Vitamin D alleviates cognitive dysfunction and brain damage induced by copper sulfate intake in experimental rats: focus on its combination with donepezil.

This study aimed to demonstrate the potential benefits of donepezil (DPZ) and vitamin D (Vit D) in combination to counteract the neurodegenerative disorders induced by CuSO4 intake in experimental rats. Neurodegeneration (Alzheimer-like) was induced in twenty-four male Wistar albino rats by CuSO4 supplement to drinking water (10 mg/L) for 14 weeks. AD rats were divided into four groups: untreated AD group (Cu-AD) and three treated AD groups; orally treated for 4 weeks with either DPZ (10 mg/kg/day), Vit D (500 IU/kg/day), or DPZ + Vit D starting from the 10th week of CuSO4 intake. Another six rats were used as normal control (NC) group. The hippocampal tissue content of ß-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 and the cortical content of acetylcholine (Ach), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured. Cognitive function tests (Y-maze) and histopathology studies (hematoxylin and eosin and Congo red stains) and immunohistochemistry for neurofilament. Vit D supplementation alleviated CuSO4-induced memory deficits including significant reduction hippocampal BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α and cortical AChE and MDA. Vit D remarkably increased cortical Ach, TAC, and hippocampal Bcl-2. It also improved neurobehavioral and histological abnormalities. The effects attained by Vit D treatment were better than those attained by DPZ. Furthermore, Vit D boosted the therapeutic potential of DPZ in almost all AD associated behavioral and pathological changes. Vit D is suggested as a potential therapy to retard neurodegeneration.

Thyroid Stem Cells But Not Differentiated Thyrocytes Are Sensitive to Slightly Increased Concentrations of Heavy Metals.

Thyroid cancer incidence is markedly increased in volcanic areas where residents are biocontaminated by chronic lifelong exposure to slightly increased metals in the environment. Metals can influence the biology of living cells by a variety of mechanisms, depending not only on the dose and length of exposure but also on the type and stage of differentiation of target cells. We explored the effect of five heavy metals (Cu, Hg, Pd, W and Zn) at nanomolar concentrations (the biocontamination level in residents of the volcanic area in Sicily where thyroid cancer is increased) on stimulating the proliferation of undifferentiated (thyrospheres) and differentiated human thyroid cells. Thyrosphere proliferation was significantly increased after exposure to each individual metal and a greater stimulating effect was observed when a mixture of the examined metals was used. No effect was seen in differentiated thyrocytes. For all metals, the dose-response curve followed a biphasic pattern that is typical of hormesis. Thyrosphere growth concerned the size rather than number, except with the metal mixture. An altered morphology was also observed in metal-treated thyrospheres. Metal-induced proliferation was due to activation of the ERK1/2 pathway, as confirmed by growth inhibition when ERK1/2 signaling was blocked. These studies show that stem/precursor thyroid cells are sensitive to small increases in environmental metal concentrations that are harmless for differentiated thyrocytes.

RETROSPECTIVE REVIEW OF COPPER SULFATE IMMERSION TREATMENT IN MARINE TELEOSTS DURING QUARANTINE AT THE NATIONAL AQUARIUM OF BALTIMORE FROM 2004 TO 2016.

