The deposition of lanthanum carbonate may activate macrophages to induce gastrointestinal mucosal injury in patients with chronic kidney disease: an in vitro caco-2/THP-1 macrophage coculture model study.

The aim of this study was to investigate the effect and possible underlying mechanism of La2(CO3)3 deposition on GI mucosal inflammation. Our results showed that La2(CO3)3 can dissolve in artificial gastric fluids and form lanthanum phosphate (LaPO4) precipitates with an average size of about 1 µm. To mimic the intestinal mucosa and epithelial barrier, we established a Caco-2/THP-1 macrophage coculture model and a Caco-2 monoculture model, respectively. Our findings demonstrated that the medium of THP-1 macrophages stimulated by LaPO4 particles can damage the Caco-2 monolayer integrity in the coculture model, while the particles themselves had no direct impact on the Caco-2 monolayer integrity in the monoculture model. We measured values of trans-epithelial electrical resistance and detected images using a laser scanning confocal microscope. These results indicate that continuous stimulation of LaPO4 particles on macrophages can lead to a disruption of intestinal epithelium integrity. In addition, LaPO4 particles could stimulate THP-1 macrophages to secrete both IL-1ß and IL-8. Although LaPO4 particles can also promote Caco-2 cells to secrete IL-8, the secretion was much lower than that produced by THP-1 macrophages. In summary, the deposition of La2(CO3)3 has been shown to activate macrophages and induce damage to intestinal epithelial cells, which may exacerbate inflammation in patients with chronic kidney disease. Therefore, patients taking lanthanum carbonate, especially those with gastrointestinal mucosal inflammation, should be mindful of the potential for drug deposition in the GI system.

Lanthanum carbonate, a potent and selective phosphate binder, is transported and absorbed mainly via M cells in gastrointestinal tract.

This study aimed to investigate the transportation and absorption mechanism of lanthanum carbonate [La2(CO3)3] through the gastrointestinal (GI) tract using in vitro and in vivo models. The results demonstrated that La2(CO3)3 can be dissolved in gastric fluids and precipitated into lanthanum phosphate as the main transformed specie in intestinal fluid. Using Caco-2 cell monoculture and Caco-2/Raji B cell coculture models to simulate the intestinal epithelium and microfold (M) cells, it was found that the amount of lanthanum transported in Caco-2/Raji B coculture model was significantly higher than that in Caco-2 monoculture model (about 50 times higher), indicating that M cells play an important role in the intestinal absorption of La2(CO3)3. Furthermore, oral administration of La2(CO3)3 to Balb/c mice demonstrated that lanthanum can be absorbed by both Peyer's patches (PPs) and non-PPs intestinal epithelium, with a higher amount of absorption in the PPs per unit weight. This finding further confirmed that the lanthanum absorption in GI tract could be mainly due to the contribution of M cells. Meanwhile, the administration of La2(CO3)3 caused a marked lanthanum accumulation in liver, accompanied by the activation of Kupffer cells. This study clarified how La2(CO3)3 is absorbed through the GI tract to enter the body and would be helpful to evaluate its potential biological consequences of accumulation in human beings.

Bis(ethylmaltolato)oxidovanadium (IV) attenuates amyloid-beta-mediated neuroinflammation by inhibiting NF-κB signaling pathway via a PPARγ-dependent mechanism.

