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Although the production and use of nickel oxide nanoparticles (NiONP) are widespread, environmental and public health problems are associated with it. The kidney is the primary organ in excretion and is among the target organs in nanoparticle toxicity. This study aimed to compare the renal toxicity of nickel oxide (NiO) microparticles and nickel oxide nanoparticles by different routes of administration, such as oral, intraperitoneal (IP), and intravenous (IV). Seven groups were formed, with 42 male rats and six animals in each group. NiO oral (150 mg/kg), NiO IP (20 mg/kg), NiO IV (1 mg/kg), NiONP oral (150 mg/kg), NiONP IP (20 mg/kg), and NiONP IV (1 mg/kg) was administered for 21 days. After NiO and NiONP administration, a decrease in antioxidant activities and an increase in lipid peroxidation occurred in the kidney tissue of rats. Increased kidney urea, uric acid, and creatinine levels were observed. Inhibition of acetylcholinesterase activity and an increase in interleukin 1 beta were detected. Apoptotic markers, Bax, caspase-3, and p53 up-regulation and Bcl-2 down-regulation were observed. In addition, histopathological changes occurred in the kidney tissue. In general, it was observed that nickel oxide microparticles and nickel oxide nanoparticles cause inflammation by causing oxidative stress in the kidney tissue, and NiONP IV administration is more effective in renal toxicity., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Competing Interests: D.S. receives royalties from UpToDate (Wolters Kluwer Health). C.B.M. has no funding or conflicts of interest to declare.

Background: In Sweden, cobalt chloride 0.5% has been included in the baseline series since the mid-1980s. A recent study from Stockholm showed that cobalt chloride 1% petrolatum (pet.) was more suitable than 0.5%. Cobalt chloride at 1.0% has been patch tested for decades in many European countries and around the world., Objectives: To study the suitability of patch testing to cobalt 1.0% vs 0.5% and to analyze the co-occurrence of allergy to cobalt, chromium, and nickel., Results: Contact allergy to cobalt was shown in 90 patients (6.6%). Eighty (5.9%) patients tested positive to cobalt 1.0%. Thirty-seven of the 90 patients (41.1%) with cobalt allergy were missed by cobalt 0.5% and 10 (0.7%) were missed by cobalt 1.0% (P < .001). No case of patch test sensitization was reported. Allergy to chromium was seen in 2.6% and allergy to nickel in 13.3%. Solitary allergy to cobalt without nickel allergy was shown in 61.1% of cobalt-positive individuals. Female patients had larger proportions of positive reactions to cobalt (P = .036) and nickel (P < .001) than males., Conclusion: The results speak in favor of replacing cobalt chloride 0.5% with cobalt chloride 1.0% pet. in the Swedish baseline series, which will be done 2021., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The risk assessment conducted by the European Food Safety Authority stated some concerns regarding the chronic exposure of the European population to nickel due to food intake. This study aimed to evaluate the extent of the Belgian population's exposure to nickel via intake of different foods/drinks available in their market. Ni concentrations were measured in selected foods consumed in Belgium, and exposures from this limited group of foods were estimated for consumers of these foods. Legumes, soy products, breakfast cereals, and chocolate spreads were responsible for 26%, 14%, 11% and 8% of the overall exposure (overall chronic exposure through consuming all the included food types in this study except tap water) of children (3-9 years) to nickel. For adolescents (10-17 years), the highest percentage of overall chronic exposure again originated from legumes (19%). This was followed by breakfast cereals (14%), soy products (11%) and chocolate spreads (11%). For adults (18-64 years), major contributors to the overall chronic daily exposure were legumes (16%), dark chocolate (15%) and breakfast cereals (10%). The aggregate exposure assessment, including the highest contaminated foods, for different sub-populations, revealed mean exposure levels of 1.02, 0.60 and 0.34 μg kg -1 b.w. day -1 for children, adolescents, and adults respectively. The mean, P75, P90 and P95 values for aggregate chronic exposure of the overall consumer's population were 0.62, 0.80, 1.5 and 210 μg kg -1 b.w. day -1 respectively. This study recommends controlling the intake of food products with elevated nickel content especially for the more vulnerable sub-population groups such as children with lower body weight and nickel sensitised individuals. It also demonstrates a shift in potential risk on human health to nickel exposure due to the transition towards a more plant-based diet.

Dietary exposure of the Italian population to nickel has been assessed in the national Total Diet Study (TDS). Occurrence data were combined with national individual consumption data to estimate mean and high level dietary exposure of population subgroups according to age and gender, both at the national level and for the four main geographical areas of Italy. The mean chronic dietary exposure of infants and toddlers, children, adolescents, adults, and the elderly were 4.00, 4.57, 2.57, 1.55, and 1.47 μg/kg bw per day, respectively. These intakes lie in the intermediate range of exposure estimates from TDS carried out in other countries. Main contributors to the total nickel exposure for children and adolescents were 'sweet products' and 'cereals and cereal products'. In adults and the elderly nearly 30% of the exposure was associated to the consumption of 'cereals and cereal products'. Mean and 95th percentile chronic dietary exposure was below the TDI in all age groups. For the risk characterisation of acute oral exposure, exposure data for consumers only in the adult population were compared with the reference point for systemic contact dermatitis. Consumption of 'cocoa', 'chocolate', 'crustaceans and molluscs', 'pulses' had remarkable potential to elicit adverse effects in nickel-sensitised individuals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: This study was designed to report the biological effect of nickel oxide nanoparticles (NiO NPs) in albino mice., Material and Methods: Five weeks old albino mice of both sex were intraperitoneally injected either with 20 mg (low dose) or 50 mg/mL saline/kg body weight (high dose) of NiO NPs for 14 days. Saline-treated controls were maintained in parallel. Complete blood count, selected serum biochemical parameters and oxidative stress biomarkers from vital organs were determined in all subjects., Results: Male mice treated with NiO NPS had increased blood urea nitrogen, elevated superoxide dismutase (SOD) in liver elevated MDA in liver, kidney and heart and reduced catalase activity in heart and kidney. Female mice treated with NiO NPs had significantly reduced serum albumin and total proteins, SOD in lungs and elevated MDA in liver., Discussion: We are reporting that intraperitoneal injections of NiO NPs for 14 days drastically affect blood serum parameters and oxidative stress biomarkers from vital organs of albino mice., Conclusion: Toxic effects of NiO NPs were dose and sex dependent and they were more pronounced at higher dose and in male mice.

Adaptive features of natural killer (NK) cells have been reported in various species with different underlying mechanisms. It is unclear, however, which NK cell populations are capable of mounting antigen-specific recall responses and how such functions are regulated at the molecular level. Here, we identify and characterize a discrete population of CD49a + CD16 - NK cells in the human liver that displays increased epigenetic potential to elicit memory responses and has the functional properties to exert antigen-specific immunity in the skin as an effector site. Integrated chromatin-based epigenetic and transcriptomic profiling revealed unique characteristics of hepatic CD49a + CD16 - NK cells when compared with conventional CD49a - CD16 + NK cells, thereby defining active genomic regions and molecules underpinning distinct NK cell reactivity. In contrast to conventional NK cells, our results suggest that adaptive CD49a + CD16 - NK cells are able to bypass the KIR receptor-ligand system upon antigen-specific stimulation. Furthermore, these cells were highly migratory toward chemokine gradients expressed in epicutaneous patch test lesions as an effector site of adaptive immune responses in the skin. These results define pathways operative in human antigen-specific adaptive NK cells and provide a roadmap for harnessing this NK cell subset for specific therapeutic or prophylactic vaccine strategies., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Suprabasin (SBSN) is expressed not only in epidermis but also in epithelial cells of the upper digestive tract where metals such as nickel are absorbed. We have recently shown that SBSN level is decreased in the stratum corneum and serum of atopic dermatitis (AD) patients, especially in intrinsic AD, which is characterized by metal allergy. By using SBSN-null (Sbsn -/- ) mice, this study was conducted to investigate the outcome of SBSN deficiency in relation to AD. Sbsn -/- mice exhibited skin barrier dysfunction on embryonic day 16.5, but after birth, their barrier function was not perturbed despite the presence of ultrastructural changes in stratum corneum and keratohyalin granules. Sbsn -/- mice showed a comparable ovalbumin-specific skin immune response to wild type (WT) mice and rather lower contact hypersensitivity (CHS) responses to haptens than did WT mice. The blood nickel level after oral feeding of nickel was significantly higher in Sbsn -/- mice than in WT mice, and CHS to nickel was elevated in Sbsn -/- mice under nickel-loading condition. Our study suggests that the completely SBSN deficient mice retain normal barrier function, but harbor abnormal upper digestive tract epithelium that promotes nickel absorption and high CHS to nickel, sharing the features of intrinsic AD.