Copper sulfate immersion is common for the prevention and treatment of Cryptocaryon irritans during quarantine of marine teleosts. The National Aquarium in Baltimore has followed a consistent copper sulfate protocol for marine teleost quarantine since 2004. The protocol used copper sulfate pentahydrate as a slow drip to increase copper ions over 3-5 days to a level of 0.18-0.21 mg/L. This level was maintained for 21 days, and then copper ions were rapidly removed with activated carbon filtration and water changes. Quarantine records from 2004-2016 were used to examine mortality of marine teleosts during copper treatment and identify factors that might have influenced mortality. The following records were excluded: brackish and freshwater teleosts (salinity <25 g/L); long-term treatment at subtherapeutic levels (<0.18 mg/L); intentional short courses (<14 days); and use outside of quarantine. Species, system volume, temperature, parasitic outbreaks, concurrent medications, and water quality concerns were evaluated. During this period, 4,835 individual teleosts belonging to 347 different species were treated. From 2004 to 2016, mortality during copper treatment was 4.1% (199/4,835 individuals) and was higher when treatment was started during the first week of quarantine (7.7%, 68/884) rather than later (3.3%, 131/3,951 individuals). Of the mortalities, 24.1% (48/199) occurred during the initial subtherapeutic period, and 75.9% (151/199) occurred during the therapeutic period. No mortalities occurred in 75.5% (262/347) of species during copper treatment. When using a similar methodology, copper sulfate is a safe immersion for quarantine of marine teleosts. Mortalities during copper treatment can be reduced by increasing copper ion levels to therapeutic ranges more slowly (e.g., over 7 days) and starting copper treatment after the first week of quarantine.

CG Demethylation Leads to Sequence Mutations in an Anther Culture of Barley Due to the Presence of Cu, Ag Ions in the Medium and Culture Time.

During plant tissue cultures the changes affecting regenerants have a broad range of genetic and epigenetic implications. These changes can be seen at the DNA methylation and sequence variation levels. In light of the latest studies, DNA methylation change plays an essential role in determining doubled haploid (DH) regenerants. The present study focuses on exploring the relationship between DNA methylation in CG and CHG contexts, and sequence variation, mediated by microelements (CuSO4 and AgNO3) supplemented during barley anther incubation on induction medium. To estimate such a relationship, a mediation analysis was used based on the results previously obtained through metAFLP method. Here, an interaction was observed between DNA demethylation in the context of CG and the time of culture. It was also noted that the reduction in DNA methylation was associated with a total decrease in the amount of Cu and Ag ions in the induction medium. Moreover, the total increase in Cu and Ag ions increased sequence variation. The importance of the time of tissue culture in the light of the observed changes resulted from the grouping of regenerants obtained after incubation on the induction medium for 28 days. The present study demonstrated that under a relatively short time of tissue culture (28 days), the multiplication of the Cu2+ and Ag+ ion concentrations ('Cu*Ag') acts as a mediator of demethylation in CG context. Change (increase) in the demethylation in CG sequence results in the decrease of 'Cu*Ag', and that change induces sequence variation equal to the value of the indirect effect. Thus, Cu and Ag ions mediate sequence variation. It seems that the observed changes at the level of methylation and DNA sequence may accompany the transition from direct to indirect embryogenesis.

The Activation of Heat-Shock Protein After Copper(II) and/or Arsenic(III)-Induced Imbalance of Homeostasis, Inflammatory Response in Chicken Rectum.

Arsenic and copper, two toxic pollutants, are powerful inducers of oxidative stress. Exposure to copper and arsenic can cause intestinal injury in cockerel. This study was carried out to investigate the effects of these two pollutants on the gastrointestinal tract of cockerels. Experimental results showed that the activity of antioxidant enzymes (catalase and glutathione peroxidase) was inhibited and the ionic balance was destroyed after exposure to copper sulfate (300 mg/kg) and/or arsenic trioxide (30 mg/kg). However, the expression of pro-inflammatory cytokines (nuclear factor kappa-B, cyclooxygenase-2, tumor necrosis factor-α, and prostaglandin E2 synthases) increased markedly. Damages to the biofilm structure and inflammatory cell infiltration were simultaneously observed during histological examination. Heat-shock proteins were also expressed in large quantities after exposure to the poisons. Collectively, exposure to arsenite and/or Cu2+ can cause rectal damage in cockerels, inducing inflammation and an imbalance in immune system responses. Sometimes, exposure to both pollutants can produce even more toxic effects. Heat-shock proteins can protect the tissue from the exotoxins but the specific mechanisms require exploration. After oral ingestion of toxins, the rectum can still be damaged, necessitating attention to the safety of poultry breeding, human food safety, and environmental protection.

