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Identificazione e caratterizzazione di nuovi inibitori del poro della transizione della permeabilità mitocondriale
No full textWe have characterized the mitochondrial and cellular effects of two molecules identified by Genextra's S.p.A from a chemical library by high throughput screening (HTS) designed to identify novel inhibitors of the mitochondrial permeability transition pore (PTP). The screening, based on in vitro calcium-induced mitochondrial swelling, yielded several PTP inhibitory compounds and two of them, CngPtP003 and CngPtP006, have been selected for the present study. We studied the inhibitory properties of CngPtP003 and CngPtP006 on PTP in isolated mouse liver mitochondria with the Calcium Retention Capacity (CRC) assay, and the inhibitory profiles compared with those displayed by the well known PTP inhibitor cyclosporin A (CsA). From this first set of experiments we confirmed that both compounds are PTP inhibitors with different biological potency and efficacy, and that their molecular targets are not the same as that of CsA, with which both compounds displayed additive effects. In a second set of experiments we studied the mitochondrial effects of CngPtP003 and CngPtP006 in intact HeLa cells with the tetramethylrhodamine methyl ester (TMRM) assay, which measures the mitochondrial membrane potential. We found that only CngPtP003 is able to protect the cells from the depolarization and from cell death caused by the PTP inducer arachidonic acid. Lack of inhibition by CngPtP006 data has been confirmed both in HeLa isolated mitochondria and in several human permeabilized cell lines, indicating that the inhibitory properties of CngPtP006 are limited to mouse mitochondria, which were used in the primary screening. These results validate the HTS approach for the identification of novel PTP inhibitors, whose suitability for drug development is currently under investigation
Soluble phenyl-valerate esterases of hen sciatic nerve and the potentiation of organophosphate induced delayed polyneuropathy
No full textRilascio di metalli da protesi d’anca metallo-su-metallo
Full text linkLe protesi d’anca metallo-su-metallo possono essere causa di un aumento della concentrazione ematica de metalli che costituiscono la protesi, in particolare cromo (Cr) e cobalto (Co). In genere un incremento dei metalli nei liquidi biologici è osservabile circa tre mesi dopo la sostituzione dell’anca con la nuova protesi, senza ulteriori aumenti ad un anno. Il livello di metalli sembra quindi declinare lentamente nei successivi cinque anni. Qualora la protesi sia ben funzionante, la quota circolante di Cr e Co è generalmente modesta, mentre l’usura sembra essere il responsabile di un più rilevante incremento, dovuto ad un effetto combinato della corrosione dell’impianto e delle particelle rilasciate. A livello tissutale, il Co si trova in genere allo stato metallico mentre il Cr si trova sotto forma di fosfato [Cr(III)PO4] nel suo stato di ossidazione 3+. Una causa importante di usura e quindi di rilascio di metalli è la mobilizzazione della protesi. Ulteriori significativi fattori di rischio sembrano essere il sesso femminile e il diametro della testa, maggiore è il diametro, maggiore è il rischio di usura. Fattore non favorente sembra invece essere l’attività fisica. Il rischio principale è la metallosi, ovvero l’eccessiva usura della protesi con infiltrazione di detriti metallici accompagnata da flogosi cronica nei tessuti periprotesici, evento che può essere causa di intossicazione da metalli anche grave. Il presente studio ha preso in esame le concentrazioni ematiche e urinarie di Cr e Co in 30 pazienti portatori di protesi metallo-su-metallo senza segni di usura (19 maschi e 11 femmine, età media 61 anni, mediamente 3 anni dopo l’intervento) e di 6 pazienti (4 maschi e 2 femmine, età media 54 anni, mediamente 5 anni dopo l’intervento) con protesi recanti chiari segni di usura e metallosi. Nessuno dei 36 pazienti presentava una anamnesi significativa per esposizione lavorativa a metalli pesanti. La determinazione nei liquidi biologici ha dimostrato nei portatori di protesi non usurate una concentrazione dei metalli (media geometrica) solo modicamente aumentata (CoS 0,5 μg/l, CoU 5,7 μg/l, CrS 0,8 μg/l, CrU 3,4 μg/l) rispetto ai valori di riferimento, mentre l’usura è stata causa di un rilevante aumento della concentrazione sia del Co (CoS 94,6 μg/l, CoU 334,5 μg/l) che del Cr (CrS 57,7 μg/l, CrU 89,4 μg/l). Come dimostrano i risultati, le protesi ben funzionanti non sembrano essere causa di particolari rischi per i pazienti, in accordo con la letteratura, mentre all’usura