Gastric carcinoma is one of the most lethal malignant tumors. As part of our long-term efforts on seeking effective diagnosis and therapeutic strategies of gastric cancer, we present herein novel ternary copper-based chalcogenide nanoplatform CuS-NiS 2 nanomaterials with outstanding photothermal (PT)/photodynamic (PD) property that could effectively suppress human gastric cancer in vitro and in vi vo without obvious side effects. We revealed that CuS-NiS 2 induced reactive oxygen species (ROS) generation, leading to apoptosis through Bcl-2/Bax pathway of human gastric cancer cells under 808 nm near-infrared (NIR) irradiation. In addition, we also confirmed that the combination of CuS-NiS 2 and 808 nm NIR laser treatment triggered necroptosis by regulating the novel pathway MLKL/CAPG of human gastric cancer cells. Moreover, the CuS-NiS 2 exhibited excellent contrast enhancement according to magnetic resonance imaging (MRI). Taken together, we reported new ternary copper-based chalcogenide nanomaterials CuS-NiS 2 , which could be successfully applied for MRI-guided PT/PD therapy of gastric carcinoma through mitochondria-mediated apoptosis and MLKL/CAPG-mediated necroptosis.

Nickel oxide nanoparticle (NiO NPs) has been widely used in various fields such as catalysts, radiotherapy, and nanomedicine. The aim of this study was to compare the effects of nickel oxide (NiO) and NiO NPs on oxidative stress biomarkers and histopathological changes in brain tissue of rats. In this study, 49 male rats were randomly divided into one control group and 6 experimental groups (n = 7). The control group received normal saline and the treatment groups received NiO and NiO NPs at doses of 10, 25, and 50 mg/kg intraperitoneally for 8 days. After 8 days, animal was sacrificed, brain excised, homogenized, centrifuged, and then supernatant was collected for antioxidant assays. The results showed that activity of GST in NiO NPs groups with doses of 10, 25, and 50 mg/kg (79.42 ± 4.24, p = 0.035; 78.77 ± 8.49, p = 0.041; 81.38 ± 12.39, p = 0.042 to 47.26 ± 7.17) and catalase in NiO NPs groups with concentrations of 25 and 50 mg/kg (69.95 ± 8.65 to 39.75 ± 5.11, p = 0.02) and (68.80 ± 4.18 to 39.75 ± 5.11 p = 0.027) were significantly increased compared with the control, respectively. Total antioxidant capacity in NiONPs group with doses of 50 mg/kg was significantly decreased (345.00 ± 23.62, p = 0.015 to 496.66 ± 25.77) compared with control. The GSH level in all doses NiO and NiONPs was significantly decreased compared with the control (p = 0.002). MDA level in NiONPs and NiO groups with doses of 50 mg/kg was significantly increased (13.03 ± 1.29, p = < 0.01; 15.61 ± 1.08, p = < 0.001 to 7.32 ± 0.51) compared with the control, respectively. Our results revealed a range of histopathological changes, including necrosis, hyperemia, gliosis, and spongy changes in brain tissue. Thus, increasing level of MDA, GST, and CAT enzymes and decreasing GSH and TAC and also histopathological changes confirmed NiONPs and NiO toxicity.

To study the toxicity induced by Nickel sulfate (NiSO 4 ) on thyroid tissue, and investigate the role of apoptosis as the possible mechanism, thirty-two male Wistar rats were randomly divided into control group (normal saline, ip), low dose group (2.5 mg/kg day NiSO 4 , ip), middle dose group (5 mg/kg day NiSO 4 , ip), high dose group (10 mg/kg day NiSO 4 , ip). After 40 consecutive days of treatment, there were obvious pathological changes in the thyroids of high dose group. Free T 4 (FT 4 ) and thyroid-stimulating hormone (TSH) were significantly lower in the NiSO 4 -treated groups than those in the control group (F = 4.992, p = 0.016; F = 4.524, p = 0.012). The mRNA expression of Caspase-3 was significantly higher (F = 10.259, p = 0.014) in all NiSO 4 -treated groups, and the mRNA expression of Bcl-2 was significantly lower (F = 9.225, p = 0.018) only in the high dose group. Both control group and the NiSO 4 -treated groups showed no changes in the mRNA expression of Bax gene. The ratio of Bcl-2/Bax decreased with the increase in exposure dose of NiSO 4 (F = 13.382, p = 0.015). The mRNA expression of Fas went up in high dose group (F = 66.632, p < 0.001). The Caspase-3, Fas, and the Bax protein expressions measured by immunohistochemistry were consistent with the mRNA expression. The expression of Bcl-2 protein was significantly lower in the test groups than in the control group (F = 3.873, p = 0.025). NiSO 4 as an Endocrine Disrupting Chemical may induce the thyroid injury through apoptosis and lead to hypothyroidism. Also, apoptosis in thyroid tissues was closely related to the alternations of Caspase-3, Bcl-2, and Fas mRNA and protein expression.

Background: Nickel (Ni) oral consumption may elicit systemic reactions in patients affected by systemic nickel allergy syndrome (SNAS), including gastrointestinal symptoms, which in turn are associated with gut dysbiosis. We evaluated the effects of a low-Ni diet alone or in combination with the oral consumption of appropriate probiotics on Ni-sensitivity and urinary dysbiosis markers in SNAS patients., Methods: n = 51 patients with SNAS and concomitant intestinal dysbiosis were enrolled in the study. According to the urinary indican/skatole levels, quantified through a colorimetric and a high-performance liquid chromatographic method, respectively, patients were assigned to a dysbiosis type/grade and followed a low-Ni diet for three months. Along with the diet, 22 patients also consumed probiotics based on the dysbiosis type. In particular, a Lactobacilli- or Bifidobacteria-containing formulation was administered to patients with fermentative or putrefactive dysbiosis, respectively, while a broad-spectrum probiotic formulation containing both Lactobacilli and Bifidobacteria was administered to patients with mixed dysbiosis. After three months, patients were invited to repeat the Ni-stimulation and the dysbiosis tests., Results: The fermentative dysbiosis group represented the largest group followed by the mixed dysbiosis group, while only two patients had putrefactive dysbiosis. Overall, at three months of treatment in general (diet alone with or without probiotics), the Ni-sensitivity and dysbiosis levels were strongly ameliorated. The association of a low-Ni diet with a specific probiotic oral supplementation was significantly more effective in decreasing dysbiosis levels or reaching eubiosis than with diet alone., Conclusion: Our results, while confirming the benefits of a low-Ni diet in SNAS patients, strongly support that appropriate adjuvant treatment with probiotics significantly helps to improve intestinal dysbiosis or restore a healthy microbiota., Competing Interests: The authors declare no conflict of interest.

