The effect of dihydroceramide desaturase 1 inhibition on endothelial impairment induced by indoxyl sulfate.

Protein-bound uremic toxins (PBUTs) have adverse effects on vascular function, which is imperative in the progression of cardiovascular and renal diseases. The role of sphingolipids in PBUT-mediated vasculo-endothelial pathophysiology is unclear. This study assessed the therapeutic potential of dihydroceramide desaturase 1 (Des1) inhibition, the last enzyme involved in de novo ceramide synthesis, to mitigate the vascular effects of the PBUT indoxyl sulfate (IS). Rat aortic rings were isolated and vascular reactivity was assessed in organ bath experiments followed by immunohistochemical analyses. Furthermore, cultured human aortic endothelial cells were assessed for phenotypic and mechanistic changes. Inhibition of Des1 by a selective inhibitor CIN038 (0.1 to 0.3 µM) improved IS-induced impairment of vasorelaxation and modulated immunoreactivity of oxidative stress markers. Des1 inhibition also reversed IS-induced reduction in endothelial cell migration (1.0 µM) by promoting the expression of angiogenic cytokines and reducing inflammatory and oxidative stress markers. These effects were associated with a reduction of TIMP1 and the restoration of Akt phosphorylation. In conclusion, Des1 inhibition improved vascular relaxation and endothelial cell migration impaired by IS overload. Therefore, Des1 may be a suitable intracellular target to mitigate PBUT-induced adverse vascular effects.

Dihydrosphingosine driven enrichment of sphingolipids attenuates TGFß induced collagen synthesis in cardiac fibroblasts.

The sphingolipid de novo synthesis pathway, encompassing the sphingolipids, the enzymes and the cell membrane receptors, are being investigated for their role in diseases and as potential therapeutic targets. The intermediate sphingolipids such as dihydrosphingosine (dhSph) and sphingosine (Sph) have not been investigated due to them being thought of as precursors to other more active lipids such as ceramide (Cer) and sphingosine 1 phosphate (S1P). Here we investigated their effects in terms of collagen synthesis in primary rat neonatal cardiac fibroblasts (NCFs). Our results in NCFs showed that both dhSph and Sph did not induce collagen synthesis, whilst dhSph reduced collagen synthesis induced by transforming growth factor ß (TGFß). The mechanisms of these inhibitory effects were associated with the increased activation of the de novo synthesis pathway that led to increased dihydrosphingosine 1 phosphate (dhS1P). Subsequently, through a negative feedback mechanism that may involve substrate-enzyme receptor interactions, S1P receptor 1 expression (S1PR1) was reduced.

Sphingolipid imbalance and inflammatory effects induced by uremic toxins in heart and kidney cells are reversed by dihydroceramide desaturase 1 inhibition.

Non-dialysable protein-bound uremic toxins (PBUTs) contribute to the development of cardiovascular disease (CVD) in chronic kidney disease (CKD) and vice versa. PBUTs have been shown to alter sphingolipid imbalance. Dihydroceramide desaturase 1 (Des1) is an important gatekeeper enzyme which controls the non-reversible conversion of sphingolipids, dihydroceramide, into ceramide. The present study assessed the effect of Des1 inhibition on PBUT-induced cardiac and renal effects in vitro, using a selective Des1 inhibitor (CIN038). Des1 inhibition attenuated hypertrophy in neonatal rat cardiac myocytes and collagen synthesis in neonatal rat cardiac fibroblasts and renal mesangial cells induced by the PBUTs, indoxyl sulfate and p-cresol sulfate. This is at least attributable to modulation of NF-κB signalling and reductions in ß-MHC, Collagen I and TNF-α gene expression. Lipidomic analyses revealed Des1 inhibition restored C16-dihydroceramide levels reduced by indoxyl sulfate. In conclusion, PBUTs play a critical role in mediating sphingolipid imbalance and inflammatory responses in heart and kidney cells, and these effects were attenuated by Des1 inhibition. Therefore, sphingolipid modifying agents may have therapeutic potential for the treatment of CVD and CKD and warrant further investigation.

