A New Photoactivatable Ruthenium(II) Complex with an Asymmetric Bis-Thiocarbohydrazone: Chemical and Biological Investigations

The synthesis, photoactivation and biological activity of a new piano-stool Ru(II) complex is herein reported. The peculiarity of this complex is that its monodentate ligand which undergoes the photodissociation is an asymmetric bis-thiocarbohydrazone ligand that possesses a pyridine moiety binding to Ru(II) and the other moiety contains a quinoline that endows the ligand with the capacity of chelating other metal ions. In this way, upon dissociation, the ligand can be released in the form of a metal complex. In this article, the double ability of this new Ru(II) complex to photorelease the ligand and to chelate copper and nickel is explored and confirmed. The biological activity of this compound is studied in cell line A549 revealing that, after irradiation, proliferation inhibition is reached at very low half maximal inhibitory concentration (IC50) values. Further, biological assays reveal that the dinuclear complex containing Ni is internalized in cells

Experimental model of lead nephropathy. I. Continuous high-dose lead administration

Experimental model of lead nephropathy. I. Continuous high-dose lead administration. This study followed the progression of lead nephropathy in male Sprague-Dawley rats (E) administered lead acetate (0.5%) continuously in drinking water for periods ranging from 1 to 12 months. Control animals (C) were pair-fed. Observations included renal pathology by light and electron microscopy, wet and dry kidney weights, and glomerular filtration rate (GFR) to assess renal function. Urinary excretion of lead, the enzymes N-acetyl-beta-D-glucosaminidase (NAG) and glutathione-S-transferase (GST), and brush border antigens (BB50, CG9, and HF5) were utilized to explore possible markers of kidney injury. GFR was increased significantly after three months of lead exposure, but was decreased significantly after 12 months. Kidney wet weights were significantly greater in E than C from three months on. Kidney dry weight/wet weight ratio was constant up to three months, but decreased in E at 12 months. Glomerular diameters were normal at all time periods; the nephromegaly was related primarily to hypertrophy of proximal tubules. Lead inclusion bodies were found in nuclei of proximal convoluted tubules and pars recta at all times. Tubular atrophy and interstitial fibrosis first appeared at six months, and increased in severity thereafter. Brush borders of proximal tubules were disrupted at one and three months, but recovered thereafter. Focal and segmental glomerulosclerosis was observed in 2 of 10 rats at 12 months. Arteries and arterioles remained normal at all time periods. Urinary NAG was elevated in E above C after three months of lead exposure. However, urinary NAG in C also increased with age, obscuring changes in the 12 month E rats. GST was elevated after three months of lead administration in E, not without an attendant age-related increase in C rats. In three-month E rats, urinary brush border antigens were increased above C, but were decreased at six and 12 months, correlating with the morphologic changes in brush border. We conclude that a high dose of lead in rats may initially stimulate both renal cortical hypertrophy and an increase in GFR. Later, the adverse effects of lead on the tubulointerstitium predominate, and GFR falls. The urinary marker, NAG, was abnormal in the early stages of the disease, but age-related changes obscured its utility at later stages; urinary GST appeared to be a more consistent marker of injury

Autophagy and apoptosis: studies on the effects of bisthiosemicarbazone copper(II) complexes on p53 and p53-null tumour cell lines

A comparative study between two bisthiosemicarbazones, 2,3-butanedione bis(4,4-dimethyl-3-thiosemicarbazone) and 2,3-butanedione bis(2-methyl-3-thiosemicarbazone), and their copper(II) complexes is reported. The four compounds have been tested on leukemia cell line U937 and on adenocarcinoma cell line A549. The study includes cell viability, cell cycle, morphological changes, assessment of apoptosis, analysis of autophagy, measurement of reactive oxygen species (ROS) and of lipid peroxidation, protein determination, assessment of the expression of p53 and cellular uptake of metal complexes. Tests about the copper uptake under normoxic and hypoxic conditions were also carried out on solid tumour cell line A549. The four compounds under study elicit different effects on the two lines adopted as representatives of p53 and p53-null cells. The role of the metal is relevant and it is likely that the metal-mediated oxidative stress plays an essential role in the whole process. The mechanisms induced by these molecules differ not only as a function of cell line but also of dose. The responses include two distinct self-destructive processes, autophagy and apoptosis

Exposure to hydrocarbons and renal disease: an experimental animal model.