The transition metal nickel is used in a wide variety of alloys and medical devices. Nickel can cause a range of toxicities from allergy in humans to tumors when implanted in animals. Several microarray studies have examined nickel toxicity, but so far none have comprehensively profiled expression over an extended period. In this work, male mice were implanted with a single nickel pellet in the muscle of the right leg with the left leg used as a control. At 3 week intervals up to 12 months, nickel concentrations in bioflulids and microarrays of surrounding tissue were used to track gene expression patterns. Pellet biocorrosion resulted in varying levels of systemic nickel over time, with peaks of 600 μg L -1 in serum, while global gene expression was cyclical in nature with immune related genes topping the list of overexpressed genes. IPA and KEGG pathway analyses was used to attribute overall biological function to changes in gene expression levels, supported by GO enrichment analysis. IPA pathways identified sirtuin, mitochondria, and oxidative phosphorylation as top pathways, based predominantly on downregulated genes, whereas immune processes were associated with upregulated genes. Top KEGG pathways identified were lysosome, osteoclast differentiation, and phasgosome. Both pathway approaches identified common immune responses, as well as hypoxia, toll like receptor, and matrix metalloproteinases. Overall, pathway analysis identified a negative impact on energy metabolism, and a positive impact on immune function, in particular the acute phase response. Inside the cell the impacts were on mitochondria and lysosome. New pathways and genes responsive to nickel were identified from the large dataset in this study which represents the first long-term analysis of the effects of chronic nickel exposure on global gene expression.

This study aimed to evaluate the mean concentration of cadmium (Cd), chromium (Cr), copper (Cu), nickel (Ni), and lead (Pb) in the meat and offal of cow and sheep. Also, the estimated daily intake (EDI) and health risk of these metals were calculated. Analysis of metals was undertaken by the use of an inductively coupled plasma-optic emission spectroscopy (ICP-OES). All samples were contaminated with all metals. Principal component analysis (PCA) showed a clear differentiation of cow and sheep in both the kidney and liver samples. In the liver and kidney, level of Cd, Cu, and Pb were positively correlated. The highest target hazard quotients (THQs) were calculated for Pb. Cd level in cow kidney had the highest carcinogenic rate (CR). Although, hazard index (HI) was lower than one, consumption of muscle especially in children should be noticed in both national and international consumers due to higher level of HI.

Background: Patch testing with a baseline series is a common tool employed when the sensitizing agent in contact dermatitis is unclear. However, for Asian countries, there are no locally validated baseline series to utilize in screening., Methods: We completed a retrospective analysis of all patients that had undergone patch testing with the European Baseline series, Shoe Series or Comprehensive International Baseline series, over 7 years from 2012 to 2018 in a tertiary care reference dermatology clinic in Sri Lanka to evaluate the suitability of these investigations to identify causes for contact dermatitis in the local study population., Results: Out of 438 patients tested, 239 (54.8%) reacted to at least one substance in the series. The Shoe Series was significantly more likely to yield a positive result than the European Baseline Series (70.2% vs 46.9%, p < 0.05). The top three sensitizers identified by all series were nickel sulfate (16%, 70/438), p-phenylenediamine (12.3%, 54/438) and 2-mercaptobenzothiazole or mercapto mix (10.5%, 46/438)., Conclusion: Shoe series has a comparatively high yield in the local population compared to European Baseline series. Since little less than half of the study population did not have any reactivity to any of the allergens tested it is important to develop or modify and validate a locally relevant, more suitable baseline series which is based on the Shoe Series in Sri Lanka. This is further evidence for the continuously changing nature of allergens in the environment and the need to modify existing patch testing standards accordingly.

Despite the increasing use of nickel oxide (NiO) nanoparticles (NPs), limited information is available on their toxicological effects. Health consequences of 28 days repeated oral exposure to NiO NPs have not been explored thoroughly. Hence, toxicity investigations were performed after 28-day daily exposure in albino Wistar rats with NiO NPs following Organization for Economic Co-operation and Development test guideline 407. Histopathology, biochemical indices including oxidative stress and biodistribution patterns were evaluated to decipher the toxicological impact of NiO NPs. NiO NP characterization by transmission electron microscopy showed an average size of 12.9 (±3.4) nm. Histological studies depicted a prominent impact on the vital organs of the rats. A dose-dependent rise in both aminotransferase enzyme values was recorded in the homogenates of liver and kidney tissues. A significant decrease in superoxide dismutase activity and increase in catalase activity was noted. Further, a dose-dependent decrease in reduced glutathione content was recorded in rats, which suggested generation of reactive oxygen species and oxidative stress. Increase in the malondialdehyde levels was observed with an increase in the dose substantiating the antioxidant enzyme activity profiles. Biodistribution studies indicated maximum accumulation of Ni content in liver followed by kidney. Excretion of Ni was predominantly through feces and a little through renal clearance. Our study indicated that NiO NPs adversely alter the biochemical profile of the rats and cause histological damage. Further investigations are warranted to address the mechanism by which physiological path these NiO NPs exhibit their toxic nature in in vivo., (© 2019 John Wiley & Sons, Ltd.)

Nickel oxide nanoparticles (NiO NPs) are utilized in various industries and their release into the environment may lead to the pollution of agricultural areas. However, assessing the toxicity of NiO NPs in major food crops is difficult due to the limited information available on their toxicity. The present investigation was carried out to evaluate how NiO NPs affect plant growth, photosynthetic efficiency, and phytochemical content, as well as changes at the transcriptional level of these phytochemicals in Chinese cabbage seedlings. Chlorophyll, carotenoid, and sugar contents were reduced, while proline and the anthocyanins were significantly upregulated in NiO NPs-treated seedlings. The levels of malondialdehyde, hydrogen peroxide, and reactive oxygen species, as well as peroxidase (POD) enzyme activity, were all enhanced in seedlings exposed to NiO NPs. The levels of glucosinolates and phenolic compounds were also significantly increased in NiO NPs-treated seedlings compared to control seedlings. The expression of genes related to oxidative stress (CAT, POD, and GST), MYB transcription factors (BrMYB28, BrMYB29, BrMYB34, and BrMYB51), and phenolic compounds (ANS, PAP1, and PAL) were significantly upregulated. We suggest that NiO NPs application stimulates toxic effects and enhances the levels of phytochemicals (glucosinolates and phenolic compounds) in Chinese cabbage seedlings., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Nickel, a silver-colored metal found in nature, is a common cause of allergic contact dermatitis. Nevertheless, the existence of inflammatory reaction to oral nickel exposure remains controversial. The following study investigates whether oral nickel can change the intestinal microflora in mice. A total of 20 female ICR mice were randomly divided into two groups: the oral nickel group (Group O) and the control group (Group C). Group O received water containing 400 µM NiSO4·6H2O, while group C was given pure water for 21 days. The content of nickel in the kidneys was determined by atomic absorption spectrophotometry, while the composition of bacterial community in the cecum was detected by 16S rDNA sequencing. The results were subsequently validated by real-time quantitative PCR with genus and species specific primers. Compared to Group C, significantly higher nickel levels were observed in Group O (P = 0.016); however, our data suggested that oral administration of 400 µM NiSO4·6H2O was nontoxic to the animals. (No statistical difference in body animal weight was found between Group O and Group C, before and after oral administration of nickel.) At the genus level, significantly higher relative abundance of Bacteroides (P = 0.016) and Intestinimonas (P = 0.018), and significantly lower relative abundance of Lachnospiraceae&#95;NK4A136&#95;group (P = 0.002) and Lachnospiraceae&#95;UCG-001&#95;group (P = 0.042) were observed in the oral nickel group compared to the control group. In addition, Group O had significantly lower ratio of Firmicutes/Bacteroides (P = 0.008). The results of real-time quantitative PCR further confirmed that the amplicon mass of Bacteroides and B. fragilis in the Group O was significantly higher compared to C group (P = 0.034 and P = 0.02). Oral nickel could change the intestinal microflora in mice, thus suggesting that oral nickel alters the interaction between the host and the intestinal flora.

