Molybdenum-Copper Antagonism In Metalloenzymes And Anti-Copper Therapy.

The connection between 3d (Cu) and 4d (Mo) via the "Mo-S-Cu" unit is called Mo-Cu antagonism. Biology offers case studies of such interactions in metalloproteins such as Mo/Cu-CO Dehydrogenases (Mo/Cu-CODH), and Mo/Cu Orange Protein (Mo/Cu-ORP). The CODH significantly maintains the CO level in the atmosphere below the toxic level by converting it to non-toxic CO2 for respiring organisms. Several models were synthesized to understand the structure-function relationship of these native enzymes. However, this interaction was first observed in ruminants, and they convert molybdate (MoO4 2- ) into tetrathiomolybdate (MoS4 2- ; TTM), reacting with cellular Cu to yield biological unavailable Mo/S/Cu cluster, then developing Cu-deficiency diseases. These findings inspire the use of TTM as a Cu-sequester drug, especially for treating Cu-dependent human diseases such as Wilson diseases (WD) and cancer. It is well known that a balanced Cu homeostasis is essential for a wide range of biological processes, but negative consequence leads to cell toxicity. Therefore, this review aims to connect the Mo-Cu antagonism in metalloproteins and anti-copper therapy.

All-in-One Engineering Multifunctional Nanoplatforms for Sensitizing Tumor Low-Temperature Photothermal Therapy In Vivo.

Low-temperature photothermal therapy (PTT) is a noninvasive method that harnesses the photothermal effect at low temperatures to selectively eliminate tumor cells, while safeguarding normal tissues, minimizing thermal damage, and enhancing treatment safety. First we evaluated the transcriptome of tumor cells at the gene level following low-temperature treatment and observed significant enrichment of genes involved in cell cycle and heat response-related signaling pathways. To address this challenge, we have developed an engineering multifunctional nanoplatform that offered an all-in-one strategy for efficient sensitization of low-temperature PTT. Specifically, we utilized MoS2 nanoparticles as the photothermal core to generate low temperature (40-48 °C). The nanoplatform was coated with DPA to load CPT-11 and Fe2+ and was further modified with PEG and iRGD to enhance tumor specificity (MoS2/Fe@CPT-11-PEG-iRGD). Laser- and acid-triggered release of CPT-11 can significantly increase intracellular H2O2 content, cooperate with Fe2+ ions to increase intracellular lipid ROS content, and activate ferroptosis. Furthermore, CPT-11 induced cell cycle arrest in the temperature-sensitive S-phase, and increased lipid ROS levels contributed to the degradation of HSPs protein expression. This synergistic approach could effectively induce tumor cell death by the sensitized low-temperature PTT and the combination of ferroptosis and chemotherapy. Our nanoplatform can also maximize tumor cell eradication and prolong the survival time of tumor-bearing mice in vivo. The multifunctional approach will provide more possibilities for clinical applications of low-temperature PTT and potential avenues for the development of multiple tumor treatments.

Z-scheme MoS2/Co3S4@PEG nanoflowers: Intracellular NIR-II photocatalytic O2 production facilitating hypoxic tumor therapy.

Intratumoral hypoxia, which is in favour of cancer cell proliferation, invasion and metastasis, also inhibits photodynamic therapy (PDT) badly. Herein, second near-infrared (NIR-II) photocatalytic O2 production is established to realize hypoxia relief. MoS2/Co3S4@PEG (MSCs@PEG) nanoflowers (100-150 nm) are prepared via a two-step hydrothermal method. These samples possess high NIR-II harvest and photothermal conversion (39.8 %, 1064 nm) ability. That not only reveals photothermal therapy (PTT) but also lifts the thermal energy of nanomaterials to replenish extra energy, making sure the co-excitation of MoS2 (1.14 eV) and Co3S4 (1.40 eV) by low-energy NIR-II (1064 nm, 1.16 eV) laser. The investigation of band structure further displays the Z-Scheme characterization of MSCs heterostructure. These photo-excited holes/electrons hold great redox ability to form O2 (water splitting) and reactive oxygen species (ROS), simultaneously. In addition, MSC-2@PEG can be served to mimic catalase, peroxidase, and glutathione (GSH) oxidase to further boost oxidative stress. It is noted that heterostructure discovers the greater nanozyme activity, attributing to the lower resistance for charge transfer. Moreover, MSC-2@PEG displays a novel biodegradation ability to induce the elimination via urine and faeces within 14 days. Given the superparamagnetic and photothermal effect, the nanocomposite can be used as magnetic resonance and photothermal imaging (MRI and PTI) contrast. Associated with dual-imaging, intracellular O2 supplementation, and synergistic chemotherapy (CDT)/PTT/PDT, MSC-2@PEG possess great tumor inhibition that also efficiently motivates immune response for anticancer.

