Therapeutic Uses of Molybdenum

Molybdenum is an essential trace element and is a component of vitamin and mineral supplements. Some therapeutic uses of molybdenum compounds are described in this section.

THERAPEUTIC

Cationic octahedral molybdenum cluster complexes functionalized with mitochondria-targeting ligands: photodynamic anticancer and antibacterial activities

Octahedral molybdenum cluster complexes have recently come forth as pertinent singlet oxygen photosensitizers towards biological applications. Still, their phototoxic efficiency in the absence of nanocarriers remains limited due to their poor cellular uptake. Here, two cationic octahedral molybdenum cluster complexes, bearing carboxylate ligands with triphenylphosphonium (1) or N-methyl pyridinium (2) mitochondria-targeting terminal functions, have been designed and synthesized. Their photophysical properties in water and in vitro biological activity were investigated in the context of blue-light photodynamic therapy of cancer and photoinactivation of bacteria. Upon blue light irradiation, complex 1 displays red luminescence with a quantum yield of 0.24 in water, whereas complex 2 is much less emissive (PhiL < 0.01). Nevertheless, both complexes efficiently produce singlet oxygen, O2(1Deltag). Complex 1 is rapidly internalized into HeLa cells and accumulated in mitochondria, followed by relocation to lysosomes and clearance at longer times. In contrast, the more hydrophilic 2 is not internalized into HeLa cells, highlighting the effect of the apical ligands on the uptake properties. The treatment with 1 results in an intensive phototoxic effect under 460 nm irradiation (IC50 = 0.10 +/- 0.02 muM), which exceeds by far those previously reported for octahedral cluster-based molecular photosensitizers. The ratio between phototoxicity and dark toxicity is approximately 50 and evidences a therapeutic window for the application of 1 in blue-light photodynamic therapy. Complex 1 also enters and efficiently photoinactivates Gram-positive bacteria Enterococcus faecalis and Staphylococcus aureus, documenting its suitability as a blue-light photosensitizer for antimicrobial applications.

K. Kirakci, J. Zelenka, M. Rumlova, J. Cvacka, T. Ruml, and K. Lang,Cationic octahedral molybdenum cluster complexes functionalized with mitochondria-targeting ligands: photodynamic anticancer and antibacterial activities, Biomaterials science, 2019.

 

               

THERAPEUTIC USES OF MOLYBDENUM

Antibacterial MoO3

Bactericidal efficacy of molybdenum oxide nanoparticles against antimicrobial-resistant pathogens

Multidrug-resistant bacteria pose a major threat to effective antibiotics and alternatives to fight multidrug-resistant pathogens are needed. We synthetized molybdenum oxide (MoO3) nanoparticles (NP) and determined their antibacterial activity against 39 isolates: (i) eight Staphylococcus aureus, including representatives of methicillin-resistant S. aureus epidemic clones; (ii) six enterococci, including vancomycin-resistant isolates; and (iii) 25 Gram-negative isolates (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacter cloacae), including extended spectrum beta-lactamases and carbapenemases producers. All isolates showed a MoO3 NP MIC of 700-800 mg l(-1). MoO3 NP produced a clear inhibition zone for S. aureus and all Gram-negative isolates at concentrations >/=25 mg ml(-1) and >/=50 mg ml(-1) for enterococci. When the NP solutions were adjusted to pH ~7, the biocidal activity was completely abolished. MoO3 NP create an acidic pH and show a universal antimicrobial activity against susceptible and resistant isolates belonging to the most relevant bacterial species responsible for hospital-acquired infections.

E. Lopes, S. Picarra, P. L. Almeida, H. de Lencastre, and M. Aires-de-Sousa,Bactericidal efficacy of molybdenum oxide nanoparticles against antimicrobial-resistant pathogens, Journal of medical microbiology, 2018.

 

Skin Cancer MoO3

Selectivity and sensitivity of molybdenum oxide-polycaprolactone nanofiber composites on skin cancer: Preliminary in-vitro and in-vivo implications

Cancer nanomedicine has emerged as a revolution in the last decade opening up promising strides for the cancer treatment. The major challenge in these therapeutic approaches resides in the failure of clinical trials owing to the immunological cancer microenvironment. Therefore, the success of next generation nanomedicine depends on tunable physicochemical nanomaterial design and corresponding clinical trials by integrating targeted delivery with mitigated toxicity. The present study deals with the fabrication of nanofibrous scaffold impregnated with molybdenum nanoparticles for targeted skin cancer therapeutics. Molybdenum oxide, a transitional metal oxide is gaining rapid importance due to its vital role in cellular and molecular metabolism. Polycaprolactone nanofibers were chosen as a matrix to localize the nanoparticles topically facilitating selective apoptosis of the tumor cells over the normal cells with mitigated side effects. The scaffold was designed to tailor the physicochemical, mechanical and biological suitability for skin cancer (melanoma and non melanoma). The designed scaffold was found to reduce more than 50% cell viability of the cancer cells selectively through apoptosis as confirmed using AO/PI staining and the probable mechanism could be attributed to the induction of mitochondria dependent apoptosis as observed by JC1 dye staining. In-vivo trials in zebra fish were found to reduce cancer progression by more than 30% in 14 days. The fabricated molybdenum trioxide nano constructs not only serve as tunable targeted systems but also open venues capable of ferrying chemotherapeutic drugs sparing normal cells alleviating the trauma due to side effects.

Janani, R. Lakra, M. S. Kiran, and P. S. Korrapati,Selectivity and sensitivity of molybdenum oxide-polycaprolactone nanofiber composites on skin cancer: Preliminary in-vitro and in-vivo implications, Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS), 2018, 49, 60-71

Liver Cancer

Crystal Structure and Biological Evaluation of Two Novel Organic-Inorganic Hybrid Materials as Antitumor Agents in the Treatment of Liver Cancer

Two novel organic-inorganic hybrid materials {(Hbiz)(6)[(As2AsMo18O62)-As-III-Mo-V-O-VI]}center dot H2O (1, biz = benzimidazole) and (dim) [AS(2)(III)As(V)Mo(18)(VI)O(62)] [2, dim = 1,6-bis(imidazol)hexane] have been successfully obtained by using the molybdenum arsenate and different N donor organic compounds and determined through X-ray single-crystal diffraction technique. The in vitro cytotoxicity of compounds 1 and 2 was then investigated against three human liver tumor cell lines (SMMC7721, Bel-7402, and MHCC97) by MIT assay. It was found that the two compounds showed potent use as antitumor agents against the aforementioned cell lines.

B. H. Song, C. Li, and G. F. An,Crystal Structure and Biological Evaluation of Two Novel Organic-Inorganic Hybrid Materials as Antitumor Agents in the Treatment of Liver Cancer, Journal of Chemistry, 2018.

 

 

 

 

Facile preparation of molybdenum (VI) oxide - Modified graphene oxide nanocomposite for specific enrichment of phosphopeptides

To promote the development of phosphoproteome analysis in highly selective efficient tracing phosphorylated proteins or peptides, views of researches should not confined with intrinsic materials and their modification. New materials are supposed to be explored for phosphoproteome analysis. In this work, we first introduced Molybdenum (VI) oxide (MoO3) into phosphoproteome, loading on the graphene oxide (GO) nanosheets forming MoO3/GO nanocomposites by a simple two-step strategy. The GO nanosheets offered MoO3 a perfect stable platform for separation and concentration and MoO3 exhibited wonderful property in enriching phosphopeptides with highly selectivity and sensitivity on GO nanosheets. Specifically, the as-synthesized MoO3/GO nanocomposites exhibited excellent specificity (beta-casein: BSA = 1:1000), high detection sensitivity (1 fmol/mL) and well recovery (91.13%) in enriching phosphopeptides by metal oxide affinity chromatography (MOAC). Moreover, the as-synthesized MoO3/GO nanocomposites provided effective enrichment of phosphopeptides from nonfat milk (a total of twelve phosphopeptides signals) and human serum (a total of four endogenous phosphopeptides signals), displaying great biological compatibility, which demonstrated that the MoO3/GO nanocomposites is a promising candidate in selectively identifying and determining low-abundance phosphorylated peptides in biological sample. (C) 2017 Elsevier B.V. All rights reserved.

Sun, H. F., Zhang, Q. Q., Zhang, L., Zhang, W. B., and Zhang, L. Y.,Facile preparation of molybdenum (VI) oxide - Modified graphene oxide nanocomposite for specific enrichment of phosphopeptides, Journal of Chromatography A, 2017, 1521, 36-43

Effects of two-dimensional materials on human mesenchymal stem cell behaviors

Graphene, a typical two-dimensional (2D) material, is known to affect a variety of stem cell behaviors including adhesion, spreading, growth, and differentiation. Here, we report for the first time the effects of four different emerging 2D materials on human adipose-derived mesenchymal stem cells (hADMSCs). Graphene oxide (GO), molybdenum sulfide (MoS2), tungsten sulfide (WS2), and boron nitride (BN) were selected as model two-dimensional materials and were coated on cell-culture substrates by a drop-casting method. Acute toxicity was not observed with any of the four different 2D materials at a low concentration range (<5 mug/ml). Interestingly, the 2D material-modified substrates exhibited a higher cell adhesion, spreading, and proliferation when compared with a non-treated (NT) substrate. Remarkably, in the case of differentiation, the MoS2-, WS2-, and BN-modified substrates exhibited a better performance in terms of guiding the adipogenesis of hADMSCs when compared with both NT and GO-modified substrates, based on the mRNA expression level (qPCR) and amount of lipid droplets (ORO staining). In contrast, the osteogenesis was found to be most efficiently induced by the GO-coated substrate (50 mug/mL) among all 2D-material coated substrates. In summary,.

Suhito, I. R., Han, Y., Kim, D. S., Son, H., and Kim, T. H.,Effects of two-dimensional materials on human mesenchymal stem cell behaviors, Biochemical and biophysical research communications, 2017, 493, 578-584.

Label-free and recalibrated multilayer MoS2 biosensor for point-of-care diagnostics

Molybdenum disulfide (MoS2) field-effect transistor (FET)-based biosensors have attracted a significant attention as promising candidates for highly sensitive, label-free biomolecule detection devices. In this paper, toward practical applications of biosensors, we demonstrate reliable and quantitative detection of a prostate cancer biomarker using the MoS2-FET biosensor in a non-aqueous environment by reducing non-specific molecular binding events and realizing uniform chemisorption of anti-PSA onto the MoS2 surface. A systematic and statistical study on the capability of the proposed device is presented, and the biological binding events are directly confirmed and characterized through intensive structural and electrical analysis. Our proposed biosensor can reliably detect various PSA concentrations with a limit of 100 fg/mL. Moreover, rigorous theoretical simulations provide a comprehensive understanding of the operating mechanism of the MoS2-FET biosensors, and further suggests the enhancement of the sensitivity through engineering device design parameters.

Park, H., Han, G. C., Lee, S. W., Lee, H., Jeong, S. H., Naqi, M., AlMutairi, A., Kim, Y. J., Lee, J., Kim, W. J., Kim, S., Yoon, Y., and Yoo, G.,Label-free and recalibrated multilayer MoS2 biosensor for point-of-care diagnostics, ACS Appl Mater Interfaces, 2017.

Enhancing the colloidal stability and surface functionality of molybdenum disulfide (MoS2) nanosheets with hyperbranched polyglycerol for photothermal therapy

Molybdenum disulfide (MoS2) nanosheets are gaining increasing attention due to their attractive properties and myriads of potential applications. However, challenges in the enhancement of their colloidal stability and surface functionality still remain and significantly restrict their practical applications. Herein, we present a viable approach to functionalize MoS2 nanosheets with multihydroxy hyperbranched polyglycerol (HPG) shell by surface-initiated ring-opening polymerization technique. The grafting of HPG from the surface of MoS2 nanosheet yielded MoS2-g-HPG nanohybrid with excellent water dispersibility, good biocompatibility, and greatly enhanced colloidal stability against pH change, ionic strength variation and long-term storage. The MoS2-g-HPG also exhibited excellent light-to-heat conversion capability for in vitro photothermal therapy application. Meanwhile, the MoS2-g-HPG showed favorable surface functionality owing to its numerous surface hydroxyl groups, as demonstrated by the conjugation of functional molecules such as fluorescent dye rhodamine B. As such, this paper opens up new opportunities to empower MoS2 nanosheets and other two-dimensional inorganic nanosheets with desired properties for various applications.

Huang, B., Wang, D., Wang, G., Zhang, F., and Zhou, L.,Enhancing the colloidal stability and surface functionality of molybdenum disulfide (MoS2) nanosheets with hyperbranched polyglycerol for photothermal therapy, Journal of colloid and interface science, 2017, 508, 214-221.

