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Article ; Online: Zinc Preconditioning Provides Cytoprotection following Iodinated Contrast Media Exposure in In Vitro Models.

Perera, Marlon / Ischia, Joseph / Bolton, Damien / Shulkes, Arthur / Baldwin, Graham S / Patel, Oneel

2021 Volume 2021, Page(s) 6686803

Abstract: Methods: Normal human proximal renal kidney cells (HK-2) were preconditioned with either increasing doses of ZnCl: Results: Contrast media induced a dose-dependent reduction in survival of HK-2 cells. Compared to control, contrast media at 150, 225, ... ...

Abstract	Methods: Normal human proximal renal kidney cells (HK-2) were preconditioned with either increasing doses of ZnCl Results: Contrast media induced a dose-dependent reduction in survival of HK-2 cells. Compared to control, contrast media at 150, 225, and 300 mg I Conclusions: Zinc preconditioning reduces oxidative stress following exposure to radiographic contrast media which in turn results in increased survival of renal cells. Translation of this
MeSH term(s)	Animals ; Apoptosis/drug effects ; Cell Line ; Contrast Media/pharmacology ; Cytoprotection/drug effects ; Humans ; Iohexol/pharmacology ; Kidney/diagnostic imaging ; Kidney/drug effects ; Kidney/pathology ; Kidney Tubules, Proximal/drug effects ; Oxidative Stress/drug effects ; Zinc/pharmacology
Chemical Substances	Contrast Media ; Iohexol (4419T9MX03) ; Zinc (J41CSQ7QDS)
Language	English
Publishing date	2021-02-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2232678-9
ISSN	1555-4317 ; 1555-4309
ISSN (online)	1555-4317
ISSN	1555-4309
DOI	10.1155/2021/6686803
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Article ; Online: Why is it worth testing the ability of zinc to protect against ischaemia reperfusion injury for human application.

Ischia, Joseph / Bolton, Damien M / Patel, Oneel

Metallomics : integrated biometal science

2019 Volume 11, Issue 8, Page(s) 1330–1343

Abstract: Ischaemia (interruption in the blood/oxygen supply) and subsequent damage induced by reperfusion (restoration of blood/oxygen supply) ultimately leads to cell death, tissue injury and permanent organ dysfunction. The impact of ischaemia reperfusion ... ...

Abstract	Ischaemia (interruption in the blood/oxygen supply) and subsequent damage induced by reperfusion (restoration of blood/oxygen supply) ultimately leads to cell death, tissue injury and permanent organ dysfunction. The impact of ischaemia reperfusion injury (IRI) is not limited to heart attack and stroke but can be extended to patients undergoing surgeries such as partial nephrectomy for renal cancer, liver resection for colorectal cancer liver metastasis, cardiopulmonary bypass, and organ transplantation. Unfortunately, there are no drugs that can protect organs against the inevitable peril of IRI. Recent data show that a protocol incorporating specific Zn formulation, dosage, number of dosages, time of injection, and mode of Zn delivery (intravenous) and testing of efficacy in a large preclinical sheep model of IRI strongly supports human trials of Zn preconditioning. No doubt, scepticism still exists among funding bodies and research fraternity on whether Zn, a naturally occurring metal, will work where everything else has failed. Therefore, in this article, we review the conflicting evidence on the promoter and protector role of Zn in the case of IRI and highlight factors that may help explain the contradictory evidence. Finally, we review the literature related to the knowledge of Zn's mechanism of action on ROS generation, apoptosis, HIF activation, inflammation, and signal transduction pathways, which highlight Zn's likelihood of success compared to various other interventions targeting IRI.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Humans ; Inflammation/metabolism ; Inflammation/prevention & control ; Protective Agents/administration & dosage ; Protective Agents/pharmacology ; Protective Agents/therapeutic use ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/drug therapy ; Reperfusion Injury/metabolism ; Reperfusion Injury/prevention & control ; Signal Transduction/drug effects ; Zinc/administration & dosage ; Zinc/pharmacology ; Zinc/therapeutic use
Chemical Substances	Protective Agents ; Reactive Oxygen Species ; Zinc (J41CSQ7QDS)
Language	English
Publishing date	2019-06-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2474317-3
ISSN	1756-591X ; 1756-5901
ISSN (online)	1756-591X
ISSN	1756-5901
DOI	10.1039/c9mt00079h
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Article: Corrigendum to "Targeting HIF-1

Sethi, Kapil / Rao, Kenny / Shulkes, Arthur / Baldwin, Graham / Bolton, Damien / Patel, Oneel / Ischia, Joseph

International journal of cell biology

2019 Volume 2019, Page(s) 9598038

Abstract: This corrects the article DOI: 10.1155/2018/9852791.]. ...