Molybdenum-Iodine Cluster Loaded Polymeric Nanoparticles Allowing a Coupled Therapeutic Action with Low Side Toxicity for Treatment of Ovarian Cancer.

The ability of cancer cells to develop resistance to anti-cancer drugs, known as multidrug resistance, remains a major cause of tumor recurrence and cancer metastasis. This work explores the double mechanism of toxicity of (D, L-lactide-co-glycolide) acid (PLGA) nanoparticles encapsulating a molybdenum cluster compound, namely Cs2[{Mo6I8}(OOCC2F5)6] (CMIF). Hemocompatibility and biocompatibility assays show the safe potential of CMIF loaded nanoparticles (CNPs) as delivery systems intended for tumor targeting for PDT of ovarian cancer with a slight hemolytic activity and a lack of toxicity up to 50 µM CMIF concentration. Cellular uptake shows a preferential uptake of CNPs in lysosomes, which is not interfering with CMIF activity. The double mechanism of CNPs consists in a production of ROS and a DNA damage activity, from 5 µM and 0.5 µM respectively (CMIF concentration). The cellular death mechanism comprises 80% of necrosis and 20% of direct apoptosis by direct DNA damages. This work confirms CMIF loaded PLGA nanoparticles as an efficient and relevant delivery system for PDT.

Confined Construction of Ultrasmall Molybdenum Disulfide-Loaded Porous Silica Particles for Efficient Tumor Therapy.

Recently, molybdenum sulfide (MoS2) has shown great application potential in tumor treatment because of its good photothermal properties. Unfortunately, most of the current molybdenum disulfide-based nanotherapeutic agents suffer from complex preparation processes, low photothermal conversion efficiencies, and poor structural/compositional regulation. To address these issues, in this paper, a facile "confined solvothermal" method is proposed to construct an MoS2-loaded porous silica nanosystem (designated as MoS2@P-hSiO2). The maximum photothermal efficiency of 79.5% of molybdenum-based materials reported in the literature at present was obtained due to the ultrasmall MoS2 nanoclusters and the rich porous channels. Furthermore, both in vitro and in vivo experiments showed that the cascade hybrid system (MoS2/GOD@P-hSiO2) after efficient loading of glucose oxidase (GOD) displayed a significant tumor-suppressive effect and good biosafety through the combined effects of photothermal and enzyme-mediated cascade catalytic therapy. Consequently, this hybrid porous network system combining the in situ solvothermal strategy of inorganic functional components and the efficient encapsulation of organic enzyme macromolecules can provide a new pathway to construct synergistic agents for the efficient and safe treatment of tumors.

Differential Efficacy of B-Ultrasound Combined with Molybdenum Target Detection Mode for Breast Cancer Staging and Correlation of Blood Flow Parameters with IGF-1 and IGF-2 Expression Level and Prognosis.

The study investigates the diagnostic efficacy of ultrasound combined with the molybdenum target mode in breast cancer staging and the relationship between blood flow parameters and the expression of insulin-like growth factor 1 (IGF-1) and factor 2 (IGF-2) and prognosis. A total of 96 patients admitted to hospital from January 2020 to January 2021 are included in the breast cancer group, and 58 patients admitted to our hospital during the same period are included in the control group, who are diagnosed with benign breast lesions. All patients receive clinicopathological diagnosis, ultrasound detection, and X-ray molybdenum detection. Ultrasound detection, molybdenum target detection, ultrasound combined with the molybdenum target detection mode, and clinicopathological diagnosis results are compared. B-ultrasound combined with the molybdenum target detection mode has high efficiency in diagnosing breast cancer and differentiating pathological stages. Besides, blood flow parameters of patients are closely related to IGF-1 and IGF-2, and IGF-1 and IGF-2 expressions are closely related to the prognosis of patients. Subsequent diagnosis of the disease degree of breast cancer patients can be carried out by ultrasound combined with the molybdenum target detection mode. In addition, the expression of IGF-1 and IGF-2 in patients can be monitored to improve the clinical diagnosis and treatment plan to improve the prognosis of patients, which has a high clinical application value and is worth promoting.