Modified cyclopentadienyl molybdenum compounds with enhanced cytotoxic activity towards MOLT-4 leukaemia cells

A series of new cyclopentadienyl molybdenum compounds bearing substituted phenanthroline ligands [(eta(5)-C5H4CH2C6H4X-4)Mo(CO)2(L-N,L-N)][BF4] (X = F, Cl, Br; L-N,L-N=phen, 5-NH2-phen, 4,7-Ph-2-phen) was prepared and characterized using infrared and NMR spectroscopies. Crystal structures of [(eta(5)-C5H4CH2C6H4F-4)Mo(CO)(2)(NCMe)(2)][BF4], [(eta(5)-C5H4CH2C6H4X-4)Mo(CO)(2)(phen)][BF4] (X = F, Cl, Br) and [(eta(5)-C5H4CH2C6H4Cl-4)Mo(CO)(2)(4,7-Ph-2-phen)][BF4](4,7-Ph-2-phen)HBF4 were determined using X-ray diffraction analysis. Biological studies revealed a strong cytotoxic effect of the chelating ligands. Although the cytostatic effect of the halogen in the side chain of the cyclopentadienyl ring is negligible, it could be used for future post-modification of these types of cytotoxic active molybdenum-based compounds.

Honzickova, I., Vinklarek, J., Ruzickova, Z., Rezacova, M., and Honzicek, J.,Modified cyclopentadienyl molybdenum compounds with enhanced cytotoxic activity towards MOLT-4 leukaemia cells, Applied Organometallic Chemistry, 2017, 31.

MoS2-based sensor for the detection of miRNA in serum samples related to breast cancer

Early diagnosis of cancer is critical for the treatment of patients, and can reduce the risk of death. Breast cancer is one of the most common malignant tumors in women, and miR-21, as an important breast cancer biomarker, can be helpful for the early diagnosis of breast cancer. In this work, we have developed an efficient, sensitive and specific fluorescence sensor based on the novel nanomaterial molybdenum disulfide (MoS2) to detect miR-21. The novel nanomaterial MoS2 was introduced to a fluorescent dye-labeled DNA probe to fabricate the fluorescence sensor, and then non-complementary miRNA, one-base mismatched miRNA and complementary miR-21 were separately introduced to the sensor to hybridize with the DNA probe. By monitoring the change of the fluorescence signal before and after DNA-miRNA hybridization, miR-21 could be detected. We found that the sensor could discriminate complementary miR-21 from one-base mismatched miRNA and non-complementary miRNA successfully. Furthermore, the biosensor was able to detect miR-21 down to a concentration of 500 pM, and the detection could be completed in only 40 min. The novel MoS2 fluorescence sensor, with the advantages of fast analysis, high sensitivity and specificity, and low cost, is suitable for miR-21 detection which is of great importance for the early diagnosis of breast cancer. What's more, the novel sensor, with high sensitivity and selectivity, was also used to detect miR-21 in serum samples, making it a promising method for detection in real samples from patients with cancer. Thus the novel MoS2 fluorescence sensor shows huge potential for early diagnosis of cancer.

B. J. Cai, S. Guo, and Y. Li,MoS2-based sensor for the detection of miRNA in serum samples related to breast cancer, Analytical Methods, 2018, 10, 230-236.

Corrosion and surface modification on biocompatible metals: A review

Corrosion prevention in biomaterials has become crucial particularly to overcome inflammation and allergic reactions caused by the biomaterials' implants towards the human body. When these metal implants contacted with fluidic environments such as bloodstream and tissue of the body, most of them became mutually highly antagonistic and subsequently promotes corrosion. Biocompatible implants are typically made up of metallic, ceramic, composite and polymers. The present paper specifically focuses on biocompatible metals which favorably used as implants such as 316L stainless steel, cobalt-chromium-molybdenum, pure titanium and titanium -based alloys. This article also takes a close look at the effect of corrosion towards the implant and human body and the mechanism to improve it. Due to this corrosion delinquent, several surface modification techniques have been used to improve the corrosion behavior of biocompatible metals such as deposition of the coating, development of passivation oxide layer and ion beam surface modification. Apart from that, surface texturing methods such as plasma spraying, chemical etching, blasting, electropolishing, and laser treatment which used to improve corrosion behavior are also discussed in detail. Introduction of surface modifications to biocompatible metals is considered as a "best solution" so far to enhanced corrosion resistance performance; besides achieving superior biocompatibility and promoting osseointegration of biocompatible metals and alloys. (C) 2017 Elsevier B.V. All rights reserved.

R. I. M. Asri, W. S. W. Harun, M. Samykano, N. A. C. Lah, S. A. C. Ghani, F. Tarlochan, and M. R. Raza,Corrosion and surface modification on biocompatible metals: A review, Materials Science & Engineering C-Materials for Biological Applications, 2017, 77, 1261-1274.

 

Neutron-activatable needles for radionuclide therapy of solid tumors

Various approaches have been undertaken to enhance the delivery of therapeutic agents, including tissue-killing radionuclides, into solid tumors. Here, we describe the preparation of conical needles composed of Ti and Mo coated by pulsed laser deposition or chemical vapor deposition with elements (Ho and Re) that can readily yield radioactive isotopes following irradiation in a neutron flux. The radioactive needles, whose design were based on solid microneedle arrays used in transdermal drug delivery, can be produced with minimal handling of radioactivity and subsequently inserted into tumors as a means of internal radiation therapy. Ho and Re were specifically chosen because of their large neutron capture cross-sections as well as the desirable radiotherapeutic properties of the resultant radionuclides. Neutron-absorbing shields were also developed to prevent the production of unwanted radionuclides after neutron irradiation of the needle base materials. Neutron activation calculations showed that therapeutically significant amounts of radionuclides can be produced for treating solid tumors. Stability studies demonstrated that Re did not leach off the Mo needles. These coated neutron-activatable needles offer a new approach to internal radiation therapy of tumors that allows precise tailoring of the absorbed radiation dose delivered to the tumor by controlling the coating thickness and the irradiation time. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3273-3280, 2017.

J. Kim, R. J. Narayan, X. Lu, and M. Jay,Neutron-activatable needles for radionuclide therapy of solid tumors, Journal of biomedical materials research. Part A, 2017, 105, 3273-3280.

MoS2 nanosheets encapsulated in sodium alginate microcapsules as microwave embolization agents for large orthotopic transplantation tumor therapy

In recent years, it is prevalent to treat various kinds of the tumors through microwave ablation method. However, it is still very difficult to ablate large tumors by the traditional microwave ablation therapy. In this work, an effective microwave embolization agent designed by encapsulating molybdenum sulfide nanosheets in the sodium alginate microcapsules, denoted as MSMCs, was prepared for the effective therapy of large tumor. The toxicity evaluation showed that MSMC had a good biocompatibility in vitro. The in vitro and in vivo experiments demonstrated that the MSMC was an excellent embolic and microwave susceptible agent that could be used for dual-enhanced microwave ablation therapy. As such, the MSMC showed excellent tumor therapeutic effect with 5 times larger ablation zone observed by magnetic resonance (MR) imaging than the microwave alone after 3 days treating. Besides, the tumor is nearly completely ablated and can not be recurrent due to the persistent hyperthermia. Moreover, MSMCs have a good biocompatibility and can be degraded and cleared from the body. It is believed that the MSMC is demonstrated to be a promising multifunctional theranostic agent used for treating the larger tumor via the synergistic therapy of enhanced microwave ablation and transcatheter arterial embolization (TAE).

Fu, C. H., He, F., Tan, L. F., Ren, X. L., Zhang, W., Liu, T. L., Wang, J. Z., Ren, J., Chen, X. D., and Meng, X. W.,MoS2 nanosheets encapsulated in sodium alginate microcapsules as microwave embolization agents for large orthotopic transplantation tumor therapy, Nanoscale, 2017, 9, 14846-14853.

 

Anticancer

Bioresponsive Polyoxometalate Cluster for Redox-Activated Photoacoustic Imaging-Guided Photothermal Cancer Therapy

Although various types of imaging agents have been developed for photoacoustic (PA) imaging, relatively few imaging agents exhibit high selectivity/sensitivity to the tumor microenvironment for on-demand PA imaging and therapy.
Herein, molybdenum-based polyoxometalate (POM) clusters with the highest oxidation state of Mo(VI) (denoted as Ox-POM) were designed as novel agents for redox-activated PA imaging-guided photothermal therapy. Capable of escaping from recognition and capture by the liver and spleen, these renal clearable clusters with ultrasmall size (hydrodynamic size: 1.9 nm) can accumulate in the tumor, self-assemble into larger nanoclusters at low pH, and are reduced to NIR absorptive agents in the tumor microenvironment.
Studies in 4T1 tumor-bearing mice indicated that these clusters could be employed for bioresponsive PA imaging-guided tumor ablation in vivo.
Our finding is expected to establish a new physicochemical paradigm for the design of PA imaging agents based on clusters, bridging the conventional concepts of "molecule" and "nano" in the bioimaging field.

Ni, D., Jiang, D., Valdovinos, H. F., Ehlerding, E. B., Yu, B., Barnhart, T. E., Huang, P., and Cai, W.,Bioresponsive Polyoxometalate Cluster for Redox-Activated Photoacoustic Imaging-Guided Photothermal Cancer Therapy, Nano Lett, 2017, 17, 3282-3289.

 

MoS2 Alzheimer's

Molybdenum Disulfide Nanoparticles as Multifunctional Inhibitors against Alzheimer's Disease

The complex pathogenic mechanisms of Alzheimer's disease (AD) include the aggregation of beta-amyloid peptides (Abeta) into oligomers or fibrils as well as Abeta-mediated oxidative stress, which require comprehensive treatment. Therefore, the inhibition of Abeta aggregation and free-radical scavenging are essential for the treatment of AD. Nanoparticles (NPs) have been found to influence Abeta aggregation process in vitro. Herein, we report the inhibition effects of molybdenum disulfide (MoS2) NPs on Abeta aggregation. Polyvinylpyrrolidone-functionalized MoS2 NPs were fabricated by a pulsed laser ablation method. We find that MoS2 NPs exhibit multifunctional effects on Abeta peptides: inhibiting Abeta aggregation, destabilizing Abeta fibrils, alleviating Abeta-induced oxidative stress, as well as Abeta-mediated cell toxicity. Moreover, we show that MoS2 NPs can block the formation of the Ca2+ channel induced by Abeta fibrils in the cell membrane for the first time. Thus, these observations suggest that MoS2 NPs have great potential for a multifunctional therapeutic agent against amyloid-related diseases.
Han, Q., Cai, S., Yang, L., Wang, X., Qi, C., Yang, R., and Wang, C.,Molybdenum Disulfide Nanoparticles as Multifunctional Inhibitors against Alzheimer's Disease, ACS Appl Mater Interfaces. 2017 Jun 28;9(25):21116-21123. doi: 10.1021/acsami.7b03816. Epub 2017 Jun 14.

 

THERAPEUTIC

Lung and breast cancer cells

223 Sustainable one-step synthesis of hierarchical microspheres of PEGylated MoS2 nanosheets and MoO3 nanorods: Their cytotoxicity towards lung and breast cancer cells

Nanotechnology provides an emerging potent alternate mode of cancer therapy. Nanomaterials dispersion or solubility is of particular concern in utilising their full potential applications in biomedical fields. PEGylation of nanomaterials is considered to provide products with stealth properties, and physiological environment with no obvious adverse effects.

The purpose of this work was to develop a sustainable one-step method for fabrication of hierarchical microspheres of PEGylated MoS2 nanosheets using a stoichiometric ratio of Mo(VI) and thiourea.

This study further investigated the cytotoxicity of the PEGylated MoS2 nanosheets towards lung (A549) and breast cancer (MCF-7) cell lines by analysing morphological changes and performing dose-dependent cell proliferation, and cytotoxicity analysis using adenosine 5'-triphosphate (ATP), and lactate dehydrogenase (LDH) assay.

For comparison, MoO3 nanorods were synthesised by simple chemical route and their cytotoxicity towards lung (A549) and breast cancer (MCF-7) cell lines were checked.

The findings suggested that PEGylated MoS2 nanosheets have excellent cytotoxicity towards breast cancer (MCF-7) cell lines, and MoO3 have better cytotoxicity towards lung (A549) cancer cell lines.

This work envisages an accessible foundation for engineering sophisticated biomolecule-MoS2 nanosheets conjugation due to the defect-rich biocompatible surface, to achieve great versatility, additional functions, and further advances in the biomedical field. (C) 2016 Elsevier B.V. All rights reserved.