Background: Patch testing is the "gold standard" to identify culprit allergen(s) causing allergic contact dermatitis (ACD), but there are limited studies of patch testing from allergy practice settings., Objective: We sought to explore patch test findings in a large academic allergy practice, including patch testing results, history of atopy, location of dermatitis, and referral source. We also wanted to determine whether patch testing using an extended panel, such as the North American screening series, compared with a limited series, such as the Thin-Layer Rapid-Use Epicutaneous (T.R.U.E.) Test, increased the sensitivity., Methods: A retrospective chart review was conducted of patients referred for patch testing over a 6-year period., Results: A total of 585 patients (mean age 48.7 years, 71.6 % female) underwent patch testing over the 6-year period, of which 369 (63%) had a positive test. Of those who tested positive, 202 (55%) reported a history of atopy. The extremities were the most commonly involved site, followed by the head/neck and trunk. The 5 most common positive allergens were nickel sulfate, gold sodium thiosulfate, methylchloroisothiazolinone, thimerosal, and bacitracin. Three hundred fourteen (53.6%) patients were positive to at least 1 allergen on TRUE testing. Extended screening series identified an additional 10.8% of patients with positive tests who were negative to T.R.U.E. test allergens., Conclusion: Patch testing is a valuable diagnostic tool for the practicing allergist and provides early identification of culprit allergens in ACD. Performing an extended screening series such as the North American Contact Dermatitis Group (NACDG) or supplemental panel of allergens increased sensitivity when compared with a limited series., (Copyright © 2019 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Nickel and chromium existing in stainless-steel crowns (SSCs, used in pediatric dentistry) might be cytotoxic and allergenic. However, no in vivo studies have examined their salivary levels in children using SSCs, or in young children without SSCs. Also, the effect of acidity on metal ion release has not yet been evaluated in any previous in vivo studies in the whole literature. Therefore, this preliminary before-after clinical trial was conducted. Salivary nickel/chromium levels of 30 children before and after 2 months of placement of SSCs were measured using atomic absorption spectrophotometry. Salivary pH was measured with a digital pH meter. The effects of treatment, pH, number of SSCs, gender, and age on salivary ions were analyzed statistically (α = 0.05, β = 0.15). Salivary nickel concentrations increased from 4.9010 ± 4.7390 to 5.6320 ± 4.7210 μg/L (P = 0.000, paired t test). Chromium increased from 0.3273 ± 0.5214 to 0.4199 ± 0.6404 μg/L (P = 0.016). Saliva pH increased from 6.81 ± 0.52 to 7.04 ± 0.47 (P = 0.000). Ion levels were not correlated with pH (P > 0.14), except chromium in the follow-up (rho = - 0.435, P = 0.016). Nickel increase (but not chromium increase) was correlated with pH increase (rho = 0.367, P = 0.046). Age was only correlated with baseline chromium (rho = 0.373, P = 0.042). Being male was associated with baseline/follow-up nickel levels (P ≤ 0.030). SSC number was not correlated with ions or pH (P > 0.36). It was shown for the first time that SSCs might increase salivary nickel and chromium concentrations and reduce saliva acidity. Nickel increase might be in line with pH elevation. The raised pH might be associated with reduced chromium release. Boys might have higher nickel levels than might girls, with or without SSCs.

Background: The European Chemical Agency (ECHA) definition of prolonged contact was introduced in 2014 and has not been evaluated clinically., Objectives: To assess whether nickel-sensitized individuals react on patch testing with high nickel-releasing metal discs for short and repetitive periods., Materials and Methods: We patch tested 45 nickel-sensitized individuals double-blind with 2 different types of high nickel-releasing discs for 10, 30 and 60 minutes on 3 occasions over a period of 2 weeks, and for 1 longer period. Discs were tested for nickel release., Results: Nickel release from both discs significantly exceeded the 0.5 μg Ni/cm 2 /week limit of the EU REACH nickel restriction. However, only 1 individual tested had a largely dose-dependent allergic reaction., Conclusions: The majority of nickel-allergic subjects did not react to nickel discs after 2 hours or after repetitive exposures of up to 30 minutes on 3 occasions over a period of 2 weeks. The length of time needed to cause nickel allergic contact dermatitis in most nickel-allergic individuals is longer than the ECHA guidance definition. Longer test times are needed to define the time required to cause dermatitis in most nickel-allergic individuals. As a limitation, the test conditions did not adequately assess real-life factors such as friction, which is relevant for some uses of nickel., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Knowledge about the required duration of exposure for elicitation of allergic nickel dermatitis in nickel-allergic individuals is limited. However, it often has been proposed that short skin contact is safe., Objectives: To examine whether repeated skin contact with nickel over short time periods (3 × 10 min) can elicit allergic nickel dermatitis., Methods: Sixteen nickel-allergic adults and 10 controls were exposed to, respectively, nickel- and aluminium-containing discs on each volar forearm and on each earlobe for 3 × 10 min. One arm was pretreated for 24 h with sodium lauryl sulfate (SLS) 0·5% under occlusion before exposure. One aluminium and one nickel exposure site were clinically evaluated, and blood flow was measured with laser Doppler flowmetry at day 2 and day 4., Results: Ten of 16 (63%) nickel-allergic participants developed allergic nickel dermatitis on SLS-pretreated arm skin and three of 16 (19%) developed it on normal skin on the earlobe. On the SLS-pretreated arms of nickel-allergic participants, blood flow increased significantly more on the nickel-exposed skin than on the aluminium-exposed skin on days 2 and 4. No change in clinical reactivity or blood flow was found on normal forearm skin in nickel-allergic participants or on any skin in controls., Conclusions: This experimental study showed that relatively short repeated skin contact (3 × 10 min) with metallic nickel elicits allergic nickel dermatitis in irritated skin and at sites with previous dermatitis. The results support the restrictions in current nickel regulation., (© 2018 British Association of Dermatologists.)

Background: Nickel is among the most common contact allergens found on patch testing worldwide and, because of its ubiquitous nature in our environment, often has important implications for allergen avoidance strategies. In both North America and Europe, nickel positivity is found in approximately 20% of patients who undergo patch testing. Whereas in North America, nickel sulfate is typically tested at a concentration of 2.5%, in Europe, it is tested at a 5% concentration., Objective: The primary objective was to assess the differences in patch test positivity to nickel sulfate 2.5% and 5%., Methods: We investigated 205 consecutive patients between September 2017 and February 2018 who were tested to nickel sulfate at concentrations of both 2.5% and 5%., Results: Among the 205 patients tested, 33% were positive (+, ++, or +++) to at least 1 concentration of nickel sulfate, 20% were positive to nickel sulfate 2.5%, and 31% were positive to nickel sulfate 5% (χ1(N = 205) = 16.1, P = 0.0001). Patients were 6.5 times more likely to have a positive reaction to nickel sulfate 5% than 2.5% (odds ratio 95% confidence interval, 2.3-25.6)., Conclusions: Given our findings, we propose an additional evaluation of nickel sulfate 5% as a standard allergen for patch testing in North America.