Pirometaxine™ (Narlisim™) in pediatric nasal congestion: a retrospective study.

BACKGROUND: Nasal congestion represents a troublesome health issue which is especially and invalidating in children. Effective nasal drugs, such as sympathomimetic drugs, are usually forbidden in children under 12 years of age because of their potential systemic adverse effects. Hypertonic nasal physiological solutions have recently been successfully used to decongest nasal mucosa in children: its mechanical activity has been universally recognized as safe and effective and it represents a well-established, useful treatment in children. METHODS: We have retrospectively analyzed a case series of 40 children treated for 4 days (96 hours) with a new class 1s medical device nasal hypertonic spray containing Pirometaxine™ (Narlisim™) in outpatient affected by nasal congestion due to common cold. Every child was evaluated on a 3-point symptom assessment scale (0: no symptom; 1: mild symptom; 2: moderate symptom; 3: severe symptom) at the beginning of the trial (T0) and after 48 (T1) and 96 hours (T2). The symptoms assessed were nasal obstruction, nasal secretion, headache, flash of cold, pharyngodynia, cough, and sneeze. RESULTS: The results, in terms of short-term efficacy to control nasal obstruction (T1 vs. T0: P<0.0001; T2 vs. T0: P<0.0001), nasal secretion (T1 vs. T0: P<0.0001; T2 vs. T0: P<0.0001) and all the symptoms related to common cold have supported the efficacy of this hypertonic nasal solution. No adverse events have been pointed out during the trial supporting the safety of this new nasal hypertonic approach. CONCLUSIONS: The absence of adverse events after 48-96 hours along with the short-term effectiveness of this new treatment seems to represent a new, safe option to treat children affected by nasal congestion secondary to common cold. Considering the current lack of safe treatments for children under 12 years of age, Narlisim™ can be considered as a useful short-term option to control nasal congestion in children.

Antibiotics and chemical disease-control agents reduce innate disease resistance in crayfish.

The aquaculture industry has developed rapidly in recent years, and in China Crayfish Procambarus clarkii represent an important aquaculture fishery. However, bacterial and viral diseases are becoming an increasingly serious threat, causing considerable economic losses. Farmers use a large number of drugs and chemicals to destroy pathogenic microorganisms and to purify aquaculture water. The purpose of this study was to assess the effects of such drugs on crayfish immune systems. Five of the most commonly used fishery drugs and water treatment chemicals were analyzed: norfloxacin, calcium hypochlorite, quick lime, povidone iodine and copper sulfate. Crayfish immune activity tests revealed that total hemocytes counts, as well as the activities of phenoloxidase and superoxide dismutase, decreased following exposure to all five treatments. These treatments, especially calcium hypochlorite and norfloxacin, significantly enhanced hemocyte apoptosis in crayfish, regardless of disease status. Calcium hypochlorite, in particular, led to a significant decrease in the survival rates of crayfish infected with white spot syndrome virus or Vibrio alginolyticus. Our results indicate that water treatment and disease control compounds commonly used in aquaculture can reduce the innate immunity and therefore disease resistance of crayfish.

Involvement of the Prion Protein in the Protection of the Human Bronchial Epithelial Barrier Against Oxidative Stress.

