Effect of chaethomellic acid on renal function in rat model of chronic renal failure

To study the effect of chronic treatment with chaethomellic acid (CA), a highly specific inhibitor of ras farnesyl-protein transferase, on the renal function of rats with renal failure induced by renal mass reduction. Male Wistar rats were subjected to 5/6 nephrectomy (RMR) or sham-operated (SO). One week after surgery, rats have been placed in four experimental groups: RMR: rats without treat- ment (n=13); RMR+CA: rats treated with CA (n=13); SO: rats without treatment (n=13); SO+AC: rats treated with CA (n=13). CA was intraperitoneally administered in a dose of 0.23 g/Kg three times a week for 6 months. Creatinine, blood urea nitrogen (BUN) and protein were measured in serum and/or urine by routine laboratory techniques. BUN, creatinine, and proteinuria were significantly lower and creatinine clearance was significantly higher in SO and SO+AC groups when compared with RMR and RMR+AC groups. There were no differ- ences in creatinine, proteinuria and creatinine clearance between RMR and RMR+AC groups. Anyway, RMR+AC group showed significant lower BUN and lower creatinine and proteinuria, and higher creatinine clearance than RMR group. In a model of renal failure induced by RMR, 6 months of treatment with CA may have some beneficial effect on renal function

Effect of chaethomellic acid on renal function in a rat model of chronic renal failure

To study the effect of chronic treatment with chaethomellic acid (CA), a highly specific inhibitor of ras farnesyl-protein transferase, on the renal function of rats with renal failure induced by renal mass reduction. Male Wistar rats were subjected to 5/6 nephrectomy (RMR) or sham-operated (SO). One week after surgery, rats have been placed in four experimental groups: RMR: rats without treat- ment (n=13); RMR+CA: rats treated with CA (n=13); SO: rats without treatment (n=13); SO+AC: rats treated with CA (n=13). CA was intraperitoneally administered in a dose of 0.23 g/Kg three times a week for 6 months. Creatinine, blood urea nitrogen (BUN) and protein were measured in serum and/or urine by routine laboratory techniques. BUN, creatinine, and proteinuria were significantly lower and creatinine clearance was significantly higher in SO and SO+AC groups when compared with RMR and RMR+AC groups. There were no differ- ences in creatinine, proteinuria and creatinine clearance between RMR and RMR+AC groups. Anyway, RMR+AC group showed significant lower BUN and lower creatinine and proteinuria, and higher creatinine clearance than RMR group. In a model of renal failure induced by RMR, 6 months of treatment with CA may have some beneficial effect on renal function

Reference intervals for haematological parameters in the Lusitano horse breed

The Lusitano horse is an autochthonous Portuguese breed with a growing worldwide expansion. Our objective was to establish reference intervals for haematological parameters using the haematological cell counter LaserCyte (IDEXX). For this purpose, blood samples from 100 healthy adult horses (13 females and 87 males, ranging from 3 to 25 years of age) were analysed. The reference intervals were estimated following the ASVCP guidelines with the Reference Value Advisor software. The obtained reference intervals were 6.4–10.1 × 1012/L for red blood cells, 30.6–45.1% for haematocrit, 11.6–17.1 g/dL for haemoglobin, 42.8–53.2 fL for mean corpuscular volume (MCV), 15.5–20.8 pg for mean corpuscular haemoglobin (MCH), 33.7–39.4 g/dL for mean corpuscular haemoglobin concentration, 17.8–20.3% for red cell distribution width (RDW), 4.5–10.1 × 109/L for white blood cells, 2.2–6.0 × 109/L for neutrophils, 0.9–4.9 × 109/L for lymphocytes, 0.2–0.5 × 109/L for monocytes, 0.1–0.6 × 109/L for eosinophils, 0.0–0.1 × 109/L for basophils, 78.5–172.2 K/mL for platelets, 4.3–9.4 fL for mean platelet volume, 18.8–24.2% for platelet distribution width, and 0.06–0.12% for plateletcrit. LaserCyte equine reference intervals are transferable to the Lusitano horse for 18 of the 22 analytes studied. Regarding age, significant statistical differences were observed for MCV, RDW, neutrophils and lymphocytes between the mean values of young (3–6 years old), middle-aged (7–14 years old) and old (< 15 years old) age groups. MCH means were statistically significantly different between the three age groups. The haematological reference intervals established in this study might represent a valuable and applicable tool for haematological assessment of adult Lusitano horses, providing useful information that helps clinicians to interpret clinical data

