Boric Acid Activation of eIF2α and Nrf2 Is PERK Dependent: a Mechanism that Explains How Boron Prevents DNA Damage and Enhances Antioxidant Status.

Boron is abundant in vegetables, nuts, legumes, and fruit and intake is associated with reduced risk of cancer and DNA damage and increased antioxidant status. Blood boric acid (BA) levels are approximately 10 μM BA in men at the mean US boron intake. Treatment of DU-145 human prostate cancer cells with 10 μM BA stimulates phosphorylation of elongation initiation factor 2α (eIF2α) at Ser51 leading to activation of the eIF2α/ATF4 pathway which activates the DNA damage-inducible protein GADD34.

Activation of the EIF2α/ATF4 and ATF6 Pathways in DU-145 Cells by Boric Acid at the Concentration Reported in Men at the US Mean Boron Intake.

Fruits, nuts, legumes, and vegetables are rich sources of boron (B), an essential plant nutrient with chemopreventive properties. Blood boric acid (BA) levels reflect recent B intake, and men at the US mean intake have a reported non-fasting level of 10 μM. Treatment of DU-145 prostate cancer cells with physiological concentrations of BA inhibits cell proliferation without causing apoptosis and activates eukaryotic initiation factor 2 (eIF2α).

Associations of immunity-related single nucleotide polymorphisms with overall survival among prostate cancer patients.

The progression of prostate cancer is influenced by systemic inflammation, and may be attributed, in part, to genetic predisposition. Single nucleotide polymorphisms associated with the immune response may help mediate prostate cancer progression. We analyzed data from a hospital-based case-control study of 164 prostate cancer patients and 157 healthy male controls from the Memorial Sloan Kettering Cancer Center.

Boric acid induces cytoplasmic stress granule formation, eIF2α phosphorylation, and ATF4 in prostate DU-145 cells.

Dietary boron intake is associated with reduced prostate and lung cancer risk and increased bone mass. Boron is absorbed and circulated as boric acid (BA) and at physiological concentrations is a reversible competitive inhibitor of cyclic ADP ribose, the endogenous agonist of the ryanodine receptor calcium (Ca(+2)) channel, and lowers endoplasmic reticulum (ER) [Ca(2+)]. Low ER [Ca(2+)] has been reported to induce ER stress and activate the eIF2α/ATF4 pathway.

Identification of ryanodine receptor isoforms in prostate DU-145, LNCaP, and PWR-1E cells.

The ryanodine receptor (RyR) is a large, intracellular calcium (Ca(2+)) channel that is associated with several accessory proteins and is an important component of a cell's ability to respond to changes in the environment. Three isoforms of the RyR exist and are well documented for skeletal and cardiac muscle and the brain, but the isoforms in non-excitable cells are poorly understood. The aggressiveness of breast cancers in women has been positively correlated with the expression of the RyR in breast tumor tissue, but it is unknown if this is limited to specific isoforms.

Receptor activated Ca(2+) release is inhibited by boric acid in prostate cancer cells.

Background: The global disparity in cancer incidence remains a major public health problem. We focused on prostate cancer since microscopic disease in men is common, but the incidence of clinical disease varies more than 100 fold worldwide. Ca(2+) signaling is a central regulator of cell proliferation, but has received little attention in cancer prevention.

Boric acid inhibits stored Ca2+ release in DU-145 prostate cancer cells.

Boron (B) is a developmental and reproductive toxin. It is also essential for some organisms. Plants use uptake and efflux transport proteins to maintain homeostasis, and in humans, boron has been reported to reduce prostate cancer.

Evaluation of ecological and in vitro effects of boron on prostate cancer risk (United States).

Objective: To determine: (1) the correlation of prostate cancer incidence and mortality with groundwater boron and selenium concentrations; and (2) the impact of boron on prostate cancer cell proliferation during co-treatment with alternative chemo-preventative agents, along with boron pre-treatment effects on cell sensitivity to ionizing radiation.

Methods: For regression analysis, data on prostate cancer incidence and mortality were obtained from the Texas Cancer Registry, while groundwater boron and selenium concentrations were derived from the Texas Water Development Board. Cultured DU-145 prostate cancer cells were used to assess the impact of boric acid on cell proliferation when applied in combination with selenomethionine and genistein, or preceding radiation exposure.

Boric acid inhibits adenosine diphosphate-ribosyl cyclase non-competitively.

Adenosine diphosphate-ribosyl cyclase (ADP-ribosyl cyclase) is a ubiquitous enzyme in eukaryotes that converts NAD+ to cyclic-ADP-ribose (cADPR) and nicotinamide. A quantitative assay for cADPR was developed using capillary electrophoresis to separate NAD+, cADPR, ADP-ribose, and ADP with UV detection (254 nm). Using this assay, the apparent Km and Vmax for Aplysia ADP-ribosyl cyclase were determined to be 1.

Cellular changes in boric acid-treated DU-145 prostate cancer cells.

Epidemiological, animal, and cell culture studies have identified boron as a chemopreventative agent in prostate cancer. The present objective was to identify boron-induced changes in the DU-145 human prostate cancer cell line. We show that prolonged exposure to pharmacologically-relevant levels of boric acid, the naturally occurring form of boron circulating in human plasma, induces the following morphological changes in cells: increases in granularity and intracellular vesicle content, enhanced cell spreading and decreased cell volume.

Boric acid inhibits human prostate cancer cell proliferation.