Neuroinflammation plays a pivotal role in the pathophysiology of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. During brain neuroinflammation, activated microglial cells resulting from amyloid-beta (Aß) overload trigger toxic proinflammatory responses. Bis(ethylmaltolato)oxidovanadium (BEOV) (IV), an important vanadium compound, has been reported to have anti-diabetic, anti-cancer, and neuroprotective effects, but its anti-inflammatory property has rarely been investigated. In the present study, the inhibitory effects of BEOV on neuroinflammation were revealed in both Aß-stimulated BV2 microglial cell line and APPswe/PS1E9 transgenic mouse brain. BEOV administration significantly decreased the levels of tumor necrosis factor-α, interleukin-6, interleukin-1ß, inducible nitric oxide synthase, and cyclooxygenase-2 both in the hippocampus of APPswe/PS1E9 mice and in the Aß-stimulated BV2 microglia. Furthermore, BEOV suppressed the Aß-induced activation of nuclear factor-κB (NF-κB) signaling and upregulated the protein expression level of peroxisome proliferator-activated receptor gamma (PPARγ) in a dose-dependent manner. PPARγ inhibitor GW9662 could eliminate the effect of BEOV on Aß-induced NF-κB activation and proinflammatory mediator production. Taken altogether, these findings suggested that BEOV ameliorates Aß-stimulated neuroinflammation by inhibiting NF-κB signaling pathway through a PPARγ-dependent mechanism.

The Effect of Thymoquinone on the Characteristics of the Brain Extracellular Space in Transient Middle Cerebral Artery Occlusion Rats.

The extracellular space (ECS) is the space between the neurons and the capillaries in the brain. The volume fraction (α) and the tortuosity (λ) are the main parameters used to describe its characteristics. Thymoquinone has been proved to possess anti-oxidant and anti-inflammatory activity. In this study, we used a gadolinium-diethylenetriaminepentacetate (Gd-DTPA)-enhanced magnetic resonance imaging (MRI) system to determine the effects of thymoquinone on ECS parameters in transient middle cerebral artery occlusion rats (tMCAO) to prove the neuroprotective effect of thymoquinone on brain tissue damage caused by ischemic stroke. Neurological examinations, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (H&E) staining and assaying of ECS parameters using MRI were performed 24 h after surgery. We found that thymoquinone could improve the behavioural performance by neurological examinations. TTC staining indicated that thymoquinone significantly decreased the percentage of hemi-cerebral infarction. Also, H&E staining showed that thymoquinone could inhibit the neuron necrosis in the hippocampal CA1 region. We found that thymoquinone treatment could inhibit the changes in ECS diffusion parameters, which might prove that thymoquinone might protect brain tissue damage caused by ischemic stroke. Thymoquinone can protect the brain against cerebral ischemia-reperfusion injury, effectively ameliorate abnormalities in characteristics of ECS and decrease cerebral infarction in tMCAO rats.

Correction: Bis(ethylmaltolato)oxidovanadium(iv) inhibited the pathogenesis of Alzheimer's disease in triple transgenic model mice.

Correction for 'Bis(ethylmaltolato)oxidovanadium(iv) inhibited the pathogenesis of Alzheimer's disease in triple transgenic model mice' by Zhijun He et al., Metallomics, 2020, DOI: 10.1039/c9mt00271e.

Bis(ethylmaltolato)oxidovanadium(iv) inhibited the pathogenesis of Alzheimer's disease in triple transgenic model mice.

