The effect of free gallium and gallium in liposomes on cytokine and nitric oxide secretion from macrophage-like cells in vitro

Makkonen, Niina; Hirvonen, M.-R.; Savolainen, Kai; Lapinjoki, Seppo; Mönkkönen, Jukka

doi:10.1007/bf01757356

Cited by 23 publications

(12 citation statements)

References 24 publications

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“…We compared the biocompatibility of cells exposed to GNDs with that of cells exposed to the same concentration of Ga 3+ (source from Ga(NO 3 ) 3 ). The GNDs showed better biocompatibility than Ga 3+ , which presented overt cytotoxicity in RAW 264.7 cells for concentrations above 525 μM in our work (Figure S6) and from 700 μM in a previous report . The cytotoxicity of Ga 3+ may be contributed by changing the pH of the cell culture medium, generating protein precipitation, which is not seen in GNDs groups (Figure S7).…”

Section: Results and Discussionsupporting

confidence: 46%

“…Gallium (Ga) compounds, as the source of Ga ions (Ga 3+ ), have historically been shown to present anti-inflammatory effects by modulating the production of nitric oxide (NO) and pro-inflammatory cytokines from the activated immune cells. − Currently, proposed mechanisms of the anti-inflammatory effects shown in Ga 3+ are rationalized on the basis of their similarities with ferric ions (Fe 3+ ), which permits Ga 3+ to act as a nonfunctional Fe 3+ mimetic to bind with Fe-binding proteins . Substitution of Ga 3+ prohibits the native protein functions and further disturbs Fe homeostasis in the immune cells .…”

Section: Introductionmentioning

confidence: 99%

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Gallium Nanodroplets are Anti-Inflammatory without Interfering with Iron Homeostasis

et al. 2022

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Gallium (Ga) compounds, as the source of Ga ions (Ga3+), have been historically used as anti-inflammatories. Currently, the widely accepted mechanisms of the anti-inflammatory effects for Ga3+ are rationalized on the basis of their similarities to ferric ions (Fe3+), which permits Ga3+ to bind with Fe-binding proteins and subsequently disturbs the Fe homeostasis in the immune cells. Here in contrast to the classic views, our study presents the mechanisms of Ga as anti-inflammatory by delivering Ga nanodroplets (GNDs) into lipopolysaccharide-induced macrophages and exploring the processes. The GNDs show a selective inhibition of nitric oxide (NO) production without affecting the accumulation of pro-inflammatory mediators. This is explained by GNDs disrupting the synthesis of inducible NO synthase in the activated macrophages by upregulating the levels of eIF2α phosphorylation, without interfering with the Fe homeostasis. The Fe3+ transferrin receptor-independent endocytosis of GNDs by the cells prompts a fundamentally different mechanism as anti-inflammatories in comparison to that imparted by Ga3+. This study reveals the fundamental molecular basis of GND–macrophage interactions, which may provide additional avenues for the use of Ga for anti-inflammatory and future biomedical and pharmaceutical applications.

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Section: Results and Discussionsupporting

confidence: 46%

Section: Introductionmentioning

confidence: 99%

Gallium Nanodroplets are Anti-Inflammatory without Interfering with Iron Homeostasis

et al. 2022

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“…Based on the studies presented here, we conclude that they do not involve the induction of Hsp70-dependent cytoprotection and the inhibition of adhesion of leukocytes to the endothelium during the early stages of inflammation. Gallium nitrate inhibits the release of the inflammatory mediators IL-6, TNF-␣, and nitric oxide from activated macrophage-like RAW 264 cells (Makkonen et al 1995). When coupled to transferrin, gallium inhibits the mitogen-induced proliferative response of peripheral blood mononuclear cells; in the same study, administration of gallium significantly prolonged survival in mice undergoing severe graft-vshost disease (Drobyski et al 1996).…”

Section: Discussionmentioning

confidence: 94%

Effects of heat shock, stannous chloride, and gallium nitrate on the rat inflammatory response