Abstract	[This corrects the article DOI: 10.1155/2018/9852791.].
Language	English
Publishing date	2019-04-10
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2536742-0
ISSN	1687-8884 ; 1687-8876
ISSN (online)	1687-8884
ISSN	1687-8876
DOI	10.1155/2019/9598038
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Article ; Online: Zinc ion dyshomeostasis increases resistance of prostate cancer cells to oxidative stress via upregulation of HIF1α.

Wetherell, David / Baldwin, Graham S / Shulkes, Arthur / Bolton, Damien / Ischia, Joseph / Patel, Oneel

Oncotarget

2018 Volume 9, Issue 9, Page(s) 8463–8477

Abstract: Zinc ions ( ... ...

Abstract	Zinc ions (Zn
Language	English
Publishing date	2018-02-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.23893
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Article: Targeting HIF-1

Sethi, Kapil / Rao, Kenny / Bolton, Damien / Patel, Oneel / Ischia, Joseph

International journal of cell biology

2018 Volume 2018, Page(s) 9852791

Abstract: Partial nephrectomy (open or minimally invasive) usually requires temporary renal arterial occlusion to limit intraoperative bleeding and improve access to intrarenal structures. This is a time-critical step due to the critical ischemia period of renal ... ...

Abstract	Partial nephrectomy (open or minimally invasive) usually requires temporary renal arterial occlusion to limit intraoperative bleeding and improve access to intrarenal structures. This is a time-critical step due to the critical ischemia period of renal tissue. Prolonged renal ischemia may lead to irreversible nephron damage in the remaining tissue and, ultimately, chronic kidney disease. This is potentiated by the incompletely understood ischemia-reperfusion injury (IRI). A key mechanism in IRI prevention appears to be the upregulation of an intracellular transcription protein, Hypoxia-Inducible Factor (HIF). HIF mediates metabolic adaptation, angiogenesis, erythropoiesis, cell growth, survival, and apoptosis. Upregulating HIF-1
Language	English
Publishing date	2018-11-25
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2536742-0
ISSN	1687-8884 ; 1687-8876
ISSN (online)	1687-8884
ISSN	1687-8876
DOI	10.1155/2018/9852791
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Article ; Online: Zinc supplementation as an adjunct therapy for COVID-19: Challenges and opportunities.

Chinni, Vidyasagar / El-Khoury, John / Perera, Marlon / Bellomo, Rinaldo / Jones, Daryl / Bolton, Damien / Ischia, Joseph / Patel, Oneel

British journal of clinical pharmacology

2021 Volume 87, Issue 10, Page(s) 3737–3746

Abstract: An outbreak of a novel coronavirus (COVID-19 or 2019-CoV) infection has posed significant threats to international health and the economy. Patients with COVID-19 are at risk of cytokine storm, acute respiratory distress syndrome (ARDS), reduced blood ... ...

Abstract	An outbreak of a novel coronavirus (COVID-19 or 2019-CoV) infection has posed significant threats to international health and the economy. Patients with COVID-19 are at risk of cytokine storm, acute respiratory distress syndrome (ARDS), reduced blood oxygenation, mechanical ventilation, and a high death rate. Although recent studies have shown remdesivir and dexamethasone as treatment options, there is an urgent need to find a treatment to inhibit virus replication and to control the progression of the disease. Essential biometal zinc has generated a lot of excitement as one of the promising candidates to reduce the severity of COVID-19 infection. Several published observations outlined in the review are the reasons why there is a global enthusiasm that zinc therapy could be a possible therapeutic option. However, the biggest challenge in realising the therapeutic value of zinc is lack of optimal treatment modalities such as dose, duration of zinc supplementation and the mode of delivery. In this review, we discuss the regulatory mechanism that hinges upon the bioavailability of zinc. Finally, we propose that intravenous zinc could circumvent the confounding factors affecting the bioavailability of zinc and allow zinc to achieve its therapeutic potential. If successful, due to advantages such as lack of toxicity, low cost and ease of availability, intravenous zinc could be rapidly implemented clinically.
MeSH term(s)	COVID-19 ; Cytokine Release Syndrome ; Dietary Supplements ; Humans ; SARS-CoV-2 ; Zinc
Chemical Substances	Zinc (J41CSQ7QDS)
Language	English
Publishing date	2021-06-02
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/bcp.14826
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Zs.A 1118: Show issues

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Article: The Protective Effect of Zinc Against Liver Ischaemia Reperfusion Injury in a Rat Model of Global Ischaemia.