Vanadium compounds have been reported to mimic the anti-diabetes effects of insulin on rodent models, but their effects on Alzheimer's disease (AD) have rarely been explored. In this paper, 9-month-old triple transgenic AD model mice (3×Tg-AD) received bis(ethylmaltolato)oxidovanadium(iv) (BEOV) at doses of 0.2 mmol L-1 (68.4 µg mL-1) and 1.0 mmol L-1 (342 µg mL-1) for 3 months. BEOV at both doses was found to improve contextual memory and spatial learning in AD mice. It also improved glucose metabolism and protected neuronal synapses in the AD brain, as evidenced respectively by 18F-labeled fluoro-deoxyglucose positron emission tomography (18F-FDG-PET) scanning and by transmission electron microscopy. Inhibitory effects of BEOV on ß-amyloid (Aß) plaques and neuronal impairment in the cortex and hippocampus of fluorescent AD mice were visualized three-dimensionally by applying optical clearing technology to brain slices before confocal laser scanning microscopy. Western blot analysis semi-quantitatively revealed the altered levels of Aß42 in the brains of wildtype, AD, and AD treated with 0.2 and 1.0 mmol L-1 BEOV mice (70.3%, 100%, 83.2% and 56.8% in the hippocampus; 82.4%, 100%, 66.9% and 42% in the cortex, respectively). The mechanism study showed that BEOV increased the expression of peroxisome proliferator-activated receptor γ (PPARγ) (140%, 100%, 142% and 160% in the hippocampus; 167%, 100%, 124% and 133% in the cortex) to inactivate the JAK2/STAT3/SOCS-1 pathway and to block the amyloidogenesis cascade, thus attenuating Aß-induced insulin resistance in AD models. BEOV also reduced protein tyrosine phosphatase 1B (PTP1B) expression (74.8%, 100%, 76.5% and 53.8% in the hippocampus; 71.8%, 100%, 94.2% and 81.8% in cortex) to promote insulin sensitivity and to stimulate the PI3K/Akt/GSK3ß pathway, subsequently reducing tau hyperphosphorylation (phosphorylated tau396 levels were 51.1%, 100%, 56.1% and 50.2% in the hippocampus; 22.2%, 100%, 36.1%, and 24% in the cortex). Our results suggested that BEOV reduced the pathological hallmarks of AD by targeting the pathways of PPARγ and PTP1B in 3×Tg AD mice.

Health Benefits of Vanadium and Its Potential as an Anticancer Agent.

Vanadium compounds have been known to have beneficial therapeutic properties since the turn of the century, but it was not until 1965 when it was discovered that those effects could be extended to treating cancer. Some vanadium compounds can combat common markers of cancer, which include metabolic processes that are important to initiating and developing the phenotypes of cancer. It is appropriate to consider vanadium as a treatment option due to the similarities in some of the metabolic pathways utilized by both diabetes and cancer and therefore is among the few drugs that are effective against more than one disease. The development of vanadium compounds as protein phosphatase inhibitors for the treatment of diabetes may be useful for potential applications as an anticancer agent. Furthermore, the ability of vanadium to redox cycle is also important for biological properties and is involved in the pathways of reactive oxygen species. Early agents including vanadocene and peroxovanadium compounds have been investigated in detail, and the results can be used to gain a better understanding of how some vanadium compounds are modifying the metabolic pathways potentially developing cancer. Considering the importance of coordination chemistry to biological responses, it is likely that proper consideration of compound formulation will improve the efficacy of the drug. Future development of vanadium-based drugs should include consideration of drug formulation at earlier stages of drug development.

Bis(acetylacetonato)-oxidovanadium(IV) and sodium metavanadate inhibit cell proliferation via ROS-induced sustained MAPK/ERK activation but with elevated AKT activity in human pancreatic cancer AsPC-1 cells.

In this study, the antiproliferative effect of bis(acetylacetonato)-oxidovanadium(IV) and sodium metavanadate and the underlying mechanisms were investigated in human pancreatic cancer cell line AsPC-1. The results showed that both exhibited an antiproliferative effect through inducing G2/M cell cycle arrest and can also cause elevation of reactive oxygen species (ROS) levels in cells. Moreover, the two vanadium compounds induced the activation of both PI3K/AKT and MAPK/ERK signaling pathways dose- and time-dependently, which could be counteracted with the antioxidant N-acetylcysteine. In the presence of MEK-1 inhibitor, the degradation of Cdc25C, inactivation of Cdc2 and accumulation of p21 were relieved. However, the treatment of AKT inhibitor did not cause any significant effect. Therefore, it demonstrated that the ROS-induced sustained MAPK/ERK activation rather than AKT contributed to vanadium compounds-induced G2/M cell cycle arrest. The current results also exhibited that the two vanadium compounds did not induce a sustained increase of ROS generation, but the level of ROS reached a plateau instead. The results revealed that an intracellular feedback loop may be against the elevated ROS level induced by vanadate or VO(acac)2, evidenced by the increased GSH content, the unchanged level at the expression of antioxidant enzymes. Therefore, vanadium compounds can be regarded as a novel type of anticancer drugs through the prolonged activation of MAPK/ERK pathway but retained AKT activity. The present results provided a proof-of-concept evidence that vanadium-based compounds may have the potential as both antidiabetic and antipancreatic cancer agents to prevent or treat patients suffering from both diseases.