The role of boron in biology includes coordinated regulation of gene expression in mixed bacterial populations and the growth and proliferation of higher plants and lower animals. Here we report that boric acid, the dominant form of boron in plasma, inhibits the proliferation of prostate cancer cell lines, DU-145 and LNCaP, in a dose-dependent manner. Non-tumorigenic prostate cell lines, PWR-1E and RWPE-1, and the cancer line PC-3 were also inhibited, but required concentrations higher than observed human blood levels.

Borate-nucleotide complex formation depends on charge and phosphorylation state.

Flow injection analysis with electrospray ionization mass spectrometry was used to investigate borate-nucleotide complex formation. Solutions containing 100 microM nucleotide and 500 microM boric acid in water-acetonitrile-triethylamine (50:50:0.2, v/v/v; pH 10.

Dietary boron intake and prostate cancer risk.

Boron affects human steroid hormone levels. Circulating testosterone and estradiol levels have been proposed to modify prostate cancer risk. However, the association between dietary boron intake and the risk of prostate cancer has not been evaluated by any epidemiological study.

Esterification of borate with NAD+ and NADH as studied by electrospray ionization mass spectrometry and 11B NMR spectroscopy.

This paper describes for the first time the direct measurement of boric acid (B(OH)(3)) and borate (B(OH)(4) (-)) adduction to NAD(+) and NADH by electrospray ionization mass spectrometry (ESI-MS) and (11)B NMR spectroscopy. The analysis demonstrates that borate binds to both cis-2,3-ribose diols on NAD(+) forming borate monoesters (1 : 1 addition), borate diesters (1 : 2 addition) and diborate esters (2 : 1 addition), whereas, only borate monoesters were formed with NADH. MS in the negative ion mode showed borate was bound to a cis-2,3-ribose diol and not to the hydroxyl groups on the phosphate backbone of NAD(+), and MS/MS showed that the 1 : 1 addition monoester contained borate bound to the adenosine ribose.

Boron stimulates yeast (Saccharomyces cerevisiae) growth.

Boron is required for the growth of vascular plants and embryonic development in fish. The molecular basis of boron's essentiality, however, remains unknown for both. The objective of this study was to determine whether yeast (Saccharomyces cerevisiae) could be used as a model for the evaluation of intracellular boron trafficking.

Boron is required for zebrafish embryogenesis.

Boron is the only element known to be essential for plants, but only circumstantial evidence for essentiality exists in animals. We report here that boron is essential for the embryonic development of zebrafish (Danio rerio). Zebrafish were maintained in water with a boron concentration of 0.

The response of trout and zebrafish embryos to low and high boron concentrations is U-shaped.

Fish in the embryo-larval stage of development have been shown to be sensitive to boron (B) at both ends of the dose-response curve (1,2). The present study evaluated the health effects of low and high B concentrations on rainbow trout (Oncorhynchus mykiss), a cold water species, and zebrafish (Danio rerio), a warm water species. Rainbow trout embryos were incubated from day 1 until 2 wk posthatch in Type 1 ASTM ultrapure-grade water (12.

Boron stimulates embryonic trout growth.

Boron is present in our soil, water and air. Cyanobacteria require it for nitrogen fixation, and vascular plants require it for the formation of cell walls and membranes. I report here how boron affects the growth of embryonic rainbow trout (Oncorhynchus mykiss).

Parenteral nutrition is associated with intestinal morphologic and functional changes in humans.

Background: Numerous animal studies have demonstrated intestinal villus atrophy occurs when luminal nutrition is withheld and total parenteral nutrition (TPN) is provided. Intestinal morphologic and functional changes have not been well studied in humans during TPN.

Methods: Eight normal volunteers were hospitalized in the Clinical Research Center for 3 weeks.

Photoreceptor damage following exposure to excess riboflavin.

Flavins generate oxidants during metabolism and when exposed to light. Here we report that the photoreceptor layer of retinas from black-eyed rats is reduced in size by a dietary regime containing excess riboflavin. The effect of excess riboflavin was dose-dependent and was manifested by a decrease in photoreceptor length.

A comparison of the effects of dietary selenium on selenoprotein expression in rat brain and liver.

In studies with rodents, when dietary supplies of the essential nutrient Se are restricted, in most tissues there are parallel substantial losses of the element and the important antioxidant selenoenzyme glutathione peroxidase (GPx) for which it is a cofactor. In brain, however, there appears to be both a sequestration of Se and a conservation of GPx activity when dietary Se is limited. To further explore the relation between these phenomena, we have undertaken a comparison of the effects of diets low, normal and high in Se on GPx activity, and labeling of selenoproteins following short-term (72 h) in vivo exposure to 75Se, in subcellular fractions from rat brain and liver, the latter serving as a representative tissue which does not retain Se and is depleted of most GPx activity following dietary restriction.

Influence of selenium on the microvasculature of the retina.

The impact of small differences in selenium exposure during the first year of life was investigated in male Wistar rats. Forty-five rats were evaluated in two experiments. Rats were provided diets that contained sucrose as the sole carbohydrate to induce an elevation in blood triglycerides, cholesterol, glucose, and insulin.

Microvascular changes in rat glomeruli as a consequence of small differences in selenium exposure.

This paper evaluates the effect of small differences in selenium exposure, within the safe range, on the glomerular vascular tufts of rats fed high-sucrose diets. In the first experiment male Wistar rats were housed in galvanized cages and were provided sucrose-based diets to induce a mild chronic insult to the microcirculation. One group of rats received the diet prepared to contain 0.