si associano elevati livelli dei metalli nei liquidi biologici. In caso di metallosi, sono stati descritti casi di polineuropatia legata alla tossicità dei metalli. Al momento, i 6 pazienti con usura della protesi non presentano segni e sintomi collegabili ad una intossicazione da metalli, ma l’elevata concentrazione potrebbe essere causa di insorgenza di danni soprattutto renali, neurologici, tiroidei e cardiaci. Le protesi metallo-su-metallo usurate associate a metallosi dovrebbero essere sostituite per prevenire potenziali danni ai pazienti, anche se sono necessari ulteriori studi prospettici per valutare l’effettiva correlazione tra elevate concentrazioni di metalli e conseguenti effetti tossici
Testosterone and estradiol affect renal oxidative metabolism and glutathione pathway of Wistar rats
Full text linkThe impact of sexual hormones on kidney metabolism may be relevant to modulate the effect of nephrotoxic substances. In the present research the effects of castration, testosterone, and estradiol on renal oxidative metabolism [cytochrome P-450 (CYP)], the glutathione pathway [glutathione content (GSH), glutathione S-transferases (GST) and cysteine-conjugate ß-lyase as glutamine transaminase K (GTK) activities have been studied. Naive male rats have a significantly lower GSH content but show significantly higher GST activities and CYP content than females, whereas no sex difference was for GTK activity. Castration significantly reduces GSH content and GTK activity in females and CYP content in males, which is partially but significantly restored by testosterone. Testosterone significantly increases GSH content and GTK activity in males and GTK activity and CYP content in females. Estradiol increases GSH content in males, but decreases GST activities in females and CYP content in both sexes. Castration followed by testosterone treatment increases GTK activity in both sexes but increases CYP content and reduces GSH content in females. Castration followed by estradiol treatment increases GSH content and reduces GST activities in males and CYP content in both sexes. In conclusion, the results suggest that sex hormones influence metabolic pathways of the kidney and that they are probably responsible of the sex-related differences of chemical-induced nephrotoxicity. An univocal model to define sex-related toxicity of xenobiotic substances is yet to be identified
Reliability of urinary excretion rate adjustment in measurements of urinary hippuric acid.
No full textThe urinary excretion rate is calculated based on short-term, defined time sample collections with a known sample mass, and this measurement can be used to remove the variability in urine concentrations due to urine dilution. Adjustment to the urinary excretion rate of hippuric acid was evaluated in 31 healthy volunteers (14 males and 17 females). Urine was collected as short-term or spot samples and tested for specific gravity, creatinine and hippuric acid. Hippuric acid values were unadjusted or adjusted to measurements of specific gravity, creatinine or urinary excretion rate. Hippuric acid levels were partially independent of urinary volume and urinary flow rate, in contrast to specific gravity and creatinine, which were both highly dependent on the hippuric acid level. Accordingly, hippuric acid was independent on urinary specific gravity and creatinine excretion. Unadjusted and adjusted values for specific gravity or creatinine were generally closely correlated, especially in spot samples. Values adjusted to the urinary excretion rate appeared well correlated to those unadjusted and adjusted to specific gravity or creatinine values. Thus, adjustment of crude hippuric acid values to the urinary excretion rate is a valid procedure but is difficult to apply in the field of occupational medicine and does not improve the information derived from values determined in spot urine samples, either unadjusted or adjusted to specific gravity and creatinine
Gold(III)-pyrrolidinedithiocarbamato Derivatives as Antineoplastic Agents
Full text linkTransition metals offer many possibilities in developing potent
chemotherapeutic agents. They are endowed with a variety of
oxidation states, allowing for the selection of their coordination
numbers and geometries via the choice of proper ligands,
leading to the tuning of their final biological properties. We
report here on the synthesis, physico-chemical characterization,
and solution behavior of two gold(III) pyrrolidinedithiocarbamates
(PDT), namely [AuIIIBr2(PDT)] and [AuIIICl2(PDT)]. We
found that the bromide derivative was more effective than the
chloride one in inducing cell death for several cancer cell lines.