The complete mitochondrial genome of Fujian rod gugeon Microphysogobio fukienensis (Nichols) (Cypriniformes, Cyprinidae).

In this study, the complete mitogenome sequence of the Fujian rod gugeon, Microphysogobio fukienensis (Nichols) (Cypriniformes, Cyprinidae, Gobioninae) has been amplified. The mitogenome, consisting of 16,600 bp, had the typical vertebrate mitochondrial gene arrangement, including 13 protein-coding genes, 22 transfer RNAs, 2 ribosomal RNAs genes and a noncoding control region (CR). CR of 930 bp length is located between tRNA(Pro) and tRNA(Phe). The overall base composition of M. fukienensis is 31.0% for A, 26.0% for C, 26.6% for T and 16.4% for G, with higher AT content of 57.0%. The complete mitogenome may provide rather essential and important DNA molecular data for further phylogenetic analysis for not only congeneric species but also higher different taxa of Cyprinid fishes.

The gadolinium-based contrast agent Omniscan® promotes in vitro fibroblast survival through in situ precipitation.

The current study aims to explore how the gadolinium (Gd)-based contrast agent (GBCA) Omniscan® enhanced cell viability of murine fibroblasts. The results of scanning electron microscopy showed that Omniscan® can precipitate in cell culture media and deposit on cell membranes. Energy-dispersive X-ray analysis and Fourier-transform infrared spectroscopy demonstrated the presence of Gd and phosphates in the agglomerated particles. By filtering the Omniscan®-containing medium through a 220 nm filter, it can be clearly found that the increased cell viability should be mainly attributed to the insoluble species of gadolinium rather than to chelated gadolinium. Moreover, the effects of other gadolinium-based contrast agents, Magnevist® and Dotarem®, were compared with that of Omniscan®. It is noted that the three contrast agents differed in their ability to induce cell viability, which is possibly ascribed to the different chemical stabilities of gadolinium chelates as demonstrated by the attenuation in cell growth upon the addition of excess ligands to the compounds. The results of flow cytometry analysis also showed that Omniscan® can promote cell growth via an increase in the S-phase cell population as evidenced by the elevated levels of cell cycle associated proteins cyclin D, cyclin A and the phosphorylated Rb protein. Furthermore, our results revealed that integrin-mediated signaling may play an important role in both Omniscan® and Magnevist®-enhanced focal adhesion formation since the blockade of integrins decreased the level of ERK phosphorylation induced by the two GBCAs. Taken together, these data suggested that in situ gadolinium phosphate precipitation formation mediated Omniscan®-promoted fibroblast survival, which is similar to that of gadolinium chloride. It was demonstrated that the application of GBCAs with more stable thermodynamic stability may cause less dissociation of the gadolinium ion and thus resulted in less precipitation, finally leading to lower occurrence of nephrogenic systemic fibrosis. The obtained results would also be helpful for the development of safe gadolinium-based contrast agents.

[Community structure of phytoplankton in Haizhou bay and adjacent waters and its relationships with environmental factors].