Aim: Bronchial epithelium acts as a defensive barrier against inhaled pollutants and microorganisms. This barrier is often compromised in inflammatory airway diseases that are characterized by excessive oxidative stress responses, leading to bronchial epithelial shedding, barrier failure, and increased bronchial epithelium permeability. Among proteins expressed in the junctional barrier and participating to the regulation of the response to oxidative and to environmental stresses is the cellular prion protein (PrPC). However, the role of PrPC is still unknown in the bronchial epithelium. Herein, we investigated the cellular mechanisms by which PrPC protein participates into the junctional complexes formation, regulation, and oxidative protection in human bronchial epithelium. Results: Both PrPC messenger RNA and mature protein were expressed in human epithelial bronchial cells. PrPC was localized in the apical domain and became lateral, at high degree of cell polarization, where it colocalized and interacted with adherens (E-cadherin/γ-catenin) and desmosomal (desmoglein/desmoplakin) junctional proteins. No interaction was detected with tight junction proteins. Disruption of such interactions induced the loss of the epithelial barrier. Moreover, we demonstrated that PrPC protection against copper-associated oxidative stress was involved in multiple processes, including the stability of adherens and desmosomal junctional proteins. Innovation: PrPC is a pivotal protein in the protection against oxidative stress that is associated with the degradation of adherens and desmosomal junctional proteins. Conclusion: Altogether, these results demonstrate that the loss of the integrity of the epithelial barrier by oxidative stress is attenuated by the activation of PrPC expression, where deregulation might be associated with respiratory diseases.

Haemolytic anaemia and hepatocitolysis associated with hypermagnesaemia by repeated exposures to copper-calcium fungicides.

For the medical practice, our manuscript acts as a signal, despite only presenting three cases which feature the association between hepatocytolysis, haemolysis and hypermagnesaemia. This clinical-biologic triad was highlighted with the workers who through the nature of their profession were exposing themselves periodically to vapours which contained copper sulphate neutralised with calcium hydroxide, a fungicide used for fruit trees. We are exclusively assessing the haematological perturbation. In this aetiological context, the generating mechanism for haemolysis is very probable biochemical, where hypercupraemia interferes with cellular antioxidant defence mechanisms. Hypothetically, the role of the redox homeostasis disorder in the intravascular destruction of erythrocytes is sustained, and particularly the coexistence of cell cytolysis in the medullary erythroid compartment, which can be assimilated with a possible ineffective erythropoiesis.

Analysis of 28 trace elements in the blood and serum antioxidant status in chickens under arsenic and/or copper exposure.

This study aimed to evaluate the 28 trace elements in the blood and serum antioxidant status in chickens under arsenic (As) and/or copper (Cu) exposure. A total of 200 1-day-old male Hy-Line chickens were fed either a commercial diet (C-group) or arsenic trioxide (30 mg/kg) and/or cupric sulfate (300 mg/kg) for 90 days. The 28 trace element levels in the blood were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). The concentrations of As in the blood of chickens were elevated approximately 17.15-fold, 2.30-fold, and 13.37-fold in the As-group, Cu-group, and As + Cu-group, respectively, at 90 days. The concentrations of Cu did not change in the As-group and increased approximately 29.53 and 23.37% in the Cu-group and As + Cu-group, respectively, at 90 days. Moreover, As exposure caused ion profile disorders in the blood, including increased concentrations of Na, Mg, Si, K, Cr, Fe, and Se and reduced B, Ca, Ti, V, Mn, Co, Ni, Zn, Sr, and Mo. Cu exposure increased the contents of Mg, Si, Ca, Ti, V, Cr, Mn, Fe, Co, Zn, and Se and decreased the content of B, Ca, Al, Ni, and Mo. As + Cu exposure increased the contents of Mg, Si, Cr, Fe, Zn, and Se and decreased the content of B, Ca, Ti, Co, Ni, Sr, and Mo. Moreover, As and/or Cu exposure induced oxidative stress in the blood of chickens. In conclusion, the results indicated that the mixture of As and Cu caused a synergistic effect via disturbing homeostasis of trace elements and oxidative stress in the blood of chickens.

Apoptotic Process Induced by Oxaliplatin in Rat Hippocampus Causes Memory Impairment.