Simultaneous glutamine metabolism and PD-L1 inhibition to enhance suppression of triple-negative breast cancer.

Blockade of programmed cell death 1 ligand (PD-L1) has been used to treat triple-negative breast cancer (TNBC), and various strategies are under investigation to improve the treatment response rate. Inhibition of glutamine metabolism can reduce the massive consumption of glutamine by tumor cells and meet the demand for glutamine by lymphocytes in tumors, thereby improving the anti-tumor effect on the PD-L1 blockade therapy. Here, molybdenum disulfide (MoS2) was employed to simultaneously deliver anti-PDL1 antibody (aPDL1) and V9302 to boost the anti-tumor immune response in TNBC cells. The characterization results show that MoS2 has a dispersed lamellar structure with a size of about 181 nm and a size of 232 nm after poly (L-lysine) (PLL) modification, with high stability and biocompatibility. The loading capacity of aPDL1 and V9302 are 3.84% and 24.76%, respectively. V9302 loaded MoS2 (MoS2-V9302) can effectively kill 4T1 cells and significantly reduce glutamine uptake of tumor cells. It slightly increases CD8+ cells in the tumor and promotes CD8+ cells from the tumor edge into the tumor core. In vivo studies demonstrate that the combination of aPDL1 and V9302 (MoS2-aPDL1-V9302) can strongly inhibit the growth of TNBC 4T1 tumors. Interestingly, after the treatment of MoS2-aPDL1-V9302, glutamine levels in tumor interstitial fluid increased. Subsequently, subtypes of cytotoxic T cells (CD8+) in the tumors were analyzed according to two markers of T cell activation, CD69, and CD25, and the results reveal a marked increase in the proportion of activated T cells. The levels of cytokines in the corresponding tumor interstitial fluid are also significantly increased. Additionally, during the treatment, the body weights of the mice remain stable, the main indicators of liver and kidney function in the blood do not increase significantly, and there are no obvious lesions in the main organs, indicating low systemic toxicity. In conclusion, our study provides new insights into glutamine metabolism in the tumor microenvironment affects immune checkpoint blockade therapy in TNBC, and highlights the potential clinical implications of combining glutamine metabolism inhibition with immune checkpoint blockade in the treatment of TNBC.

Tumor acidity and near-infrared light responsive drug delivery MoS2-based nanoparticles for chemo-photothermal therapy.

The rational design of tumor microenvironment (TME)- multifunctional stimuli-responsive nanocomposites is appealing for effective cancer treatment. However, multidrug resistance remains an obstacle to construct responsive oncotherapy. Herein, a novel MoS2/PDA-TPP nanocomposite loaded with chemotherapy drug of doxorubicin (DOX) is designed for TME dual-response and synergistically enhanced anti-tumor therapy based on the tumor-specific mitochondria accumulation ability and photothermal (PTT) therapy. In detail, the designed MoS2/PDA-TPP nanoplatform can act as a pH-responsive dissociation to endow fast release of DOX under an acidic TME and simultaneously improve the efficiency of PTT. Moreover, the mechanism shows that MoS2/PDA-TPP trigger mitochondrial-dependent apoptosis by producing reactive oxygen species (ROS) and reducing mitochondrial membrane potential (MMP). Most importantly, during PTT procedure, hyperthermia up to 50 °C can effectively induce tumor cell death without causing severe inflammation to adjacent tissues. Tumor targeting double stimulation response of nanocomposites is a novel idea to overcome drug resistance, which will provide a more effective strategy for solving practical problems.

Antiproliferative and antiangiogenic effects of ammonium tetrathiomolybdate in a model of endometriosis.