We investigated the effects of nickel oxide nanoparticles (NiONPs) on the pulmonary inflammopathology. NiONPs were intratracheally installed into mice, and lung injury and inflammation were evaluated between 1 and 28 days. NiONPs caused significant increases in LDH, total protein, and IL-6 and a decrease in IL-10 in the BALF and increases in 8-OHdG and caspase-3 in lung tissues at 24 h. Airway inflammation was present in a dose-dependent manner from the upper to lower airways at 24 h of exposure as analyzed by SPECT. Lung parenchyma inflammation and small airway inflammation were observed by CT after NiONP exposure. 8-OHdG in lung tissues had increased with formation of fibrosis at 28 days. Focal adhesion was the most important pathways identified at 24 h as determined by protemics, whereas glutathione metabolism was the most important identified at 28 days. Our results demonstrated the pulmonary inflammopathology caused by NiONPs based on image-to-biochemical approaches., (Copyright © 2017 Elsevier Inc. All rights reserved.)

It is difficult to develop highly selective substrate-based fluorescent nanoprobes for specific matrix metalloproteinases (MMPs) due to overlapping substrate specificities among the family of MMP enzymes. To resolve this issue, we have developed novel fluorescent nanoprobes that are highly selective for soluble MMP-2. Herein, MMP-2-responsive nanoprobes were prepared by immobilizing fluorescent fusion proteins on nickel ferrite nanoparticles via the His-tag nickel chelation mechanism. The fusion protein consisted of a fluorescent mCherry protein with a cell penetrating peptide (CPP) moiety. An MMP-2 cleavage site was also introduced within the fusion protein, which was directly linked to the nickel ferrite nanoparticles. The selectivity of nanoprobes was modulated by hiding the cleavage site of MMP-2 substrates deeply inside the system, which could result in strong steric hindrance between the nanoprobes and MMPs, especially for membrane-tethered MMPs such as MMP-14. A cell-based assay demonstrated that the nanoprobes could only be activated by tumor cells secreting soluble MMP-2, but not membrane-tethered MMP-14. To further evaluate the contribution of the steric hindrance effect on the nanoprobes, a truncated recombinant MMP-14 was employed to confer their cleavage activity as compared to native membrane-tethered MMP-14. Furthermore, a designed probe with a diminished steric hindrance effect was proved to be activated by membrane-tethered type MMP-14. The results indicated that the design of fluorescent nanoprobes employing the steric hindrance effect can greatly enhance the selectivity of MMP-responsive nanoprobes realizing the specific detection of soluble MMP-2 in a tumor microenvironment. We believe that highly selective MMP-2-responsive fluorescent nanoprobes have broad impacts on biomedical applications including molecular imaging and labeling for tumor detection.

There is a proposed link between prenatal nickel (Ni) exposure and preterm low birth weight (PLBW); however, this association remains unclear. Selenium (Se) may modify this relationship by protecting against Ni toxicity. Concentrations of Ni and Se were measured in urine samples collected from 408 pregnant women (102 PLBW cases and 306 matched controls) in China. Conditional logistic regression was utilized to explore the association between Ni levels and PLBW, as well as the effect modification by Se on this association. A significant association was observed between higher maternal urinary Ni levels and risk of PLBW [adjusted odds ratio (OR) = 2.80 (95% confidence interval (CI): 1.44, 5.44) for the highest tertile], and this association was more apparent among female infants than that among male infants. Further analyses showed that mothers with high urinary Ni and low urinary Se levels had a significantly increased risk for PLBW [adjusted OR = 2.87 (95% CI: 1.09, 7.56)] compared with the mothers with low urinary Ni and high urinary Se levels. Our study indicates that prenatal exposure to Ni was a risk factor for PLBW. Se might provide protection against the toxicity of Ni.

Objective: To evaluate factors associated with treatment quality of ex vivo root canal treatments performed by undergraduate dental students using different endodontic treatment systems., Material and Methods: Four students performed root canal treatment on 80 extracted human teeth using four endodontic treatment systems in designated treatment order following a Latin square design. Lateral seal and length of root canal fillings was radiographically assessed; for lateral seal, a graded visual scale was used. Treatment time was measured separately for access preparation, biomechanical root canal preparation, obturation and for the total procedure. Mishaps were registered. An ANOVA mirroring the Latin square design was performed., Results: Use of machine-driven nickel-titanium systems resulted in overall better quality scores for lateral seal than use of the manual stainless-steel system. Among systems with machine-driven files, scores did not significantly differ. Use of machine-driven instruments resulted in shorter treatment time than manual instrumentation. Machine-driven systems with few files achieved shorter treatment times. With increasing number of treatments, root canal-filling quality increased, treatment time decreased; a learning curve was plotted. No root canal shaping file separated., Conclusions: The use of endodontic treatment systems with machine-driven files led to higher quality lateral seal compared to the manual system. The three contemporary machine-driven systems delivered comparable results regarding quality of root canal fillings; they were safe to use and provided a more efficient workflow than the manual technique. Increasing experience had a positive impact on the quality of root canal fillings while treatment time decreased.

Context: Nickel oxide (NiO) nanoparticles (NPs) with appropriate surface chemistry have been widely used for their potential new applications in biomedical industry. Increased usage of these NPs enhances the chance of exposure of personnel involved in the work place., Objective: This study was designed to assess the ability of NiO NPs to cause biochemical alterations post-acute oral exposure in female Wistar rats., Materials and Methods: Rats were administered with 125, 250, and 500 mg/kg doses of NiO NPs for haematological, biochemical, and histopathological studies. Biodistribution patterns of NiO NPs in female Wistar rats were also monitored., Results: NiO NPs caused significant (p < 0.01) inhibition of RBC and brain AchE of treated rats at the high dose. Activation of the hepatotoxicity marker enzymes, aminotransferases, was recorded in serum and liver, whereas inhibition was observed in kidney. The activity of antioxidant enzymes was also altered by NiO NPs in a dose-dependent manner and found to be significant at the high dose of exposure., Conclusions: This study revealed that exposure to nanosized NiO particles at acute doses may cause adverse changes in animal biochemical profiles. Further, the in vivo studies on toxicity evaluation help in biomonitoring of the potential contaminants.

Background: The toxicokinetics of nanomaterials are an important factor in toxicity, which may be affected by slow clearance and/or distribution in the body., Methods: Four types of nickel oxide (NiO) nanoparticles were single-administered intratracheally to male F344 rats at three doses of 0.67-6.0 mg/kg body weight. The rats were sacrificed under anesthesia and the lung, thoracic lymph nodes, bronchoalveolar lavage fluid, liver, and other organs were sampled for Ni burden measurement 3, 28, and 91 days post-administration; Ni excretion was measured 6 and 24 h after administration. Solubility of NiO nanoparticles was determined using artificial lysosomal fluid, artificial interstitial fluid, hydrogen peroxide solution, pure water, and saline. In addition, macrophage migration to trachea and phagosome-lysosome-fusion rate constants were estimated using pulmonary clearance and dissolution rate constants., Results: The wire-like NiO nanoparticles were 100% dissolved by 24 h when mixed with artificial lysosomal fluid (dissolution rate coefficient: 0.18/h); spherical NiO nanoparticles were 12% and 35% dissolved after 216 h when mixed with artificial lysosomal fluid (1.4 × 10 -3 and 4.9 × 10 -3 /h). The largest irregular-shaped NiO nanoparticles hardly dissolved in any solution, including artificial lysosomal fluid (7.8 × 10 -5 /h). Pulmonary clearance rate constants, estimated using a one-compartment model, were much higher for the NiO nanoparticles with a wire-shape (0.069-0.078/day) than for the spherical and irregular-shaped NiO nanoparticles (0-0.012/day). Pulmonary clearance rate constants of the largest irregular-shaped NiO nanoparticles showed an inverse correlation with dose. Translocation of NiO from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner for three spherical and irregular-shaped NiO nanoparticles, but not for the wire-like NiO nanoparticles. Thirty-five percent of the wire-like NiO nanoparticles were excreted in the first 24 h after administration; excretion was 0.33-3.6% in that time frame for the spherical and irregular-shaped NiO nanoparticles., Conclusion: These findings suggest that nanomaterial solubility differences can result in variations in their pulmonary clearance. Nanoparticles with moderate lysosomal solubility may induce persistent pulmonary inflammation.