Cheung, Ernest / Nikfarjam, Mehrdad / Jackett, Louise / Bolton, Damien M / Ischia, Joseph / Patel, Oneel

Journal of clinical and experimental hepatology

2019 Volume 10, Issue 3, Page(s) 228–235

Abstract: Background: Ischaemia-reperfusion injury (IRI) is a major obstacle during liver transplantation and resection surgeries for cancer, with a need for effective and safe drugs to reduce IRI. Zinc preconditioning has been shown to protect against liver IRI ... ...

Abstract	Background: Ischaemia-reperfusion injury (IRI) is a major obstacle during liver transplantation and resection surgeries for cancer, with a need for effective and safe drugs to reduce IRI. Zinc preconditioning has been shown to protect against liver IRI in a partial (70%) ischaemia model. However, its efficacy against a clinically relevant Pringle manoeuvre that results in global liver ischaemia (100%) is unknown. Aims: The aim of this study was to test the efficacy of zinc preconditioning in a rat model of global liver ischaemia. Methods: Rats were preconditioned via subcutaneous injection of 10 mg/kg of ZnCl Results: On a two-way repeated-measures analysis of variance, there was a statistically significant (p = 0.025) difference in the mean ALT levels between saline- and ZnCl Conclusion: Zinc preconditioning reduces the overall hepatocellular damage from IRI. These results lay the foundation to assess the benefit of zinc preconditioning for clinical applications.
Language	English
Publishing date	2019-07-24
Publishing country	India
Document type	Journal Article
ISSN	0973-6883
ISSN	0973-6883
DOI	10.1016/j.jceh.2019.07.006
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Article ; Online: Preconditioning against renal ischaemia reperfusion injury: the failure to translate to the clinic.

O'Kane, Dermot / Baldwin, Graham S / Bolton, Damien M / Ischia, Joseph J / Patel, Oneel

Journal of nephrology

2019 Volume 32, Issue 4, Page(s) 539–547

Abstract: Acute kidney injury (AKI) as a result of ischaemia-reperfusion represents a major healthcare burden worldwide. Mortality rates from AKI in hospitalized patients are extremely high and have changed little despite decades of research and medical advances. ... ...

Abstract	Acute kidney injury (AKI) as a result of ischaemia-reperfusion represents a major healthcare burden worldwide. Mortality rates from AKI in hospitalized patients are extremely high and have changed little despite decades of research and medical advances. In 1986, Murry et al. demonstrated for the first time the phenomenon of ischaemic preconditioning to protect against ischaemia-reperfusion injury (IRI). This seminal finding paved the way for a broad body of research, which attempted to understand and ultimately harness this phenomenon for human application. The ability of preconditioning to limit renal IRI has now been demonstrated in multiple different animal models. However, more than 30 years later, a safe and consistent method of protecting human organs, including the kidneys, against IRI is still not available. This review highlights agents which, despite strong preclinical data, have recently failed to reduce AKI in human trials. The multiple reasons which may have contributed to the failure to translate some of the promising findings to clinical therapies are discussed. Agents which hold promise in the clinic because of their recent efficacy in preclinical large animal models are also reviewed.
MeSH term(s)	Acetylcysteine/therapeutic use ; Acute Kidney Injury/etiology ; Acute Kidney Injury/prevention & control ; Animals ; Chelating Agents/pharmacology ; Disease Models, Animal ; Diuretics, Osmotic/therapeutic use ; Endpoint Determination ; Free Radical Scavengers/therapeutic use ; Humans ; Hypoxia-Inducible Factor 1/drug effects ; Ischemic Preconditioning/methods ; Kidney/blood supply ; Mannitol/therapeutic use ; Oligopeptides/therapeutic use ; Reperfusion Injury/complications ; Reperfusion Injury/prevention & control ; Reproducibility of Results ; Translational Medical Research
Chemical Substances	Chelating Agents ; Diuretics, Osmotic ; Free Radical Scavengers ; Hypoxia-Inducible Factor 1 ; Oligopeptides ; THR-184 ; Mannitol (3OWL53L36A) ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2019-01-11
Publishing country	Italy
Document type	Journal Article ; Review
ZDB-ID	1093991-x
ISSN	1724-6059 ; 1120-3625 ; 1121-8428
ISSN (online)	1724-6059
ISSN	1120-3625 ; 1121-8428
DOI	10.1007/s40620-019-00582-6
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Zs.A 3369: Show issues

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Article ; Online: Randomised controlled trial for high-dose intravenous zinc as adjunctive therapy in SARS-CoV-2 (COVID-19) positive critically ill patients

Paul Johnson / John El Khoury / Vidyasagar Chinni / Damien Bolton / Daryl Jones / Oneel Patel / Joseph Ischia

BMJ Open, Vol 10, Iss

trial protocol

2020 Volume 12

Abstract: Introduction SARS-CoV-2 (COVID-19) has caused an international pandemic of respiratory illness, resulting in significant healthcare and economic turmoil. To date, no robust vaccine or treatment has been identified. Elemental zinc has previously been ... ...

