Extracellular calcium stimulates DNA synthesis in synergism with zinc, insulin and insulin‐like growth factor I in fibroblasts

Huang, Jinsheng; Mukherjee, Jagat J.; Chung, Taeowan; Crilly, Karan S.; Kiss, Zoltán

doi:10.1046/j.1432-1327.1999.00932.x

Cited by 42 publications

(23 citation statements)

References 41 publications

(50 reference statements)

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“…Elevated extracellular zinc concentrations stimulated protein tyrosine phosphorylation and MAPK (mitogen-activated protein kinases) activity in cells [429]. A synergistic effect of zinc and calcium on MAP kinases, DNA synthesis and mitogenic signalling was detected in NIH3T3 cells [430].…”

Section: Mercury and Stress Proteinsmentioning

confidence: 93%

Metals, Toxicity and Oxidative Stress

Valko

Morris²,

Cronin

2005

CMC

4,226

2,664

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Metal-induced toxicity and carcinogenicity, with an emphasis on the generation and role of reactive oxygen and nitrogen species, is reviewed. Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsaturated fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal and other exocyclic DNA adducts (etheno and/or propano adducts). Whilst iron (Fe), copper (Cu), chromium (Cr), vanadium (V) and cobalt (Co) undergo redox-cycling reactions, for a second group of metals, mercury (Hg), cadmium (Cd) and nickel (Ni), the primary route for their toxicity is depletion of glutathione and bonding to sulfhydryl groups of proteins. Arsenic (As) is thought to bind directly to critical thiols, however, other mechanisms, involving formation of hydrogen peroxide under physiological conditions, have been proposed. The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Common mechanisms involving the Fenton reaction, generation of the superoxide radical and the hydroxyl radical appear to be involved for iron, copper, chromium, vanadium and cobalt primarily associated with mitochondria, microsomes and peroxisomes. However, a recent discovery that the upper limit of "free pools" of copper is far less than a single atom per cell casts serious doubt on the in vivo role of copper in Fenton-like generation of free radicals. Nitric oxide (NO) seems to be involved in arsenite-induced DNA damage and pyrimidine excision inhibition. Various studies have confirmed that metals activate signalling pathways and the carcinogenic effect of metals has been related to activation of mainly redox-sensitive transcription factors, involving NF-kappaB, AP-1 and p53. Antioxidants (both enzymatic and non-enzymatic) provide protection against deleterious metal-mediated free radical attacks. Vitamin E and melatonin can prevent the majority of metal-mediated (iron, copper, cadmium) damage both in vitro systems and in metal-loaded animals. Toxicity studies involving chromium have shown that the protective effect of vitamin E against lipid peroxidation may be associated rather with the level of non-enzymatic antioxidants than the activity of enzymatic antioxidants. However, a very recent epidemiological study has shown that a daily intake of vitamin E of more than 400 IU increases the risk of death and should be avoided. While previous studies have proposed a deleterious pro-oxidant effect of vitamin C (ascorbate) in the presence of iron (or copper), recent results have shown that even in the presence of redox-active iron (or copper) and hydrogen peroxide, ascorbate acts as an antioxidant that prevents lipid peroxidation and does not promote protein oxidation in humans in vitro. Experimental results have also shown a link ...

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Section: Mercury and Stress Proteinsmentioning

confidence: 93%

Metals, Toxicity and Oxidative Stress

Valko

Morris²,

Cronin

2005

CMC

4,226

2,664

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“…The effect of calcium alginate dressings on cell proliferation is mediated by the release of ionized calcium into the wound bed. Increasing the ionized calcium concentration in the wound bed thus promotes improved healing [20], [26]. However, the greatest improvements occur in chronic wounds, such as venous ulcers [24].…”