Apoptosis signal-regulating kinase 1 inhibition reverses deleterious indoxyl sulfate-mediated endothelial effects.

AIMS: Indoxyl sulfate (IS), a protein-bound uremic toxin, is implicated in endothelial dysfunction, which contributes to adverse cardiovascular events in chronic kidney disease. Apoptosis signal regulating kinase 1 (ASK1) is a reactive oxygen species-driven kinase involved in IS-mediated adverse effects. This study assessed the therapeutic potential of ASK1 inhibition in alleviating endothelial effects induced by IS. MAIN METHODS: IS, in the presence and absence of a selective ASK1 inhibitor (GSK2261818A), was assessed for its effect on vascular reactivity in rat aortic rings, and cultured human aortic endothelial cells where we evaluated phenotypic and mechanistic changes. KEY FINDINGS: IS directly impairs endothelium-dependent vasorelaxation and endothelial cell migration. Mechanistic studies revealed increased production of reactive oxygen species-related markers, reduction of endothelial nitric oxide synthase and increased protein expression of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). IS also increases angiopoietin-2 and tumour necrosis factor α gene expression and promotes transforming growth factor ß receptor abundance. Inhibition of ASK1 ameliorated the increase in oxidative stress markers, promoted autocrine interleukin 8 pro-angiogenic signalling and decreased anti-angiogenic responses at least in part via reducing TIMP1 protein expression. SIGNIFICANCE: ASK1 inhibition attenuated vasorelaxation and endothelial cell migration impaired by IS. Therefore, ASK1 is a viable intracellular target to alleviate uremic toxin-induced impairment in the vasculature.

Attenuating PI3K/Akt- mTOR pathway reduces dihydrosphingosine 1 phosphate mediated collagen synthesis and hypertrophy in primary cardiac cells.

Cardiac fibrosis and myocyte hypertrophy play contributory roles in the progression of diseases such as heart Failure (HF) through what is collectively termed cardiac remodelling. The phosphoinositide 3- kinase (PI3K), protein kinase B (Akt) and mammalian target for rapamycin (mTOR) signalling pathway (PI3K/Akt- mTOR) is an important pathway in protein synthesis, cell growth, cell proliferation, and lipid metabolism. The sphingolipid, dihydrosphingosine 1 phosphate (dhS1P) has been shown to bind to high density lipids in plasma. Unlike its analog, spingosine 1 phosphate (S1P), the role of dhS1P in cardiac fibrosis is still being deciphered. This study was conducted to investigate the effect of dhS1P on PI3K/Akt signalling in primary cardiac fibroblasts and myocytes. Our findings demonstrate that inhibiting PI3K reduced collagen synthesis in neonatal cardiac fibroblasts (NCFs), and hypertrophy in neonatal cardiac myocytes (NCMs) induced by dhS1P, in vitro. Reduced activation of the PI3K/Akt- mTOR signalling pathway led to impaired translation of fibrotic proteins such as collagen 1 (Coll1) and transforming growth factor ß (TGFß) and inhibited the transcription and translation of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). PI3K inhibition also affected the gene expression of S1P receptors and enzymes such as the dihydroceramide delta 4 desaturase (DEGS1) and sphingosine kinase 1 (SK1) in the de novo sphingolipid pathway. While in myocytes, PI3K inhibition reduced myocyte hypertrophy induced by dhS1P by reducing skeletal muscle α- actin (αSKA) mRNA expression, and protein translation due to increased glycogen synthase kinase 3ß (GSK3ß) mRNA expression. Our findings show a relationship between the PI3K/Akt- mTOR signalling cascade and exogenous dhS1P induced collagen synthesis and myocyte hypertrophy in primary neonatal cardiac cells.

Cardiorenal syndrome: Multi-organ dysfunction involving the heart, kidney and vasculature.

