Peroxoniobium inhibits leukemia cell growth

A new class of polyoxoniobate complex has been synthesized and characterized as a novel anticancer agent for photodynamic therapy. The complex inhibits the growth of chronic myelogenous leukemia cells with an IC₅₀ value of 30 μM, in the dark. However, upon exposure to light (365 nm) there is a fivefold increase in the cytotoxic activity. Light radiation activate the complex with the formation of radical species capable of interacting with DNA according to our experimental and theoretical data.

A new class of polyoxoniobate complex has been synthesized and characterized as a novel anticancer agent for photodynamic therapy.

In this work, we prepared a photosensitive peroxoniobium complex presenting a balance with an active radical phase when illuminated with radiation of 365 nm. A versatile niobium species of amorphous structure was obtained by the reaction of niobium ammonium oxalate with ammonium hydroxide up to pH 7. The material obtained, a niobium oxyhydroxide (NbO₂(OH)) (white solid),^1,2 can be modified with the generation of NbO₂(OH)O₂˙⁻ peroxo groups (yellow solid).³ The yellow compound is formed by treatment with H₂O₂. The absorption radiation in the visible region due to the charge transfer transition between the peroxo group and the niobium is shown in Fig. 1.Open in a separate windowFig. 1UV-Vis profile of the catalysts.This complex with the radical as an intermediate is favored in the presence of visible and UV radiation. This property is of interest for photodynamic therapy of cancer (PDT), which involves the exposure of malignant cells containing a photosensitizer molecule to light irradiation, in the presence of oxygen species. The photoactivated drug produces reactive oxygen species that initiate a series of events, resulting in cell death. Selective light activation allows a preferential tumor destruction in comparison to healthy tissues.⁴ Several metal complexes exhibit photocytotoxicity under UV or visible light,^5,6 but data about niobium compounds are very scarce in the literature.⁷The polyoxoniobate, generated from niobium oxyhydroxide described here can be very active in the treatment of diseased cells when illuminated with visible or UV radiation due to its light absorption capacity because of the peroxo groups formed. The peroxoniobium complex has some advantages, such as ease synthesis and in mild conditions, high solubility, low activity under light off, and resistance to inactivation by thiol reagents. Moreover, it is nontoxic⁸ and does not employ noble metals like most of the compounds proposed in the literature. Actually, niobium oxide was tested as a bone implant component and showed absence of inflammatory cells or degeneration of the osteoblasts without any sign of damage to the preexisting bone tissue, showing compatibility with the bone tissue.^9–11The innovative part in the process of obtaining the polyoxoniobate complex presented in this work consists in the leaching of the complex when treating the niobium oxyhydroxide with H₂O₂. With the treatment, a yellow solid and a leached yellow liquid is obtained, which is the complex containing peroxoniobium in its structure, sensitive to the UV-Vis radiation generating radical species. This species generated with the leaching at neutral pH presents high negative charge and a kinetic volume of 223 nm. The XRD of the lyophilized polyoxoniobate indicated strong amorphous character. However, the polyoxoniobate is known to form well defined polyoxometalates such as Lindqvist ([Nb₆O₁₉]⁸⁻) and decaniobate ([Nb₁₀O₂₈]⁶⁻). Fig. 2 shows a comparison between the experimental and PBE/LANL2DZ/aug-cc-pVDZ DFT IR spectra. It is clear that the pattern of the decaniobate structure is closer to the experimental spectrum. One should keep in mind that DFT frequencies are normally 10% underestimated with respect to the experimental values. The broader absorption below 600 cm⁻¹ can be attributed to the interaction between different decaniobate structures forming the amorphous solid. The calculated peaks at 710, 760 and 860 cm⁻¹ are related to the experimental peaks of 800, 870 and 910 cm⁻¹ indicating that decaniobate is the local arrangement of the polyoxoniobate complex.Open in a separate windowFig. 