Effects of zinc acetate on splenocytes of endotoxemic mice: Enhanced immune response, reduced apoptosis, and increased expression of heat shock protein 70

Unoshima, Masako; Nishizono, Akira; Takita-Sonoda, Yoshiko; Iwasaka, Hideo; Noguchi, Takayuki

doi:10.1067/mlc.2001.111514

Cited by 25 publications

(28 citation statements)

References 35 publications

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“…ZnPT-dependent upregulation of the cellular heat shock response observed here in cultured human skin cells is consistent with earlier findings that demonstrated the ability of zinc ions to induce the heat shock response involved in cytoprotective and cytotoxic activities of this micronutrient in mammalian cells (Hatayama et al 1993;Lee et al 2000;Unoshima et al 2001). Upregulation of the cellular heat shock response in human epidermal cells occurred at submicromolar doses of ZnPT that also induced inhibition of cell proliferation and cell death (Figs.…”

Section: Discussionsupporting

confidence: 79%

The topical antimicrobial zinc pyrithione is a heat shock response inducer that causes DNA damage and PARP-dependent energy crisis in human skin cells

Lamore

Cabello

Wondrak

2010

Cell Stress and Chaperones

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The differentiated epidermis of human skin serves as an essential barrier against environmental insults from physical, chemical, and biological sources. Zinc pyrithione (ZnPT) is an FDA-approved microbicidal agent used worldwide in clinical antiseptic products, over-thecounter topical antimicrobials, and cosmetic consumer products including antidandruff shampoos. Here we demonstrate for the first time that cultured primary human skin keratinocytes and melanocytes display an exquisite vulnerability to nanomolar concentrations of ZnPT resulting in pronounced induction of heat shock response gene expression and impaired genomic integrity. In keratinocytes treated with nanomolar concentrations of ZnPT, expression array analysis revealed massive upregulation of genes encoding heat shock proteins (HSPA6, HSPA1A, HSPB5, HMOX1, HSPA1L, and DNAJA1) further confirmed by immunodetection. Moreover, ZnPT treatment induced rapid depletion of cellular ATP levels and formation of poly (ADP-ribose) polymers. Consistent with an involvement of poly(ADP-ribose) polymerase (PARP) in ZnPT-induced energy crisis, ATP depletion could be antagonized by pharmacological inhibition of PARP. This result was independently confirmed using PARP-1 knockout mouse embryonic fibroblasts that were resistant to ATP depletion and cytotoxicity resulting from ZnPT exposure. In keratinocytes and melanocytes, single-cell gel electrophoresis and flow cytometric detection of γ-H2A.X revealed rapid induction of DNA damage in response to ZnPT detectable before general loss of cell viability occurred through caspase-independent pathways. Combined with earlier experimental evidence that documents penetration of ZnPT through mammalian skin, our findings raise the possibility that this topical antimicrobial may target and compromise keratinocytes and melanocytes in intact human skin.

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Section: Discussionsupporting

confidence: 79%

The topical antimicrobial zinc pyrithione is a heat shock response inducer that causes DNA damage and PARP-dependent energy crisis in human skin cells

Lamore

Cabello

Wondrak

2010

Cell Stress and Chaperones

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“…One report [198] of improved survival following intraperitoneal (ip) Zn was shown to be an indirect effect, where uptake of toxin from the peritoneum was limited by ip Zn treatment. This should be kept in mind when interpreting the results of other studies where ip Zn apparently limits the toxicity of ip LPS [199]. In a porcine model of endotoxemia [200], pretreatment with Zn prior to LPS infusion was shown to limit the production of IL-6, TNF-a and other inflammatory mediators.…”

Section: Mt and Inflammationmentioning

confidence: 96%

Metallothionein: the multipurpose protein

Coyle¹,

Philcox²,

Lc³

et al. 2002

Cellular and Molecular Life Sciences (CMLS)

1,160

803

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Metallothioneins (MTs) are intracellular, low molecular, low molecular weight, cysteine-rich proteins. Ubiquitous in eukaryotes, MTs have unique structural characteristics to give potent metal-binding and redox capabilities. A primary role has not been identified, and remains elusive, as further functions continue to be discovered. The most widely expressed isoforms in mammals, MT-1 and MT-2, are rapidly induced in the liver by a wide range of metals, drugs and inflammatory mediators. In teh gut and pancreas, MT responds mainly to Zn status. A brain isoform, MT-3, has a specific neuronal growth inhibitory activity, while MT-1 and MT-2 have more diverse functions related to their thiolate cluster structure. These include involvement in Zn homeostasis, protection against heavy metal (especially Cd) and oxidant damage, and metabolic regulation via Zn donation, sequestration and/or redox control. Use of mice with altered gene expression has enhance our understanding of the multifaceted role of MT, emphasised in this review.

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“…In splenocytes of endotoxemic mice, the application of zinc enhances the immune response and reduces the rate of apoptosis [4]. Porcine endothelial cell monolayers are protected by zinc from TNF-induced disruption [5], and zinc inhibits TNFmediated DNA fragmentation and cytolysis [6].…”

Section: Introductionmentioning

confidence: 99%

Effect of zinc pretreatment on pulmonary endothelial cells in vitro and pulmonary function in a porcine model of endotoxemia

Krones¹,

Klosterhalfen

Butz³

et al. 2005

Journal of Surgical Research

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Effects of zinc acetate on splenocytes of endotoxemic mice: Enhanced immune response, reduced apoptosis, and increased expression of heat shock protein 70

Cited by 25 publications

References 35 publications

The topical antimicrobial zinc pyrithione is a heat shock response inducer that causes DNA damage and PARP-dependent energy crisis in human skin cells

The topical antimicrobial zinc pyrithione is a heat shock response inducer that causes DNA damage and PARP-dependent energy crisis in human skin cells

Metallothionein: the multipurpose protein

Effect of zinc pretreatment on pulmonary endothelial cells in vitro and pulmonary function in a porcine model of endotoxemia

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