T cell mediated hypersensitivity to nickel (Ni 2+ ) is one of the most common causes of allergic contact dermatitis. Ni 2+ sensitization may also contribute to the failure of Ni 2+ containing joint implants, and revision to non-Ni 2+ containing hardware can be costly and debilitating. Previously, we identified Ni 2+ mimotope peptides, which are reactive to a CD4 + T cell clone, ANi2.3 (Vα1, Vβ17), isolated from a Ni 2+ hypersensitive patient with contact dermatitis. This T cell is restricted to the major histocompatibility complex class II (MHCII) molecule, Human Leukocyte Antigen (HLA)-DR52c (DRA, DRB3*0301). However, it is not known if Ni 2+ induced T cell responses in sensitized joint replacement failure patients are similar to subjects with Ni 2+ induced contact dermatitis. Here, we generated DR52c/Ni 2+ mimotope tetramers, and used them to test if the same Ni 2+ T cell activation mechanism could be generalized to Ni 2+ sensitized patients with associated joint implant failure. We confirmed the specificity of these tetramers by staining of ANi2.3T cell transfectomas. The DR52c/Ni 2+ mimotope tetramer detected Ni 2+ reactive CD4 + T cells in the peripheral blood mononuclear cells (PBMC) of patients identified as Ni 2+ sensitized by patch testing and a positive Ni 2+ LPT. When HLA-typed by a DR52 specific antibody, three out of four patients were DR52 positive. In one patient, Ni 2+ stimulation induced the expansion of Vβ17 positive CD4 + T cells from 0.8% to 13.3%. We found that the percentage of DR52 positivity and Vβ17 usage in Ni 2+ sensitized joint failure patients are similar to Ni sensitized skin allergy patients. Ni 2+ independent mimotope tetramers may be a useful tool to identify the Ni 2+ reactive CD4 + T cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Keys are a significant source of exposure to metal allergens and can be a relevant problem for nickel-allergic individuals. This study aimed to perform nickel and cobalt spot testing among the 5 most common Brazilian brands of keys. Among the tested keys, 100% showed positive result to nickel spot test, 83,3% presented strong positive reaction. 50% exhibited cobalt release as well. Nickel release from keys is very common in our country and may cause a negative impact on sensitized individual's quality of life. Study's results highlight the importance of establishing directives to regulate nickel release in Brazil.

In this study, long-term effects of Ni, a widespread heavy metal in the aquatic ecosystems, have been determined on growth and lethality of the clam Ruditapes philippinarum, a known bioindicator of the marine environment. Three/four-month-old bivalves have been exposed to different concentrations of Ni dissolved in synthetic seawater. Growth and lethality as endpoints after 28 days of treatment have been observed. Obtained results are the following: EC 25  = 3.97 ± 0.94 and 9.45 ± 1.59 mg/L and NOEC = 1.56 and 6.25 mg/L for growth and mortality, respectively. Moreover, this study can be considered a new tool for the evaluation of fitness of bivalve clam, together with other biological responses following to the biological impacts of metal pollution.

The chief chemotherapeutic drug, cisplatin had common bad effects such as nephrotoxicity, ototoxicity and bone marrow depression. This led us to develop a new potential anticancer drug based on nickel metal ion that may be less toxic. Nickel(II) diacetyl monoxime-2-pyridyl hydrazone complex cytoprotective effect, superoxide dismutase (SOD)-like activity and anticancer activities were studied. In vitro, the complex showed SOD-like activity of 86.62%. It was capable to kill 90.2% of Ehrlich ascites carcinoma (EAC) cells and to protect 92.48% of human RBCs. In vivo, the complex lowered the tumor burden markedly in a concentration-dependent manner. Noticeably, solid tumor growth was suppressed; tumor volume and weight were reduced and mice life span was lengthened. The hematological indices were improved, catalase activity was re-elevated and malondialdehyde (MDA) level was reversed towards normal. Nucleic acids, cholesterol, triglycerides, liver enzymes, urea and creatinine contents were reduced to near normal ranges. Glutathione (GSH), SOD, albumin and total protein levels were increased. In conclusion, our results revealed that the complex has the ability to suppress Ehrlich solid tumor growth in mice with minimal side effects. This may possibly via its redox activity. Surprisingly, nickel complex antitumor activities were more potent than those of cisplatin., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Aims: The aim of this study was to evaluate the quality of various filling techniques in distal canals of mandibular molars instrumented with different single-file nickel-titanium (NiTi) systems., Materials and Methods: A total of 150 distal roots of mandibular molar teeth were randomly assigned into three main groups and instrumented by using Reciproc (VDW, Munich, Germany), WaveOne (Dentsply Tulsa, Tulsa, OK, USA), or One Shape (MicroMega, Besancon, France) NiTi file systems. The roots were then treated using one of five filling techniques: (1) Matched-single-cone, (2) cold lateral compaction with matched gutta-percha (GP) cone, (3) Thermafil filling, (4) System B/Obtura II, and (5) lateral compaction with standardized GP cones. The roots were then sectioned at three levels (coronal, middle, and apical). Photographs were acquired under a stereomicroscope, and the percentage of GP-filled areas (PGFAs), percentage of sealer-filled areas (PSFAs), and voids were measured using the ImageJ software. Comparisons between groups were applied using Student's t-test or one-way ANOVA for normally distributed data. The Mann-Whitney U-test or Kruskal-Wallis test was used when variables were not normally distributed., Results: Canals filled with the System B/Obtura showed the highest PGFA and lowest PSFA, whereas those filled with matched-single-cone showed the highest PSFA and lowest PGFA (P < 0.05). The cold lateral compaction with matched GP cone group, lateral compaction group, and Thermafil filling group showed no statistically significant differences in PSFA and PGFA (P > 0.05)., Conclusions: System B/Obtura technique appears to be the best technique to properly fill root canals, whereas the matched-single-cone technique in oval-shaped distal canals of mandibular molars was inadequate.

The International Commission on Radiological Protection (ICRP) is updating its suite of reference biokinetic models for internally deposited radionuclides. This paper reviews data for nickel and proposes an updated biokinetic model for systemic (absorbed) nickel in adult humans for use in radiation protection. Compared with the ICRP's current model for nickel, the proposed model is based on a larger set of observations of the behavior of nickel in human subjects and laboratory animals and provides a more realistic description of the paths of movement of nickel in the body. For the two most important radioisotopes of nickel, Ni and Ni, the proposed model yields substantially lower dose estimates per unit of activity reaching blood than the current ICRP model.

In this study, Paclitaxel (PTX) containing, bovine serum albumin (BSA) nanoparticles were fabricated via a simple approach. Folic acid (FA) was conjugated to chitosan (CS)/carboxymethyl cellulose (CMC) through an esterification reaction to produce BSA-CS-FA or BSA-CMC-FA conjugates. NiFe 2 O 4 noncore (NFs) and PTX were loaded through a heat treatment and by a diffusion process. NFs-BSA-CS and NFs-BSA-CMC-FA with size of about 80nm, showed superior transversal R 2 relaxation rate of 349 (mM) -1 s -1 along with folate receptor-targeted and magnetically directed functions. NFs-BSA-CS-FA or NFs-BSA-CS-FA were found stable and biocompatible. Application of an external magnetic field effectively enhanced the PTX release from PTX-NFs-BSA-CS-FA or PTX-NFs-BSA-CS-FA and hence tumor inhibition rate. This study validate that NFs-BSA-CS-FA or NFs-BSA-CMC-FA and PTX-NFs-BSA-CS-FA or PTX-NFs-BSA-CS-FA are suitable systems for tumor diagnosis and therapy., (Copyright © 2016. Published by Elsevier B.V.)