AIMS: Copper (Cu) is involved in the endometriosis progression. Herein, an experimental endometriosis model was used to evaluate whether its chelation with ammonium tetrathiomolybdate (TM) affects the proliferation and angiogenesis in endometriotic-like lesions and the participation of oxidative stress in these processes. MAIN METHODS: Female C57BL/6 mice were divided into three groups: sham-operated mice, endometriosis-induced mice, and TM-treated endometriosis-induced mice. Each animal in the third group received 0.3 mg of TM/day in their drinking water from the postoperative 15th day. The samples were collected after one month of induced pathology. In peritoneal fluids, Cu and estradiol levels were determined by electrothermal atomic absorption spectrometry and electrochemiluminescence, respectively. Endometriotic-like lesions were processed for the analysis of cell proliferation by PCNA immunohistochemistry, the expression of angiogenic markers by RT-qPCR, the presence of endothelial cells by immunofluorescent staining, and oxidative stress applying spectrophotometric methods. KEY FINDINGS: TM treatment decreased Cu and estradiol levels, which were increased by this pathology. In lesions, TM induced: (a) a decrease in tissue weight and volume, (b) a decrease in PCNA-positive cells, (c) antiangiogenic effects by decreasing the number of blood vessels, the mRNA expression of fibroblast growth factor 2 (Fgf2) and platelet-derived growth factor subunit B (Pdgfb), and the presence of endothelial cells, (d) a decrease in antioxidant activity and an increase in lipid peroxidation. SIGNIFICANCE: TM is a highly effective antiproliferative and antiangiogenic agent, modulating oxidative imbalance in endometriosis. Its anti-endometriotic potential is an attractive feature of TM as a possible non-hormonal treatment.

Transition-Metal Dichalcogenide Artificial Antibodies with Multivalent Polymeric Recognition Phases for Rapid Detection and Inactivation of Pathogens.

Antibodies are recognition molecules that can bind to diverse targets ranging from pathogens to small analytes with high binding affinity and specificity, making them widely employed for sensing and therapy. However, antibodies have limitations of low stability, long production time, short shelf life, and high cost. Here, we report a facile approach for the design of luminescent artificial antibodies with nonbiological polymeric recognition phases for the sensitive detection, rapid identification, and effective inactivation of pathogenic bacteria. Transition-metal dichalcogenide (TMD) nanosheets with a neutral dextran phase at the interfaces selectively recognized S. aureus, whereas the nanosheets bearing a carboxymethylated dextran phase selectively recognized E. coli O157:H7 with high binding affinity. The bacterial binding sites recognized by the artificial antibodies were thoroughly identified by experiments and molecular dynamics simulations, revealing the significance of their multivalent interactions with the bacterial membrane components for selective recognition. The luminescent WS2 artificial antibodies could rapidly detect the bacteria at a single copy from human serum without any purification and amplification. Moreover, the MoSe2 artificial antibodies selectively killed the pathogenic bacteria in the wounds of infected mice under light irradiation, leading to effective wound healing. This work demonstrates the potential of TMD artificial antibodies as an alternative to antibodies for sensing and therapy.

2D LDH-MoS2 clay nanosheets: synthesis, catalase-mimic capacity, and imaging-guided tumor photo-therapy.

Owing to the hypoxia status of the tumor, the reactive oxygen species (ROS) production during photodynamic therapy (PDT) of the tumor is less efficient. Herein, a facile method which involves the synthesis of Mg-Mn-Al layered double hydroxides (LDH) clay with MoS2 doping in the surface and anionic layer space of LDH was presented, to integrate the photo-thermal effect of MoS2 and imaging and catalytic functions of Mg-Mn-Al LDH. The designed LDH-MoS2 (LMM) clay composite was further surface-coated with bovine serum albumin (BSA) to maintain the colloidal stability of LMM in physiological environment. A photosensitizer, chlorin e6 (Ce6), was absorbed at the surface and anionic layer space of LMM@BSA. In the LMM formulation, the magnetic resonance imaging of Mg-Mn-Al LDH was enhanced thanks to the reduced and acid microenvironment of the tumor. Notably, the ROS production and PDT efficiency of Ce6 were significantly improved, because LMM@BSA could catalyze the decomposing of the overexpressed H2O2 in tumors to produce oxygen. The biocompatible LMM@BSA that played the synergism with tumor microenvironment is a promising candidate for the effective treatment of cancer.

Evaluation of the release of nickel and titanium under orthodontic treatment.

