The effects of lithium and potassium on macromolecular synthesis in herpes simplex virus-infected cells

Hartley, C. E.; Buchan, A.; Randall, S.; Skinner, G. R. B.; Osborne, Michael P.; Tomkins, L. M.

doi:10.1099/0022-1317-74-8-1519

Cited by 15 publications

(10 citation statements)

References 26 publications

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“…Cell-based photographic images, flow cytometry, and real-time-based cellular assays are used to effectively present visual evidence that lithium exerts its anti-inflammatory effects in these activated macrophages without inducing detrimental morphological pressure or cell death. Although concentrations of lithium above 20 mM were used in various in vitro models [ 21 , 22 ], this study has considered limiting concentrations of LiCl to 10 mM, since this has been demonstrated ( Figure 1(a) ) to be the highest lithium concentration with no effect on Raw 264.7 cell proliferation [ 20 ]. Although previous studies have suggested the narrow spectrum of action/activity shown by lithium at therapeutic concentrations (0.4–2.0 mM LiCl) [ 2 , 23 ], this work, along with other studies performed at extratherapeutic dosages [ 24 – 26 ], explored the effects of lithium above those concentration limits so as to provide substantive molecular data on inflammation beyond the narrow spectrum.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Lithium on Inflammation-Associated Genes in Lipopolysaccharide-Activated Raw 264.7 Macrophages

Makola

Mbazima

Mokgotho

et al. 2020

International Journal of Inflammation

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Lithium remains the preferred Food and Drug Administration- (FDA-) approved psychiatric drug for treatment of bipolar disorders since its medical establishment more than half a century ago. Recent studies revealed a promising role for lithium in the regulation of inflammation, oxidative stress, and neurodegeneration albeit unclear about its exact mode of action. Thus, the intention of this study is to delineate the regulatory mechanisms of lithium on oxidative stress in lipopolysaccharide- (LPS-) activated macrophages by evaluating its effects on nuclear factor-κB (NF-κB) activity and mRNA expression of multiple oxidative stress-related NF-κB genes. Raw 264.7 macrophages were treated with up to 10 mM lithium, and no change in cell proliferation, viability, growth, and cell adhesion was observed in real time. Pretreatment with low doses of lithium was shown to reduce nitric oxide (NO) production in LPS-activated macrophages. A reduced internal H2DCFDA fluorescence intensity, indicative of reduced reactive oxygen species (ROS) production, was observed in LPS-activated Raw 264.7 macrophages treated with lithium. Lithium has been shown to lower the production of the chemokine RANTES; furthermore, this inhibitory action of lithium has been suggested to be independent of glycogen synthase kinase-3 β (GSK3β) activity. It is shown here that lithium modulates the expression of several inflammatory genes including IκB-α, TRAF3, Tollip, and NF-κB1/p50 which are regulators of the NF-κB pathway. Moreover, lithium inhibits NF-κB activity by lowering nuclear translocation of NF-κB in LPS-activated macrophages. This is the first study to associate Tollip, Traf-3, and IκB-α mRNA expression with lithium effect on NF-κB activity in LPS-activated Raw 264.7 macrophages. Although these effects were obtained using extratherapeutic concentrations of lithium, results of this study provide useful information towards understanding the mode of action of lithium. This study associates lithium with reduced oxidative stress in LPS-activated Raw 264.7 macrophages and further suggests candidate molecular targets for the regulation of oxidative stress-related diseases using lithium beyond bipolar disorders.

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Section: Discussionmentioning

confidence: 99%

The Effect of Lithium on Inflammation-Associated Genes in Lipopolysaccharide-Activated Raw 264.7 Macrophages

Makola

Mbazima

Mokgotho

et al. 2020

International Journal of Inflammation

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“…In addition, it has been reported the relevance of intracellular K + to the viral replication on in vitro studies [Nagai et al, ; Hartley et al, ; Hartley et al, ]. There is notable evidence indicating modification of cellular membrane structure following HSV infections [Hackstadt and Mallavia, ; Palu et al, ; Bertol et al, ].…”

Section: Discussionmentioning

confidence: 99%

Diphenyl Diselenide Reduces Oxidative Stress and Toxicity Caused by HSV‐2 Infection in Mice