Kumar, N., George, B. P. A., Abrahamse, H., Parashar, V., and Ngila, J. C.,Sustainable one-step synthesis of hierarchical microspheres of PEGylated MoS2 nanosheets and MoO3 nanorods: Their cytotoxicity towards lung and breast cancer cells, Applied Surface Science, 2017, 396, 8-18.

[PEGylated MoS2: lipoic acid-terminated polyethylene glycol (LA-PEG) grafted  onto the surface of MoS2 nanoflakes endowing the nanoflakes with high colloidal stability and very low cytotoxicity.

See Wei Feng, Liang Chen, Ming Qin, Xiaojun Zhou, Qianqian Zhang, Yingke Miao, Kexin Qiu, Yanzhong Zhang and Chuanglong He. Flower-like PEGylated MoS2 nanoflakes for near-infrared photothermal cancer therapy. Scientific Reports 5, Article number: 17422 (2015). doi:10.1038/srep17422.]

 

MoS2 cancer therapy

Investigation of Thermally Induced Cellular Ablation and Heat Response Triggered by Planar MoS2-based Nanocomposite

In comparison to conventional tumor treatment methods, photothermal therapy (PTT) is one of the innovative therapeutic strategies that employs light to produce the localized heat for targeted ablation of cancer cells.

Among various kinds of heat generation nanomaterials, transition metal dichalcogenide nanosheets, especially-molybdenum disulfide (MoS2) have recently been investigated as one of the promising PTT candidates because of their strong absorbance in the near-infrared (NIR) tissue transparency window and excellent photothermal conversion capability.

In line with the great potential of MoS2-based nanomaterials in biomedical applications, their intrinsic therapeutic performance and corresponding cellular response are required to be continually investigated.

In order to further improve MoS2-based PTT efficacy and dissect the molecular mechanism during heat stimuli, in this study, we successfully designed a novel and effective PTT platform by integration of MoS2 nanosheets with peptide-based inhibition molecules to block the function of heat shock proteins (Hsp90), one type of chaperon proteins that play the protective roles in living system against cellular photothermal response.

Such combined nanosystem could effectively induce cell ablation and viability assays indicated approximately five folds higher PTT treatment efficacy (8.8 % viability) than that of MoS2 itself (48 % viability) upon 808 nm light irradiation.

Moreover, different from the case based on MoS2 alone that could cause tumor ablation through the process of necrosis, the detailed mechanism analysis revealed the inhibition of Hsp90 could significantly increase the photothermal-mediated apoptosis, hence resulting in remarkable enhancement of photothermal treatment.

Such promising studies provide the great opportunity to better understand the cellular basis of light triggered thermal response. Moreover, they can also facilitate the rational design of new generations of PTT platforms toward future theranostics.

Ariyasu, S., Mu, J., Zhang, X., Huang, Y., Yeow, E. K., Zhang, H., and Xing, B.,Investigation of Thermally Induced Cellular Ablation and Heat Response Triggered by Planar MoS2-based Nanocomposite, Bioconjugate chemistry, 2017.

 

Insulin mimetic

Exposure to sodium molybdate results in mild oxidative stress in Drosophila melanogaster

OBJECTIVES: The study was conducted to assess the redox status of Drosophila flies upon oral intake of insulin-mimetic salt, sodium molybdate (Na2MoO4).

METHODS: Oxidative stress parameters and activities of antioxidant and associated enzymes were analyzed in two-day-old D. melanogaster insects after exposure of larvae and newly eclosed adults to three molybdate levels (0.025, 0.5, or 10 mM) in the food.

RESULTS: Molybdate increased content of low molecular mass thiols and activities of catalase, superoxide dismutase, glutathione-S-transferase, and glucose-6-phosphate dehydrogenase in males. The activities of these enzymes were not affected in females. Males exposed to molybdate demonstrated lower carbonyl protein levels than the control cohort, whereas females at the same conditions had higher carbonyl protein content and catalase activity than ones in the control cohort. The exposure to 10 mM sodium molybdate decreased the content of protein thiols in adult flies of both sexes. Sodium molybdate did not affect the activities of NADP-dependent malate dehydrogenase and thioredoxin reductase in males or NADP-dependent isocitrate dehydrogenase in either sex at any concentration.

DISCUSSION: Enhanced antioxidant capacity in upon Drosophila flies low molybdate levels in the food suggests that molybdate can be potentially useful for the treatment of certain pathologies associated with oxidative stress.

Perkhulyn, N. V., Rovenko, B. M., Lushchak, O. V., Storey, J. M., Storey, K. B., and Lushchak, V. I.,Exposure to sodium molybdate results in mild oxidative stress in Drosophila melanogaster, Redox report : communications in free radical research, 2017, 1-10.

[Drosophila melanogaster = fruit fly. See https://en.wikipedia.org/wiki/Drosophila_melanogaster and Similarity to humans:

“A March 2000 study by National Human Genome Research Institute comparing the fruit fly and human genome estimated that about 60% of genes are conserved between the two species.[32] About 75% of known human disease genes have a recognizable match in the genome of fruit flies,[33] and 50% of fly protein sequences have mammalian homologs. An online database called Homophila is available to search for human disease gene homologues in flies and vice versa.[34] Drosophila is being used as a genetic model for several human diseases including the neurodegenerative disorders Parkinson's, Huntington's, spinocerebellar ataxia and Alzheimer's disease. The fly is also being used to study mechanisms underlying aging and oxidative stress, immunity, diabetes, and cancer, as well as drug abuse.”

Antioxidant and associated enzymes. See http://www.news-medical.net/health/Antioxidant-Enzyme-Systems.aspx Enzymes that catalyze reactions to neutralize free radicals and reactive oxygen species: superoxide dismutase, glutathione peroxidise, glutathione reductase, catalases, lipoic acid. They require co-factors such as selenium, iron, copper, zinc, and manganese for optimum catalytic activity.

“These form the body’s endogenous defence mechanisms to help protect against free radical-induced cell damage. The antioxidant enzymes – glutathione peroxidase, catalase, and superoxide dismutase (SOD) – metabolize oxidative toxic intermediates.]

The Production of Medical ISOTOPES without Nuclear Reactors or Uranium Enrichment

This article examines the current capability of accelerator technology, which is rapidly improving, to produce medical isotopes. A detailed analysis of 12 medical isotopes that are in active diagnostic and therapeutic use and typically made in nuclear reactors shows that accelerator-based technologies, such as linear accelerators, cyclotrons, and spallation neutron sources, could meet medical demand for these isotopes, without the use of enriched uranium and with low proliferation risk. The feasibility of accelerator-based production of an additional 70 isotopes that have a potential medical use is also discussed. A simple estimate suggests that accelerators can produce isotopes at a cost comparable to reactors. This article includes four case studies that illustrate the recent choices that emerging market countries have made when expanding domestic medical isotope production. Technical, commercial, and regulatory steps for commercialization are also described. The article concludes with policy suggestions that would increase the adoption of accelerator-based medical isotope production.

Hoedl, S. A., and Updegraff, W. D.,The Production of Medical Isotopes without Nuclear Reactors or Uranium Enrichment, Science & Global Security, 2015, 23, 121-153.

Synthesis, Structural Characterization and Preliminary Biological Studies of Several Heterocyclic Transition Metal CARBONYL COMPLEXES

The reaction of molybdenum, tungsten and manganese carbonyls with several thiazole heterocycle ligands yielded a number of coordinated transition metal complexes 1-10. Of these complexes 16 are new compounds which have not been reported to date. The structures of new compounds were characterized by FT-IR and H-1-NMR spectroscopy as well as single-crystal X-ray diffraction analysis. Complexes 1-10 are carbon monoxide releasing molecules that show structure-related anti-cancer activity. The cytotoxicity of all compounds on Hela cells was evaluated by MTT assay, and the results show that carbon monoxide releasing molecules containing such Schiff base ligands may have biomedical applications for their anti-tumor effect.

Hu, S. F., Cui, X. W., He, W. M., Chen, X. Y., Gu, Z. K., Zhao, J. Z., Zeng, G., Shi, Z., Zhu, L., and Nie, H. M.,Synthesis, Structural Characterization and Preliminary Biological Studies of Several Heterocyclic Transition Metal Carbonyl Complexes, Zeitschrift Fur Anorganische Und Allgemeine Chemie, 2015, 641, 2452-2459.

The Biochemical Role of Macro and Micro-Minerals in the Management of DIABETES MELLITUS and its Associated Complications: A Review

Diabetes mellitus is a chronic physiological glucose metabolic disorder. Its high prevalence globally has a significant impact on the quality of life. The management of diabetes includes non-pharmacological and glucose lowering agents. Although these methods are effective, they have drawbacks. This has led to a search for alternative therapy in macro and micro-minerals from dietary foods and plants. There is therefore a need to review, identify and classify their modes of action in diabetes mellitus therapy.

Materials and Methods: This review was carried out using comprehensive literature reports on the use of mineral elements in the management of diabetes. Empirical online searches were conducted for different elements that have been studied for their anti-diabetic potentials both in vivo and in vitro. The University of Fort Hare's online database was also used.

Results and Discussion: The results indicate that magnesium, molybdenum, zinc, vanadium and manganese facilitate glucose catabolism. Chromium, vanadium, zinc, molybdenum and magnesium can enhance insulin activity while molybdenum, manganese and zinc stimulate lipogenesis. Zinc and iron can modulate glucose, metabolizing enzymes in the gastrointestinal tract and limit oxidative stress, respectively. These agents have similar mechanisms to conventional drugs in ameliorating diabetic status and other associated complications. Conclusion: The mechanisms of these elements are well known, however, the synergetic effects of their combinations are still obscure. Literature on their safe dose(s) is still scanty. Evaluation of other useful macro and micro-minerals should also be undertaken. It is envisaged that the use of mineral supplements will promote good health in diabetics.

Kibiti, C. M., and Afolayan, A. J.,The Biochemical Role of Macro and Micro-Minerals in the Management of Diabetes Mellitus and its Associated Complications: A Review, International Journal for Vitamin and Nutrition Research, 2015, 85, 88-103.

[Lipogenesis is the process by which acetyl-CoA is converted to fatty acids. Acetyl-CoA is an intermediate stage in metabolism of simple sugars, such as glucose, a source of energy of living organisms. Through lipogenesis and subsequent triglyceride synthesis, the energy can be efficiently stored in the form of fats. https://en.wikipedia.org/wiki/Lipogenesis.]

Application of computational models to estimate organ radiation dose in rainbow trout from uptake of MOLYBDENUM-99 with comparison to iodine-131

This study compares three anatomical phantoms for rainbow trout (Oncorhynchus mykiss) for the purpose of estimating organ radiation dose and dose rates from molybdenum-99 (Mo-99) uptake in the liver and GI tract. Model comparison and refinement is important to the process of determining accurate doses and dose rates to the whole body and the various organs. Accurate and consistent dosimetry is crucial to the determination of appropriate dose-effett relationships for use in environmental risk assessment. The computational phantoms considered are (1) a geometrically defined model employing anatomically relevant organ size and location, (2) voxel reconstruction of internal anatomy obtained from CT imaging, and (3) a new model utilizing NURBS surfaces to refine the model in (2). Dose Conversion Factors (DCFs) for whole body as well as selected organs of O. mykiss were computed using Monte Carlo modeling and combined with empirical models for predicting activity concentration to estimate dose rates and ultimately determine cumulative radiation dose (mu Gy) to selected organs after several half-lives of Mo-99. The computational models provided similar results, especially for organs that were both the source and target of radiation (less than 30% difference between all models). Values in the empirical model as well as the 14 day cumulative organ doses determined from Mo-99 uptake are compared to similar models developed previously for I-131. Finally, consideration is given to treating the GI tract as a solid organ compared to partitioning it into gut contents and GI wall, which resulted in an order of magnitude difference in estimated dose for most organs. (C) 2015 Elsevier Ltd. All rights reserved.

Martinez, N. E., Johnson, T. E., and Pinder, J. E.,Application of computational models to estimate organ radiation dose in rainbow trout from uptake of molybdenum-99 with comparison to iodine-131, Journal of Environmental Radioactivity, 2016, 151, 468-479.