The metal alloys used in dentistry are made mainly of nickel (Ni), titanium (Ti), and other elements such as molybdenum (Mo), zirconium (Zr), iron (Fe), tin (Sn), chrome (Cr), carbon (C), copper (Cu) and niobium (Nb) which can release metal ions in unstable environments. The aim of this work was determine the salivary pH before and during orthodontic treatment; evaluate the release of metal ions, mainly Ni and Ti, in urine and saliva using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES); and evaluate the corrosion using Scanning Electronic Microscopy (SEM). In this study, we selected 35 individuals under orthodontic treatment, from whom saliva and urine samples were collected in 3 stages: (a) basal, (b) at 3 and (c) 6 months after the placement of the fixed appliances. SEM analyzed the Ni-Ti (0.016″) and stainless steel (SS) (0.016 × 0.022″) archs after 1 month of being in contact with the oral cavity. Statistical analysis was performed with Stata using the ANOVA model of repeated measures with a p < 0.05. A statistically significant difference in the concentration of Ni in saliva were found between 3 and 6 months of intervention and Ti in urine was found 3 and 6 months.

Wilson disease.

PURPOSE OF REVIEW: The aim of this article is to review recent developments in the areas of the disease features and treatment of Wilson disease, and survey disorders that share its pathophysiology or clinical symptoms. RECENT FINDINGS: Knowledge of the clinical spectrum of Wilson disease has expanded with recognition of patients who present in atypical age groups - patients with very early onset (<5 years) and those in whom symptoms present in mid-to-late adulthood. A disease phenotype with dominant psychiatric features and increased risk of cardiac problems and various sleep disorders have been identified.In addition to a better understanding of the phenotype of Wilson disease itself, features of some related disorders ('Wilson disease-mimics') have been described leading to a better understanding of copper homeostasis in humans. These disorders include diseases of copper disposition, such as mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratoderma syndrome, Niemann-Pick type C, and certain congenital disorders of glycosylation, as well as analogous disorders of iron and manganese metabolism.Outcomes for existing treatments, including in certain patient subpopulations of interest, are better known. Novel treatment strategies being studied include testing of bis-choline tetrathiomolybdate in phase 2 clinical trial as well as various preclinical explorations of new copper chelators and ways to restore ATP7B function or repair the causative gene. SUMMARY: Recent studies have expanded the phenotype of Wilson disease, identified rare inherited metal-related disorders that resemble Wilson disease, and studied long-term outcomes of existing treatments. These developments can be expected to have an immediate as well as a long-term impact on the clinical management of the disease, and point to promising avenues for future research.

Inhibition of BCL2 Family Members Increases the Efficacy of Copper Chelation in BRAFV600E-Driven Melanoma.

The principal unmet need in BRAFV600E-positive melanoma is lack of an adequate therapeutic strategy capable of overcoming resistance to clinically approved targeted therapies against oncogenic BRAF and/or the downstream MEK1/2 kinases. We previously discovered that copper (Cu) is required for MEK1 and MEK2 activity through a direct Cu-MEK1/2 interaction. Repurposing the clinical Cu chelator tetrathiomolybdate (TTM) is supported by efficacy in BRAFV600E-driven melanoma models, due in part to inhibition of MEK1/2 kinase activity. However, the antineoplastic activity of Cu chelators is cytostatic. Here, we performed high-throughput small-molecule screens to identify bioactive compounds that synergize with TTM in BRAFV600E-driven melanoma cells. Genetic perturbation or pharmacologic inhibition of specific members of the BCL2 family of antiapoptotic proteins (BCL-W, BCL-XL, and MCL1) selectively reduced cell viability when combined with a Cu chelator and induced CASPASE-dependent cell death. Further, in BRAFV600E-positive melanoma cells evolved to be resistant to BRAF and/or MEK1/2 inhibitors, combined treatment with TTM and the clinically evaluated BCL2 inhibitor, ABT-263, restored tumor growth suppression and induced apoptosis. These findings further support Cu chelation as a therapeutic strategy to target oncogene-dependent tumor cell growth and survival by enhancing Cu chelator efficacy with chemical inducers of apoptosis, especially in the context of refractory or relapsed BRAFV600E-driven melanoma. SIGNIFICANCE: This study unveils a novel collateral drug sensitivity elicited by combining copper chelators and BH3 mimetics for treatment of BRAFV600E mutation-positive melanoma.

A disease-modifying treatment for Alzheimer's disease: focus on the trans-sulfuration pathway.