Aspects of memory involved in cognitive mechanisms were investigated in rat after oxaliplatin (OX) chemotherapy using animal behavioural assessment of passive avoidance and social learning paradigms, which are both hippocampus-sensitive. Rodents, previously subjected to 2-week OX treatment, showed passive avoidance and social learning impairment and apoptotic processes in the hippocampus. Apoptosis rate significantly increased in cultured hippocampal cells exposed to OX at increasing doses, and this effect was dose-dependent. Ex vivo experiments showed that cell damage and apoptosis were blocked in the hippocampus from OX rats cotreated with copper sulphate (CS) which precludes OX transport inside the cell. In vivo, passive avoidance and social learning impairment could not be observed in OX rats co-administered with CS. Thus, a site of action of OX treatment on memory impairment appears to be located at the hippocampus. These findings strongly support that cellular damage induced by OX in rodent hippocampus underlies the weakening of some memory functions.

Interventions for treating phosphorus burns.

BACKGROUND: Phosphorus burns are rarely encountered in usual clinical practice and occur mostly in military and industrial settings. However, these burns can be fatal, even with minimal burn area, and are often associated with prolonged hospitalisation. OBJECTIVES: To summarise the evidence of effects (beneficial and harmful) of all interventions for treating people with phosphorus burns. SEARCH METHODS: In October 2013 for this first update we searched the Cochrane Wounds Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library);Ovid OLDMEDLINE; Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; EBSCO CINAHL and Conference Proceedings Citation Index - Science (CPCI-S). We did not apply any methodological filters or restrictions on the basis of study design, language, date of publication or publication status. SELECTION CRITERIA: Any comparisons of different ways of managing phosphorus burns including, but not restricted, to randomised trials. DATA COLLECTION AND ANALYSIS: We found two non-randomised comparative studies, both comparing patients treated with and without copper sulphate. MAIN RESULTS: These two comparative studies provide no evidence to support the use of copper sulphate in managing phosphorus burns. Indeed the small amount of available evidence suggests that it may be harmful. AUTHORS' CONCLUSIONS: First aid for phosphorus burns involves the common sense measures of acting promptly to remove the patient's clothes, irrigating the wound(s) with water or saline continuously, and removing phosphorus particles. There is no evidence that using copper sulphate to assist visualisation of phosphorus particles for removal is associated with better outcome, and some evidence that systemic absorption of copper sulphate may be harmful. We have so far been unable to identify any other comparisons relevant to informing other aspects of the care of patients with phosphorus burns. Future versions of this review will take account of information in articles published in languages other than English, which may contain additional evidence based on treatment comparisons.

Effect of a tea tree oil and organic acid footbath solution on digital dermatitis in dairy cows.

Copper sulfate is the industry gold standard footbath ingredient for controlling dairy cow digital dermatitis. However, when used footbath solutions are deposited on soil, high levels of copper in the soil may result, which can have toxic and negative effects on plant growth. An alternative to copper sulfate is Provita Hoofsure Endurance (Provita Eurotech Ltd., Omagh, UK), which is a biodegradable solution containing organic acids, tea tree oil, and wetting agents. The objective of this study was to quantify changes in digital dermatitis frequency when using Provita Hoofsure Endurance and copper sulfate in a split footbath in 3 commercial dairy herds. This study was conducted from January 5, 2012, to March 19, 2012, in 3 commercial Kentucky dairies with 120, 170, and 200 milking Holstein cows. None of the herds was using a footbath for digital dermatitis control before the study. Footbath solutions were delivered using a split footbath. During the study, a 3% Hoofsure Endurance solution for the left hooves and a 5% copper sulfate solution for the right hooves was used. Digital dermatitis was scored every 3wk using the M0 to M4 system, where M0=a claw free of signs of digital dermatitis; M1=a lesion <2cm that is not painful; M2=the ulcerative stage, with lesion diameter of >2cm, and painful to the touch; M3=the healing stage and covered by a scab; and M4=the chronic stage and characterized by dyskeratosis or proliferation of the surface that is generally not painful. McNemar's test statistic suggested that a statistically significant difference existed in the proportions of M1 and M2 lesions between the beginning and end of the study for both treatments. This indicates that each solution was effective in decreasing the proportion of M1 or M2 lesions from baseline to the last time point. A chi-square test calculated using PROC FREQUENCY of SAS (SAS Institute Inc., Cary, NC) indicated that no statistically significant relationship existed between the treatments among changes in digital dermatitis frequency from the baseline to the end of the study. Performance of the 2 footbath solutions was comparable throughout the study. No significant differences were observed between the copper sulfate and Provita Hoofsure Endurance.