Abstract	Introduction SARS-CoV-2 (COVID-19) has caused an international pandemic of respiratory illness, resulting in significant healthcare and economic turmoil. To date, no robust vaccine or treatment has been identified. Elemental zinc has previously been demonstrated to have beneficial effects on coronaviruses and other viral respiratory infections due to its effect on RNA polymerase. Additionally, zinc has well-demonstrated protective effects against hypoxic injury—a clear mechanism of end-organ injury in respiratory distress syndrome. We aimed to assess the effect of high-dose intravenous zinc (HDIVZn) on SARS-CoV-2 infection. The end of study analyses will evaluate the reduction of impact of oxygen saturations or requirement of oxygen supplementation.Methods and analysis We designed a double-blind randomised controlled trial of daily HDIVZn (0.5 mg/kg) versus placebo. Primary outcome measures are lowest oxygen saturation (or greatest level of supplemental oxygenation) for non-ventilated patients and worst PaO2/FiO2 for ventilated patients. Following power calculations, 60 hospitalised patients and 100 ventilated patients will be recruited to demonstrate a 20% difference. The duration of follow-up is up to the point of discharge.Ethics and dissemination Ethical approval was obtained through the independent Human Research Ethics Committee. Participant recruitment will commence in May 2020. Results will be published in peer-reviewed medical journals.Trial registration number ACTRN126200000454976.
Keywords	Medicine ; R
Subject code	610
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	BMJ Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A pilot double-blind safety and feasibility randomized controlled trial of high-dose intravenous zinc in hospitalized COVID-19 patients.

Patel, Oneel / Chinni, Vidyasagar / El-Khoury, John / Perera, Marlon / Neto, Ary S / McDonald, Christine / See, Emily / Jones, Daryl / Bolton, Damien / Bellomo, Rinaldo / Trubiano, Jason / Ischia, Joseph

Journal of medical virology

2021 Volume 93, Issue 5, Page(s) 3261–3267

Abstract: Zinc inhibits replication of the SARS-CoV virus. We aimed to evaluate the safety, feasibility, and biological effect of administering high-dose intravenous zinc (HDIVZn) to patients with COVID-19. We performed a Phase IIa double-blind, randomized ... ...

Abstract	Zinc inhibits replication of the SARS-CoV virus. We aimed to evaluate the safety, feasibility, and biological effect of administering high-dose intravenous zinc (HDIVZn) to patients with COVID-19. We performed a Phase IIa double-blind, randomized controlled trial to compare HDIVZn to placebo in hospitalized patients with COVID-19. We administered trial treatment per day for a maximum of 7 days until either death or hospital discharge. We measured zinc concentration at baseline and during treatment and observed patients for any significant side effects. For eligible patients, we randomized and administered treatment to 33 adult participants to either HDIVZn (n = 15) or placebo (n = 18). We observed no serious adverse events throughout the study for a total of 94 HDIVZn administrations. However, three participants in the HDIVZn group reported infusion site irritation. Mean serum zinc on Day 1 in the placebo, and the HDIVZn group was 6.9 ± 1.1 and 7.7 ± 1.6 µmol/l, respectively, consistent with zinc deficiency. HDIVZn, but not placebo, increased serum zinc levels above the deficiency cutoff of 10.7 µmol/l (p < .001) on Day 6. Our study did not reach its target enrollment because stringent public health measures markedly reduced patient hospitalizations. Hospitalized COVID-19 patients demonstrated zinc deficiency. This can be corrected with HDIVZn. Such treatment appears safe, feasible, and only associated with minimal peripheral infusion site irritation. This pilot study justifies further investigation of this treatment in COVID-19 patients.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; COVID-19/drug therapy ; Dose-Response Relationship, Drug ; Double-Blind Method ; Feasibility Studies ; Female ; Humans ; Injections, Intravenous ; Inpatients ; Male ; Middle Aged ; Oxygen/blood ; Pilot Projects ; Respiration, Artificial ; SARS-CoV-2 ; Zinc/administration & dosage ; Zinc/therapeutic use
Chemical Substances	Zinc (J41CSQ7QDS) ; Oxygen (S88TT14065)
Language	English
Publishing date	2021-03-09
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial
ZDB-ID	752392-0
ISSN	1096-9071 ; 0146-6615
ISSN (online)	1096-9071
ISSN	0146-6615
DOI	10.1002/jmv.26895
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