2Infrared spectra for experimental procedures, Lindqvist and decaniobate structures (simulated). The line shape chosen was Lorentzian and the half-width is about 20.The generation of reactive oxygen under radiation was confirmed by the reaction of the complex with an organic dye, which was monitored by UV-Vis spectroscopy (Fig. 3). The spectrum of the dye solution shows the characteristic peak of the methylene blue (MB) at 663 nm (black trace). It can be clearly seen that in the presence of the peroxoniobium complex and radiation (365 nm) the signal decreased indicating the reaction of the peroxoniobium complex with the dye (blue trace). In the absence of light, there is no decrease in the signal related to the dye, indicating the need of the radiation to activate the oxidation action of the peroxoniobium complex. The equilibrium in which the radical species forms it is not necessary to use a photosensitizer agent, such as porphyrins.⁴ A further investigation was carried out by ³¹P NMR (Fig. S1^†) using guanosine as model molecule able to react with the peroxoniobium complex. The ³¹P NMR spectrum shown in Fig. S1-a^† corresponds to 5-GMP and revealed that the phosphorus atom in the structure exhibits a chemical shift at δ 5.93. When 5-GMP and the polyoxoniobate are in contact, no significant changes are observed in the ³¹P spectrum, only a small displacement of the phosphorus signal to δ 5.90 (Fig. S1-b^†). However, when the 5-GMP and polyoxoniobate mixture is submitted to radiation (Fig. S1-c^†), an interaction between the compounds occurs, giving rise to a new species that presents a different chemical shift in the P spectrum (δ 5.27).Open in a separate windowFig. 3UV-Vis profile of the reaction of the Nb complex with the organic dye (10 mg L⁻¹).The effect of the peroxoniobium on the growth of K562 cells was evaluated after 4 h of incubation. The compound inhibits K562 cell growth in a concentration-dependent manner, with an IC₅₀ of 30.0 ± 1.5 μmol L⁻¹. Ammonium niobate(v) oxalate was also tested and it has no effect on K562 cells up to 100 μM. The cytotoxic activity of polyoxoniobate increases by 5 times upon 5 min of UV-A light irradiation, with an IC₅₀ value of 6.2 ± 0.4 μmol L⁻¹ (Fig. 4). The higher activity, when exposed to light, associated to the low toxicity of niobium compounds place the peroxoniobium complex as a candidate for photodynamic therapy.Open in a separate windowFig. 4Photocytotoxic effect of the peroxoniobium complex. K562 cells were incubated for 4 h in the presence of different complex concentrations, in the dark (black bars) and after 5 min of UV-A light exposure (red bars). The values are the average of three independent experiments.There are few reports in the literature about the cytotoxic activity of niobium compounds. A peroxo niobium complex with ascorbic acid (K₃[Nb(Asc)(O₂)₃]) is moderately active in HL60 human leukemia cells but not in K562 human myelogenous leukemia cells.¹² A tetrameric Nb28-containing cluster inhibits the growth of the human breast cancer MCF-7 cells line with an IC₅₀ value of 5.21, after 48 h of incubation.¹³Methylene blue (MB) is one of the main photosensitizing agents used in PDT due to its good tissue penetration and low cytotoxicity.¹⁴ It is active in several types of tumors upon irradiation with red laser light.¹⁵ This fact allied to the ability of the peroxoniobium compound to interact with MB (Fig. 3) prompted us to investigate its effect in the MB photocytotoxicity. We have first checked that exposure to UV-A light did not affect the cytotoxicity of MB in K562 cells (

