The Zinc Ionophore Clioquinol Reduces Parkinson's Disease Patient-Derived Brain Extracts-Induced Neurodegeneration.

Parkinson's disease (PD) is pathologically characterized by intracellular α-synuclein-rich protein aggregates, named Lewy bodies (LB), and by the progressive loss of dopaminergic neurons in the substantia nigra. Several heavy metals, including zinc (Zn), have been suggested to play a role in PD progression, although the exact role of Zn in neurodegeneration remains to be fully elucidated. To address this gap, we investigated the effects of Zn modulation on the progression of degeneration in mice injected with PD patient-derived LB-extracts carrying toxic α-synuclein aggregates. Zn modulation was achieved using either a clioquinol-enriched diet, a Zn ionophore that redistributes cellular Zn, or a Zn-enriched diet that increases Zn levels. Clioquinol treatment significantly prevented dopaminergic neurodegeneration and reduced α-synuclein-associated pathology in LB-injected mice, while no differences were observed with Zn supplementation. Biochemical analyses further demonstrate that the expression levels of vesicle-specific Zn transporter ZnT3 in the striatum of LB-injected mice treated with clioquinol were decreased, suggesting an intracellular redistribution of Zn. Additionally, we found that clioquinol modulates the autophagy-lysosomal pathway by enhancing lysosomal redistribution within the neuronal compartments. Collectively, we found that in vivo pharmacological chelation of Zn, by dampening Zn-mediated cytotoxicity, can result in an overall attenuation of PD-linked lysosomal alterations and dopaminergic neurodegeneration. The results support zinc chelation as a disease-modifying strategy for treating PD.

Repurposing the Ionophore, PBT2, for Treatment of Multidrug-Resistant Neisseria gonorrhoeae Infections.

Multidrug-resistant (MDR) N. gonorrhoeae is a current public health threat. New therapies are urgently needed. PBT2 is an ionophore that disrupts metal homeostasis. PBT2 administered with zinc is shown to reverse resistance to antibiotics in several bacterial pathogens. Here we show that both N. meningitidis and MDR N. gonorrhoeae are sensitive to killing by PBT2 alone. PBT2 is, thus, a candidate therapeutic for MDR N. gonorrhoeae infections.

20-Week Study of Clinical Outcomes of Over-the-Counter COVID-19 Prophylaxis and Treatment.

OBJECTIVES AND SETTING.: As the lethal COVID-19 pandemic enters its second year, the need for effective modalities of alleviation remains urgent. This includes modalities that can readily be used by the public to reduce disease spread and severity. Such preventive measures and early-stage treatments may temper the immediacy of demand for advanced anti-COVID measures (drugs, antibodies, vaccines) and help relieve strain also on other health system resources. DESIGN AND PARTICIPANTS.: We present results of a clinical study with a multi-component OTC "core formulation" regimen used in a multiply exposed adult population. Analysis of clinical outcome data from our sample of over 100 subjects - comprised of roughly equal sized regimen-compliant (test) and non-compliant (control) groups meeting equivalent inclusion criteria - demonstrates a strong statistical significance in favor of use of the core formulations. RESULTS.: While both groups were moderate in size, the difference between them in outcomes over the 20-week study period was large and stark: Just under 4% of the compliant test group presented flu-like symptoms, but none of the test group was COVID-positive; whereas 20% of the non-compliant control group presented flu-like symptoms, three-quarters of whom (15% overall of the control group) were COVID-positive. CONCLUSIONS.: Offering a low cost, readily implemented anti-viral approach, the study regimen may serve, at the least, as a stopgap modality and, perhaps, as a useful tool in combatting the pandemic.

Can food and food supplements be deployed in the fight against the COVID 19 pandemic?