The association between hydrocarbon exposure and chronic glomerulonephritis is still a controversial scientific issue. Recent epidemiological evidence suggests a role of exposure to hydrocarbons in the progression of glomerulonephritis towards chronic renal failure. The present experimental study on rats has been designed to assess the possible role of styrene in the progression of adriamycin (ADR) nephrosis, a well known model of renal fibrosis following nephrotic syndrome induced by ADR. Female Sprague-Dawley rats were exposed to styrene, 300 ppm, 6 h/day, 5 days/week for 12 weeks (group 1); treated with ADR, 2 mg/Kg, i.v., twice on day 1 and day 15 of the study (group 2); Additional groups of animals received both the styrene and ADR treatments (group 3) or served as controls (group 4). The urinary excretion of total and single proteins (albumin, Retinol-Binding Protein (RBP), Clara Cell 16 Kd protein (CC16), fibronectin) was measured monthly, whereas histopathology and determinations requiring blood sampling were carried out at the end of the experiment. A progressive increase in total proteinuria, falling in the nephrotic range already by the 6th week was observed in ADR-treated groups. Styrene exposure caused up to a 3- to 5-fold increase as compared to controls. Co-exposure to ADR and styrene also resulted in a proteinuria much greater than that caused by ADR alone. The interactive effect of styrene and ADR was statistically significant for albuminuria and urinary fibronectin. A similar response was observed for glomerular filtration rate at the end of the experiment, styrene-exposed animals showing hyperfiltration as compared to their respective control group. At the end of the experiment, histopathological scoring for interstitial infiltration and fibrosis was also significantly higher in styrene-treated animals as compared to their respective control groups. In ADR-treated rats, low molecular weight proteinuria (l.m.w.p.) was only slightly affected, suggesting minimal tubular dysfunction associated with extensive tubular atrophy. However, styrene-exposed animals showed l.m.w.p. higher than their respective controls. In summary, in this animal model we were able to confirm both styrene-induced microproteinuria, mainly albuminuria and minor increases in l.m.w.p., observed among occupationally exposed workers and the role of hydrocarbon exposure as a factor accelerating the progression of renal disease suggested by epidemiological investigations in patients suffering from chronic renal disease. Whereas in rats exposed to styrene only, microproteinuria was stable over time and minor histopathological changes were noted at the end of the experiment, evidence of a role of solvent exposure in the progression of ADR nephropathy was obtained in terms of both renal dysfunction and interstitial fibrosis. The mechanistic basis of styrene-ADR interaction is unclear. However, experimental evidence is consistent with epidemiological findings suggesting the need to avoid solvent exposure in patients suffering from renal diseases

Synthetic recovery of impulse propagation in myocardial infarction via silicon carbide semiconductive nanowires

: Myocardial infarction causes 7.3 million deaths worldwide, mostly for fibrillation that electrically originates from the damaged areas of the left ventricle. Conventional cardiac bypass graft and percutaneous coronary interventions allow reperfusion of the downstream tissue but do not counteract the bioelectrical alteration originated from the infarct area. Genetic, cellular, and tissue engineering therapies are promising avenues but require days/months for permitting proper functional tissue regeneration. Here we engineered biocompatible silicon carbide semiconductive nanowires that synthetically couple, via membrane nanobridge formations, isolated beating cardiomyocytes over distance, restoring physiological cell-cell conductance, thereby permitting the synchronization of bioelectrical activity in otherwise uncoupled cells. Local in-situ multiple injections of nanowires in the left ventricular infarcted regions allow rapid reinstatement of impulse propagation across damaged areas and recover electrogram parameters and conduction velocity. Here we propose this nanomedical intervention as a strategy for reducing ventricular arrhythmia after acute myocardial infarction

Titanium dioxide nanoparticles promote arrhythmias via a direct interaction with rat cardiac tissue