Based on the data collected from four seasonal surveys in 2011 in Haizhou Bay and adjacent waters, community structure of phytoplankton was studied and their relationships with environmental factors were evaluated by canonical correlation analysis (CCA). A total of 113 phytoplankton species belonging to 3 phyla and 44 genera were collected, among which Bacillariophyta species were the most abundant species, which included 39 genera and 99 species, accounting for 87.6% of total taxa, followed by Pyrrophyta, which included 4 genera and 13 species, accounting for 11.5 percent of total taxa. And the least abundant species were Chrysophyta species, which had only 1 species belonging to 1 genus. Among these dominant species, Coscinodiscus and Chaetoceros were the dominant groups in Bacillariophyta, while Ceratium was the dominant group in Dinophyta, and the dominant species were Meuniera membranacea, Coscinodiscus subtilis var. subtilis, Eucampia zodiacus and Bacillaria paxillifera. There were obvious seasonal variations in the species composition and predominant species. The abundances of phytoplankton in all the stations ranged from 0.08 x 10(5) cells m(-3) to 108.48 x 10(5) cells x m(-3) in Haizhou Bay. The average annual density of phytoplankton was 10.71 x 10(5) cells x m(-3), being the highest in autumn (29.08 x 10(5) cells x m(-3)) and the lowest in summer (1.69 x 10(5) cells x m(-3)). The Shannon index, Pielou index and Margalef index of the phytoplankton community were higher in summer and autumn than in winter and spring. CCA suggested that the main factors affecting the phytoplankton community were sea surface temperature (SST), followed by nutrients (NO(3-)-N, PO4(3-)-P, SiO3(2-)-Si) and dissolved oxygen (DO). The abundances and distribution of some dominant species were closely related with these main factors.

Design, synthesis and properties of artificial nucleic acids from (R)-4-amino-butane-1,3-diol.

A new artificial nucleic acid analogue, (R)-Am-BuNA, was developed with a simplified acyclic (R)-4-amino-butane-1,3-diol phosphodiester backbone. Phosphoramidite monomers of (R)-Am-BuNA were incorporated into DNA oligonucleotides (ODNs) and G-quadruplexes. Their thermal stability, conformation change and biological stability were further investigated using UV-melting, circular dichroism (CD) and gel electrophoresis. The results suggested that thermal stability of the duplexes of (R)-Am-BuNA modified ODNs and their complementary ODN is highly dependent on the substitution position. Substitution of thymidine at the 7th position in a thrombin-binding DNA aptamer (TBA) results in a slight increase in Tm with no effect on quadruplex conformation on the CD spectrum in comparison to that of the natural G-quadruplex. Further enzymatic experiments with fetal bovine serum (FBS) and snake venom phosphodiesterase (SVPDE) indicated that only single replacement of a (R)-Am-BuNA modified nucleobase greatly inhibited oligonucleotide degradation, which shows their promising applications as capping nucleotides in nucleic acid drugs.

Lanthanides inhibit adipogenesis with promotion of cell proliferation in 3T3-L1 preadipocytes.

Lanthanides are widely used in various fields for industrial, agricultural and medical purposes. They have also been used in Chinese agriculture either as fertilizers in plant production or as performance-enhancers in animal nutrition for many years. In view of their possible application for growth enhancing purposes and new medical applications, detailed information on how lanthanides influence physiological processes in biological systems is indispensable. In the present work, the effects of lanthanides (LaCl3, CeCl3 and GdCl3) on cell proliferation and adipogenesis in 3T3-L1 preadipocytes were evaluated. The results demonstrate that lanthanides inhibit adipogenesis in 3T3-L1 preadipocytes, evidenced by decreased triglyceride content and expression of C/EBPα and PPARγ. Simultaneously, the results show that lanthanides can promote cell proliferation during the different stages of differentiation. Firstly, prior to the addition of differentiation inducers (MDI), all the three types of lanthanides resulted in a significant increase of cell growth. Secondly, during the mitotic clonal expansion (MCE) process, GdCl3, as a representative compound, is able to promote cell-cycle entry into the S phase and levels of cell cycle-regulating proteins. Third, at the late stage of the terminal differentiation, on day 8, in the presence of GdCl3, cells exhibited higher levels of G1/S regulatory proteins and proliferating cell nuclear antigen (PCNA). In addition, GdCl3 caused stronger sustained ERK activation during the differentiation process of 3T3-L1 cells. The present study demonstrates that lanthanides may modulate lipid metabolism by inhibition of adipocyte differentiation. The sustained activation of the ERK pathway might be responsible for their inhibition of differentiation and a possible link between their pro-proliferative ability and inhibition of the differentiation process is indicated.