Magnetic resonance spectroscopy with transcranial direct current stimulation to explore the underlying biochemical and physiological mechanism of the human brain: A systematic review

A large body of molecular and neurophysiological evidence connects synaptic plasticity to specific functions and energy metabolism in particular areas of the brain. Furthermore, altered plasticity and energy regulation has been associated with a number of neuropsychiatric disorders. A favourable approach enabling the modulation of neuronal excitability and energy in humans is to stimulate the brain using transcranial direct current stimulation (tDCS) and then to observe the effect on neurometabolites using magnetic resonance spectroscopy (MRS). In this way, a well‐defined modulation of brain energy and excitability can be achieved using a dedicated tDCS protocol to a predetermined brain region. This systematic review was guided by the preferred reporting items for systematic reviews and meta‐analysis and summarises recent literature studying the effect of tDCS on neurometabolites in the human brain as measured by proton or phosphorus MRS. Limitations and recommendations are discussed for future research. The findings of this review provide clear evidence for the potential of using tDCS and MRS to examine and understand the effect of neurometabolites in the in vivo human brain.     

Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children

OBJECTIVE: Meningococcal sepsis invariably is associated with coagulopathy. We have previously reported an association between mortality rate in meningococcal disease and the functional 4G/5G promoter polymorphism of the plasminogen-activator-inhibitor (PAI)-1 gene in a small patient cohort. In a much larger cohort, we aimed to confirm these results and further investigate the role of the 4G/5G polymorphism in determining susceptibility, outcome, and complications of disease.DESIGN Susceptibility was investigated in two separate studies, a case-control study and a family-based transmission study, each test using a separate patient cohort. Severity was investigated using clinical diagnosis, the presence of vascular complications, Pediatric Risk of Mortality (PRISM)-predicted morality, and actual mortality. SETTING: University hospital and laboratories. SUBJECTS: Subjects were 510 UK pediatric patients, 210 parents of patients, and 155 UK Caucasian controls. INTERVENTIONS: DNA extraction and 4G/5G PAI-1 genotyping was carried out using published techniques. MEASUREMENTS AND MAIN RESULTS: Predicted mortality distribution differed significantly between genotypes (p =.05) with a significantly higher median PRISM in the 4G/4G (41.1%) than the 4G/5G (23.4%) and 5G/5G (19.0%) genotyped patients combined (p =.02). Actual mortality rate was significantly associated with both genotype (chi-square = 14.8, p =.001) and allele frequencies (chi-square = 14.0, p <.0001), with more deaths in the 4G/4G (28.4%) than the 4G/5G and 5G/5G genotyped patients combined (14.9%; chi-square = 7.9; p =.005; risk ratio, 1.9; 95% confidence interval, 1.2-3.0). Logistic regression indicated a 40% and 91% reduction in the odds of dying if a patient was either 4G/5G or 5G/5G, respectively, in comparison to a 4G homozygous patient. When analyzed by clinical diagnosis, the association with death was found only in the sepsis group (chi-square = 18.7, p <.0001; risk ratio, 2.7; 95% confidence interval, 1.6-4.6). In survivors of disease, a significantly higher proportion of 4G/4G patients suffered from vascular complications (chi-square = 6.7, p =.03; risk ratio, 2.4; 95% confidence interval, 1.1-5.0). The 4G/5G polymorphism was not associated or linked with susceptibility (case-control result, p =.6; family-based transmission study results, p =.2). CONCLUSIONS: This study confirms that Caucasian pediatric patients carrying the functional PAI-1 4G/4G genotype are at an increased risk of developing vascular complications and dying from meningococcal disease.     

Yoga for patients and carers in a palliative day care setting

This study suggests that yoga can be of benefit to patients (and carers) in palliative care settings. Complementary therapies have been employed in our day care unit for several years--aromatherapy, reflexology and massage--and have grown in popularity, enabling relaxation and a feeling of well-being. For patients striving to remain physically fit and, in consultation with our physiotherapist, we felt there may be a role for a gentle form of yoga. A study of the literature yielded information on yoga and cancer but little evidence of its use in palliative care. Having identified a form of yoga that could be adapted for those with physical frailties-- Dru yoga--a 12-week pilot project was introduced into the day care unit. This proved to be highly successful and has now been incorporated as part of our therapeutic service.     