Study of ANTITUMOR effect of selected vanadium and molybdenum organometallic complexes in human leukemic T-cells

This work describes cytotoxic effect of non-platinum metal-based compounds on the human T-leukemic cells with different p53 status (p53 wild-type MOLT-4 and p53-deficient Jurkat cells). The cytotoxic and apoptosis-inducing effect of the vanadium complex [(mu5-C5H5)2v(5-NH2-phen)]OTf (V1) and molybdenum complex [(mu3-C3H5)Mo(CO)2(phen)Cl] (Mo1) were studied using flow cytometry, spectrophotometry and Western blotting. We found that the cytotoxic effect of both tested complexes after 24 h is higher against the both examined cell lines than that of cis-platin (cis-DDP). At later investigated time intervals of 48 and 72 h, the cytotoxic effect of the cis-DDP increased but the values of the cytotoxicity of the tested V1 and Mol complexes remained unchanged, with the cytotoxicity of V1 comparable to that of cis-DDP. Furthermore we observed that the apoptotic process was induced by the activation of the caspases 9 (intrinsic pathway) and 8 (extrinsic pathway) in cells exposed to evaluated complexes. In case of the p53 wild-type MOLT-4 cells, the expression of the tumor-suppressor protein p53 and its form phosphorylated at the serine 15 increased after both V1 and Mo1 treatment, similar to the effect of cis-DDP. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Sebestova, L., Havelek, R., Rezacova, M., Honzicek, J., Krocova, Z., and Vinklarek, J.,Study of antitumor effect of selected vanadium and molybdenum organometallic complexes in human leukemic T-cells, Chemico-Biological Interactions, 2015, 242, 61-70.

Molybdenum disulphide. Injectable 2D MoS -Integrated Drug Delivering Implant for Highly Efficient NIR-Triggered Synergistic Tumor Hyperthermia

MoS2 nanosheets and a doxorubicin (DOX)-containing poly (lactic-co-glycolic acid) (PLGA)/ MoS2 /DOX composite implant is successfully constructed based on the unique phase-changing behavior of PLGA/ MoS2 /DOX oleosol within tumors. The fast phase transformation can firmly restrict MoS2 and DOX within tumors, and the integrated MoS2and DOX can endow the implant with high synergistic photothermal and chemotherapeutic efficiency against tumors.

Wang, S., Chen, Y., Li, X., Gao, W., Zhang, L., Liu, J., Zheng, Y., Chen, H., and Shi, J.,Injectable 2D MoS -Integrated Drug Delivering Implant for Highly Efficient NIR-Triggered Synergistic Tumor Hyperthermia, Advanced materials (Deerfield Beach, Fla.), 2015.

 

MoS2 nanoplates. Aptamer loaded MoS2 nanoplates as nanoprobes for detection of intracellular ATP and controllable photodynamic therapy

In this work we designed a MoS2 nanoplate-based nanoprobe for fluorescence imaging of intracellular ATP and photodynamic therapy (PDT) via ATP-mediated controllable release of O2-1. The nanoprobe was prepared by simply assembling a chlorine e6 (Ce6) labelled ATP aptamer on MoS2 nanoplates, which have favorable biocompatibility, unusual surface-area-to-mass ratio, strong affinity to single-stranded DNA, and can quench the fluorescence of Ce6. After the nanoprobe was internalized into the cells and entered ATP-abundant lysosomes, its recognition to ATP led to the release of the single-stranded aptamer from MoS2 nanoplates and thus recovered the fluorescence of Ce6 at an excitation wavelength of 633 nm, which produced a highly sensitive and selective method for imaging of intracellular ATP. Meanwhile, the ATP-mediated release led to the generation of O-1(2) under 660 nm laser irradiation, which could induce tumor cell death with a lysosomal pathway. The controllable PDT provided a model approach for design of multifunctional theranostic nanoprobes. These results also promoted the development and application of MoS2 nanoplate-based platforms in biomedicine.

Jia, L., Ding, L., Tian, J. W., Bao, L., Hu, Y. P., Ju, H. X., and Yu, J. S.,Aptamer loaded MoS2 nanoplates as nanoprobes for detection of intracellular ATP and controllable photodynamic therapy, Nanoscale, 2015, 7, 15953-15961.

[Aptamers: oligonucleotide or peptide molecules that bind to a specific target molecule. Theranostics:  developing specific, individualized therapies for diseases combining diagnostic and therapeutic capabilities into a single agent. Nanoparticle-based theranostic agents www.ncbi.nlm.nih.gov/pmc/articles/PMC2988080/.]

Molybdenum nanoparticles antioxidative and cytoprotective response in human cells

Nanotechnology based therapeutics can offer an alternative platform in a wide variety of biomedical applications. Here we report novel cytotoxicity preventive potential of molybdenum nanoparticles (Mo NPs) in human breast (MCF-7) and fibrosarcoma (HT-1080) cells compromised with oxidant exposure. Physicochemical properties such as size, crystallinity, purity and band gap (an optical characteristic) of Mo NPs were characterized respectively by field emission transmission electron microscopy (FETEM), X-ray diffraction (XRD), energy dispersive spectrum (EDS) and UV-vis absorption spectroscopy. The average size of crystalline Mo NPs was found to be 35 nm with a band gap of 1.4 eV. Potential cytotoxicity of Mo NPs was evaluated by a battery of cell viability and oxidative stress parameters. Cell viability and oxidative stress data suggested Mo NPs to be reasonably non-cytotoxic. Cytotoxic preventive and GSH [glutathione] restoring potential of Mo NPs was determined against cytotoxicity and oxidative stress induced by H2O2 (and ZnO NPs) in two cells. Mo NPs significantly increased GSH level in MCF-7 and HT-1080 cells, an activity that was comparable to antioxidant N-acetyl cysteine (NAC). GSH level was increased 1.56 times in MCF-7 cells and 1.25 times in HT-1080 cells by 100 mug/ml of Mo NPs relative to control cells in 24 h. End-point data clearly suggest that Mo NPs significantly protected cells against cytotoxicity induced by H2O2 and ZnO (NPs) (p<0.05). Our study warrants further investigation about Mo NPs that could be exploited in myriads of nanotechnology applications.

 

Akhtar, M. J., Ahamed, M., Alhadlaq, H. A., Alshamsan, A., Khan, M. A., and Alrokayan, S. A.,Antioxidative and cytoprotective response elicited by molybdenum nanoparticles in human cells, Journal of colloid and interface science, 2015, 457, 370-7.

Antitumor effect of selected vanadium and molybdenum organometallic complexes in human leukemic T-cells

This work describes cytotoxic effect of non-platinum metal-based compounds on the human T-leukemic cells with different p53 status (p53 wild-type MOLT-4 and p53-deficient Jurkat cells). The cytotoxic and apoptosis-inducing effect of the vanadium complex [(eta5-C5H5)2V(5-NH2-phen)]OTf (V1) and molybdenum complex [(eta3-C3H5)Mo(CO)2(phen)Cl] (Mo1) were studied using flow cytometry, spectrophotometry and Western blotting. We found that the cytotoxic effect of both tested complexes after 24 h is higher against the both examined cell lines than that of cis-platin (cis-DDP). At later investigated time intervals of 48 and 72 h, the cytotoxic effect of the cis-DDP increased but the values of the cytotoxicity of the tested V1 and Mo1 complexes remained unchanged, with the cytotoxicity of V1 comparable to that of cis-DDP. Furthermore we observed that the apoptotic process was induced by the activation of the caspases 9 (intrinsic pathway) and 8 (extrinsic pathway) in cells exposed to evaluated complexes. In case of the p53 wild-type MOLT-4 cells, the expression of the tumor-suppressor protein p53 and its form phosphorylated at the serine 15 increased after both V1 and Mo1 treatment, similar to the effect of cis-DDP.

Sebestova, L., Havelek, R., Rezacova, M., Honzicek, J., Krocova, Z., and Vinklarek, J.,Study of antitumor effect of selected vanadium and molybdenum organometallic complexes in human leukemic T-cells, Chemico-biological interactions, 2015, 242, 61-70.

Molybdenum-99 medical radioisotope shortages

Since June 2009, the NEA and its High-level Group on the Security of Supply of Medical Radioisotopes (HLG-MR) have examined the causes of Mo-99 /(99)mTc supply shortages and developed a policy approach, including principles and supporting recommendations to address those causes. The NEA has also reviewed the global Mo-99 /(99)mTc supply situation periodically, using the most up-to-date data from supply chain participants, to highlight periods of reduced supply and underscore the case for implementing the HLG-MR policy approach in a timely and globally-consistent manner. In 2012, the NEA released a Mo-99 supply and demand update for the period up to 2030 (A Supply and Demand Update of the Molybdenum-99 Market, OECD/NEA, 2012), identifying periods of low supply relative to demand. This paper presents the preliminary results from an updated Mo-99 supply and demand forecast, focusing on the potentially critical 2015-2020 period, when two major Mo-99 producers (the NRU reactor in Canada and the OSI-RIS reactor in France). are scheduled to cease 99Mo irradiations. On the demand side, the NM had previously released a study with the results from a global survey of future demand for Mo-99 /(99)mTc (OECD-NEA, 2011), devising a scenario based on a data assessment by an expert advisory group. In the current analysis, the expected demand growth rate and total demand have been modified,,based on the latest information from supply chain participants. On the supply side, the NM has updated the list of current and planned new Mo-99 /(99)mTc irradiation and processing projects. The modelling results incorporate revisions to production start/end dates, potential additional projects, and impacts of converting to the use of low-enriched uranium (LEU) targets on Mo-99 /(99)mTc capacity and production. The supply forecast horizon (2015 to 2020) has been chosen to reflect upcoming, important changes in global production capacity the planned shutdowns in Canada and France, and the expected commissioning of new reactor- and non-reactor-based projects in Europe, the United States, South America, and Australia

Peykov, P. and Cameron, R., Are Radioisotope Shortages a Thing of the Past?, Atw-International Journal for Nuclear Power, 2014, 59, 551-+.

Treatment of anaemia

Magnesium molybdate in daily doses of 0.06-0.20 g Mo has been used in the treatment of various conditions including anaemia and as a general tonic for restoring appetite after convalescence [Vignoli and Defretin, 1963].

Vignoli L.and Defretin, J. P., Biologie medicale, 1963, 52, 319.

A sustained-release preparation of a molybdenised iron(II) sulfate is capable of promptly correcting iron deficiency anaemia and is prescribed for this purpose [Mouratoff and Batterman, 1961; Stevenson, 1962; Rudolph et al., 1963].

Mouratoff, G. L. and Batterman, R. C., J. New Drugs, 1961,1,157.
Stevenson, T. D., Current Therapeutic Research, 1962, 4, 107.
Rudolph, I., Ongchangco, M. N. and Fink, H., Current Therapeutic Research, 1963, 5, 517.

Prevention of dental caries

It is well known that fluoride is effective against the development of dental caries in experimental animals and in human beings. There is evidence that trace elements, particularly molybdenum, in the water supply and in food, enhance the cariostatic effect of fluoride [Schutte, 1964]. For example, children fed on vegetables from the molybdenum-rich Napier area of New Zealand had fewer caries than children from other areas. Similar epidemiological studies in Europe and the United States have confirmed the cariostatic effect of molybdenum [Lossee and Bibby, 1970; Hadjimarkos, 1966; Anderson, 1969; Jenkins, 1967; Lossee and Adkins, 1971].

Schutte, K. H., The Biology of the Trace Elements, Crosby Lockwood and Son Ltd., London, 1964, 92.
Lossee, F. L. and Bibby, B. G., New York State Dental Journal, 1970, 36, 15.
Hadjimarkos, D. M., Anderson, R. J., Caries Res., 1969, 3, 75.
Arch. Environ. Health, 1966, 13, 102.
Jenkins, G., British Dental Journal, 1967, 435, 500, 545.
Lossee, F. L. and Adkins, B. L., Geol. Soc. Amer., Mem., 1971, 123, 203.

The incidence of dental caries is lower in parts of Hungary than would be expected from the fluoride content of the water supply. On investigation it was found that the molybdenum content of the drinking water was high. Further studies from New Zealand, from the cities of Hastings and Napier, showed that the incidence of caries in Napier was significantly less than in Hastings, although both towns had the same water supply. However, the inhabitants of Napier ate vegetables grown in soil that had been under the sea until raised by an earthquake 30 years ago; the concentration of molybdenum was much higher in this soil than in that around Hastings. The molybdenum content of the teeth of boys living in Napier was higher than that of boys in Hastings, although the hair content of molybdenum in boys from both cities was the same. Another piece of evidence suggesting that deficiency of molybdenum plays a part in dental caries is that in Somerset UK the incidence of caries is high in children from areas where the cattle suffer from molybdenum deficiency.