Bis(acetylacetonato)-oxovanadium(iv), bis(maltolato)-oxovanadium(iv) and sodium metavanadate induce antilipolytic effects by regulating hormone-sensitive lipase and perilipin via activation of Akt.

The increased plasma free fatty acid levels due to the deregulated lipolysis in adipocytes are considered as one of the major risk factors for developing type II diabetes. Vanadium compounds are well-known for their antidiabetic effects both on glucose and lipid metabolism, but the mechanisms are still not completely understood. The present study suggests a mechanism for how vanadium compounds exert antilipolytic effects. It demonstrates that all the three vanadium compounds, bis(acetylacetonato)-oxovanadium(iv) (VO(acac)2), bis(maltolato)-oxovanadium(iv) (VO(ma)2) and sodium metavanadate (NaVO3), attenuated basal lipolysis in 3T3L1 adipocytes in a dose- (from 100 to 400 µM for VO(acac)2 and VO(ma)2, 1.0 to 4.0 mM for vanadate) and time-dependent (from 0.5 to 4 h) manner using the glycerol release as a marker of lipolysis. In addition, the three compounds inhibited lipolysis to a different extent. Among them, VO(acac)2 (from 100 to 400 µM) exerted the most potent effect and reduced the lipolysis to ∼60-20% of control after 4 h treatment. The antilipolytic effects of vanadium compounds were further evidenced by a decrease of the levels of phosphorylated HSL at Ser660 and phosphorylated perilipin, which were counteracted by inhibitors of PI3K or Akt but not by an MEK inhibitor. This indicates that though both Akt and ERK pathways are activated by the vanadium compounds, only Akt activation contributes to the antilipolytic effect of the vanadium compounds, without the involvement of ERK activation. We previously demonstrated that VO(acac)2 can block cell cycle progression at the G1/S phase via a highly activated ERK signal in human hepatoma HepG2 cells. Together with this study, we show that similar activated pathways may lead to differential biological consequences for cancer cells and adipocytes, indicating that vanadium compounds may be used in the prevention and treatment of both diabetes and cancer.

Chemical, biochemical, and biological behaviors of vanadate and its oligomers.

Vanadate is widely used as an inhibitor of protein tyrosine phosphatases (PTPase) and is routinely applied in cell lysis buffers or immunoprecipitations of phosphotyrosyl proteins. Additionally, vanadate has been extensively studied for its antidiabetic and anticancer effects. In most studies, orthovanadate or metavanadate was used as the starting compound, whereas these "vanadate" solutions may contain more or less oligomerized species. Whether and how different species of vanadium compounds formed in the biological media exert specific biological effect is still a mystery. In the present commentary, we focus on the chemical, biochemical, and biological behaviors of vanadate. On the basis of species formation of vanadate in chemical and biological systems, we compared the biological effects and working mechanism of monovanadate with that of its oligomers, especially the decamer. We propose that different oligomers may exert a specific biological effect, which depends on their structures and the context of the cell types, by different modes of action.

Reactive-oxygen-species-mediated Cdc25C degradation results in differential antiproliferative activities of vanadate, tungstate, and molybdate in the PC-3 human prostate cancer cell line.