BACKGROUND: Due to lack of approved drugs and vaccines, the medical world has resorted to older drugs, produced for viral infections and other diseases, as a remedy to combat COVID-19. The accumulating evidence from in vitro and in vivo studies for SARS-CoV and MERS-CoV have demonstrated that several polyphenols found in plants and zinc- polyphenol clusters have been in use as herbal medicines have antiviral activities against viruses with various mechanisms. SCOPE OF REVIEW: Curcumin, zinc and zinc-ionophores have been considered as nutraceuticals and nutrients showing great antiviral activities with their medicinal like activities. MAJOR CONCLUSIONS: In this work, we discussed the potential prophylactic and/or therapeutic effects of curcumin, zinc and zinc-ionophores in treatment of viral infections including COVID-19. GENERAL SIGNIFICANCE: Curcuminoids and Zinc classified as nutraceuticals under GRAS (Generally Recognized As Safe) by FDA can provide complementary treatment for COVID 19 patients with their immunity-boosting and antiviral properties.

Zn-DTSM, A Zinc Ionophore with Therapeutic Potential for Acrodermatitis Enteropathica?

Acrodermatitis enteropathica (AE) is a rare disease characterised by a failure in intestinal zinc absorption, which results in a host of symptoms that can ultimately lead to death if left untreated. Current clinical treatment involves life-long high-dose zinc supplements, which can introduce complications for overall nutrient balance in the body. Previous studies have therefore explored the pharmacological treatment of AE utilising metal ionophore/transport compounds in an animal model of the disease (conditional knockout (KO) of the zinc transporter, Zip4), with the perspective of finding an alternative to zinc supplementation. In this study we have assessed the utility of a different class of zinc ionophore compound (zinc diethyl bis(N4-methylthiosemicarbazone), Zn-DTSM; Collaborative Medicinal Development, Sausalito, CA, USA) to the one we have previously described (clioquinol), to determine whether it is effective at preventing the stereotypical weight loss present in the animal model of disease. We first utilised an in vitro assay to assess the ionophore capacity of the compound, and then assessed the effect of the compound in three in vivo animal studies (in 1.5-month-old mice at 30 mg/kg/day, and in 5-month old mice at 3 mg/kg/day and 30 mg/kg/day). Our data demonstrate that Zn-DTSM has a pronounced effect on preventing weight loss when administered daily at 30 mg/kg/day; this was apparent in the absence of any added exogenous zinc. This compound had little overall effect on zinc content in various tissues that were assessed, although further characterisation is required to more fully explore the cellular changes underlying the physiological benefit of this compound. These data suggest that Zn-DTSM, or similar compounds, should be further explored as potential therapeutic options for the long-term treatment of AE.

Repurposing Ionophores as novel antimicrobial agents for the treatment of bovine mastitis caused by Gram-positive pathogens.

Increasing reports of multidrug-resistant bacterial infections in animals has created a need for novel antimicrobial agents that do not promote cross-resistance to critically important antimicrobial classes used in human medicine. In response to the recent emergence of antimicrobial resistance in several bovine mastitis pathogens, in vitro antimicrobial susceptibility was determined for four polyether ionophores (lasalocid, monensin, narasin and salinomycin) against Staphylococcus spp. and Streptococcus spp. isolated from clinical cases. In addition, erythrocyte haemolysis and WST-1 cell proliferation assays were used to assess in vitro mammalian cell cytotoxicity and biofilm susceptibility testing was performed using the minimum biofilm eradication concentration (MBEC™) biofilm assay. Lasalocid, monensin, narasin and salinomycin exhibited bacteriostatic antimicrobial activity against all pathogens tested, including methicillin-resistant staphylococci, with MIC90 values <16 µg/ml. Narasin and monensin displayed the least toxicity against mammalian cell lines and all compounds significantly reduced viable cell numbers in a Staphylococcus aureus biofilm. Based on in vitro characterization, all four ionophores offer potentially novel treatments against bovine mastitis but in vivo studies will be essential to determine whether acceptable safety and efficacy is present following intramammary administration.

Polyether ionophores-promising bioactive molecules for cancer therapy.