Behavioral evidence of thermal hyperalgesia and mechanical allodynia induced by intradermal cinnamaldehyde in rats

TRPA1 agonists cinnamaldehyde (CA) and mustard oil (allyl isothiocyanate = AITC) induce heat hyperalgesia and mechanical allodynia in human skin, and sensitize responses of spinal and trigeminal dorsal horn neurons to noxious skin heating in rats. TRPA1 is also implicated in cold nociception. We presently used behavioral methods to investigate if CA affects sensitivity to thermal and mechanical stimuli in rats. Unilateral intraplantar injection of CA (5–20%) induced a significant, concentration-dependent reduction in latency for ipsilateral paw withdrawal from a noxious heat stimulus, peaking (61.7% of pre-injection baseline) by 30 min with partial recovery at 120 min. The highest dose of CA also significantly reduced the contralateral paw withdrawal latency. CA significantly reduced mechanical withdrawal thresholds of the injected paw that peaked sooner (3 min) and was more profound (44.4% of baseline), with no effect contralaterally. Bilateral intraplantar injections of CA resulted in a significant cold hyperalgesia (cold plate test) and a weak enhancement of innocuous cold avoidance (thermal preference test). The data are consistent with roles for TRPA1 in thermal (hot and cold) hyperalgesia and mechanical allodynia.     

A longitudinal study of various crevicular fluid components as markers of periodontal disease activity

Abstract In order to examine the relationship of possible crevicular biochemical parameters to attachment loss (ALOSS), 330 sites from & untreated adult patients were monitored longitudinally at 3-month intervals, for up to 1 year. Attachment levels were measured with a force-sensing probe and an acrylic stent in duplicates at each study point. Crevicular samples were collected and used for the determination of the following 11 markers: number of polymorphonuclear leukocytes (PMNs), prostaglandin E₂ (PGE₂), osteocalcin (OC), alkaline phosphatase (ALP), collagenase (COL), β-glucuromdase (BG), antigenic and functional elastase (AEL and FEL), α-1 antitrypsin (alAT), α-2 macroglobulin (a2M) and aspartate aminotransferase (AST). 10 sites with ALOSS of 1.5 mm per 3 months (active sites) and 43 sites with negligible changes (inactive sites) were identified. Total amounts of ALP, BG and COL were found to be significantly higher in active as compared to inactive sites, prior to significant ALOSS, without any significant differences in crevicular fluid volume and clinical indices. When biochemical parameters were expressed as ratios to the number of PMNs, PGE₂/PMNs was significantly elevated in active sites. The capacity of such individual parameters to distinguish between active and inactive sites was limited. However, linear discriminant analysis using total amounts of PGE₂, COL, ALP, a2M, OC and AEL showed more significant diagnostic values (sensitivity: 80%. specificity: 91%). These findings suggest that the combination of several biochemical parameters in crevicular fluid could give more information to predict future clinical ALOSS.     

Association study of sporadic Parkinson's disease genetic risk factors in patients from Russia by APEX technology

Most patients with Parkinson's disease (PD) have sporadic form of the disease with a multifactorial etiology due to interactions between environmental conditions and the genetic constitution of the individuals. We have analyzed by APEX technology 50 single nucleotide polymorphisms (SNPs) in 19 genes related to cholecystokinin, serotonin, dopamine and opioid neurotransmission. Significant differences in the allele and genotype frequencies between the controls and PD patients were detected for four SNPs from three genes (serotonin 2A receptor (rs6311, P = 0.043), Wolfram syndrome 1 (rs1801211, P = 0.007), proopiomelanocortin (rs28930368, P = 0.026 and rs2071345, P = 0.027) genes). Two SNPs in proopiomelanocortin (POMC) gene were also associated with different clinical forms of PD. Our data suggest that at least three genes involved in neurotransmitter systems may have more specific role in genetic predisposition to PD.     

Brain abscesses resulting from Bacillus cereus and an Aspergillus-like mold

An 11-year-old boy with alveolar rhabdomyosarcoma of the thigh experienced three instances of catheter-related bacteremia resulting from After two episodes of seizures, two low-density lesions in the right parietal lobe and the left corpus callosum with enhanced pericavitary opacity were detected. The catheter was removed. A brain biopsy sample grew and revealed dichotomously branched septate hyphae compatible with The patient was treated with ceftriaxone and liposomal amphotericin B for 12 and 52 weeks, respectively, until biopsy-confirmed resolution of the infections.