Cardiorenal syndrome (CRS) is a multi-organ disease, encompassing heart, kidney and vascular system dysfunction. CRS is a worldwide problem, with high morbidity, mortality, and inflicts a significant burden on the health care system. The pathophysiology is complex, involving interactions between neurohormones, inflammatory processes, oxidative stress and metabolic derangements. Therapies remain inadequate, mainly comprising symptomatic care with minimal prospect of full recovery. Challenges include limiting the contradictory effects of multi-organ targeted drug prescriptions and continuous monitoring of volume overload. Novel strategies such as multi-organ transplantation and innovative dialysis modalities have been considered but lack evidence in the CRS context. The adjunct use of pharmaceuticals targeting alternative pathways showing positive results in preclinical models also warrants further validation in the clinic. In recent years, studies have identified the involvement of gut dysbiosis, uraemic toxin accumulation, sphingolipid imbalance and other unconventional contributors, which has encouraged a shift in the paradigm of CRS therapy.

Exogenous dihydrosphingosine 1 phosphate mediates collagen synthesis in cardiac fibroblasts through JAK/STAT signalling and regulation of TIMP1.

Cardiac fibrosis and myocyte hypertrophy are hallmarks of the cardiac remodelling process in cardiomyopathies such as heart failure (HF). Dyslipidemia or dysregulation of lipids contribute to HF. The dysregulation of high density lipoproteins (HDL) could lead to altered levels of other lipid metabolites that are bound to it such as sphingosine-1- phosphate (S1P). Recently, it has been shown that S1P and its analogue dihydrosphingosine-1-phosphate (dhS1P) are bound to HDL in plasma. The effects of dhS1P on cardiac cells have been obscure. In this study, we show that extracellular dhS1P is able to increase collagen synthesis in neonatal rat cardiac fibroblasts (NCFs) and cause hypertrophy of neonatal cardiac myocytes (NCMs). The janus kinase/signal transducer and activator (JAK/STAT) signalling pathway was involved in the increased collagen synthesis by dhS1P, through sustained increase of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). Extracellular dhS1P increased phosphorylation levels of STAT1 and STAT3 proteins, also caused an early increase in gene expression of transforming growth factor-ß (TGFß), and sustained increase in TIMP1. Inhibition of JAKs led to inhibition of TIMP1 and TGFß gene and protein expression. We also show that dhS1P is able to cause NCM hypertrophy through S1P-receptor-1 (S1PR1) signalling which is opposite to that of its analogue, S1P. Taken together, our results show that dhS1P increases collagen synthesis in cardiac fibroblasts causing fibrosis through dhS1P-JAK/STAT-TIMP1 signalling.

Molecular mechanisms of protein-bound uremic toxin-mediated cardiac, renal and vascular effects: underpinning intracellular targets for cardiorenal syndrome therapy.

Cardiorenal syndrome (CRS) remains a global health burden with a lack of definitive and effective treatment. Protein-bound uremic toxin (PBUT) overload has been identified as a non-traditional risk factor for cardiac, renal and vascular dysfunction due to significant albumin-binding properties, rendering these solutes non-dialyzable upon the state of irreversible kidney dysfunction. Although limited, experimental studies have investigated possible mechanisms in PBUT-mediated cardiac, renal and vascular effects. The ultimate aim is to identify relevant and efficacious targets that may translate beneficial outcomes in disease models and eventually in the clinic. This review will expand on detailed knowledge on mechanisms involved in detrimental effects of PBUT, specifically affecting the heart, kidney and vasculature, and explore potential effective intracellular targets to abolish their effects in CRS initiation and/or progression.

The role of dihydrosphingolipids in disease.