Many workers have given molybdenum to animals and confirmed its anti-cariogenic properties, although in some cases the dose of molybdenum was high. It is not yet established what is the effective anti-cariogenic dose of molybdenum, at what stage in tooth formation it acts, or whether there is any relation between fluoride and molybdenum. Molybdenum has been shown to reduce the solubility of teeth in acid and also to reduce the acid output by the salivary glands. It is more likely that molybdenum acts by affecting the morphology of teeth than by other mechanisms. There is an additive effect between the benefits of fluoride and molybdenum, though fluoride is undoubtedly the more important. Molybdenum increases the absorption of fluoride from the stomach.

The route by which molybdenum reached individuals living in areas of molybdenum-rich soils was through locally produced and consumed vegetables and especially milk [Anderson, 1969]. Water supplies do not make an important contribution to the daily intake of molybdenum [Hadjimarkos, 1966]. The effect of molybdenum and other trace elements on the development of dental caries in experimental animals has been studied [Navia, 1970; Bertrand et al., 1972; Helsby, 1973]. Molybdenum and also vanadium and strontium were mildly cariostatic. There are indications that ammonium molybdate, (NH4)2MoO4, is cariostatic but that ammonium heptamolybdate, (NH4)6Mo7O24.4H2O, is not [Jenkins, 1967]. The enamel of rat teeth formed in the presence of molybdenum and fluoride has been examined by electron microscopy [Kruger, 1969]. Both elements influence mineralisation. The cariostatic effect of molybdenum is well established and there is need for more research, especially on the mechanism of its action, the level required, and the method of administration.

Hadjimarkos, 1966; Anderson, 1969; Jenkins, 1967; Lossee and Adkins, 1971].
Navia, J. M., Advan. Chem. Ser., 1970, 94, 123.
Bertrand, G., Blanquet, P. and Laparra, J. C. R. Soc. Biol., 1972, 166, 353.
Helsby, C. A., Caries Res., 1973, 7, 332.
Jenkins, G., British Dental Journal, 1967, 435, 500, 545.
Kruger, B. J., J. Dent. Res., 1969, 48, 1303.

Effect of molybdenum on the immunological reactivity of organisms

The addition of molybdenum as an aqueous solution of ammonium molybdate in amounts of 50-250 mg/kg to the diet of rabbits daily for up to 12 months increased the immunological reaction towards Bact. proteus OX19 culture. The optimum dose was 250 mg/kg when the amount of antibodies and phagocytes was two to three times higher than in control animals [Devyatka et al., 1971].

Devyatka, D. G., Val'chuk, N. K., Voronina, T. Z. and Bukhovets, V. J., Gig. Sanit., 1971, 36, 104.

Molybdenum and cancer

For a review see

Metal passivity as mechanism of metal carcinogenesis: Chromium, nickel, iron, copper, cobalt, platinum, molybdenum, CORNELIA RICHARDSON-BOEDLER Toxicological & Environmental Chemistry, Jan–Mar 2007; 89(1): 15–70.

There are indications of a relationship between molybdenum deficiency and the development of various tumours. The incidence of oesophageal cancer in areas of South Africa varies depending on location [Davies, 1975; Rose, 1968; Burrell et al., 1966]. The gardens of a group of Bantu women who died of cancer were less fertile and less productive than those of tumour-free women. Severe signs of molybdenum deficiency were noted in plants grown in gardens of the cancer sufferers. It is suggested that the molybdenum deficiency resulted in the plants being more prone to attack by fungi, e.g. Aspergillus flavus, which has been implicated as a cause of liver cancer in animals. The distribution of molybdenum in mouse liver and Sarcoma 180 was determined following the intraperitoneal injection daily for 6 d of various molybdenum compounds [Caruthers and Regelson, 1963]. With Na4SiMol2O40, MoCl5, and MoBr2 there was an accumulation of molybdenum in the liver and the tumour but with (NH4)6Mo7O24.4H2O and Mo3(H2C2O4).2H2O there was no such accumulation. The copper and zinc contents of the liver and the tumour were not affected by any of the molybdenum compounds nor was the growth rate of the tumour. It is possibly relevant that the concentration of xanthine oxidase is relatively low in various tumours and that tumour growth in mice was decreased by treatment with xanthine oxidase concentrates [Bray, 1963].

Davies, I. J. T., Intake (British Medical Journal. Advertiser's Supplement), 1975, 39, 4.
Rose, E. F., Cancer Research, 1968, 28, 2390.
Burrell, R. J. W., Roach, W. A. and Shadwell, A., J. Nat. Cancer Inst., 1966, 36, 201, 211.
Caruthers C.and Regelson, W.,Oncologia, 1963, 16, 101.
Bray, R. C., in The Enzymes, ed. Boyer, P. D., Hardy, L. and Myrback, K., Academic Press, New York, 2nd Edn., 1963, 7, 533.

Structures, DNA binding, DNA cleavage, and antitumor investigations of a series of molybdenum(VI) complexes with some N(4) methyl and ethyl thiosemicarbazone ligands
Four dioxomolybdenum(VI) complexes were synthesized by reaction of [MoO2(acac)2] with thiosemicarbazones derived from 5-allyl-2-hydroxy-3-methoxybenzaldehyde (1), 2-hydroxynaphthaldehyde (2), 2,3-dihydroxybenzaldehyde (3), or 5-tert-butyl-2-hydroxybenzaldehyde (4).

The ligands were coordinated to molybdenum as tridentate ONS donors. X-ray crystallography showed that the distorted octahedral coordination of molybdenum is completed by methanol (D) in 1a, 3a, and 4a or H2O in 2a. The molecular structures of 1, 3, and 4, and the complexes were determined by single-crystal X-ray crystallography.

Binding of the ligand and complexes with calf thymus DNA were investigated by UV, fluorescence titrations, and viscosity measurements.

Gel electrophoresis revealed that all the complexes can cleave pBR322 plasmid DNA.
The cytotoxic properties of the complexes against human colorectal (HCT 116) cell line showed strong antiproliferative activities in relative order 4a > 3a > 1a > 2a with IC50 values of 1.6, 4.0, 4.8, and 6.7 mu M, respectively.

The complexes exhibited more activity than the standard reference drug, 5-fluorouracil (IC50 7.3 mu M).
These studies show that dioxomolybdenum(VI) complexes have potential use in chemotherapy

Hussein, M. A., Guan, T. S., Haque, R. A., Ahamed, M. B. K., and Majid, A. M. S. A., Structures, DNA binding, DNA cleavage, and antitumor investigations of a series of molybdenum(VI) complexes with some N(4) methyl and ethyl thiosemicarbazone ligands, Journal of Coordination Chemistry, 2014, 67, 714-727Water soluble molybdenocene complexes: Synthesis, cytotoxic activity and binding studies to ubiquitin by fluorescence spectroscopy, circular dichroism and molecular modeling
Four new molybdenocene complexes, Cp2Mo(L-ascorbato), Cp2Mo(6-O-palmitoyl-L-ascorbato), [Cp2Mo(ethyl maltolato)]Cl and Cp2Mo((2S)-2-amino-3-methyl-3-thiolato-butanoato), were synthesized and structurally characterized by standard analytical methods.

The cytotoxicity of these complexes was assessed on colon HT-29 and breast MCF-7 cancer cell lines using the 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay.

A higher cytotoxic activity was shown by all the new complexes on the MCF-7 cells over the Cp2MoCl2 complex.
The complexes Cp2Mo(L-ascorbato), Cp2Mo(6-O-palmitoyl-L-ascorbato) and [Cp2Mo(ethyl maltolato)]Cl displayed a stronger cytotoxic activity on colon cancer HT-29 cell line, over the molybdenocene dichloride (Cp2MoCl2).

In contrast, Cp2Mo((2S)-2-amino-3-methyl-3-thiolato-butanoato) exhibited proliferative properties on this cell line.
Ubiquitin (Ub)-molybdenocene interactions were investigated using cyclic voltammetry, fluorescence quenching spectroscopy, circular dichroism (CD) and molecular modeling. The thermodynamic parameters (Delta H and Delta S) obtained using fluorescence quenching spectra and van't Hoff plot indicate the Ub-molybdenocene interactions are mainly hydrophobic. The CD data also support hydrophobic interactions with conformational changes in the Ub protein. Docking studies using molecular modeling revealed the amino adds involved in the Ub-molybdenocene interactions and corroborated the hydrophobic nature of the binding combined with hydrogen bonding. (C) 2013 Elsevier Inc All rights reserved

Narvaez-Pita, X., Ortega-Zuniga, C., Acevedo-Morantes, C. Y., Pastrana, B., Olivero-Verbel, J., Maldonado-Rojas, W., Ramirez-Vick, J. E., and Melendez, E., Water soluble molybdenocene complexes: Synthesis, cytotoxic activity and binding studies to ubiquitin by fluorescence spectroscopy, circular dichroism and molecular modeling, Journal of Inorganic Biochemistry, 2014, 132, 77-91.Low Cytotoxicity of Inorganic Nanotubes and Fullerene-Like Nanostructures in Human Bronchial Epithelial Cells: Relation to Inflammatory Gene Induction and Antioxidant Response
The cytotoxicity of tungsten disulfide nano tubes (INT-WS2) and inorganic fullerene-like molybdenum disulfide (IF-MoS2) nanoparticles (NPs) used in industrial and medical applications was evaluated in comparison to standard environmental particulate matter.

The IF-MoS2 and INT-WS2 reside in vesicles/inclusion bodies, suggestive of. endocytic vesicles. In cells representing the respiratory, immune and metabolic systems, both IF-MoS2 and INT-WS2 NPs remained nontoxic compared to equivalent concentrations (up to 100 mu g/mL in the medium) of silica dioxide (SiO2), diesel engine-derived and carbon black NPs, which induced cell death.

Associating with this biocompatibility of IF-MoS2INT-WS2, we demonstrate in nontransformed human bronchial cells (NL-20) relative low induction of the pro-inflammatory cytokines IL-1 beta, IL-6, IL-8, and TNF-alpha.
Moreover, IF-MoS2 and INT-WS2 activated antioxidant response as measured by the antioxidant response element (ARE) using a luciferase reporter, and induced Nrf2-mediated Phase II detoxification genes.
Collectively, our findings suggest that the lower cytotoxicity of IF-MoS2 and INT-WS2 NPs does not reflect general biological inertness. Rather, compared to other NP's, it likely results from decreased proinflammatory activation, but a comparable significant capacity to induce protective antioxidant/detoxification defense mechanisms

Pardo, M., Shuster-Meiseles, T., Levin-Zaidman, S., Rudich, A., and Rudich, Y., Low Cytotoxicity of Inorganic Nanotubes and Fullerene-Like Nanostructures in Human Bronchial Epithelial Cells: Relation to Inflammatory Gene Induction and Antioxidant Response, Environmental Science & Technology, 2014, 48, 3457-3466

Anticancer Activity of Metal Complexes: Involvement of Redox Processes

Cells require tight regulation of the intracellular redox balance and consequently of reactive oxygen species for proper redox signaling and maintenance of metal (e. g., of iron and copper) homeostasis. In several diseases, including cancer, this balance is disturbed. Therefore, anticancer drugs targeting the redox systems, for example, glutathione and thioredoxin, have entered focus of interest. Anticancer metal complexes (platinum, gold, arsenic, ruthenium, rhodium, copper, vanadium, cobalt, manganese, gadolinium, and molybdenum) have been shown to strongly interact with or even disturb cellular redox homeostasis. In this context, especially the hypothesis of "activation by reduction" as well as the "hard and soft acids and bases" theory with respect to coordination of metal ions to cellular ligands represent important concepts to understand the molecular modes of action of anticancer metal drugs. The aim of this review is to highlight specific interactions of metal-based anticancer drugs with the cellular redox homeostasis and to explain this behavior by considering chemical properties of the respective anticancer metal complexes currently either in (pre)clinical development or in daily clinical routine in oncology. Antioxid. Redox Signal. 15, 1085-1127

Jungwirth, U., Kowol, C. R., Keppler, B. K., Hartinger, C. G., Berger, W., and Heffeter, P., Anticancer Activity of Metal Complexes: Involvement of Redox Processes, Antioxidants & Redox Signaling, 2011, 15, 1085-1127.

Two randomised nutrition intervention trials were conducted in Linxian, an area of north central China with some of the world's highest rates of oesophageal and stomach cancer and a population with a chronically low intake of several nutrients. to assess the effects in nearly 30 000 participants of daily supplementation with: retinol and zinc; riboflavin and niacin; vitamin C and molybdenum; and beta-carotene, alpha-tocopherol, and selenium. The second trial provided daily multiple vitamin-mineral supplementation; or placebo in 3318 persons with oesophageal dysplasia, a precursor to oesophageal cancer. After supplements were given for 5.25 y in the general population trial, small but significant reductions in total relative risk [(RR) = 0.91] and cancer (RR = 0.87) mortality were observed in subjects receiving beta-carotene, alpha-tocopherol, and selenium but not the other nutrients. The largest reductions were for cerebrovascular disease mortality, but the effects differed by sex: a significant reduction was observed in men (RR = 0.45) but not women (RR = 0.90).Restoring adequate intake of certain nutrients may help to lower the risk of cancer and other diseases in this high-risk population [Blot et al., 1995].