[Allergies to dental materials and effectiveness of treatment in the north-eastern region of Hungary]. / Fogászati anyagokkal szemben kialakuló allergiás megbetegedések és ellátásuk hatékonyságának vizsgálata az észak-alföldi régióban.

The recognition and treatment of allergy is a great challenge for all fields of medicine. The high prevalence of allergic reactions to dental materials and the related financial burden of their treatment make investigation of this disease very important. Our investigation was carried out on patients assigned to our outpatient department for dental allergy test between 1996 and 1998. We determined the distribution of gender and age among the allergic patients in the examined population. We also studied the prevalence of allergic reactions to different dental allergens and the distribution of dental allergens. In a follow-up study we determined the proportion of those patients, who were retreated in conformity with the results of epicutan tests and we followed up the positive effects of these treatments. We have found that dental allergy occurred five times more frequently in women (84%) than in men (16%) and the most affected age group was between 20 to 39 and 40-49 years (31%). Seventy-five percent of the patients suffered from a combination of metal and polymer allergy. The most frequent metal allergen was TEGDMA (triethylene glycol dimethacrylate) (49.7%). The suggested treatment plan was carried out in 63% of the allergic patients. The applied treatment was successful in 48% of these cases. We experienced that 48% of these patients got rid of their earlier signs and symptoms.

Zinc therapy improves deleterious effects of chronic copper administration on mice testes: histopathological evaluation.

This study was set to investigate whether the adverse effects of long-term copper (Cu) consumption on testicular tissue could be prevented by zinc (Zn) administration. Forty-five mature male mice were randomly divided into one control and two treatment groups. The first treatment group received copper sulphate (Cu experimental group). The second treatment group was given combined treatment of copper sulphate and zinc sulphate (ZC experimental group). Control animals received normal saline using the same volume. Five mice from each group were sacrificed on day 14, 28 and 56 from the beginning of treatments. Left testes were removed for histopathological and histomorphometrical evaluations. Morphometrically, the diameter of seminiferous tubules and Sertoli cell nuclei, epithelial height, meiotic index and the percentage of spermatogenesis in Cu groups showed significant decrease compared to those of the control groups (P < 0.05). A partial improvement was seen in the percentage of spermatogenesis and meiotic index (P < 0.05) in ZC groups, whereas a complete recovery was observed in the rest of parameters in ZC group after 56 days compared to the control group (P > 0.05). Results showed that long-term administration of Cu leads to histological impairments of testis and zinc supplementation might offset these damaging effects.

Toxicity of copper sulfate to Flavobacterium psychrophilum and Rainbow Trout eggs.

Tests were conducted to determine the concentrations of copper sulfate needed to kill Flavobacterium psychrophilum, the cause of bacterial coldwater disease, either in vitro or on Rainbow Trout Oncorhynchus mykiss eggs. For the in vitro test, a plastic strip dipped in a solution of F. psychrophilum was exposed for 15 min to copper sulfate solutions of 0, 1, 5, 10, 20, 35, 50, 75, or 100 mg/L. Bacteria were "too numerous to count" at concentrations ≤10 mg/L CuSO4; significant reductions in prevalence relative to untreated controls were noted for concentrations ≥35 mg/L. However, CFUs were still observed at 50 and 75 mg/L (20% of plates with tryptone yeast extract salts media). No yellow-pigmented CFUs typical of F. psychrophilum were observed at 100 mg/L CuSO4. For the in vivo test, eggs were exposed for 15 min to 100, 300, 500, and 700 mg/L CuSO4 or 100 mg/L iodine (control). Survival to hatch was significantly lower at 500 (44.3 ± 15.2%, mean ± SD) or 700 mg/L CuSO4 (1.7 ± 0.8%) than for controls treated with 100 mg/L iodine (93.6 ± 0.9%) or at copper sulfate concentrations ≤300 mg/L. The 15-min LD50 and LD10 for copper sulfate were 461 mg/L (95% confidence interval: 457-466 mg/L) and 259 mg/L (251-266 mg/L). The prevalence of yellow CFUs at 100 mg/L CuSO4 (40.0%) was significantly higher than in untreated controls. Significant reductions in yellow CFUs were achieved using 300, 500, or 700 mg/L CuSO4 (7.5, 2.5, or 0.0% of plates with CFUs, respectively) or 100 mg/L iodine (2.5%), relative to untreated control eggs. Overall, since the concentrations of copper sulfate required to eliminate F. psychrophilum were toxic to the eggs, copper sulfate is not recommended for coldwater disease control in Rainbow Trout eggs based on conditions and parameters in this study.