BackgroundIn light of recent developments in nanotechnologies, interest is growing to better comprehend the interaction of nanoparticles with body tissues, in particular within the cardiovascular system. Attention has recently focused on the link between environmental pollution and cardiovascular diseases. Nanoparticles <50 nm in size are known to pass the alveolar¿pulmonary barrier, enter into bloodstream and induce inflammation, but the direct pathogenic mechanisms still need to be evaluated. We thus focused our attention on titanium dioxide (TiO2) nanoparticles, the most diffuse nanomaterial in polluted environments and one generally considered inert for the human body.MethodsWe conducted functional studies on isolated adult rat cardiomyocytes exposed acutely in vitro to TiO2 and on healthy rats administered a single dose of 2 mg/Kg TiO2 NPs via the trachea. Transmission electron microscopy was used to verify the actual presence of TiO2 nanoparticles within cardiac tissue, toxicological assays were used to assess lipid peroxidation and DNA tissue damage, and an in silico method was used to model the effect on action potential.ResultsVentricular myocytes exposed in vitro to TiO2 had significantly reduced action potential duration, impairment of sarcomere shortening and decreased stability of resting membrane potential. In vivo, a single intra-tracheal administration of saline solution containing TiO2 nanoparticles increased cardiac conduction velocity and tissue excitability, resulting in an enhanced propensity for inducible arrhythmias. Computational modeling of ventricular action potential indicated that a membrane leakage could account for the nanoparticle-induced effects measured on real cardiomyocytes.ConclusionsAcute exposure to TiO2 nanoparticles acutely alters cardiac excitability and increases the likelihood of arrhythmic events

Contribution of studies on renal effects of heavy metals and selected organic compounds to our understanding of the progression of chronic nephropathies towards renal failure.

Risk assessment for a number of workplace or environmental chemicals, especially heavy metals and industrial organic compounds, relies mostly on clinical and epidemiologic findings. The low incidence of chronic nephropathies raises methodological issues in carrying out and interpreting human data on the progression of early changes towards end-stage renal disease. To overcome such limitations of epidemiological studies, two main approaches have been explored: (i) human studies relying on biomarkers and (ii) experimental animal models. Animal experiments have been useful to characterize early changes, such as hyperfiltration, eventually leading to chronic renal failure. Animal studies provided insights into the mechanisms underlying microalbuminuria and microproteinuria. Such biomarkers of early changes, developed for use at the workplace, have then been used to monitor such chronic disorders and multifactorial diseases as diabetes and arterial hypertension. Another area where Occupational Medicine has provided evidence is the effectiveness of primary prevention over other possible approaches. Avoidance of exposure to heavy metals and volatile hydrocarbons and their derivatives, mainly in individuals with diagnosed renal disorders, remains the best approach towards a substantial reduction in the burden of renal diseases

Early Markers of Nephrotoxicity in Patients With Metal-on-metal Hip Arthroplasty

BACKGROUND: Metal ions released from arthroplasty devices are largely cleared in urine, leading to high exposure in renal tissues. Validated early markers of renal damage are routinely used to monitor workers in heavy metal industries, and renal risk can be quantified in these industries. It is unclear if the ion levels in patients with metal-on-metal hips are sufficient to cause renal damage. QUESTION: Does metal-on-metal (MOM) bearing use over a 10-year period lead to elevation of early renal markers compared with the levels expected in subjects with no metal exposure? METHODS: We retrospectively reviewed 31 patients who underwent MOM hip resurfacings 10 years earlier. Whole blood specimens were collected for metal ion analysis, serum for creatinine estimation, and urine for timed metal ion output and renal markers. The renal marker levels of 30 age- and gender-matched subjects with no metal exposure and no known renal problems or diabetes mellitus were used as controls for renal markers. RESULTS: Median serum creatinine level in the MOM group was 1.1 mg/dL (interquartile range, 1.0–1.2 mg/dL) and median creatinine clearance was 79.2 mL/min. In this cohort, the number of patients with markers of renal damage above the reference range was comparable to the controls. None of the renal markers were associated with metal levels. CONCLUSION: The absence of elevation of renal markers in this cohort 10 years after MOM bearing implantation is reassuring. However, we believe surveillance through further longer-term, large-scale controlled trials are needed to monitor this arthroplasty-induced low-intensity (but long-term) trace element exposure to rule out potential nephrotoxicity. LEVEL OF EVIDENCE: Level III, retrospective comparative study. See Guidelines for Authors for a complete description of levels of evidence

Lack of correlation between blood lead and serum prolactin levels among lead exposed workers

A cross sectional case (241 males occupationally exposed to lead)–control (102 males unexposed to lead) study was performed with the aim of evaluating the relationship between serum prolactin (S-PRL) and lead blood (PbB) levels. A meta-analysis of S-PRL levels in similar studies was also carried out. No difference of S-PRL between groups or any relationship between PbB and S-PRL levels was found. The meta-analysis showed a slight increase of S-PRL levels among exposed people, the weighted means falling within the reference values of the biomarker. The results do not support a routine use of S-PRL as a biomarker of effect in lead exposed workers