High homocysteine levels in Alzheimer's disease (AD) result from low activity of the trans-sulfuration pathway. Glutathione levels are also low in AD. L-cysteine is required for the synthesis of glutathione. The synthesis of coenzyme A (CoA) requires L-cysteine, which is synthesized via the trans-sulfuration pathway. CoA is required for the synthesis of acetylcholine and appropriate cholinergic neurotransmission. L-cysteine is required for the synthesis of molybdenum-containing proteins. Sulfite oxidase (SUOX), which is a molybdenum-containing protein, could be dysregulated in AD. SUOX detoxifies the sulfites. Glutaminergic neurotransmission could be dysregulated in AD due to low levels of SUOX and high levels of sulfites. L-cysteine provides sulfur for iron-sulfur clusters. Oxidative phosphorylation (OXPHOS) is heavily dependent on iron-sulfur proteins. The decrease in OXPHOS seen in AD could be due to dysregulations of the trans-sulfuration pathway. There is a decrease in aconitase 1 (ACO1) in AD. ACO1 is an iron-sulfur enzyme in the citric acid cycle that upon loss of an iron-sulfur cluster converts to iron regulatory protein 1 (IRP1). With the dysregulation of iron-sulfur cluster formation ACO1 will convert to IRP1 which will decrease the 2-oxglutarate synthesis dysregulating the citric acid cycle and also dysregulating iron metabolism. Selenomethionine is also metabolized by the trans-sulfuration pathway. With the low activity of the trans-sulfuration pathway in AD selenoproteins will be dysregulated in AD. Dysregulation of selenoproteins could lead to oxidant stress in AD. In this article, we propose a novel treatment for AD that addresses dysregulations resulting from low activity of the trans-sulfuration pathway and low L-cysteine.

Ammonium tetrathiomolybdate enhances the antitumor effect of cisplatin via the suppression of ATPase copper transporting beta in head and neck squamous cell carcinoma.

Platinum­based antitumor agents have been widely used to treat head and neck squamous cell carcinoma (HNSCC) and numerous other malignancies. Cisplatin is the most frequently used platinum­based antitumor agent, however drug resistance and numerous undesirable side effects limit its clinical efficacy for cancer patients. Cancer cells discharge cisplatin into the extracellular space via copper transporters such as ATPase copper transporting beta (ATP7B) in order to escape from cisplatin­induced cell death. In the present study, it was demonstrated for the first time that the copper chelator ammonium tetrathiomolybdate (TM) has several promising effects on cisplatin and HNSCC. First, TM suppressed the ATP7B expression in HNSCC cell lines in vitro, thereby enhancing the accumulation and apoptotic effect of cisplatin in the cancer cells. Next, it was revealed that TM enhanced the antitumor effect of cisplatin in HNSCC cell tumor progression in a mouse model of bone invasion, which is important since HNSCC cells frequently invade to facial bone. Finally, it was demonstrated that TM was able to overcome the cisplatin resistance of a human cancer cell line, A431, via ATP7B depression in vitro.

The theranostic nanoagent Mo2C for multi-modal imaging-guided cancer synergistic phototherapy.

Multifunctional theranostic platforms, especially single component-based platforms, enable both cancer treatment and real-time imaging as well as enhance the efficiency of treatment. In this study, 50 nm Mo2C nanospheres were explored as a "one-for-all" theranostic agent. The light-harvesting of Mo2C covered the entire near infrared region, and NIR irradiation concurrently triggered hyperthermia and reactive oxygen species (ROS) production; thus, synergistic outcomes of photothermal and photodynamic therapy could be realized. Both in vitro and in vivo experiments have confirmed the superiority of the synergistic phototherapy in killing cancer cells and removing solid tumors; moreover, Mo2C proposed herein has been proven to be applicable as a photoacoustic imaging and CT imaging contrast agent for in vivo tumor depiction; furthermore, Mo2C demonstrates excellent biocompatibility, showing minimal hematotoxicity and tissue toxicity. A theoretical simulation performed by density functional theory revealed that the metallic character and the interband/intraband transition of Mo2C accounted for its broad photoabsorption. The antitumor mechanism of Mo2C was investigated on a solid tumor by B-mode ultrasonography (US) and magnetic resonance imaging (MRI), revealing a typical liquefactive necrosis process; hence, herein, the dual-imaging guided phototherapy was efficiently mediated by Mo2C.