The natural polyether ionophore antibiotics might be important chemotherapeutic agents for the treatment of cancer. In this article, the pharmacology and anticancer activity of the polyether ionophores undergoing pre-clinical evaluation are reviewed. Most of polyether ionophores have shown potent activity against the proliferation of various cancer cells, including those that display multidrug resistance (MDR) and cancer stem cells (CSC). The mechanism underlying the anticancer activity of ionophore agents can be related to their ability to form complexes with metal cations and transport them across cellular and subcellular membranes. Increasing evidence shows that the anticancer activity of polyether ionophores may be a consequence of the induction of apoptosis leading to apoptotic cell death, arresting cell cycle progression, induction of the cell oxidative stress, loss of mitochondrial membrane potential, reversion of MDR, synergistic anticancer effect with other anticancer drugs, etc. Continued investigation of the mechanisms of action and development of new polyether ionophores and their derivatives may provide more effective therapeutic drugs for cancer treatments.

Sodium bentonite and monensin under chronic aflatoxicosis in broiler chickens.

Clay feed additives have been increasingly incorporated into animal diets to prevent aflatoxicosis. Due to the nonselective nature of the binding interaction, many important components of the diets could also be made unavailable because of these feed additives. The anticoccidial monensin (MON) could also be sequestered by these clays. The use of sodium bentonite (Na-B) from a mine in the province of Mendoza, Argentina, was investigated as a sequestering agent to prevent the effects of 100 µg/kg of dietary aflatoxin B(1) (AFB(1)). In vitro studies demonstrated that the above Na-B was a good candidate to prevent aflatoxicosis. They also showed that MON competes with AFB(1) for the adsorption sites on the clay surface and effectively displaces the toxin when it is in low concentration. Even though the levels of MON in diets, approximately 55 mg/kg, are high enough to not be significantly changed as a consequence of the adsorption, they can further affect the ability of the clays to bind low levels of AFB(1). An in vivo experiment carried out with poultry showed that 100 µg/kg of AFB(1) does not significantly change productive or biochemical parameters. However, liver histopathology not only confirmed the ability of this particular Na-B to prevent aflatoxicosis but also the decrease of this capacity in the presence of 55 mg/kg of MON. This is the first report stressing this fact and further research should be performed to check if this behavior is a characteristic of the assayed Na-B or of this type of clay. On the other hand, the presence of MON should also be taken into account when assaying the potential AFB(1) binding ability of a given bentonite.

Synthesis and anticancer properties of water-soluble zinc ionophores.

Several water-solubilized versions of the zinc ionophore 1-hydroxypyridine-2-thione (ZnHPT), synthesized as part of the present study, have been found both to increase the intracellular concentrations of free zinc and to produce an antiproliferative activity in exponential phase A549 human lung cancer cultures. Gene expression profiles of A549 cultures treated with one of these water-soluble zinc ionophores, PCI-5002, reveal the activation of stress response pathways under the control of metal-responsive transcription factor 1 (MTF-1), hypoxia-inducible transcription factor 1 (HIF-1), and heat shock transcription factors. Additional oxidative stress response and apoptotic pathways were activated in cultures grown in zinc-supplemented media. We also show that these water-soluble zinc ionophores can be given to mice at 100 micromol/kg (300 micromol/m(2)) with no observable toxicity and inhibit the growth of A549 lung and PC3 prostate cancer cells grown in xenograft models. Gene expression profiles of tumor specimens harvested from mice 4 h after treatment confirmed the in vivo activation of MTF-1-responsive genes. Overall, we propose that water-solubilized zinc ionophores represent a potential new class of anticancer agents.

Short communication: Effects of a monensin premix on milk fatty acid content during subacute ruminal acidosis in dairy cows.

The effects of a monensin premix on milk fatty acid content during grain-induced subacute ruminal acidosis (SARA) in Holstein cows receiving a total mixed ration was investigated. Six multiparous, rumen-fistulated Holstein cows were used in a two-treatment, two-period crossover design with 6-wk periods. Experimental treatments were either a monensin premix or a placebo premix. At the beginning of wk 4, SARA was induced in experimental cows for a 10-d period using a grain challenge model. The administration of a monensin premix elevated milk fat proportion of total short-chain saturated fatty acids (sum of C4 to C15). Milk fat proportions of conjugated linoleic acid isomers were unaffected. Linolenic acid (C18:3n3) proportion in milk fat of monensin-treated cows were lower when compared with placebo-treated cows during the SARA period. Results from this study indicate that dietary supplementation with monensin during SARA had little effect on milk fatty acid content.