Thiosemicarbozone complexes that have a broad spectrum of biological activity are formed as a result of condensation reaction between thiosemicarbazide [H2N(C=S)-NH-NH2] and carbonyl-containing compounds. A new Nickel(II) complexes with N1-acetylacetone, N4-4-methoxy-salicylidene-thiosemicarbazidato ligand was synthesized and characterized. We studied the antileukemic activity of the Ni(II) thiosemicarbazone compound and assessed their potential for drug development. Specifically, the effects of this Ni(II) thiosemicarbazone compound on intracellular signal nodes and apoptotic pathways were investigated. According to our results, the Ni(II) thiosemicarbazone compound has apoptotic activity against HL60 cells. Moreover, while Ni(II) thiosemicarbazone compound significantly increased levels of p53 and cleaved caspase-3 proteins, it decreased level of Phospho-Akt1 protein in HL60 cells. The Ni(II) thiosemicarbazone compound could induce HL60 cell apoptosis through inhibiting of PI3K/Akt pathway. These results showed that Ni(II) thiosemicarbozone compound might be an antileukemic agent.

Indium is an essential element in the manufacture of liquid crystal displays and other electronic devices, and several forms of indium compounds have been developed, including nanopowders, films, nanowires, and indium metal complexes. Although there are several reports on lung injury caused by indium-containing compounds, the toxicity of nanoscale indium oxide (In2O3) particles has not been reported. Here, we compared lung injury induced by a single exposure to In2O3 nanoparticles (NPs) to that caused by benchmark high-toxicity nickel oxide (NiO) and copper oxide (CuO) NPs. In2O3 NPs at doses of 7.5, 30, and 90 cm(2)/rat (50, 200, and 600 µg/rat) were administered to 6-week-old female Wistar rats via pharyngeal aspiration, and lung inflammation was evaluated 1, 3, 14, and 28 days after treatment. Neutrophilic inflammation was observed on day 1 and worsened until day 28, and severe pulmonary alveolar proteinosis (PAP) was observed on post-aspiration days 14 and 28. In contrast, pharyngeal aspiration of NiO NPs showed severe neutrophilic inflammation on day 1 and lymphocytic inflammation with PAP on day 28. Pharyngeal aspiration of CuO NPs showed severe neutrophilic inflammation on day 1, but symptoms were completely resolved after 14 days and no PAP was observed. The dose of In2O3 NPs that produced progressive neutrophilic inflammation and PAP was much less than the doses of other toxic particles that produced this effect, including crystalline silica and NiO NPs. These results suggest that occupational exposure to In2O3 NPs can cause severe lung injury.

Nickel (Ni), one of hazardous environmental chemicals, is known to cause liver injury. Accumulating evidence showed that puerarin (PU) possessed comprehensive biological effects. The purpose of the current study was to test the hypothesis that the puerarin protects against enhanced liver injury caused by Ni in mice. ICR mice received intraperitoneally nickel sulfate (20 mg/kg/body weight, daily) for 20 days, and puerarin (200 and 400 mg/kg/body weight) was applied before Ni exposure. The results indicated that puerarin markedly inhibited Ni-induced liver injury, which was characterized by decreased aminotransferase activities and inflammation. Puerarin also inhibited the oxidative stress and decreased the metallothionein (MT) levels. Puerarin decreased the level of pro-inflammatory cytokines TNF-α and IL-6 in livers. Puerarin significantly inhibited the TLR4 activation and p38 MAPK phosphorylation, which in turn inhibited NF-κB activity. Likewise, Ni-induced inflammatory responses were diminished by puerarin as observed by a remarkable reduction in the levels of phosphorylated CREB. Furthermore, puerarin also reduced inflammatory mediators such as cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) levels in livers. Data from this study suggested that the inhibition of Ni-induced oxidative stress and inflammatory responses by puerarin is due to its ability to modulate the TLR4/p38/CREB signaling pathway., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The health risks of inhalation exposure to engineered nanomaterials in the workplace are a major concern in recent years, and hazard assessments of these materials are being conducted. The pulmonary surfactant of lung alveoli is the first biological entity to have contact with airborne nanomaterials in inhaled air. In this study, we retrospectively evaluated the pulmonary surfactant components of rat lungs after a 4-week inhalation exposure to three different nanomaterials: fullerenes, nickel oxide (NiO) nanoparticles and multi-walled carbon nanotubes (MWCNT), with similar levels of average aerosol concentration (0.13-0.37 mg/m(3)). Bronchoalveolar lavage fluid (BALF) of the rat lungs stored after previous inhalation studies was analyzed, focusing on total protein and the surfactant components, such as phospholipids and surfactant-specific SP-D (surfactant protein D) and the BALF surface tension, which is affected by SP-B and SP-C. Compared with a control group, significant changes in the BALF surface tension and the concentrations of phospholipids, total protein and SP-D were observed in rats exposed to NiO nanoparticles, but not in those exposed to fullerenes. Surface tension and the levels of surfactant phospholipids and proteins were also significantly different in rats exposed to MWCNTs. The concentrations of phospholipids, total protein and SP-D and BALF surface tension were correlated significantly with the polymorphonuclear neutrophil counts in the BALF. These results suggest that pulmonary surfactant components can be used as measures of lung inflammation.

In order to examine whether intratracheal instillation studies can be useful for determining the harmful effect of nanoparticles, we performed inhalation and intratracheal instillation studies using samples of the same nanoparticles. Nickel oxide nanoparticles (NiO) and titanium dioxide nanoparticles (TiO2) were used as chemicals with high and low toxicities, respectively. In the intratracheal instillation study, rats were exposed to 0.2 or 1 mg of NiO or TiO2. Cell analysis and chemokines in bronchoalveolar lavage fluid (BALF) were analyzed from 3 days to 6 months following the single intratracheal instillation. In the inhalation study, rats were exposed to inhaled NiO or TiO2 (1.65, 1.84 mg/m(3), respectively) for 4 weeks. The same endpoints were examined from 3 days to 3 months after the end of exposure. Inhalation of NiO induced an increase in the number of neutrophils in BALF and concentrations of cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2 and heme oxygenase (HO)-1. Intratracheal instillation of NiO induced persistent inflammation and upregulation of these cytokines was observed in the rats. However, inhalation of TiO2 did not induce pulmonary inflammation, and intratracheal instillation of TiO2 transiently induced an increase in the number of neutrophils in BALF and the concentrations of CINC-1, CINC-2 and HO-1. Taken together, a difference in pulmonary inflammation was observed between the high and low toxicity nanomaterials in the intratracheal instillation studies, as in the inhalation studies, suggesting that intratracheal instillation studies may be useful for ranking the harmful effects of nanoparticles.