[AuIIIBr2(PDT)] elicited oxidative stress with effects on the permeability
transition pore, a mitochondrial channel whose
opening leads to cell death. More efficient antineoplastic strategies
are required for the widespread burden that is cancer. In
line with this, our results indicate that [AuIIIBr2(PDT)] is a promising
antineoplastic agent that targets cellular components with
crucial functions for the survival of tumor cells
Ru(III) anticancer agents with aromatic and non-aromatic dithiocarbamates as ligands: Loading into nanocarriers and preliminary biological studies
No full textSince the discovery of cisplatin in the 1960s, other metal complexes have been investigated as potential antitumor agents to overcome the side-effects associated with the administration of the Pt-based drug. In line with our previous research, in this work we report the synthesis and characterization of mono- and dinuclear Ru(III) complexes with the pyrrolidinedithiocarbamate (PDT) ligand and the more sterically-hindered carbazole-dithiocarbamato ligand (CDT), to compare their properties (both at the chemical and antiproliferative level), in an attempt to assess a structure-activity rationale. Moreover, to overcome the scarce solubility under physiological conditions of the Ru(III)-dithiocarbamato compounds, the biocompatible copolymer Pluronic® F127 has been used, to encapsulate the metal derivatives in water-soluble micellar carriers. Finally, preliminary biological evaluations on CDT and PDT compounds along with their nanoformulations, open intriguing perspectives in anticancer chemotherapy. In particular, comparing the structure of the Ru(III) derivatives, the ionic dinuclear PDT complex shows an important cytotoxic action in comparison to its neutral counterparts. Moreover, the micellar carrier improves the overall activity of the encapsulated Ru(III)-PDT chemotherapeutics. On the other hand, the nanoformulation of the CDT derivatives allows us to solubilize both the 1:3 and the 2:5 complexes and to state their inactivity
Chemotherapeutic induction of mitochondrial oxidative stress activates GSK-3α/β and Bax, leading to permeability transition pore opening and tumor cell death
Full text linkSurvival of tumor cells is favoured by mitochondrial changes that make death induction
more difficult in a variety of stress conditions, such as exposure to chemotherapeutics. These
changes are not fully characterized in tumor mitochondria, and include unbalance of the redox
equilibrium, inhibition of permeability transition pore (PTP) opening through kinase signalling
pathways and modulation of members of the Bcl-2 protein family. Here we show that a novel
chemotherapeutic, the Gold(III)-dithiocarbamato complex AUL12, induces oxidative stress and
tumor cell death both favouring PTP opening and activating the pro-apoptotic protein Bax of the
Bcl-2 family. AUL12 inhibits the respiratory complex I and causes a rapid burst of mitochondrial
superoxide levels, leading to activation of the mitochondrial fraction of GSK-3α/β and to the
ensuing phosphorylation of the mitochondrial chaperone cyclophilin D, which in turn facilitates
PTP opening. In addition, following AUL12 treatment Bax interacts with GSK-3α/β and
translocates onto mitochondria, where it contributes to PTP induction and tumor cell death. These
findings provide evidence that targeting the redox equilibrium maintained by mitochondria in tumor
cells allow to hit crucial mechanisms that shield neoplasms from the toxicity of many anti-tumor
strategies, and identify AUL12 as a promising chemotherapeutic compound
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