Beneficial Effects of Resveratrol and γ-Cyclodextrin on the Hematological and Biochemical Parameters of Healthy Wistar Rats Treated with Cisplatin: A PCA Approach.

It is well known that platinum-based antineoplastic agents, including cisplatin (CP), have side effects that limit their use. Nefrotoxicity, neurotoxicity, and hemolytic anemia are the most common side effects. There are few studies on the reduction in these effects that involves nanoencapsulation; however, almost none involve cyclodextrins (CDs). Changes in the hematological and biochemical parameters of healthy Wistar rats treated with solutions of γ-cyclodextrin/resveratrol/cisplatin (γ-CD/Rv/CP) ternary complexes are investigated for the first time. They are intraperitoneally injected with γ-CD/Rv/CP solutions containing 5 mg CP/kg.b.w. Single shots were administered to six groups of Wistar rats (six individuals for every group) using γ-CD/Rv/CP, γ-CD/CP, γ-CD/Rv complexes, as well as positive- and negative-control groups, respectively. Thirty-two hematological and biochemical parameters were evaluated from blood samples and used as input variables for the principal component analysis (PCA) discrimination of the groups. The best protection was obtained for the γ-CD/Rv/CP ternary complex, which determined closer biochemical values to the control group. These values significantly differ from those of the γ-CD/CP treated group, especially for the IP, UA, and T-Pro kidney-related biochemical parameters. This finding proves the beneficial influence of Rv during CP administration through CD-based carriers.

Homeostatic changes of some trace elements in geriatric rats in the condition of oxidative stress induced by aluminum and the beneficial role of resveratrol.

BACKGROUND: Elderly individuals are exposed to trace element imbalances due to the reduced capacity of their organism to utilize minerals in a direct relationship with many circumstances. OBJECTIVES AND METHODS: The aim of this study was to assess the protective role of resveratrol upon the homeostatic changes of some trace elements in geriatric rats in the condition of oxidative stress induced by aluminum exposure. Forty Wistar rats, 18-20 months old, were divided randomly into four groups (n = 10): control (C) - receiving 1 ml of physiologically saline (P.S.) via intraperitoneal (i.p) administration, E1 - 1 ml of P.S. and 1000 ppb aluminum sulphate (AS) in drinking water ad libitum, E2 - 20 mg/kg-1 resveratrol, i.p. and 1000 ppb AS in drinking water, E3 - 20 mg/kg-1 resveratrol i.p. The groups C and E3 received distilled water as drinking water ad libitum. The i.p administrations were once a week for four weeks period. The levels of oxidative stress marker's were analyzed (glutathione, glutathione' peroxidase, superoxide dismutase, and catalase) of the proteins' (total protein, albumin, and hemoglobin) in serum and also the levels of the main trace elements (copper, zinc, iron, selenium, manganese and magnesium) in blood, liver, kidney and spleen. RESULTS: Significant decrease (p < 0.05) of total protein (TP), albumin (ALB), catalase (CAT), increase significant (p < 0.05) of glutathione reductase (GSH-r), glutathione peroxidase (GPx) and superoxide dismutase (SOD) in E1 groups, compared with control, E2, and E3 groups was ascertained. There were also observed significant (p < 0.05) decreases in Cu, Zn, Fe and Mg, not significant (p > 0.05) increase of Se and Mn in blood, significant (p < 0.01) increase of Cu, Zn, Mg, Se, Mn in kidney and liver and Fe, in spleen of geriatric rats from E1 group compared to the control group. Insignificant differences (p > 0.05) were recorded in groups which received resveratrol (E2 and E3) compared to the control group, but significant differences (p < 0.05), especially in blood and liver samples, compared to E1. CONCLUSIONS: The results suggest that resveratrol can prevent the homeostatic imbalance of trace elements in geriatric rats in the condition of oxidative stress induced by aluminum exposure.

Influence of novel gallium complexes on the homeostasis of some biochemical and hematological parameters in rats.