The differential antiproliferative effects of vanadate, tungstate, and molybdate on human prostate cancer cell line PC-3 were compared and the underlying mechanisms were investigated. The results demonstrate that all of the three oxoanions can cause G(2)/M cell cycle arrest, which is evidenced by the increase in the level of phosphorylated Cdc2 at its inactive Tyr-15 site. Moreover, even if the difference in cellular uptake among the three oxoanions is excluded from the possible factors affecting their antiproliferative activity, vanadate exerted a much more potent effect in PC-3 cells than the other two oxoanions. Our results also reveal that reactive oxygen species (ROS)-mediated degradation of Cdc25C rather than Cdc25A or Cdc25B is responsible for vanadate-induced G(2)/M cell cycle arrest. We propose a possible mechanism to clarify the differential effect of the three oxoanions in biological systems beyond just considering that they are structural analogs of phosphate. We suggest that ROS formation is unlikely to be involved in the biological function of tungstate and molybdate, whereas the redox properties of vanadium may be important factors for it to exert pharmacological effects. Further, given the evidence from epidemiology studies of the association between diabetes and prostate cancer, the possibility of vanadate as a good candidate as both an antidiabetic and an anticancer agent or a chemopreventive agent is indicated.

Integrin-mediated signaling contributes to gadolinium-containing-particle-promoted cell survival and G1 to S phase cell cycle transition by enhancing focal adhesion formation.

We previously reported that Gd-containing particles formed under physiological conditions act as active entities to enhance cell survival and promote S phase entry via activation of both mitogen-activated protein kinase/extracellular-signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase/Akt signaling pathways. However, how they transduce the extracellular signal inside the cell remains unclear. The present study demonstrates that Gd-containing particles can alleviate serum-deprivation-induced cell death and promote G1 to S phase cell cycle progression by enhancing cell adhesion to the extracellular matrix. As an indicator of adhesion, the vinculin distribution was detected by confocal laser scanning microscopy. The control cells exhibited fewer and less typical focal adhesions. After treatment with Gd-containing particles, a large number of vinculin-containing focal adhesions were maintained. In the presence of integrin antagonists, the percentage of S phase entry induced by Gd-containing particles was decreased and the enhancement of cell viability was also attenuated, along with a decrease in both cyclin D expression and ERK phosphorylation. In summary, the present results suggest that the integrin-mediated signaling pathway plays an important role in cell survival and G1 to S phase transition promoted by Gd-containing particles by enhancing focal adhesion formation. The results presented here provide novel evidence to advance knowledge leading to further understanding of the mechanisms of both cell proliferation and cell survival promoted by Gd and may be helpful for developing effective measures to prevent or treat nephrogenic systemic fibrosis.

Vanadium compounds discriminate hepatoma and normal hepatic cells by differential regulation of reactive oxygen species.

Our previous study indicated that vanadium compounds can block cell cycle progression at the G1/S phase in human hepatoma HepG2 cells via a highly activated extracellular signal-regulated protein kinase (ERK) signal. To explore their differential action on normal cells, we investigated the response of an immortalized hepatic cell line, L02 cells. The results demonstrated that a higher concentration of vanadium compounds was needed to inhibit L02 proliferation, which was associated with S and G2/M cell cycle arrest. In addition, in contrast to insignificant reactive oxygen species (ROS) generation in HepG2 cells, all of the vanadium compounds resulted significant increases in both O2.- and H2O2 levels in L02 cells. At the same time, ERK and c-Jun N-terminal kinase (JNK) as well as cell division control protein 2 homolog (Cdc2) were found to be highly phosphorylated, which could be counteracted with the antioxidant N-acetylcysteine (NAC). The current study also demonstrated that both the ERK and the JNK pathways contributed to the cell cycle arrest induced by vanadium compounds in L02 cells. More importantly, it was found that although NAC can ameliorate the cytotoxicity of vanadium compounds in L02 cells, it did not decrease their cytotoxicity in HepG2 cells. It thus shed light on the potential therapeutic applications of vanadium compounds with antioxidants as synergistic agents to reduce their toxicities in human normal cells without affecting their antitumor activities in cancer cells.