Sartori

Jardim

Sari

et al. 2017

J of Cellular Biochemistry

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Herpes simplex viruses can cause uncommon systemic complications as acute liver failure (ALT) or urinary tract dysfunctions. Diphenyl diselenide, (PhSe) , a classical studied organic selenium compound, has a novel antiviral action against HSV-2 infection and well-known antioxidant and anti-inflammatory properties. This study aimed to investigate if (PhSe) reduces oxidative stress and systemic toxicity caused by HSV-2 infection in mice. Adult BALB/c mice were pre-treated with (PhSe) (5 mg kg /day, intragastric, i.g.) during 5 days; at day 6 mice were infected with HSV-2 (10 μl-10 PFU/mL ) and post-treated with (PhSe) for more 5 days. At day 11, they were killed and samples of liver and kidney were obtained to determine: reactive species (RS); malondialdehyde (MDA), and non-protein thiols (NPSH) levels; the activities of antioxidant enzymes, superoxide dismutase (SOD), and catalase (CAT). The activities of adenosine deaminase (ADA), Na /K -ATPase (liver and kidney); alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the levels of urea (plasma) were determined as markers of hepatic and renal toxicity. The results revealed that (PhSe) treatment was effective against the increase of renal and hepatic oxidative stress in infected mice and also normalized hepatic and renal ADA activity. It recovered the activity of Na /K - and was not effective against the increase in urea levels in infected mice. Different from (PhSe) , acyclovir (positive control), caused an increase in ADA activity and a decrease in hepatic CAT activity. Considering the interest of alternative therapies to treat HSV-2 infections and secondary complications, (PhSe) become a notable candidate. J. Cell. Biochem. 118: 1028-1037, 2017. © 2016 Wiley Periodicals, Inc.

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“…It is well known that papillomaviruses are dependent of the milieu of the infected host cell for proliferation . More specifically, it has been shown that DNA viruses, such as HPV, rely on potassium ion influx for replication . The cardiac glycoside digoxin and loop diuretic furosemide both inhibit K + influx by interacting with the cell‐membrane ion cotransporters Na + /K + ‐ATPase and Na‐K‐Cl.…”

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confidence: 99%

A randomized controlled proof‐of‐concept trial of digoxin and furosemide in adults with cutaneous warts

et al. 2019

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SummaryBackgroundTopical ionic contraviral therapy (ICVT) with digoxin and furosemide inhibits the potassium influx on which DNA viruses rely for replication. Therefore, ICVT was hypothesized to be a potential novel treatment for cutaneous warts.ObjectivesTo assess the clinical efficacy, safety and tolerability of ICVT in adults with cutaneous warts. The secondary objective was to gain insight into the underlying working mechanism of ICVT.MethodsTreatment with ICVT was assessed for efficacy, safety and tolerability in a single‐ centre, randomized, double‐blind, placebo‐controlled phase IIA trial. Eighty adult patients with at least two cutaneous warts (plantar or common) were randomized to one of four treatments: digoxin + furosemide (0·125%), digoxin (0·125%), furosemide (0·125%) or placebo. The gel was administered once daily for 42 consecutive days. Predefined statistical analysis was performed with a mixed‐model ancova. The trial was registered at ClinicalTrials.gov with number NCT02333643.ResultsWart size and human papillomavirus (HPV) load reduction was achieved in all active treatment groups. A statistically significant reduction in wart diameter of all treated warts was shown in the digoxin + furosemide treatment group vs. placebo (−3·0 mm, 95% confidence interval −4·9 to −1·1, P = 0·002). There was a statistically significant reduction in the HPV load of all treated warts in the digoxin + furosemide group vs. placebo (−94%, 95% confidence interval −100 to −19, P = 0·03). With wart size reduction, histologically and immunohistochemically defined viral characteristics disappeared from partial and total responding warts.ConclusionsThis study demonstrates the proof of concept for the efficacy of topical ICVT in adults with cutaneous warts.

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The effects of lithium and potassium on macromolecular synthesis in herpes simplex virus-infected cells

Cited by 15 publications

References 26 publications

The Effect of Lithium on Inflammation-Associated Genes in Lipopolysaccharide-Activated Raw 264.7 Macrophages

The Effect of Lithium on Inflammation-Associated Genes in Lipopolysaccharide-Activated Raw 264.7 Macrophages

Diphenyl Diselenide Reduces Oxidative Stress and Toxicity Caused by HSV‐2 Infection in Mice

A randomized controlled proof‐of‐concept trial of digoxin and furosemide in adults with cutaneous warts

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