Background: Hattaraki pallye or prickly lettuce (Lactuca scariola Linn.) is one among several green leafy plants that grow in north Karnataka; it is usually consumed by the people of this region and is found to be antidiabetic in nature. The objective of this study is to evaluate hypoglycemic activities of supplementation with aqueous extract of prickly lettuce (L. scariola) leaves in vivo in acute and subchronic exposure with or without nickel (II) along with its glucose reduction capabilities with or without nickel (II) at pH 7.0 and 9.0 in vitro., Methods: Percentage glucose reduction (in vitro) was determined by glucose oxidase-peroxidase enzymatic method at pH 7.0 and pH 9.0 using UV-Vis spectrophotometer. Hypoglycemic activities of L. scariola were carried out in alloxan-induced male diabetic rats at both acute and subchronic exposure., Results: The results showed a significant alteration in the λmax value of Ni (II) in combination with L. scariola leaves extracts at both pH 7.0 and 9.0. The aqueous extract also produced a significant reduction in the glucose concentration at pH 7.0 and pH 9.0 even in presence of Ni (II) in vitro. Lactuca scariola leaves in either acute or subchronic supplementation showed a greater glucose tolerance and hypoglycemic regulation of blood sugar in diabetic rats with or without nickel (II) treatments., Conclusions: Lactuca scariola leaves can be a substitute for synthetic drugs to treat diabetic patients.

Stable suspensions of NiO and/or Mn3O4 nanoparticles with a mean diameter of 16.7 ± 8.2 nm and 18.4 ± 5.4 nm, respectively, prepared by laser ablation of 99.99% pure metals in de-ionized water were repeatedly injected IP to rats at a dose of 0.50 mg or 0.25 mg 3 times a week up to 18 injections, either separately or in different combinations. Many functional indices as well as histological features of the liver, spleen, kidneys and brain were evaluated for signs of toxicity. The accumulation of Ni and Mn in these organs was measured with the help of AES and EPR methods. Both metallic nanoparticles proved adversely bio-active, but those of Mn3O4 were found to be more noxious in most of the non-specific toxicity manifestations. Moreover, they induced a more marked damaging effect in the neurons of the caudate nucleus and hippocampus which may be considered an experimental correlate of manganese-induced parkinsonism. Mathematical analysis based on the Response Surface Methodology (RSM) revealed a diversity of combined toxicity types depending not only on particular effects these types are assessed for but on their level as well. The prognostic power of the RSM model proved satisfactory., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Here we showed that dietary NiCl2 in excess of 300 mg/kg caused the G2/M cell cycle arrest and the reduction of cell proportion at S phase. The G2/M cell cycle arrest was accompanied by up-regulation of phosphorylated ataxia telangiectasia mutated (p-ATM), p53, p-Chk1, p-Chk2, p21 protein expression and ATM, p53, p21, Chk1, Chk2 mRNA expression, and down-regulation of p-cdc25C, cdc2, cyclinB and proliferating cell nuclear antigen (PCNA) protein expression and the cdc25, cdc2, cyclinB, PCNA mRNA expression.

Background: The existing EU nickel restriction does not sufficiently protect the population from skin exposure to nickel. Better understanding is needed of the extent to which short and frequent contact with nickel-releasing items contributes to nickel deposition on skin., Objectives: To quantify nickel skin exposure from short and frequent contact with nickel-releasing materials., Materials/methods: Sequences of short contact events were assessed in (i) touch tests for measurement of nickel skin dose, (ii) wipe tests to similarly quantify the nickel release during a touch, and (iii) immersion tests in artificial sweat, for nickel-containing alloys and pure nickel., Results: Nickel skin doses from a single touch were 0.024-4.7 µg/cm(2) for all materials. Touching or wiping five untouched surfaces resulted in more accumulated nickel than five repeated touches of the same surface. The released amounts of nickel were generally lower at immersion, but increased with the number of repeated immersion periods., Conclusions: Nickel skin doses were quantified after one single touch for all study materials. Touch tests, and potentially wipe tests as a proxy for skin dose measurements, are preferred to immersion tests for the assessment of short and frequent skin contact with nickel., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Stable suspensions of NiO and Mn₃O₄ nanoparticles (NPs) with a mean (±s.d.) diameter of 16.7±8.2 and 18.4±5.4 nm, respectively, purposefully prepared by laser ablation of 99.99% pure nickel or manganese in de-ionized water, were repeatedly injected intraperitoneally (IP) to rats at a dose of 2.5 mg/kg 3 times a week up to 18 injections, either alone or in combination. A group of rats was injected with this combination with the background oral administration of a "bio-protective complex" (BPC) comprising pectin, vitamins A, C, E, glutamate, glycine, N-acetylcysteine, selenium, iodide and omega-3 PUFA, this composition having been chosen based on mechanistic considerations and previous experience. After the termination of injections, many functional and biochemical indices and histopathological features (with morphometric assessment) of the liver, spleen, kidneys and brain were evaluated for signs of toxicity. The Ni and Mn content of these organs was measured with the help of the atomic emission and electron paramagnetic resonance spectroscopies. We obtained blood leukocytes for performing the RAPD (Random Amplified Polymorphic DNA) test. Although both metallic NPs proved adversely bio-active in many respects considered in this study, Mn₃O₄-NPs were somewhat more noxious than NiO-NPs as concerns most of the non-specific toxicity manifestations and they induced more marked damage to neurons in the striatum and the hippocampus, which may be considered an experimental correlate of the manganese-induced Parkinsonism. The comparative solubility of the Mn₃O₄-NPs and NiO-NPs in a biological medium is discussed as one of the factors underlying the difference in their toxicokinetics and toxicities. The BPC has attenuated both the organ-systemic toxicity and the genotoxicity of Mn₃O₄-NPs in combination with NiO-NPs.

In the brain, NO is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also importantly involved in many neuronal functions and innumerable roles of NO in many brain related disorders including epilepsy, schizophrenia, drug addiction, anxiety, major depression, have been postulated. The present study aimed to explore the neuronal role exerted by the metal-nonoate compound Ni(PipNONO)Cl, a novel NO donor whose vascular protective effects have been recently demonstrated. Ni(PipNONO)Cl showed antidepressant-like properties in the tail suspension test and antiamnesic activity in the passive avoidance test in the absence of any hypernociceptive response to a mechanical stimulus. These effects were related to the NO-releasing properties of the compound within the central nervous system as demonstrated by the increase of iNOS levels in the brain, spinal cord and dura mater. The modulation of neuronal functions appeared after acute and repeated treatment, showing the lack of any tolerance to neuronal effects. At the dose used (10 mg/kg i.p.), Ni(PipNONO)Cl did not induce any visible sign of toxicity and experiments were performed in the absence of locomotor impairments. In addition to the NO-related neuronal activities of Ni(PipNONO)Cl, the decomposition control compound Ni(Pip)Cl2 showed anxiogenic-like and procognitive effects. The present findings showed neuronal modulatory activity of Ni(PipNONO)Cl through a NO-mediated mechanism. The activities of the decomposition compound Ni(Pip)Cl2 attributed to Ni(PipNONO)Cl the capability to modulate additional neuronal functions independently from NO releasing properties extending and improving the therapeutic perspectives of the NO donor., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A TAT47-57 peptide was modified on the N-terminus by elongation with a 2,3-diaminopropionic acid residue and then by coupling of two histidine residues on its N-atoms. This branched peptide could bind to Ni under physiological conditions as a 1 : 1 complex. We demonstrated that the complex was quantitatively taken up by human fibrosarcoma cells, in contrast to Ni(2+) ions. Ni localization (especially at the nuclei) was confirmed by imaging using both scanning X-ray fluorescence microscopy and Newport Green fluorescence. A competitive assay with Newport Green showed that the latter displaced the peptide ligand from the Ni-complex. Ni(2+) delivered as a complex with the designed peptide induced substantially more DNA damage than when introduced as a free ion. The availability of such a construct opens up the way to investigate the importance of the nucleus as a target for the cytotoxicity, genotoxicity or carcinogenicity of Ni(2+).