The aim of this study was to detect possible homeostasis changes in some biochemical and hematological parameters after the administration of gallium (Ga) complexes C (24) and C (85) on an experimental animal model (Wistar strain rats). In order to observe chronobiological aspects, a morning (m) and an evening (e) animal series were constituted. Further on, each series were divided into three groups: control (C), experimental I (EI), and experimental II (EII). Both Ga complexes were solubilized in a carrier solution containing polyethylene glycol (PEG) 400, water, and ethanol. Animals of the C groups received the carrier solution by intraperitoneal injection, those from the EI groups received the solubilized C(24) gallium complex, and those of the EII groups received the solubilized C(85) gallium complex. At the end of the experiment, blood and tissue samples were taken and the following parameters were determined: serum concentration of the nonprotein nitrogenous compounds (uric acid, creatinine, and blood urea nitrogen), hematological parameters (erythrocytes, hemoglobin, leukocytes, and platelets), and the kidney tissue concentration of three essential trace elements (Fe, Cu, and Zn). With the exception of uric acid, the results revealed increased concentrations of the nonprotein nitrogenous compounds both in the morning and in the evening experimental groups. Hematological data showed increased levels of erythrocytes, hemoglobin, and leukocytes and decreased platelet levels in the experimental group given the C(24) gallium complex in the morning (EI-m) group; increased levels of leukocytes and decreased levels of the other parameters in the experimental group given the C(24) gallium complex in the evening (EI-e) group; and increased levels of all hematological parameters in the experimental groups receiving the C(85) gallium complex in the morning (EII-m) group and in the evening (EII-e) group. Decreased kidney tissue concentrations of metals were found in all the experimental groups. Fe levels were significantly decreased in the EI-m receiving the C(24) gallium complex and EII-m which received the C(85) gallium complex and in the EII-e group which received the C(85) gallium complex. In the EI-e group which received the C(24) gallium complex, a significant decrease of Cu concentration was reported.

Titanocene / cyclodextrin supramolecular systems: a theoretical approach.

BACKGROUND: Recently, various metallocenes were synthesized and analyzed by biological activity point of view (such as antiproliferative properties): ruthenocenes, cobaltoceniums, titanocenes, zirconocenes, vanadocenes, niobocenes, molibdocenes etc. Two main disadvantages of metallocenes are the poor hydrosolubility and the hydrolytic instability. These problems could be resolved in two ways: synthetically modifying the structure or finding new formulations with enhanced properties. The aqueous solubility of metallocenes with cytostatic activities could be enhanced by molecular encapsulation in cyclodextrins, as well as the hydrolytic instability of these compounds could be reduced. RESULTS: This study presents a theoretical approach on the nanoencapsulation of a series of titanocenes with cytotoxic activity in α-, ß-, and γ-cyclodextrin. The HyperChem 5.11 package was used for building and molecular modelling of titanocene and cyclodextrin structures, as well as for titanocene/cyclodextrin complex optimization. For titanocene/cyclodextrin complex optimization experiments, the titanocene and cyclodextrin structures in minimal energy conformations were set up at various distances and positions between molecules (molecular mechanics functionality, MM+). The best interaction between titanocene structures and cyclodextrins was obtained in the case of ß- and γ-cyclodextrin, having the hydrophobic moieties oriented to the secondary face of cyclodextrin. The hydrophobicity of titanocenes (logP) correlate with the titanocene-cyclodextrin interaction parameters, especially with the titanocene-cyclodextrin interaction energy; the compatible geometry and the interaction energy denote that the titanocene/ß- and γ-cyclodextrin complex can be achieved. Valuable quantitative structure-activity relationships (QSARs) were also obtained in the titanocene class by using the same logP as the main parameter for the in vitro cytotoxic activity against HeLa, K562, and Fem-x cell lines. CONCLUSIONS: According to our theoretical study, the titanocene/cyclodextrin inclusion compounds can be obtained (high interaction energy; the encapsulation is energetically favourable). Further, the most hydrophobic compounds are better encapsulated in ß- and γ-cyclodextrin molecules and are more stable (from energetically point of view) in comparison with α-cyclodextrin case. This study suggests that the titanocene / ß- and γ-cyclodextrin complexes (or synthetically modified cyclodextrins with higher water solubility) could be experimentally synthesized and could have enhanced cytotoxic activity and even lower toxicity.