House

Guidon²,

Perdrizet³

et al. 2001

Cell Stress Chaper

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Heat and a variety of other stressors cause mammalian cells and tissues to acquire cytoprotection. This transient state of altered cellular physiology is nonproliferative and antiapoptotic. In this study, male Wistar rats were stress conditioned with either stannous chloride or gallium nitrate, which have immunosuppressive effects in vivo and in vitro, or heat shock, the most intensively studied inducer of cytoprotection. The early stages of inflammation in response to topical suffusion of mesentery tissue with formyl-methionyl-leucyl-phenylalanine (FMLP) were monitored using intravital microscopy. Microvascular hemodynamics (venular diameter, red blood cell velocity [Vrbc], white blood cell [WBC] flux, and leukocyte-endothelial adhesion [LEA]) were used as indicators of inflammation, and tissue levels of inducible Hsp70, determined using immunoblot assays, provided a marker of cytoprotection. None of the experimental treatments blocked decreases in WBC flux during FMLP suffusion, an indicator of increased low-affinity interactions between leukocytes and vascular endothelium known as rolling adhesion. During FMLP suffusion LEA, an indicator of firm attachment between leukocytes and vascular endothelial cells increased in placebo and gallium nitrate-treated animals but not in heat- and stannous chloride-treated animals, an anti-inflammatory effect. Hsp70 was not detected in aortic tissue from placebo and gallium nitrate-treated animals, indicating that Hsp70-dependent cytoprotection was not present. In contrast, Hsp70 was detected in aortic tissues from heat- and stannous chloride-treated animals, indicating that these tissues were in a cytoprotected state that was also an anti-inflammatory state.

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“…Gallium has been studied extensively as an antimicrobial agent. [16][17][18][19][20][21][22][23][24][25][26]47] The antimicrobial properties of gallium have been attributed to its similarities to ferric iron (Fe 3+ ). These chemical similarities result in uptake by bacteria which ultimately causes bacterial death because gallium cannot be reduced at physiological pH values for metabolic processes, whereas ferric iron can be reduced to ferrous iron.…”

Section: Discussionmentioning

confidence: 99%

Effect of gallium maltolate on a model of chronic, infected equine distal limb wounds

et al. 2020

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Distal limb wounds are common injuries sustained by horses and their healing is fraught with complications due to equine anatomy, prevalence of infection, and challenges associated with wound management. Gallium is a semi-metallic element that has been shown to possess antimicrobial properties and aid in wound healing in various preclinical models. The effects of Gallium have not been studied in equine wound healing. Therefore, the objective of this study was to compare healing rates between gallium-treated and untreated wounds of equine distal limbs and to demonstrate the antimicrobial effects of gallium on wounds inoculated with S. aureus. Using an established model of equine wound healing we demonstrated beneficial effects of 0.5% topical gallium maltolate on equine wound healing. Specifically we documented reduced healing times, reduced bioburden, and reduced formation of exuberant granulation tissue in wounds treated with gallium maltolate as compared with untreated wounds. Gallium appeared to exert its beneficial effects via its well-described antimicrobial actions as well as by altering the expression of specific genes known to be involved in wound healing of horses and other animals. Specifically, gallium maltolate appeared to increase expression of transforming growth factor-β in both infected and uninfected wounds. Further work is needed to document the effects of gallium on naturally occurring equine wounds and to compare the effects of gallium with other wound treatment options. These data, however, suggest that gallium may be an attractive and novel means of improving equine distal limb wound healing.

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The effect of free gallium and gallium in liposomes on cytokine and nitric oxide secretion from macrophage-like cells in vitro

Cited by 23 publications

References 24 publications

Gallium Nanodroplets are Anti-Inflammatory without Interfering with Iron Homeostasis

Gallium Nanodroplets are Anti-Inflammatory without Interfering with Iron Homeostasis

Effects of heat shock, stannous chloride, and gallium nitrate on the rat inflammatory response

Effect of gallium maltolate on a model of chronic, infected equine distal limb wounds

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