Atorvastatin active metabolite inhibits oxidative modification of small dense low-density lipoprotein.

We tested the hypothesis that atorvastatin active metabolite (ATM), on the basis of its distinct structural features and potent antioxidant activity, preferentially inhibits lipid oxidation in human small dense low-density lipoprotein (sdLDL) and other small lipid vesicles. LDL, sdLDL, and various subfractions were isolated from human plasma by sequential ultracentrifugation, treated with ATM, atorvastatin, pravastatin, rosuvastatin, or simvastatin and were subjected to copper-induced oxidation. Lipid oxidation was measured spectrophotometrically as a function of thiobarbituric acid reactive substances formation. Similar analyses were performed in reconstituted lipid vesicles enriched in polyunsaturated fatty acids and prepared at various sizes. ATM was found to inhibit sdLDL oxidation in a dose-dependent manner. The antioxidant effects of ATM in sdLDL were 1.5 and 4.7 times greater (P < 0.001) than those observed in large buoyant LDL and very low-density lipoprotein subfractions, respectively. ATM had similar dose- and size-dependent effects in reconstituted lipid vesicles. None of these effects were reproduced by atorvastatin (parent) or any of the other statins examined in this study. These data suggest that ATM interacts with sdLDL in a specific manner that also confers preferential resistance to oxidative stress. Such interactions may reduce sdLDL atherogenicity and improve clinical outcomes in patients with cardiovascular disease.

Contributions of rat Ctr1 to the uptake and toxicity of copper and platinum anticancer drugs in dorsal root ganglion neurons.

Dorsal root ganglion (DRG) neurons are affected by platinum-induced neurotoxicity and neurodegenerative processes associated with disturbed copper homeostasis and transport. This study aimed to understand the role of copper transporter 1 (Ctr1) in the uptake and toxicity of copper and platinum drugs in cultured rat DRG neurons, and the functional activities of rat Ctr1 (rCtr1) as a membrane transporter of copper and platinum drugs. Heterologous expression of rCtr1 in HEK293 cells (HEK/rCtr1 cells) increased the uptake and cytotoxicity of copper, oxaliplatin, cisplatin and carboplatin, in comparison to isogenic vector-transfected control cells. Cultured rat DRG neurons endogenously expressed rCtr1 protein on their neuronal cell body plasma membranes and cytoplasm, and displayed substantial capacity for taking up copper, but were resistant to copper toxicity. The uptake of copper by both cultured rat DRG neurons and HEK/rCtr1 cells was saturable and inhibited by cold temperature, silver and zinc, consistent with it being mediated by rCtr1. Cultured rat DRG neurons accumulated platinum during their exposure to oxaliplatin and were sensitive to oxaliplatin cytotoxicity. The accumulation of platinum by both cultured rat DRG neurons and HEK/rCtr1 cells, during oxaliplatin exposure, was saturable and temperature dependent, but was inhibited by copper only in HEK/rCtr1 cells. In conclusion, rCtr1 can transport copper and platinum drugs, and sensitizes cells to their cytotoxicities. DRG neurons display substantial capacity for accumulating copper via a transport process mediated by rCtr1, but appear able to resist copper toxicity and use alternative mechanisms to take up oxaliplatin.