Blot, W.J., Li, J.Y., Taylor, P.R., Guo, W.D., Dawsey, S.M., Li, B.,. The Linxian Trials - Mortality-Rates By Vitamin-Mineral Intervention Group, American Journal Of Clinical Nutrition,1995, 62, S1424-S1426.

Xanthine dehydrogenase (EC 1.1.1.204) is a molybdenum iron-sulfur, flavin hydroxylase involved in purine catabolism. Xanthine dehydrogenase-induces activation of bioreductive agents including chemotherapeutic agents requiring bioreductive activation for their antineoplastic activities. Xanthine dehydrogenase is potentially important as an enzyme targeted in chemotherapeutic regimens is discussed [Pritsos et al., 1994].

Pritsos, C.A., Gustafson, D.l., Xanthine Dehydrogenase And Its Role In Cancer-Chemotherapy, Oncology Research, 1994, 6, 477-481.

The antitumor active molybdocene dichloride Cp2MoCl2 formed two stable adducts at pD 6 which were tentatively assigned as a Cp2Mo-glutathione chelate involving coordination of the cysteine thiol and glycine carboxylate to the molybdenum centre, and a thiol centred 1:2 Cp2Mo-glutathione complex. The implications for the mechanism of antitumor action of the metallocene dihalides are discussed.

Mokdsi, G. and Harding, M. M., A H-1 NMR study of the interaction of antitumor metallocenes with glutathione, Journal of Inorganic Biochemistry, 2001, 86, 611-616.

Interest in the aqueous, bio-organometallic chemistry of metallocene dihalides has stemmed from the potent antitumor properties of titanocene dichloride, including results from human clinical trials. Key results on the biological chemistry of molybdocene dichloride are reviewed. Under physiological conditions the positively charged monoaquated species Cp2Mo(OH)(OH2)+, in equilibrium with the dipositively charged dimer Cp2Mo(mu-OH)2MoCp2, is present.Studies of the coordination chemistry of Cp2MoCl2 with nucleobases, nucleotides, single-stranded and double-stranded oligonucleotides, and calf-thymus DNA have shown that, while simultaneous phosphate(O) and heterocyclic(N) adducts are formed with nucleotides, negligible interaction with DNA occurs under physiological conditions. Cp2MoCl2 forms strong, non-labile complexes with deprotonated thiols in amino acids. Molybdocene dichloride is able to catalyse the hydrolysis of activated phosphate esters under physiological conditions, but hydrolysis of unactivated phosphodiesters is only significant at pH 4. Limited antitumor activity results, inhibition studies with protein kinase C and topoisomerase II, structure-activity and cell-uptake studies have provided some insight into possible mechanisms of antitumor action.

Waern, J.B. and Harding, M. M., Bioorganometallic chemistry of molybdocene dichloride, Journal of Organometallic Chemistry, 2004, 689, 4655-4668.

The compounds molybdenocene dichloride (Cp2MoCl2) and [Cp2Mo(L)(n)]Cl2 (n = 1, L = 6-mercaptopurine, 6- mercaptopurineribose, 2-amine-6-mercaptopurine and 2-amine-6- mercaptopurineribose and n = 2, L = D-penicillamine) have antitumour properties. Their complexes with calfthymus DNA have been investigated by cyclic voltammetry. (Cp2MoCl2) and [Cp2Mo(L)(n)]Cl2 (n = 1, L = 2-amine-6- mercaptopurine and 2-amine-6-mercaptopurineribose and n = 2, L = D-penicillamine) complexes showed weak DNA bindings (3.2- 10.1%) while the complexes containing the ligands 6- mercaptopurine and 6-mercaptopurineribose showed negligible interactions.

Rodriguez, M.I., Chavez-Gil, T., Colon, Y., Diaz, N., and Melendez, E., Molybdenocene-DNA interaction studies using electrochemical analysis, Journal of Electroanalytical Chemistry, 2005, 576, 315-322.

Mo and cancer molybdenocene

In the range 4 <=, pD <=, 9 by NMR spectroscopy the ribonucleosides and ribonucleoside monophosphates uridine, adenosine, cytidine, guanosine, 5'-UMP, 5'-AMP, 5'-CMP and 5'-GMP bind Cp2Mo2+ exclusively through the ribose moiety giving rise to the chelate complexes [Cp2Mo(urd-O2',O3')], [Cp2Mo(ade-O2',O3')], [Cp2Mo(cyd-O2',O3')], and [Cp2Mo(gua-O2',O3')]. The ribonucleotides form three types of complex with Cp2Mo2+ in neutral solution, namely N,PO-macrochelates, PO,O3'-coordinated species as well as O2',O3'-chelates, while at pD 9 only sugar coordination is observed.

Erxleben, A. and Yovkova, L., Reaction behavior of molybdocene dichloride towards ribonucleosides and ribonucleoside monophosphates: Rare example of sugar coordination, Inorganica Chimica Acta, 2006, 359, 2350-2360.
Waern, J.B., Harris, H. H., Lai, B., Cai, Z. H., Harding, M. M., and Dillon, C. T., Intracellular mapping of the distribution of metals derived from the antitumor metallocenes, Journal of Biological Inorganic Chemistry, 2005, 10, 443-452.

Bioorganometallic chemistry of molybdenocene dichloride and its derivatives: cancer therapy

The potential application of metallocene complexes into the cancer research was established by the pioneer work of Kopf-Maeir and Kopf in the late 1970s. The combination of organometallic chemistry and biochemistry created a new research area: bioorganometallic chemistry. Bioorganometallic chemistry has developed rapidly in the last thirty years leading to application of organometallic species into diagnostic, sensors, immunoassays and anticancer research among others. This review focuses on the bioorganometallic chemistry of molybdenocene dichloride and its derivatives as metal-based anticancer drugs. The anticancer properties of molybdenocene dichloride and its derivatives are described as well as the mechanism of action, aqueous and coordination chemistry, and molybdenocene-biomolecule interactions. (C) 2012 Elsevier B. V. All rights reserved

Melendez, Enrique, Bioorganometallic chemistry of molybdenocene dichloride and its derivatives, Journal of Organometallic Chemistry, 2012, 706, 4-12.

Molybdocene is cytotoxic

In V79 Chinese hamster lung cells Cp2MoCl2 produced significant genotoxic damage: 0.2 micronuclei/1000 binucleated cells were induced per mu M of Cp2MoCl2. Distinct morphological alterations of the nuclei, condensation of chromatin, and a high incidence of polynucleated cells were observed. Implications for the mechanism of antitumor action of molybdocene dichloride are discussed. (c)

Campbell, K. S., Foster, A. J., Dillon, C. T., and Harding, M. M., Genotoxicity and transmission electron microscopy studies of molybdocene dichloride, Journal of Inorganic Biochemistry, 2006, 100, 1194-1198.

Anti-cancer activity of molybdophosphate: heteropoly Mo

The review includes a useful account of the biochemical activity of molybdenum heteropoly compounds, specifically 12-molybdophosphoric acid, and applications as biomedical agents: antitumoral, anticoagulant, antibacterial, antiviral activity. The antitumour activity of molybdophosphoric acid in in vitro tests on human cervix carcinoma cells was low and less than the activity of tungstophosphoric acid. Molybdophosphoric acid did not damage red blood cells. Molybdophosphoric caused a slight increase of the coagulation time of human blood plasma (49 s compared with 40 s) but less than tungstophosphoric acid (100 s). The polyoxometallates did not exhibit antibacterial activity or antiviral activity on plant viruses.

Mioc, U. B., Todorovic, M. R., Davidovic, A., Colomban, P., and Holclajtner-Antunovic, I., Heteropoly compounds - From proton conductors to biomedical agents, Solid State Ionics, 2005, 176, 3005-3017.

Polyoxomolybdate

The polyoxomolybdate hexabis(isopropylammonium) heptamolybdate trihydrate, [NH3Pri]6[Mo7O24].3H2O (PM-8) suppressed the growth of Co-4 human colon cancer, MX-I human breast cancer and OAT human lung cancer xenografted in nude mice. In an MTS assay DNA ladder formation and detection of apoptotic bodies in nuclei showed that antitumor activity of PM-8 in MKN45 cells was due to apoptosis [programmed cell death]. PM-8 shows promise as a novel anti-cancer agent.

Mitsui, S., Ogata, A., Yanagie, H., Kasano, H., Hisa, T., Yamase, T., and Eriguchi, M., Antitumor activity of polyoxomolybdate, [NH3Pri]6[Mo7O24].3H2O, against, human gastric cancer model, Biomedicine & Pharmacotherapy, 2006, 60, 353-358.

See also

Oda, M., Inoue, M., Hino, K., Nakamura, Y., and Yamase, T., Enhancement effect of polyoxometalates on NGF-induced neurite-outgrowth of PC12 cells, Biological & Pharmaceutical Bulletin, 2007, 30, 787-790.

2,5-dihydroxybenzoate molybdenum(VI) complex

2,5-dihydroxybenzoate molybdenum(VI) complex may provide a valuable tool in cancer chemotherapy

Thomadaki, H., Karaliota, A., Litos, C., and Scorilas, A., Enhanced antileukemic activity of the novel complex 2,5-dihydroxybenzoate molybdenum(VI) against 2,5-dihydroxybenzoate, polyoxometalate of Mo(VI), and tetraphenylphosphonium in the human HL-60 and K562 leukemic cell lines, Journal of Medicinal Chemistry, 2007, 50, 1316-1321.

Molybdenum and cancer ― polyoxomolybdate anti-tumour activity

The polyoxomolybdate(V) [Me3NH]6[(H2MoV12O28)(OH)12(MoVIO3)4].2H2O] (abbreviated PM-17), is prepared by photo-reduction of the heptamolybdate, [NH3Pri]6[MoVI7O24].3H2O (PM-8). It is an anti-tumour agent inhibiting the growth of human pancreatic cancer (AsPC-1) xenografts in a nude mice model, and induced morphological alterations in tumour cells. Correspondingly, PM-17 repressed the proliferation of AsPC-1 cells and human gastric cancer cells (MKN45) depending on the dose in vitro.

It is proposed that PM-8 could be taken preferentially into tumour cells and reduced biologically probably in the mitochondrial system. PM-17 is one of the reduced species of PM-8. The effect of the biological reduction would be to inhibit ATP generation. The reduction product is ca ten-fold more toxic than PM-8. Such a difference in toxicity between PM-8 and its reduced species would lead to a tumour-selective inhibition because (a) the reduced species, on account of its greater molecular weight, would stay longer in the tumour cells (b) the tumour cells exhibit a higher metabolism.

Doses of PM-17 (125 microg and 500 microg per 100 microL 0.9% NaCl solution, per body per day) reduced the growth rate, compared with a control, of AsPC-1 tumour cells implanted in mice over a period of 40 d without affecting the growth rate of the mice. The tumour growth inhibition was greater with the higher PM-17 doses (33.5% and 68.3% after 41 days). Thus PM-17 inhibits the proliferation of AsPC-1 human pancreatic tumours in a dose-dependent manner in vivo.

An account of the possible mechanism of tumour cell death is given. PM-17 induces both apoptosis and autophagy in human pancreatic cancer AsPC-1 cells.

Sharp DNA laddering was observed after treatment with PM-17 by agarose gel electrophoresis of cell DNA extracts which fonfirmed the induction of apottosis by PM-17.

PM-17 was not toxic to mice; they showed no impaired renal or hepatic function, nor haematocytes nor less of body weight.

[Apoptosis: a form of programmed cell death in multicellular organisms from Greek: apo - from, ptosis – falling (http://en.wikipedia.org/wiki/Apoptosis). An active process requiring metabolic activity by the dying cell, often characterised by cleavage of the DNA into fragments that give a so called laddering pattern on gels. (http://cancerweb.ncl.ac.uk/cgi-bin/omd?query=apoptosis).

Autophagy: a catabolic process involving the degradation of a cell's own components through the lysosomal machineryGreek roots: auto, self, and phagy, eatinghttp://en.wikipedia.org/wiki/Autophagy.]