Section: Introductionmentioning

confidence: 99%

Calcium-Based Nanoparticles Accelerate Skin Wound Healing

et al. 2011

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IntroductionNanoparticles (NPs) are small entities that consist of a hydroxyapatite core, which can bind ions, proteins, and other organic molecules from the surrounding environment. These small conglomerations can influence environmental calcium levels and have the potential to modulate calcium homeostasis in vivo. Nanoparticles have been associated with various calcium-mediated disease processes, such as atherosclerosis and kidney stone formation. We hypothesized that nanoparticles could have an effect on other calcium-regulated processes, such as wound healing. In the present study, we synthesized pH-sensitive calcium-based nanoparticles and investigated their ability to enhance cutaneous wound repair.MethodsDifferent populations of nanoparticles were synthesized on collagen-coated plates under various growth conditions. Bilateral dorsal cutaneous wounds were made on 8-week-old female Balb/c mice. Nanoparticles were then either administered intravenously or applied topically to the wound bed. The rate of wound closure was quantified. Intravenously injected nanoparticles were tracked using a FLAG detection system. The effect of nanoparticles on fibroblast contraction and proliferation was assessed.ResultsA population of pH-sensitive calcium-based nanoparticles was identified. When intravenously administered, these nanoparticles acutely increased the rate of wound healing. Intravenously administered nanoparticles were localized to the wound site, as evidenced by FLAG staining. Nanoparticles increased fibroblast calcium uptake in vitro and caused contracture of a fibroblast populated collagen lattice in a dose-dependent manner. Nanoparticles also increased the rate of fibroblast proliferation.ConclusionIntravenously administered, calcium-based nanoparticles can acutely decrease open wound size via contracture. We hypothesize that their contraction effect is mediated by the release of ionized calcium into the wound bed, which occurs when the pH-sensitive nanoparticles disintegrate in the acidic wound microenvironment. This is the first study to demonstrate that calcium-based nanoparticles can have a therapeutic benefit, which has important implications for the treatment of wounds.

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“…In human bronchial epithelial cells subtoxic concentrations of Zn 2 activated MAP kinases and evoked an increased phosphorylation of the transcription factors Jun and ATF-2 (Samet et al 1998). A synergistic effect of zinc and calcium on MAP kinases, DNA synthesis and mitogenic signaling was detected with NIH3T3 cells (Huang et al 1999). In Swiss 3T3 cells zinc caused phosphorylation and activation of P70S6 kinase (Kim et al 2000).…”

Section: Effects Of Zinc On Protein Kinase Activitiesmentioning

confidence: 90%

Homeostasis and Cellular Functions of Zinc

Beyersmann

2002

Materialwissenschaft Werkst

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Zinc is an element that is essential for cell proliferation and differentiation. Zinc is a structural constituent of a great number of proteins including metabolic enzymes, cellular signaling proteins and transcription factors. The total intracellular concentration of zinc and the intracellular concentration of the available ion are carefully controlled. The homeostasis of zinc is maintained by regulation of zinc uptake and elimination but also on the level of intracellular sequestration in zinc storing vesicles, so-called zincosomes, and by controlled nucleo-cytoplasmic distribution. A major tool of these processes is the zinc binding protein metallothionein which serves as a zinc storing protein and a zinc transporter to the nucleus in the course of cell cycling and differentiation. There is increasing evidence for a direct signaling function of zinc at all levels of cellular signal transduction. Zinc has been found to modulate cellular signal reception, second messenger metabolism, protein kinase and protein phosphatase activities, and it may activate or inhibit the DNA binding of transcription factors. Zinc ions specifically activate the transcription factor MTF-1 which controls the expression of the genes for metallothionein and the zinc transporter protein ZnT-1. There is increasing evidence that zinc ions function as modulators of cell proliferation and differentiation. Zinc becomes cytotoxic if its extracellular concentration exceeds the capacity of the zinc homeostatic system. Elevated extracellular zinc concentrations lead to a breakdown of the zinc transporting system of the plasma membrane. The resulting enhanced intracellular zinc concentration evokes the activation of programmed cell death (apoptosis), whereas at even more elevated zinc concentration, cell necrosis is the dominant form of cell death.

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Extracellular calcium stimulates DNA synthesis in synergism with zinc, insulin and insulin‐like growth factor I in fibroblasts

Cited by 42 publications

References 41 publications

Metals, Toxicity and Oxidative Stress

Metals, Toxicity and Oxidative Stress

Calcium-Based Nanoparticles Accelerate Skin Wound Healing

Homeostasis and Cellular Functions of Zinc

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