Efficacy and tolerability assessment of a topical formulation containing copper sulfate and hypericum perforatum on patients with herpes skin lesions: a comparative, randomized controlled trial.

BACKGROUND: Topical Acyclovir has moderate efficacy on recurrent HSV symptoms, requiring repeat applications for several days. Topical Dynamiclear, which requires only a single dose application, may provide a more effective and convenient treatment option for symptomatic management of HSV. OBJECTIVES: The study assessed the comparative efficacy and tolerability of a single use, topical formulation containing copper sulfate pentahydrate and Hypericum perforatum that is marketed as Dynamiclear™ to a topical 5% Acyclovir cream standard preparation and use. METHODS: A prospective, randomized, multi-centered, comparative, open-label clinical study was conducted. A total of 149 participants between 18 and 55 years of age with active HSV-1 and HSV-2 lesions were recruited for the 14-day clinical trial. Participants were randomized into two groups: A (n=61), those receiving the Dynamiclear formulation, and B (n=59), those receiving 5% Acyclovir. Efficacy parameters were assessed via physical examination at baseline (day 1), day 2, 3, 8, and 14. Laboratory safety tests were conducted at baseline and on day 14. RESULTS: Use of the Dynamiclear formulation was found to have no significant adverse effects and was well tolerated by participants. All hematological and biochemical markers were within normal range for the Dynamiclear group. Statistically, odds for being affected by burning and stinging sensation were 1.9 times greater in the Acyclovir group in comparison to the Dynamiclear group. Similarly, the odds of being affected by symptoms of acute pain, erythema and vesiculation were 1.8, 2.4, and 4.4 times higher in the Acyclovir group in comparison to the Dynamiclear group. CONCLUSIONS: The Dynamiclear formulation was well tolerated, and efficacy was demonstrated in a number of measured parameters, which are helpful in the symptomatic management of HSV-1 and HSV-2 lesions in adult patients. Remarkably, the effects seen from this product came from a single application.

Solid gastric emptying mediated by the serotonin (5-HT)3 receptor in mice is a simple marker to predict emesis.

Nausea and emesis are often observed as side effects with many medicines and may lead to poor treatment compliance. In the present study, we aimed to establish simple methods for predicting nausea and/or emesis in mice, which do not vomit, using drugs and chemicals known to evoke nausea and/or emesis. The gastrointestinal transit test, the liquid gastric emptying by phenol red solution (Phenol red method) and the solid gastric emptying by resin beads (Beads method) were used and the effects of antispasmogenics (atropine, 0.1-3 mg/kg i.p.; salmon calcitonin, 1-30 units/kg i.m.), nauseants (copper sulfate, 1-30 mg/kg p.o.; apomorphine, 0.01-0.3 mg/kg s.c.) and chemotherapeutics (cisplatin, 0.3-10 mg/kg i.v.; doxorubicin, 0.3-10 mg/kg i.v.) were evaluated. In addition, the effects of ondansetron, a serotonin (5-HT)(3) receptor antagonist, on the inhibition of solid gastric emptying induced by salmon calcitonin, copper sulfate, cisplatin and doxorubicin were also assessed. Only the solid gastric emptying method could detect changes of gastric emptying by all drugs and chemicals. We also found that the inhibition of solid gastric emptying induced by cisplatin and doxorubicin was dose-dependently antagonized by ondansetron. However, ondansetron failed to antagonize the salmon calcitonin-induced delay, but exerted only very weak effects with copper sulfate. Solid gastric emptying may be more suitable than gastrointestinal intestinal transit or liquid gastric emptying in mice to predict nausea and/or emesis. Our results also suggest that chemotherapeutic-induced delay of solid gastric emptying mediated via 5-HT(3) receptors in mice could also be useful for prediction purposes.