Dihydrosphingolipids refer to sphingolipids early in the biosynthetic pathway that do not contain a C4-trans-double bond in the sphingoid backbone: 3-ketosphinganine (3-ketoSph), dihydrosphingosine (dhSph), dihydrosphingosine-1-phosphate (dhS1P) and dihydroceramide (dhCer). Recent advances in research related to sphingolipid biochemistry have shed light on the importance of sphingolipids in terms of cellular signalling in health and disease. However, dihydrosphingolipids have received less attention and research is lacking especially in terms of their molecular mechanisms of action. This is despite studies implicating them in the pathophysiology of disease, for example dhCer in predicting type 2 diabetes in obese individuals, dhS1P in cardiovascular diseases and dhSph in hepato-renal toxicity. This review gives a comprehensive summary of research in the last 10-15 years on the dihydrosphingolipids, 3-ketoSph, dhSph, dhS1P and dhCer, and their relevant roles in different diseases. It also highlights gaps in research that could be of future interest.

Evaluation of Xpert MTB/RIF assay in children with presumed pulmonary tuberculosis in Papua New Guinea.

BACKGROUND: The Gene Xpert MTB/ RIF assay (Xpert) is used for rapid, simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin resistance. This study examined the accuracy of Xpert in children with suspected pulmonary tuberculosis (PTB). METHODS: Children admitted to Port Moresby General Hospital with suspected PTB were prospectively enrolled between September 2014 and March 2015. They were classified into probable, possible and TB-unlikely groups. Sputum or gastric aspirates were tested by Xpert and smear microscopy; mycobacterial culture was undertaken on a subset. Children were diagnosed with TB on the basis of standard criteria which were used as the primary reference standard. Xpert, smear for acid-fast bacilli (AFB) and the Edwards TB score were compared with the primary reference standard. RESULTS: A total of 93 children ≤14 years with suspected PTB were enrolled; 67 (72%) were classified as probable, 21 (22%) possible and 5 (5.4%) TB-unlikely. Eighty were treated for TB based on the primary reference standard. Xpert was positive in 26/93 (28%) MTB cases overall, including 22/67 (33%) with probable TB and 4/21 (19%) with possible TB. Three (13%) samples identified rifampicin resistance. Xpert confirmed more cases of TB than AFB smear (26 vs 13, p = 0.019). The sensitivity of Xpert, AFB smear and an Edwards TB score of ≥7 was 31% (25/80), 16% (13/80) and 90% (72/80), respectively, and the specificity was 92% (12/13), 100% (13/13) and 31% (4/13), respectively, when compared with the primary reference standard. CONCLUSION: Xpert sensitivity is sub-optimal and cannot be relied upon for diagnosing TB, although a positive result is confirmatory. A detailed history and examination, standardised clinical criteria, radiographs and available tests remain the most appropriate way of diagnosing TB in children in resource-limited countries. Xpert helps confirm PTB better than AFB smear, and identifies rifampicin resistance. Practical guidelines should be used to identify children who will benefit from an Xpert assay.

Cardiac fibrosis in the ageing heart: Contributors and mechanisms.

Cardiac fibrosis refers to an excessive deposition of extracellular matrix (ECM) in cardiac tissue. Fibrotic tissue is stiffer and less compliant, resulting in subsequent cardiac dysfunction and heart failure. Cardiac fibrosis in the ageing heart may involve activation of fibrogenic signalling and inhibition of anti-fibrotic signalling, leading to an imbalance of ECM turnover. Excessive accumulation of ECM such as collagen in older patients contributes to progressive ventricular dysfunction. Overexpression of collagen is derived from various sources, including higher levels of fibrogenic growth factors, proliferation of fibroblasts and cellular transdifferentiation. These may be triggered by factors, such as oxidative stress, inflammation, hypertension, cellular senescence and cell death, contributing to age-related fibrotic cardiac remodelling. In this review, we will discuss the fibrogenic contributors in age-related cardiac fibrosis, and the potential mechanisms by which fibrogenic processes can be interrupted for therapeutic intent.

In vitro and in vivo evaluation of the toxicities induced by metallic nickel nano and fine particles.