Ogata, A., Yanagie, H., Ishikawa, E., Morishita, Y., Mitsui, S., Yamashita, A., Hasumi, K., Takamoto, S., Yamase, T., and Eriguchi, M., Antitumour effect of polyoxomolybdates: induction of apoptotic cell death and autophagy in in vitro and in vivo models, British Journal of Cancer, 2008, 98, 399-409.

Therapeutic antitumour

Dioxomolybdenum(VI) thiosemicarbazonato complexes were obtained by the reaction of [MoO2(acetylacetonate)] with thiosemicarbazone ligands derived from 3-thiosemicarbazide and 4-(diethylamino)salicylaldehyde, 2-hydroxy-3-methoxybenzaldehyde or 2-hydroxy-1-naphthaldehyde. When the molybdenum(VI) complexes were dissolved in water some ligand dissociation took place. The antiproliferative effects of the molybdenum(VI) complexes on the human cell lines were identical to the activity of their corresponding ligands.

Vrdoljak, V., Dilovic, I., Rubcic, M., Pavelic, S. K., Kralj, M., Matkovic-Calogovic, D., Piantanida, I., Novak, P., Rozman, A., and Cindric, M., Synthesis and characterisation of thiosemicarbazonato molybdenum(VI) complexes and their in vitro antitumor activity, European Journal of Medicinal Chemistry, 2010, 45, 38-48.

Molybdenum anti-tumour compounds

Five molybdenum-containing polyoxometalate (POM) bisphosphonate complexes have been synthesised and characterized with alendronic acid ((H2O3P)C(C3H6NH2)(OH)PO3H2 . They are water soluble. Their activities against three human tumor cell lines were investigated in vitro. The compound Na2Rb6[((Mo3O8)-O-VI)4(O3PC(C3H6NH3)(O)PO3)4]. 26H2O (a fully oxidized (molybdenum(VI) dodecanuclear POM) has IC50 values of about 10 mu m, which is about four times the activity of the parent alendronate molecule on a per-alendronate basis, which opens up the possibility of developing novel drug leads based on molybdenum bisphosphonate clusters.

Compain, J. D., Mialane, P., Marrot, J., Secheresse, F., Zhu, W., Oldfield, E., and Dolbecq, A., Tetra- to Dodecanuclear Oxomolybdate Complexes with Functionalized Bisphosphonate Ligands: Activity in Killing Tumor Cells, Chemistry-A European Journal, 2010, 16, 13741-13748.

Diabetes

Lowering blood glucose and free fatty acid levels

Both Na2MoO4 (used as a control) and cis-MoO2L22 L= maltol (3-hydroxy-2-methyl-4-pyrone) were effective in lowering blood glucose and free fatty acid levels. Diabetic rats treated with molybdate showed significant improvements in postischemic cardiac function.

Lord, S.J., Epstein, N.A., Paddock, R.L., Vogels, C.M., Hennigar, T.L., Zaworotko, M.J., Taylor, N.J., Driedzic, W.R., Broderick, T.L., Westcott, S.A., Synthesis, characterization, and biological relevance of hydroxypyrone and hydroxypyridinone complexes of molybdenum, Canadian Journal Of Chemistry-Revue Canadienne De Chimie, 1999, 77, 7, 1249-1261.

A study of molybdenum (VI) compounds as potential anti-diabetic agents is reported. Oxo anions ([MO4]2/3−, where M = V, Cr, Mo or W) have anti-diabetic properties. It is considered that oxoanions inhibit the tyrosine phosphatase enzyme by replacing phosphate in the active centers of the enzyme thereby enhancing insulin signalling.

In the body oxoanions are not absorbed via the intestine. Therefore the idea is to supply molybdenum as an uncharged hydrophobic complex capable of being absorbed in the intestine and converted in the blood stream to molybdate. The complexes should be stable under gastric and intestinal digestion conditions. The study also, incidentally, provides information on the stability and speciation of molybdenum compounds and molybdate under digestive conditions and in the blood.

The compounds studied were sodium molybdate and complexes [MoO2L2] where L is a bidentate ligand:

A: sodium molybdate, Na2[MoO4]

B: [MoO2(acac)2] (B; acacH = acetylacetone = 2,4-pentanedione) having molybdenum (VI) in distorted octahedral coordination by six oxygens

C: [MoO2(cyset)2] (C;cysetH = L-cysteine ethyl ester) having molybdenum (VI) in distorted octahedral coordination by two oxygens, two nitrogens and two sulfurs

D: [MoO2(dedtc)2](D; dedtcH = N,N-diethyldithiocarbamic acid). having molybdenum (VI) in distorted octahedral coordination by two oxygens and four sulfurs

Each complex was applied mixed with chemically inert boron nitride to simulate an oral pharmaceutical preparation. They were subjected under physiological conditions (37 °C) to: artificial gastric and intestinal digestion with semi-synthetic meal; simulated gastric juice (pH = 1.2); simulated intestinal fluid (pH = 7.5); cell culture medium (DMEM) with 10% fetal calf serum; and horse serum, heat-inactivated. Sodium molybdate was added to intact human blood then plasma separated and intact human blood then red blood cells separated. Molybdenum concentrations were 1.0 mM (100 ppm).

The compounds and their speciation were studied by Mo K-edge XANES (X-ray absorption near-edge structure) spectroscopy. The XANES spectra enable one to distinguish beween tetrahedral molybdenum(VI) (as in the molybdate anion) and octahedral molybdenum(VI) (as in the complexes) and to deduce the ligand envirionment of the molybdenum atom (2O + 4O or 2N and 2S or 4S) and hence the speciation of molybdenum(VI) under the conditions employed. The [MoO2L2] complexes decomposed under simulated gastric and intestinal digestion conditions (3 h at 37 °C), and in blood plasma and cell culture medium (24 h at 37 °C). The dithiocarbamato complex (D) was less reactive than the other complexes, decomposing in the meal but not in the gastric and intestinal liquids. The reaction products of [MoO4]2- and [MoO2L2] with the biological fluids were modelled as mixtures of tetrahedral and octahedral Mo(VI) oxo-species (i.e. having molybdenum ligated only with oxygen atoms) in various ratios depending on the nature of the medium. Red blood cells took up Mo(VI) predominantly as the [MoO4]2- ion. The octahedral oxo-Mo(VI) species were formed in more acidic media ([H+] = 2–6 M) as the monomeric [MoO2(OH2)4]2+ ion or as polynuclear molybdophosphates, e.g. [Mo5O15(PO3OR)2]2−, where R is the nucleoside residue (known to be formed in solutions of molybdate and nucleosides at pH = 4–5).

Levina, A., McLeod, A., Seuring, J., and Lay, P. A., Reactivity of potential anti-diabetic molybdenum(VI) complexes in biological media: A XANES spectroscopic study, Journal of Inorganic Biochemistry, 2007, 101, 1586-1593.

Therapeutic diabetes

Combination of molybdate with the medicinal plant Teucrium polium L. can improve islet cells function before transplantation.

Islet transplantation has become a promising treatment in the therapy of type 1 diabetes. Its function improvement, after isolation and before transplantation, is crucial because of the loss in number and function of islets after isolation. Sodium orthovanadate and sodium molybdate and the medicinal plant Teucrium polium L. possess high beneficial antioxidative potential and hypoglycemic properties via their effect on islets. Their effect on cultured islet function was evaluated. Rat pancreatic islets were cultured for 24 h then incubated with different concentrations of Teucrium polium L. (0.01 and 0.1 mg/mL) alone and in combination with sodium orthovanadate (1 mM) or sodium molybdate (1 mM). Insulin concentration in buffer media was measured as islet secretory function. Administration of Teucrium polium L. (0.01 mg/mL), sodium molybdate, and sodium orthovanadate alone or in combination with each other increased insulin secretion at high glucose concentration (16.7 mM); insulin secretion was greater in the group containing both Teucrium polium L. and sodium molybdate than other treated groups (p < 0.05).

Monfared, S. S. M. S. and Pournourmohammadi, S., Teucrium polium Complex with Molybdate Enhance Cultured Islets Secretory Function, Biological Trace Element Research, 2010, 133, 236-241.

[Note. Islet transplantation is the transplantation of isolated islets from a donor pancreas and into another person. It is an experimental treatment for type 1 diabetes mellitus. Once transplanted, the islets begin to produce insulin, actively regulating the level of glucose in the blood. Wikipedia]

Tetrathiomolybdate and Wilson’s disease

Ammonium tetrathiomolybdate treats chronic Cu poisoning in sheep and is recommended for Wilson's disease in humans (congenital inability to excrete copper resulting in its accumulation) [Haywood et al., 1998]. In the tetrathiomolybdate-treated sheep Mo accumulated in brain, liver, kidney, heart, skeletal muscle, pituitary, adrenals, testes and ovaries and was retained after cessation of treatment, except in liver, kidney and skeletal muscle. Cu increased and was retained in the cerebellum and medulla oblongata in the tetrathiomolybdate-treated high-Cu Cambridge groups. Brain Cu and Mo concentrations showed a strongly positive correlation in the high-Cu Ronaldsay group 7 months after tetrathiomolybdate treatment. Tetrathiomolybdate is not all excreted; Mo is widely distributed and retained in many organs including brain and pituitary. Tetrathiomolybdate may redistribute some displaced excess liver Cu to the brain.

Haywood, S, Dincer, Z, Holding, J, Parry, NM, Metal (molybdenum, copper) accumulation and retention in brain, pituitary and other organs of ammonium tetrathiomolybdate-treated sheep, British Journal Of Nutrition, 1998, 79, 329-331.

The uptake of tetrathiomolybdate by the liver and the removal of copper accumulating in the liver in a form bound to metallothionein by tetrathiomolybdate were studied in Long-Evans cinnamon (LEC) rats, an animal model of Wilson’s disease, in order to develop better treatments for the disease and Cu toxicity [Ogra and Suzuki, 1998]. When the dose of tetrathiomolybdate is low, tetrathiomolybdate forms a complex with Cu that can be effluxed into the bloodstream, and then binds selectively to albumin. When the dose is high, tetrathiomolybdate forms an insoluble complex, that is precipitated in the liver. Tetrathiomolybdate taken up by a cell is immobilized in the cell through the dose-dependent formation of a complex containing Cu, Mo and sulfur, which causes further uptake of tetrathiomolybdate. Tetrathiomolybdate does not remove Cu from ceruloplasmin. Tetrathiomolybdate targets a cell accumulating excess Cu as Cu- metallothionein, and removes Cu selectively without interacting with Cu in Cu-enzymes. Tetrathiomolybdate is taken up by the liver depending on the amount of Cu accumulating in the form of metallothionein, and then Cu is effluxed together with Mo in the form of Cu/tetrathiomolybdate complex into the bloodstream.

Ogra, Y., Suzuki, K.T., Targeting of tetrathiomolybdate on the copper accumulating in the liver of LEC rats, Journal Of Inorganic Biochemistry, 1998, 70, 49-55.

Tetrathiomolybdate removes copper accumulating in the form bound tometallothionein in the livers of Wilson’s disease patients and Long-Evans rats with a cinnamon-like coat color (LEC rats). Copper in Cu-containing enzymes such as Cu,Zn-superoxide dismutase in liver and ceruloplasmin in plasma was decreased by thiomolybdate; the Cu is in the plasma as a Cu/thiomolybdate/albumin complex. The decreased amounts of Cu in superoxide dismutase and ceruloplasmin were explained by the sequestration of Cu from their chaperones by thiomolybdates rather than the direct removal of Cu from the enzymes. Hepatotoxicity was observed occasionally in the clinical application of tetrathiomolybdate. The activity of glutamic-pyruvic transaminase in serum increased when Wistar rats were treated with sulfide produced through hydrolytic degradation of tetrathiomolybdate and dithiomolybdate. Hydrolytic degradation was enhanced under acidic conditions. Dithiomolybdate DTM is not appropriate as a therapeutic agent for Wilson’s disease due to its easy hydrolysis and production of sulfide.

Ogra,Y., Komada,Y., Suzuki, K.T., Comparative mechanism and toxicity of tetra- and dithiomolybdates in the removal of copper, Journal Of Inorganic Biochemistry, 1999,75, 199-204.

The chemistry, biology and therapeutic uses of the thiometallate anions of molybdenum(VI) have been reviewed.

Laurie, S.H., Thiomolybdates - Simple but very versatile reagents, European Journal of Inorganic Chemistry, 2000, 2443-2450.

Metallothionein-bound copper in the liver of Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson's disease, was removed with ammonium tetrathiomolybdate injected intravenously. In LEC rats, Cu and Mo were excreted into the bile and blood, and the bile is recognized for the first time as the major route of excretion. In Wistar rats (normal Cu metabolism) most of the Mo was excreted into the urine. The Cu excreted into both the bile and plasma was accompanied by an equimolar amount of Mo.

