Influence of heat shock protein 70 and metallothionein induction by Zinc-Bis-(DL-Hydrogenaspartate) on the release of inflammatory mediators in a porcine model of recurrent endotoxemia

Klosterhalfen, B.; Töns, C.; Hauptmann, Steffen; Tietze, L.; Offner, Felix; Küpper, Werner; Kirkpatrick, Charles James

doi:10.1016/0006-2952(96)00469-8

Cited by 52 publications

(47 citation statements)

References 42 publications

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“…Most heavy metals are toxic, but some, such, as zinc, are safe to use. Zinc is used to treat the common cold, rhinitis, pneumonia, and dermatitis (10)(11)(12)(13)(14) and zinc has been shown to protect in pig and rat models of endotoxemia (15,16). We here show that addition of zinc to the drinking water of mice protected them against TNF-induced lethal shock, metabolic disturbances, and bowel toxicity.…”

Section: Introductionmentioning

confidence: 57%

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Protection of Zinc against Tumor Necrosis Factor–Induced Lethal Inflammation Depends on Heat Shock Protein 70 and Allows Safe Antitumor Therapy

Molle¹,

Roy²,

Bogaert³

et al. 2007

Cancer Research

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Tumor necrosis factor (TNF)-induced inflammation prevents its broad application as an antitumor agent. We here report that addition of ZnSO 4 to the drinking water of mice induces expression of heat shock protein 70 (HSP70) in several organs, notably the gastrointestinal track. Zinc conferred doseresponsive protection against TNF-induced hypothermia, systemic induction of interleukin-6 and NO x , as well as against TNF-induced bowel cell death and death of the organism. The protective effect of zinc was completely absent in mice deficient in the major HSP70-inducible gene, hsp70.1, whereas transgenic mice constitutively expressing the human HSP70.A gene, under control of a B-actin promoter, was also protected against TNF, indicating that an increase in HSP70 is necessary and sufficient to confer protection. The therapeutic potential of the protection induced by ZnSO 4 was clearly shown in a TNF/IFN;-based antitumor therapy using three different tumor models. In hsp70.1 wild-type mice, but not in hsp70.1-deficient mice, zinc very significantly protected against lethality but left the antitumor effect intact. We conclude that zinc protects against TNF in a HSP70-dependent way and that protection by zinc could be helpful in developing a safer anticancer therapy with TNF/IFN;. [Cancer Res 2007;67(15):7301-7]

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Section: Introductionmentioning

confidence: 57%

“…Cancer Res 2007; 67: (15). August 1, 2007 activity of the chromogenic substrate Ac-DEVD-amc was determined as a measure of the activity of caspase-3 and caspase-7, both known as executioner caspases.…”

Section: Cancer Researchmentioning

confidence: 99%

Protection of Zinc against Tumor Necrosis Factor–Induced Lethal Inflammation Depends on Heat Shock Protein 70 and Allows Safe Antitumor Therapy

Molle¹,

Roy²,

Bogaert³

et al. 2007

Cancer Research

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“…Pretreatment with zinc protects against lethality in endotoxin-challenged mice (33) and significantly decreases TNF-␣ plasma levels in a porcine model of septic shock (34). Moreover, pretreatment with zinc attenuates LPS-induced TNF-␣ release from Kupffer cells due to suppression of NF-B activation, thereby preventing hepatotoxicity in mice (7).…”

Section: Discussionmentioning

confidence: 99%

“…Several animal studies demonstrated that zinc can protect against the inflammatory TNF-␣ response induced by endotoxin (7,33,34). Pretreatment with zinc protects against lethality in endotoxin-challenged mice (33) and significantly decreases TNF-␣ plasma levels in a porcine model of septic shock (34).…”

Section: Discussionmentioning

confidence: 99%

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Zinc-Dependent Suppression of TNF-α Production Is Mediated by Protein Kinase A-Induced Inhibition of Raf-1, IκB Kinase β, and NF-κB

Bülow

Dubben

Engelhardt

et al. 2007

The Journal of Immunology

131

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Excessive and permanent cytokine production in response to bacterial LPS causes cell and tissue damage, and hence organ failure during sepsis. We have previously demonstrated that zinc treatment prevents LPS-induced TNF-α expression and production in human monocytes by inhibiting cyclic nucleotide phosphodiesterase (PDE) activity and expression, and subsequent elevation of the cyclic nucleotide cGMP. In the present study, we investigated the molecular mechanism by which cGMP signaling affects the LPS-induced signaling cascade to suppress TNF-α transcription and release from monocytes. Zinc-mediated cGMP elevation led to cross activation of protein kinase A. This zinc-induced protein kinase A activation inhibited Raf-1 activity by phosphorylation at serine 259, preventing activation of Raf-1 by phosphorylation of serine 338. By this mechanism, zinc suppressed LPS-induced activation of IκB kinase β (IKKβ) and NF-κB, and subsequent TNF-α production. Our study shows that PDE inhibition by zinc modulates the monocytic immune response by selectively intervening in the Raf-1/IKKβ/NF-κB pathway, which may constitute a common mechanism for the anti-inflammatory action of PDE inhibitors.

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Implications of impaired zinc homeostasis in diabetic cardiomyopathy and nephropathy

et al. 2017

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Impaired zinc homeostasis is observed in diabetes mellitus (DM2) and its complications. Zinc has a specific role in pancreatic β-cells via insulin synthesis, storage, and secretion. Intracellular zinc homeostasis is tightly controlled by zinc transporters (ZnT and Zip families) and metallothioneins (MT) which modulate the uptake, storage, and distribution of zinc. Several investigations in animal models demonstrate the protective role of MT in DM2 and its cardiovascular or renal complications, while a copious literature shows that a common polymorphism (R325W) in ZnT8, which affects the protein's zinc transport activity, is associated with increased DM2 risk. Emerging studies highlight a role of other zinc transporters in β-cell function, suggesting that targeting them could make a possible contribution in managing the hyperglycemia in diabetic patients. This article summarizes the current findings concerning the role of zinc homeostasis in DM2 pathogenesis and development of diabetic cardiomyopathy and nephropathy and suggests novel therapeutic targets. © 2017 BioFactors, 43(6):770-784, 2017.

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Influence of heat shock protein 70 and metallothionein induction by Zinc-Bis-(DL-Hydrogenaspartate) on the release of inflammatory mediators in a porcine model of recurrent endotoxemia

Cited by 52 publications

References 42 publications

Protection of Zinc against Tumor Necrosis Factor–Induced Lethal Inflammation Depends on Heat Shock Protein 70 and Allows Safe Antitumor Therapy

Protection of Zinc against Tumor Necrosis Factor–Induced Lethal Inflammation Depends on Heat Shock Protein 70 and Allows Safe Antitumor Therapy

Zinc-Dependent Suppression of TNF-α Production Is Mediated by Protein Kinase A-Induced Inhibition of Raf-1, IκB Kinase β, and NF-κB

Implications of impaired zinc homeostasis in diabetic cardiomyopathy and nephropathy

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