Nickel nanoparticles (Ni NPs) have been applied in various fields along with the rapid development of nanotechnology. However, the potential adverse health effects of the Ni NPs are unclear. To investigate the cyto- and genotoxicity and compare the differences between the Ni NPs and the nickel fine particles (Ni FPs), Sprague-Dawley (SD) rats and A549 cells were treated with different doses of Ni NPs or FPs. Intra-tracheal instillation of Ni NPs and FPs caused acute toxicity in the lungs, liver and kidneys of the SD rats. Even though the histology of the lungs showed hyperplastic changes and the protein expression of HO-1 and Nrf2 detected by western blot showed lung burden overload, no significant increase was observed to the expression level of oncoprotein C-myc. The results from cell titer-Glo assay and comet assay indicated that Ni NPs were more potent in causing cell toxicity and genotoxicity in vitro than Ni FPs. In addition, Ni NPs increased the expression of C-myc in vitro, but these increases may not have been due to oxidative stress since no significant dose-dependent changes were seen in HO-1 and Nrf2 expressions. Although Ni NPs have the potential to cause DNA damage in A549 cells in vitro, the molecular mechanisms that led to these changes and their tumorigenic potential is still debatable. In short, Ni NPs were more potent in causing cell toxicity and genotoxicity in vitro than Ni FPs, and intra-tracheal instillation of Ni NPs and FPs caused toxicity in organs of the SD rats, while it showed similar to the effects for both particle types. These results suggested that both Ni NPs and FPs have the potential to be harmful to human health, and Ni NPs may have higher cyto- and genotoxic effects than Ni FPs under the same treatment dose.

Metallic nickel nanoparticles may exhibit higher carcinogenic potential than fine particles in JB6 cells.

While numerous studies have described the pathogenic and carcinogenic effects of nickel compounds, little has been done on the biological effects of metallic nickel. Moreover, the carcinogenetic potential of metallic nickel nanoparticles is unknown. Activator protein-1 (AP-1) and nuclear factor-κB (NF-κB) have been shown to play pivotal roles in tumor initiation, promotion, and progression. Mutation of the p53 tumor suppressor gene is considered to be one of the steps leading to the neoplastic state. The present study examines effects of metallic nickel fine and nanoparticles on tumor promoter or suppressor gene expressions as well as on cell transformation in JB6 cells. Our results demonstrate that metallic nickel nanoparticles caused higher activation of AP-1 and NF-κB, and a greater decrease of p53 transcription activity than fine particles. Western blot indicates that metallic nickel nanoparticles induced a higher level of protein expressions for R-Ras, c-myc, C-Jun, p65, and p50 in a time-dependent manner. In addition, both metallic nickel nano- and fine particles increased anchorage-independent colony formation in JB6 P+ cells in the soft agar assay. These results imply that metallic nickel fine and nanoparticles are both carcinogenetic in vitro in JB6 cells. Moreover, metallic nickel nanoparticles may exhibit higher carcinogenic potential, which suggests that precautionary measures should be taken in the use of nickel nanoparticles or its compounds in nanomedicine.

Acute toxicity of nickel nanoparticles in rats after intravenous injection.

This study was carried out to add scientific data in regard to the use of metallic nanoparticles in nanomedicine. The acute toxicity of nickel (Ni) nanoparticles (50 nm), intravenously injected through the dorsal penile vein of Sprague Dawley rats was evaluated in this study. Fourteen days after injection, Ni nanoparticles induced liver and spleen injury, lung inflammation, and caused cardiac toxicity. These results indicate that precautionary measures should be taken with regard to the use of Ni nanoparticles or Ni compounds in nanomedicine.

Expression and clinical significance of IGF-1, IGFBP-3, and IGFBP-7 in serum and lung cancer tissues from patients with non-small cell lung cancer.