Sheep fed grain prefer foods and solutions that attenuate acidosis.

We conducted experiments to determine whether lambs fed grain prefer foods and solutions containing sodium bicarbonate (NaHCO3) and lasalocid, compounds capable of attenuating acidosis. In Exp. 1, we determined whether lambs fed barley preferred flavored rabbit pellets (RP) containing NaHCO3 and lasalocid. Lambs in two groups (n = 10/group) were fed increasing amounts of barley on d 1 to 12 (300 to 1,100 g) and again on d 23 to 34 (300 to 1,350 g). After ingesting barley on d 1 to 12, lambs were fed ground RP containing lasalocid and NaHCO3 (i.e., medicated) and flavored with either 2% onion (group 1) or 2% oregano (group 2). During d 23 to 34, lambs were fed unmedicated RP containing NaCl and flavored with either 2% oregano (group 1) or 2% onion (group 2). During preference tests on d 35 to 40, lambs fed grain preferred RP with NaHCO3 to RP with NaCl (151 vs. 96 g; P < .01). In the Exp. 2, we determined whether wheat ingestion affected consumption of aqueous solutions containing NaHCO3. In trial 1, 28 lambs were assigned to four treatments: 1) low-wheat + 2% NaHCO3, 2) high-wheat + 2% NaHCO3, 3) low-wheat + water, and 4) high-wheat + water. For 12 d from 0800 to 0830, lambs in treatments 1 and 3 were fed 300 g of wheat and lambs in treatments 2 and 4 were fed up to 1,300 g of wheat; fluids (NaHCO3 and water) were then offered from 0930 to 1230 daily. Lambs drank more NaHCO3 on the high- than on the low-wheat diet (1,332 vs 890 g; P = .03); water consumption was similar for lambs on the high- and low-wheat diets (1,675 vs 1,700 g; P > .10). In trial 2, lambs in treatments 3 and 4 were offered a solution containing 1.4% NaCl. For 13 d from 0800 to 0830, lambs in treatments 1 and 3 were fed 500 g of wheat and lambs in treatments 2 and 4 were fed up to 1,700 g of wheat. Lambs had access to fluids from 0800 to 1200 daily. Lambs drank nearly twice as much NaHCO3 solution on the high- than on the low-wheat diet (1,066 vs 572 g), whereas they drank only 1.4 times more NaCl solution on the high- than on the low-wheat diet (888 vs. 634 g; P < .001). Fewer lambs showed signs of acidosis in treatment 2 than in treatment 4 in trials 1 (2 vs 9) and 2 (7 vs 17). Collectively, these results are consistent with the hypothesis that lambs fed grain prefer substances that attenuate acidosis.

[Ketorolac protection in damage due to myocardial ischemia and reperfusion]. / Protección por Ketorolac en el daño producido por isquemia y reperfusión miocardica.

This study shows that the nonsteroidal anti-inflammatory drug. Ketorolac, has an ionophore-like action for calcium, such a drug may transfer calcium through an hydrophobic phase. This property does not affect the respiratory rate of mitochondria. These results indicate that the ionophoretic effect is not due to an uncoupling action of Ketorolac. The effect of this compound was tested in a reperfusion model where it was observed that Ketorolac (1 mg/Kg weight) administered 30 min before an ischemic period was induced, reverts the arrhythmic effect of reperfusion. These results are in agreement with the analysis of the plasmatic concentrations of the enzymes creatine kinase and lactic dehydrogenase. It was found that the levels of such enzymes were lower in Ketorolac treated group, than in the untreated one. The results clearly indicate that Ketorolac prevents from the myocardial damage induced by reperfusion, probably by avoiding calcium overload in myocytes.