Cytokeratin 7/19 expression inN-diethylnitrosamine-induced mouse hepatocellular lesions: implications for histogenesis International

Hepatocellular carcinoma (HCC) is a common malignancy with poor clinical outcome, whose histogenesis is the subject of intense debate. Specifically, expression ofcytokeratins (CKs) 7 and 19, associated with aggressive biological behaviour, is proposed to reflect a possible progenitor cell origin or tumour dedifferentiation towardsa primitive phenotype. This work addresses that problem by studying CKs 7 and 19expression in N-diethylnitrosamine (DEN)-induced mouse HCCs. ICR mice weredivided into six DEN-exposed and six matched control groups. Samples were takenfrom each group at consecutive time points. Hyperplastic foci (13 lesions) occurredat 29-40 weeks (groups 8, 10 and 12) with diffuse dysplastic areas (19 lesions) andwith one hepatocellular adenoma (HCA) (at 29 weeks). HCCs (4 lesions) wereobserved 40 weeks after the first DEN administration (group 12). CKs 7 and 19showed identical expression patterns and located to large, mature hepatocytes, isolated or in small clusters. Hyperplastic foci and the single HCA were consistentlynegative for both markers, while dysplastic areas and HCCs were positive. Theseresults support the hypothesis that CKs 7 and 19 expression in hepatocellular malignancies results from a dedifferentiation process rather than from a possible progenitor cell origin

In vivo and in vitro effects of RAD001 on bladder cancer

Objective: To evaluate the influence of Everolimus (RAD001) on chemically induced urothelial lesions in mice and its influence on in vitro human bladder cancer cell lines. Methods: ICR male mice were given N-butyl-N-(4-hydroxybutyl) nitrosamine in drinking water for a period of 12 weeks. Subsequently, RAD001 was administered via oral gavage, for 6 weeks. At the end of the experiment, all the animals were sacrificed and tumor development was determined by means of histopathologic evaluation; mammalian target of rapamycin (mTOR) expressivity was evaluated by immunohistochemistry. Three human bladder cancer cell lines (T24, HT1376, and 5637) were treated using a range of RAD001 concentrations. MTT assay, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and flow cytometry were used to assess cell proliferation, apoptosis index, and cell cycle analysis, respectively. Immunoblotting analysis of 3 cell line extracts using mTOR and Akt antibodies was performed in order to study the expression of Akt and mTOR proteins and their phosphorylated forms. Results: The incidence of urothelial lesions in animals treated with RAD001 was similar to those animals not treated. RAD001 did not block T24 and HT1376 cell proliferation or induce apoptosis. A reduction in cell proliferation rate and therefore G0/G1 phase arrest, as well as a statistically significant induction of apoptosis (P 0.001), was only observed in the 5637 cell line. Conclusion: RAD001 seems not to have a significant effect on chemically induced murine bladder tumors. The effect of RAD001 on tumor proliferation and apoptosis was achieved only in superficial derived bladder cancer cell line, no effect was observed in invasive cell lines

Long-term treatment with chaethomellic acid A reduces glomerulosclerosis and arteriolosclerosis in a rat model of chronic kidney disease