The expression and clinical significance of insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), and insulin-like growth factor binding protein 7 (IGFBP-7) were investigated in serum and lung cancer tissues from 57 patients with non-small cell lung cancer (NSCLC). Lung cancer tissues at different pathologic stages (27 patients at stages I-II and 30 patients at stages III-IV), normal lung tissues from 17 patients with benign pulmonary disease, and serum samples from both lung cancer and benign pulmonary disease patients were collected during surgery. Enzyme-linked immunosorbent assay and avidin-biotin-peroxidase complex immunohistochemical staining were used to detect IGF-1, IGFBP-3, and IGFBP-7 expression in serum and tissues, respectively. The results show that expression of IGF-1 in lung cancer tissues and serum from NSCLC patients were significantly higher than in the control (P < 0.05). However, expression of IGFBP-3 and IGFBP-7 in cancer tissues and serum from NSCLC patients was significantly lower than in the control (P < 0.05). These results suggest that upregulation of IGF-1 and downregulation of IGFBP-3 and IGFBP-7 may be potential diagnostic biomarkers for NSCLC.

Titanium dioxide nanoparticles: a review of current toxicological data.

Titanium dioxide (TiO2) nanoparticles (NPs) are manufactured worldwide in large quantities for use in a wide range of applications. TiO2 NPs possess different physicochemical properties compared to their fine particle (FP) analogs, which might alter their bioactivity. Most of the literature cited here has focused on the respiratory system, showing the importance of inhalation as the primary route for TiO2 NP exposure in the workplace. TiO2 NPs may translocate to systemic organs from the lung and gastrointestinal tract (GIT) although the rate of translocation appears low. There have also been studies focusing on other potential routes of human exposure. Oral exposure mainly occurs through food products containing TiO2 NP-additives. Most dermal exposure studies, whether in vivo or in vitro, report that TiO2 NPs do not penetrate the stratum corneum (SC). In the field of nanomedicine, intravenous injection can deliver TiO2 nanoparticulate carriers directly into the human body. Upon intravenous exposure, TiO2 NPs can induce pathological lesions of the liver, spleen, kidneys, and brain. We have also shown here that most of these effects may be due to the use of very high doses of TiO2 NPs. There is also an enormous lack of epidemiological data regarding TiO2 NPs in spite of its increased production and use. However, long-term inhalation studies in rats have reported lung tumors. This review summarizes the current knowledge on the toxicology of TiO2 NPs and points out areas where further information is needed.

Association of GST genetic polymorphisms with the susceptibility to hepatocellular carcinoma (HCC) in Chinese population evaluated by an updated systematic meta-analysis.

BACKGROUND: Due to the possible involvement of Glutathione S-transferase Mu-1 (GSTM1) and Glutathione S-transferase theta-1 (GSTT1) in the detoxification of environmental carcinogens, environmental toxins, and oxidative stress products, genetic polymorphisms of these two genes may play important roles in the susceptibility of human being to hepatocellular carcinoma. However, the existing research results are not conclusive. METHODS: A systematic literature search using databases (PubMed, Scopus, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Wanfang Data, etc.) for the eligible studies meeting the inclusion criteria including case-control studies or cohort studies is evaluated using an updated systematic meta-analysis. RESULTS: Significant increase in the risk of HCC in the Chinese population is found in GSTM1 null genotype (OR = 1.47, 95% CI: 1.21 to 1.79, P<0.001) and GSTT1 null genotype (OR = 1.38, 95% CI: 1.14 to 1.65, P<0.001). Analysis using the random-effects model found an increased risk of HCC in GSTM1-GSTT1 dual null population (OR = 1.79, 95% CI: 1.26 to 2.53, P<0.001). In addition, subgroup analyses showed a significant increase in the association of GST genetic polymorphisms (GSTM1, GSTT1, and GSTM1-GSTT1) with HCC in southeast and central China mainland. However, available data collected by this study fail to show an association between GST genetic polymorphisms and HCC in people from the Taiwan region (for GSTM1: OR = 0.78, 95% CI: 0.60 to 1.01, P = 0.06; for GSTT1: OR = 0.94, 95% CI: 0.78 to 1.14, P = 0.546; for GSTM1-GSTT1: OR = 1.04, 95% CI: 0.81 to 1.32, P = 0.77). Sensitivity analysis and publication bias diagnostics confirmed the reliability and stability of this meta-analysis. CONCLUSIONS: Our results indicate that both GSTM1 and GSTT1 null genotypes are associated with an increased HCC risk in Chinese population. Peoples with dual null genotypes of GSTM1-GSTT1 are more susceptible to developing HCC. In conclusion, GST genetic polymorphisms play vital roles in the development of HCC in the Chinese population.