Komatsu, Y., Sadakata, I., Ogra, Y., and Suzuki, K. T., Excretion of copper complexed with thiomolybdate into the bile and blood in LEC rats, Chemico-Biological Interactions, 2000, 124, 217-231.

Wilson's disease is caused by the excessive accumulation of Cu. It is caused by the mutation of genes encoding Cu-binding ATPase for the efflux of Cu. Toxicological studies have elucidated the underlying mechanisms of the occurrence of acute hepatitis caused by the accumulation of Cu accumulating in the liver of an animal model for Wilson disease, LEC rats. Copper forms a stable ternary complex with molybdenum and sulfur under reductive conditions in the body. Tetrathiomolybdate has been applied to remove Cu from the liver of Long-Evans rats with a cinnamon-like coat color (LEC rats). An appropriate protocol for the chelation therapy is proposed together with the mechanisms underlying the occurrence of side-effects

Suzuki, K.T. and Ogura, Y., Biological regulation of copper and selective removal of copper: Therapy for Wilson disease and its molecular mechanism, Yakugaku Zasshi-Journal of the Pharmaceutical Society of Japan, 2000, 120, 899-908.
George, G.N., Pickering, I. J., Harris, H. H., Gailer, J., Klein, D., Lichtmannegger, J., and Summer, K. H., Tetrathiomolybdate causes formation of hepatic copper- molybdenum clusters in an animal model of Wilson's disease, Journal of the American Chemical Society, 2003, 125, 1704-1705.

Ammonium tetrathiomolybdate in treating copper poisoning and Wilson’s disease

Ammonium tetrathiomolybdate (TTM) is an effective treatment for chronic copper poisoning in sheep; it has also been proposed for the treatment of Wilson’s disease in humans. The long-term effects of TTM on five copper-poisoned sheep are reported. The copper-poisoned sheep, after apparently successful treatment with TTM, became infertile and progressively unthrifty and eventually died 2-3 years after treatment. In the TTM treated sheep there was minimal liver damage and no thyroid changes. There was no evidence of neuronal damage in any region of the brain. There were regressive pathological changes of the testes or ovaries, the adrenal glands and the pituitaries associated with the elevated levels of molybdenum. Excess of molybdenum was found in the pituitaries, the adrenals and the brains of affected sheep. Evidently molybdenum introduced systemically as TTM was retained within the brain, pituitary and adrenal glands and so was associated with a toxic endocrinopathy. It is postulated that molybdenum administered as thiomolybdate adversely affects the hypothalamo-adrenohypophyseal system by interfering with trophic hormone release, leading to the cessation of reproductive activity and ultimately the failure of intermediary metabolism. It was proposed that thiomolybdate, directly or indirectly, inhibits the enzyme peptidylglycine á-amidating mono-oxygenase (PAM), an enzyme crucial for the bioactivation of many peptide hormones, including neuropeptides, and a key enzyme in the correct functioning of the neuroendocrine system. PAM is a copper-dependent enzyme. It is found in high concentration in the hypothalamus. Tetrathiomolybdate, in binding to copper in the pituitary or hypothalamus, would make copper unavailable for PAM and thereby inhibit its activity.

Haywood, S., Dincer, Z., Jasani, B., and Loughran, M. J., Molybdenum-associated pituitary endocrinopathy in sheep treated with ammonium tetrathiomolybdate, Journal of Comparative Pathology, 2004, 130, 21-31.

Tetrathiomolybdate and Wilson’s disease and anti-tumour activity

Although addition of mineral acids to WS42- in water is known to lead to aggregation and formation of various polynuclear thiotungstate anions, acid hydrolysis of the MoS42- anion is reported to give mainly MoS3 or MoS2 as hydrolysis products. knowledge of the resulting product(s) from such reactions has implications on the use of tetra thiomolybdate (MOS42-) as both a potential anti-tumour drug and for the treatment of Wilson's disease. In this investigation, reaction of HCl with MOS42- in water was monitored as a function of time. Reaction mixtures of both 1:1 and 2:1 mole ratios of the acid to MOS42- were examined, as well as MOS42- reactions in simulated human stomach fluids at pH ca 2 and 3. Monitoring by electrospray mass spectrometry (ESMS), Fourier transform infrared (FTIR), and UV-visible spectroscopy clearly has revealed the formation of complex mixtures of polynuclear thiomolybdates. Generally, a two-stage consecutive reaction sequence occurs. A faster stage (k = 7.0-7.9 x 10-2 min-1), which seems to extend to trinuclear thiomolybdate species, followed by a slower second stage (k = 5.4-15.2 x 10-4 min-1) to higher polynuclear thiomolybdates. Under acidic conditions (e.g. pH ca 3) that could also mimic some human stomach fluids, and under anaerobic atmosphere where the generated hydrogen sulfide is prevented from escaping from the reaction vessel, Mo3 S92- predominates over an extended reaction period. In similar reactions under aerobic conditions and where the hydrogen sulfide is irretrievably lost from the reaction mixture the binuclear (Mo2OaS10-a2-; a = 0-3) and trinuclear (Mo3ObS9-b2-; b = 1-3) anions predominate.

Quagraine, E. K., Georgakaki, I., and Coucouvanis, D., Reactivity and kinetic studies of (NH4)2(MoS4) in acidic aqueous solution: Possible relevance to the angiostatic function of the MoS42- ligand, Journal of Inorganic Biochemistry, 2009, 103, 143-155.

Review copper-lowering therapy with tetrathiomolybdate

The use of copper-lowering therapy with tetrathiomolybdate in medicine Brewer, George J Expert Opinion on Investigational Drugs, Volume 18, Number 1, January 2009 , pp. 89-97(9)

Tetrathiomolybdate inhibits copper trafficking proteins

Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation

Tetrathiomolybdate ([MoS4]2-) is an orally active agent for treatment of disorders of copper metabolism. The paper describes how tetrathiomolybdate inhibits proteins that regulate copper physiology. The x-ray crystal structure of the stable tetrathiomolybdate complex with the metallochaperone Atx1 shows formation of a sulfur-bridged copper-molybdenum cluster reminiscent of those found in molybdenum and iron sulfur proteins. This cluster is stable in solution. It corresponds to physiological clusters isolated from tetrathiomolybdate-treated Wilson's disease animal models. The tetrathiomolybdate-metallochaperone inhibits metal transfer functions between copper-trafficking proteins. The results are consistent with a model wherein tetrathiomolybdate can directly and reversibly down-regulate copper delivery to secreted metalloenzymes and suggest that proteins involved in metal regulation might be fruitful drug targets.

Alvarez, H. M., Xue, Y., Robinson, C. D., Canalizo-Hernandez, M. A., Marvin, R. G., Kelly, R. A., Mondragon, A., Penner-Hahn, J. E., and O'Halloran, T. V., Tetrathiomolybdate Inhibits Copper Trafficking Proteins Through Metal Cluster Formation, Science, 2010, 327, 331-334

Huntington’s disease-ammonium tetrathiomolybdate as a candidate for clinical trials

Ammonium tetrathiomolybdate could be considered as a candidate for clinical trials in Huntington’s disease.Huntington’s disease is an uncommon autosomal dominant neurodegenerative disorder caused by expanded polyglutamine repeats in the huntingtin protein. The proximate mechanisms responsible for neurodegeneration are unknown. Copper ions may play a role in Huntington’s disease by promoting oligomerization of expanded polyglutamine repeat protein fragments. Ammonium tetrathiomolybdate is a copper complexing agent with demonstrated tolerability and efficacy in another neurodegenerative disorder, Wilson disease. Ammonium tetrathiomolybdate was evaluated in the R6/2 transgenic mouse model of Huntington’s disease. Ammonium tetrathiomolybdate treatment delayed the onset of motor dysfunction in R6/2 mice. There was a trend towards reduced striatal degeneration, suggesting a neuroprotective effect of ammonium tetrathiomolybdate in this model. Given its known tolerability in humans with neurodegeneration, ammonium tetrathiomolybdate could be considered as a candidate for clinical trials in Huntington’s disease

Tallaksen-Greene, S. J., Janiszewska, A., Benton, K., Hou, G. Q., Dick, R., Brewer, G. J., and Albin, R. L., Evaluation of tetrathiomolybdate in the R6/2 model of Huntington disease, Neuroscience Letters, 2009, 452, 60-62.

Trace Elements in Soil and Prevalence of Neural Tube Defects China

The study was carried out in the Lvliang region of Shanxi province, China, which is the area with the highest prevalence of neural tube defects in China. Neural tube defects are one of the most common birth defects. When the neural tube does not close completely, a neural tube defects develops causing, for example, the condition spina bifida.

A model was built to analyze the association between the trace element content of cultivated soil and the prevalence of neural tube defects. A function with different parameters described the effects of trace elements on neural tube defects. The association between neural tube defects and trace element levels was transformed into an optimization problem using the maximum likelihood method.

Birth defect cases included all live births and stillbirths from January 1,2002 to December 31, 2004. 112 villages had both records of birth defects and data on trace element content of soil samples. With a three‐year investigation, it is assumed that the surveyed data in this area accurately reflect the risk of neural tube defects in those villages. The association between the trace element content of the soil and the occurring risk of neural tube defects of those villages is relatively stable. Thus, the probability of content levels of trace elements in the soil and the occurring risk in each village can be converted into a maximum likelihood problem.

The concentration of 12 trace elements in the soil samples was measured by inductively coupled plasma mass spectroscopy (ICP‐MS). Mean molybdenum content of the soil was 12.25 ug/g compared with the background in Shi province 0.50.

For molybdenumthe ‘prevalence levels of neural tube defects’ was described as medium at 8.51 ug/mg (the threshold level). Molybdenum had a threshold value for the effect on neural tube defects. When the molybdenum content level is below the threshold (8.51 ug/mg), and when content level of it is more than that threshold, the association would become positively related, reducing and increasing content level of molybdenum would both increase the risk of neural tube defects.

Huang, J., Wu, J. L., Li, T. J., Song, X. M., Zhang, B. Z., Zhang, P. W., and Zheng, X. Y., Effect of Exposure to Trace Elements in the Soil on the Prevalence of Neural Tube Defects in a High-Risk Area of China, Biomedical and Environmental Sciences, 2011, 24, 94-101.

Atherosclerosis and copper

Copper chelation by tetrathiomolybdate inhibits vascular inflammation and atherosclerotic lesion development in apolipoprotein E-deficient mice

Endothelial activation, which is characterized by upregulation of cellular adhesion molecules and pro-inflammatory chemokines and cytokines, and consequent monocyte recruitment to the arterial intima are etiologic factors in atherosclerosis.

Redox-active transition metal ions, such as copper and iron, may play an important role in endothelial activation by stimulating redox-sensitive cell signaling pathways.

We have shown previously that copper chelation by tetrathiomolybdate (TTM) inhibits LPS-induced acute inflammatory responses invivo. Here, we investigated whether TTM can inhibit atherosclerotic lesion development in apolipoprotein E-deficient (apoE-/-) mice.

We found that 10-week treatment of apoE-/- mice with TTM (33-66ppm in the diet) reduced serum levels of the copper-containing protein, ceruloplasmin, by 47%, and serum iron by 26%. Tissue levels of "bioavailable" copper, assessed by the copper-to-molybdenum ratio, decreased by 80% in aorta and heart, whereas iron levels of these tissues were not affected by TTM treatment.

Furthermore, TTM significantly attenuated atherosclerotic lesion development in whole aorta by 25% and descending aorta by 45% compared to non-TTM treated apoE-/- mice.

This anti-atherogenic effect of TTM was accompanied by several anti-inflammatory effects, i.e., significantly decreased serum levels of soluble vascular cell and intercellular adhesion molecules (VCAM-1 and ICAM-1); reduced aortic gene expression of VCAM-1, ICAM-1, monocyte chemotactic protein-1, and pro-inflammatory cytokines; and significantly less aortic accumulation of M1 type macrophages.

In contrast, serum levels of oxidized LDL were not reduced by TTM.

These data indicate that TTM inhibits atherosclerosis in apoE-/- mice by reducing bioavailable copper and vascular inflammation, not by altering iron homeostasis or reducing oxidative stress

Wei, Hao, Zhang, Wei Jian, McMillen, Timothy S., Leboeuf, Renee C., and Frei, Balz, Copper chelation by tetrathiomolybdate inhibits vascular inflammation and atherosclerotic lesion development in apolipoprotein E-deficient mice, Atherosclerosis, 2012, 223, 306-313.