The high prevalence of end-stage renal disease emphasizes the failure to provide therapies to effectively prevent and/or reverse renal fibrosis. Therefore, the aim of this study was to evaluate the effect of long-term treatment with chaethomellic acid A (CAA), which selectively blocks Ha-Ras farnesylation, on renal mass reduction-induced renal fibrosis. Male Wistar rats were sham-operated (SO) or subjected to 5/6 renal mass reduction (RMR). One week after surgery, rats were placed in four experimental groups: SO:SO rats without treatment (n = 13); SO + CAA: SO rats treated with CAA (n = 13); RMR:RMR rats without treatment (n = 14); and RMR + CAA:RMR rats treated with CAA (n = 13). CAA was intraperitoneally administered in a dose of 0.23 μg/kg three times a week for six months. Renal fibrosis was evaluated by two-dimensional ultrasonography and histopathological analysis. The kidneys of the RMR animals treated with CAA showed a significantly decrease in the medullary echogenicity (p < 0.05) compared with the RMR rats that received no treatment. Glomerulosclerosis and arteriolosclerosis scores were significantly lower (p < 0.001) in the RMR + CAA group when compared with the RMR group. There were no significant differences in interstitial fibrosis, interstitial inflammation and tubular dilatation scores between the RMR + CAA and RMR groups. These data suggest that CAA can be a potential future drug to attenuate the progression of chronic kidney disease.This work is supported by : European Investment Funds by FEDER/COMPETE/POCI– Operacional Competitiveness and Internacionalization Programme, under Project POCI-01-0145-FEDER-006958 and National Funds by FCT - Portuguese Foundation for Science and Technology, under the project UID/AGR/04033/2013; and by European Investment Funds by FEDER/COMPETE/POCI– Operacional Competitiveness and Internacionalization Programme, under Project POCI-01-0145-FEDER-016728 and National Funds by FCT - Portuguese Foundation for Science and Technology, under the project PTDC/DTP-DES/6077/2014.info:eu-repo/semantics/publishedVersio

Biomonitoring of metals and metalloids with raptors from Portugal and Spain: a review

The analysis of metals in different tissues of raptors has been an important tool for assessing metal pollution. Several studies using a range of sentinel raptor species have been carried out in Portugal and Spain since the 1980s in order to identify the adverse effects in the animals themselves and on their populations, to identify the contamination of the food-chain, to determine the levels of environmental contamination and to estimate human health risks. The aim of this work is to provide synthesized information of the studies carried out in Portugal and Spain in the direct biomonitoring of metals and metalloids using raptors, through a systematic search of the published literature. The information is summarized taking into account specific issues such as monitored raptor species, sampling periods, monitored areas, type of samples, analytical techniques used in the determination of the metals and metalloids, the analysed metals and metalloids and overall analysis of the concentrations obtained. There is a striking difference between the number of studies performed in Portugal and Spain, and most of them have been carried out in Spain. The Eagle owl, Black kite and Common buzzard were the species from which the greatest number of individuals has been analysed. Among the most analyzed biological samples, the blood and liver samples were used to measure the concentrations of all studied metals, while bone was mainly collected to evaluate chronic exposure to lead and feathers to evaluate exposure to mercury during feather growth. Atomic Absorption Spectrometry has been the most frequently performed technique to determine the majority of metals and arsenic. In general, the concentrations of metals detected in raptor samples from Portugal and Spain are low and insufficient to produce toxic side effects. Only lead, in certain cases, can be related with toxic side effects. However, it should be given particular attention to mercury due to its high toxicity, its transport from an aquatic environment to the adjacent terrestrial food web and because mercury toxicity threshold have yet to be established for raptors. This work confirms the need for further biomonitoring studies of metals with raptors, especially in Portugal; the establishing of national programs in order to conduct long-term studies; and creating a network between Portugal and Spain in order to study environmental contamination using raptors.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Synergistic Effect between Cisplatin and Sunitinib Malate on Human Urinary Bladder-Cancer Cell Lines

The aim of this paper is to analyse sunitinib malate in vitro ability to enhance cisplatin cytotoxicity in T24, 5637, and HT1376 human urinary bladder-cancer cell lines. Cells were treated with cisplatin (3, 6, 13, and 18 μM) and sunitinib malate (1, 2, 4, 6, and 20 μM), either in isolation or combined, over the course of 72 hours. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, acridine orange, and monodansylcadaverine staining and flow cytometry were performed. The combination index (CI) was calculated based on the Chou and Talalay method. In isolation, cisplatin and sunitinib malate statistically (). Autophagy and apoptosis studies showed a greater incidence when the combined treatment was put into use. This hints at the possibility of a new combined therapeutic approach. If confirmed in vivo, this conjugation may provide a means of new perspectives in muscle-invasive urinary bladder cancer treatment