Apoptosis induced by tungsten carbide-cobalt nanoparticles in JB6 cells involves ROS generation through both extrinsic and intrinsic apoptosis pathways.

In this study, apoptosis and related signaling induced by WC-Co nanoparticles were investigated in JB6 cells and rat lung macrophages. Electron spin resonance (ESR) and fluorescent staining indicated that both WC-Co nanoparticles and fine particles stimulated reactive oxygen species (ROS) generation. Catalase exhibited an inhibitory effect on WC-Co nanoparticle-induced ROS as well as mitochondrial membrane permeability damage. Further study indicated that WC-Co nanoparticles elicited higher cytotoxicity and apoptotic induction than fine particles. Western blot analysis showed activation of proapoptotic factors including Fas, Fas-associated protein with death domain (FADD), caspase 3, 8 and 9, BID and BAX. In addition, both cytochrome c and apoptosis-inducing factor (AIF) were upregulated and released from mitochondria to the cytoplasm. Our findings demonstrate that, on a mass basis, WC-Co nanoparticles exhibit higher cytotoxicity and apoptotic induction than fine particles. Apoptosis induced by WC-Co nanoparticles and fine particles involves both extrinsic and intrinsic apoptosis pathways.

Genotoxicity and carcinogenicity of cobalt-, nickel- and copper-based nanoparticles.

The nanotechnology industry has matured and expanded at a rapid pace in the last decade, leading to the research and development of nanomaterials with enormous potential. The largest source of these nanomaterials is the transitional metals. It has been revealed that numerous properties of these nano-sized elements are not present in their bulk states. The nano size of these particles means they are easily transported into biological systems, thus, raising the question of their effects on the susceptible systems. Although advances have been made and insights have been gained on the effect of transitional metals on susceptible biological systems, there still is much ground to be covered, particularly with respect to our knowledge on the genotoxic and carcinogenic effects. Therefore, this review intends to summarize the current knowledge on the genotoxic and carcinogenic potential of cobalt-, nickel- and copper-based nanoparticles indicated in in vitro and in vivo mammalian studies. In the present review, we briefly state the sources, use and exposure routes of these nanoparticles and summarize the current literature findings on their in vivo and in vitro genotoxic and carcinogenic effects. Due to the increasing evidence of their role in carcinogenicity, we have also included studies that have reported epigenetic factors, such as abnormal apoptosis, enhanced oxidative stress and pro-inflammatory effects involving these nanoparticles.

Recent progress in studies of metallic nickel and nickel-based nanoparticles' genotoxicity and carcinogenicity.

Recently, nanoparticles have been the focus of many research and innovation. Metallic nickel and nickel-based nanoparticles are among those being exploited. Nickel fine particles are known to be genotoxic and carcinogenic. It has been discovered that many properties of nano sized elements and materials are not present in their bulk states. The nano size of these particles renders them the ability to be easily transported into biological systems, thus raising the question of their effects on the susceptible system. Therefore scientific research on the effects of nickel nanoparticles is important. This mini-review intends to summarize the current knowledge on the genotoxicity and carcinogenicity potential of metallic nickel and nickel-based nanoparticles implicated in in vitro and in vivo mammalian studies.