Ammonium tetrathiomolybdate treatment of copper-associated hepatopathy in dogs.

BACKGROUND: Copper-associated hepatopathy (CAH) is a common cause of liver disease in dogs. Although d-penicillamine can be an effective treatment, some dogs fail treatment or develop adverse effects. Ammonium tetrathiomolybdate (TTM) has been used to treat pathologic copper accumulation in other species, but its therapeutic potential for CAH is unknown. OBJECTIVES: To investigate short-term safety and efficacy of TTM for treatment of CAH. ANIMALS: Ten dogs with CAH. METHODS: Prospective study. All dogs were treated with TTM PO for 6 weeks, and hepatic biopsies were performed after the treatment course. Dog experiencing initial decreases in hepatic copper concentrations ([Cu]H ) received 6 additional weeks of TTM treatment and underwent 1 additional biopsy. Physical and laboratory examinations were performed every 2 weeks for study duration. RESULTS: Eight of 10 dogs had decreases in [Cu]H . Compared to baseline (median, 1606 µg/g; range, 572-5158 µg/g), [Cu]H were decreased at 6 weeks (1033 µg/g, 450-2975 µg/g; P = .04) and 12 weeks (931 µg/g, 218-1677 µg/g; P = .02). Hepatic molybdenum concentrations increased >50-fold (P < 0.001). Changes in histologic scores and hematologic and biochemical test results were variable and not significantly different from baseline. One dog developed presumed immune-mediated anemia and thrombocytopenia, but it was unclear if this was related to TTM administration. CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that TTM can effectively decrease [Cu]H in some dogs with CAH. Larger studies are needed to determine the overall safety and efficacy of TTM for treating CAH and how it compares with current treatments.

Tetrathiomolybdate induces dimerization of the metal-binding domain of ATPase and inhibits platination of the protein.

Tetrathiomolybdate (TM) is used in the clinic for the treatment of Wilson's disease by targeting the cellular copper efflux protein ATP7B (WLN). Interestingly, both TM and WLN are associated with the efficacy of cisplatin, a widely used anticancer drug. Herein, we show that TM induces dimerization of the metal-binding domain of ATP7B (WLN4) through a unique sulfur-bridged Mo2S6O2 cluster. TM expels copper ions from Cu-WLN4 and forms a copper-free dimer. The binding of Mo to cysteine residues of WLN4 inhibits platination of the protein. Reaction with multi-domain proteins indicates that TM can also connect two domains in the same molecule, forming Mo-bridged intramolecular crosslinks. These results provide structural and chemical insight into the mechanism of action of TM against ATPase, and reveal the molecular mechanism by which TM attenuates the cisplatin resistance mediated by copper efflux proteins.

Plasmonic MoO3-x nanoparticles incorporated in Prussian blue frameworks exhibit highly efficient dual photothermal/photodynamic therapy.

Development of near infrared (NIR) light-responsive nanomaterials for high performance multimodal phototherapy within a single nanoplatform is still challenging in technology and biomedicine. Herein, a new phototherapeutic nanoagent based on FDA-approved Prussian blue (PB) functionalized oxygen-deficient molybdenum oxide nanoparticles (MoO3-x NPs) is strategically designed and synthesized by a facile one-pot size/morphology-controlled process. The as-prepared PB-MoO3-x nanocomposites (NCs) with a uniform particle size of ∼90 nm and high water dispersibility exhibited strong optical absorption in the first biological window, which is induced by plasmon resonance in an oxygen-deficient MoO3-x semiconductor. More importantly, PB-MoO3-x NCs not only exhibited a high photothermal conversion efficiency of ∼63.7% and photostability but also offered a further approach for the generation of reactive oxygen species (ROS) upon singular NIR light irradiation which significantly improved the therapeutic efficiency of the PB agent. Furthermore, PB-MoO3-x NCs showed a negligible cytotoxic effect in the dark, but an excellent therapeutic effect toward two triple-negative breast cancer (TNBC) cell lines at a low concentration (20 µg mL-1) of NCs and a moderate NIR laser power density. Additionally, efficient tumor ablation and metastasis inhibition in a 4T1 TNBC mouse tumor model can also be realized by synergistic photothermal/photodynamic therapy (PTT/PDT) under a single continuous NIR wave laser. Taken together, this study paved the way for the use of a single nanosystem for multifunctional therapy.