk1. The escape from ACS can be disrupted by Cdc2/Cdk1 kinase inhibitors or by knockdown of Cdc2/Cdk1 with small interfering RNA and can be promoted by expression of exogenous Cdc2/Cdk1. We also present evidence that ACS occurs in vivo in human lung cancer following induction chemotherapy. Viable tumors following chemotherapy also overexpress Cdc2/Cdk1. We propose that ACS is a mechanism of in vivo tumor response and that mechanisms aberrantly up-regulate Cdc2/Cdk1 promotes escape from the senescence pathway may be involved in a subset of tumors and likely accounts for tumor recurrence/progression.

Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions.

The cellular stress response protein GADD34 mediates growth arrest and apoptosis in response to DNA damage, negative growth signals, and protein malfolding. GADD34 binds to protein phosphatase PP1 and can attenuate the translational elongation of key transcriptional factors through dephosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha). Recently, we reported the involvement of human SNF5/INI1 (hSNF5/INI1) protein in the functions of GADD34 and showed that hSNF5/INI1 binds GADD34 and stimulates the bound PP1 phosphatase activity. To better understand the regulatory and functional mechanisms of GADD34, we undertook a yeast two-hybrid screen with full-length GADD34 as bait in order to identify additional protein partners of GADD34. We report here that human cochaperone protein BAG-1 interacts with GADD34 in vitro and in SW480 cells treated with the proteasome inhibitor z-LLL-B to induce apoptosis. Two other proteins, Hsp70/Hsc70 and PP1, associate reversibly with the GADD34-BAG-1 complex, and their dissociation is promoted by ATP. BAG-1 negatively modulates GADD34-bound PP1 activity, and the expression of BAG-1 isoforms can also mask GADD34-mediated inhibition of colony formation and suppression of transcription. Our findings suggest that BAG-1 may function to suppress the GADD34-mediated cellular stress response and support a role for BAG-1 in the survival of cells undergoing stress.

The human SNF5/INI1 protein facilitates the function of the growth arrest and DNA damage-inducible protein (GADD34) and modulates GADD34-bound protein phosphatase-1 activity.

The growth arrest and DNA damage-inducible protein (GADD34) mediates growth arrest and apoptosis in response to DNA damage, negative growth signals, and protein malfolding. GADD34 binds to protein phosphatase-1 (PP1) and can attenuate translational elongation of key transcriptional factors through dephosphorylation of eukaryotic initiation factor-2alpha. We reported previously that the human trithorax leukemia fusion protein (HRX) can bind to GADD34 and abrogate GADD34-mediated apoptosis in response to UV irradiation. We found that hSNF5/INI1, a component of the hSWI/SNF chromatin remodeling complex, also binds to GADD34 and can coexist with GADD34 and HRX fusion proteins as a trimolecular complexes in vivo. In the present report, we demonstrate that hSNF5/INI1 binds to GADD34 in part through the PP1 docking site within a domain homologous to herpes simplex virus-1 ICP34.5. We found that hSNF5/INI1 can bind PP1 independently and weakly stimulate its phosphatase activity in solution and in complex with GADD34. hSNF5/INI1 and PP1 do not compete for binding to GADD34 but rather form a stable heterotrimeric complex with GADD34. We also show that Epstein-Barr nuclear protein 2, which binds hSNF5/INI1, can disrupt hSNF5/INI1 binding to GADD34 and partially reverse the GADD34-mediated growth suppression function in Ha-ras expressing HIH-3T3 (3T3-ras) cells. These results implicate hSNF5/INI1 in the function of GADD34 and suggest that hSNF5/INI1 may regulate PP1 activity in vivo.