Jan Liska

Arsenic: toxicity, oxidative stress and human disease

Arsenic (As) is a toxic metalloid element that is present in air, water and soil. Inorganic arsenic tends to be more toxic than organic arsenic. Examples of methylated organic arsenicals include monomethylarsonic acid [MMA(V)] and dimethylarsinic acid [DMA(V)]. Reactive oxygen species (ROS)‐mediated oxidative damage is a common denominator in arsenic pathogenesis. In addition, arsenic induces morphological changes in the integrity of mitochondria. Cascade mechanisms of free radical formation derived from the superoxide radical, combined with glutathione‐depleting agents, increase the sensitivity of cells to arsenic toxicity. When both humans and animals are exposed to arsenic, they experience an increased formation of ROS/RNS, including peroxyl radicals (ROO•), the superoxide radical, singlet oxygen, hydroxyl radical (OH•) via the Fenton reaction, hydrogen peroxide, the dimethylarsenic radical, the dimethylarsenic peroxyl radical and/or oxidant‐induced DNA damage. Arsenic induces the formation of oxidized lipids which in turn generate several bioactive molecules (ROS, peroxides and isoprostanes), of which aldehydes [malondialdehyde (MDA) and 4‐hydroxy‐nonenal (HNE)] are the major end products. This review discusses aspects of chronic and acute exposures of arsenic in the etiology of cancer, cardiovascular disease (hypertension and atherosclerosis), neurological disorders, gastrointestinal disturbances, liver disease and renal disease, reproductive health effects, dermal changes and other health disorders. The role of antioxidant defence systems against arsenic toxicity is also discussed. Consideration is given to the role of vitamin C (ascorbic acid), vitamin E (α‐tocopherol), curcumin, glutathione and antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase in their protective roles against arsenic‐induced oxidative stress. Copyright

MNU-induced carcinogenesis of rat mammary gland: Effect of thyroid hormone on expression of retinoic acid receptors in tumours of mammary gland

The rat model of N-methyl-N-nitrosourea (MNU)-induced mammary carcinomas is well-established animal model for breast cancer. This study was carried out to investigate whether hypothyroid (thyroidectomy or PTU treatment) or hyperthyroid status of female rats would affect MNU-induced mammary carcinogenesis with specific focus on both retinoid and rexinoid receptor expression in mammary tumours. Application of PTU before and during MNU-induced mammary gland carcinogenesis yielded in a marked decrease of the number and volume of tumours per animal, however, there was no effect of hypothyroid state in thyroidectomized rats as well as hyperthyroid state concerning the number and volume of tumours. Mammary tumours of in euthyroid group of MNU animals showed that there was no tumour, in which all of subtypes of retinoid and rexinoid receptors were expressed. A different pattern of expression of retinoid or rexinoid receptors was found either in MNU-induced mammary carcinomas in both hypothyroid and hyperthyroid rats.

MNU-induced mammary gland carcinogenesis: Chemopreventive and therapeutic effects of vitamin D and Seocalcitol on selected regulatory vitamin D receptor pathways

The effects of administration of vitamin D₃ and Seocalcitol on MNU-induced carcinogenesis of mammary gland in Sprague-Dawley rats have been investigated. Administration of both substances in a weekly dose of 7 μg/kg caused prolonged latency of mammary gland tumors. The latency of tumors was markedly prolonged for 30-40 days by Seocalcitol. Using PET analysis, reduction in [¹⁸F]2-fluoro-2-deoxy-d-glucose (FDG) uptake or tumor volume in tumors chemopreventively treated with vitamin D₃ were detected in MNU-induced tumors, vitamin D₃ reduced expression of 25-hydroxylase (25OHase) (p<0.01) and 24-hydroxylase (24OHase) (p<0.01) and Seocalcitol 24OHase. Positive regulation of 25OHase mRNA level after the treatment with vitamin D₃ was observed in liver, while in kidney, vitamin D₃ and Seocalcitol induced expression of 24OHase was significant. Our observations indicate a cross talk between respective pathways of VDR, RARs/RXRs, TRs and ERs in carcinogenesis process.

AT1 receptor and ACE mRNA are increased in chemically induced carcinoma of rat mammary gland

Angiotesin II has except of strong vasoconstrict effect also ability to potentiate protein synthesis and cellular growth. The aim of this study was to investigate the gene expression of components of the renin-angiotensin system, angiotensinogen, renin, angiotensin-converting enzyme and AT(1) receptor, in rat mammary gland and in chemically induced carcinoma of this gland. Retinoids are known to inhibit cell proliferation and induce cell differentiation so they are considered as a promising chemopreventive agents. We studied the effect of 13-cis-retinoic acid on the gene expression of mentioned elements of the renin-angiotensin system in tumour tissue. The expressions in control and carcinoma tissue were investigated using RT-PCR and activity of angiotensin-converting enzyme was measured. The amount of angiotensin-converting enzyme and AT(1) receptor mRNA and angiotensin-converting enzyme activity always showed a significant increase in the carcinoma tissue in comparison with the control. Administration of 13-cis-retinoic acid to rats with induced mammary gland carcinoma was without significant effect on either tumour numbers or tumour burden and volume. Similarly, 13-cis-retinoic acid did not change the angiotensin-converting enzyme expression and activity. The AT(1) receptor gene expression displayed a clear tendency to decrease in tumour tissue after retinoic acid treatment. Our results demonstrate the presence of angiotensin-converting enzyme and AT(1) receptor in control and carcinoma tissue of mammary gland. We assume that both proteins might play a role in development of tumour cells and vasculature.

Treatment of 1-methyl-1-nitrosourea-induced mammary tumours with immunostimulatory CpG motifs and 13-cis retinoic acid in female rats: histopathological study

Histopathological evaluation of the mammary gland tumours of Sprague-Dawley rats induced with 1-methyl-1-nitrosourea (MNU), and treated with either CpG oligodeoxynucleotides (CpG-ODN) and/or 13-cis retinoic acid has been performed in this work. Since, the treatment of animals with CpG-ODN induced a significant decrease of tumour burden and volume in comparison with MNU treated control group (Macejova et al. 2001), it was of high impact to compare histological appearance of tumours in different experimental groups (MNU, CpG-ODN, 13-cis retinoic acid, CpG-ODN plus 13-cis retinoic acid). We have found reduced number of carcinomas with necroses in the CpG motifs treated group when compared to animals treated with MNU only. From the histological point of view the treatment with the CpG-ODN may have some protective effect. Carcinoma patterns proportion in the group treated with CpG-ODN was found to be different in comparison with other experimental groups. Treatment of rats with CpG-ODN had no apparent effect on invasiveness of developed carcinomas.

Relationship between histology, development and tumorigenesis of mammary gland in female rat

The mammary gland is a dynamic organ that undergoes structural and functional changes associated with growth, reproduction, and post-menopausal regression. The postnatal transformations of the epithelium and stromal cells of the mammary gland may contribute to its susceptibility to carcinogenesis. The increased cancer incidence in mammary glands of humans and similarly of rodents in association with their development is believed to be partly explained by proliferative activity together with lesser degree of differentiation, but it is not completely understood how the virgin gland retains its higher susceptibility to carcinogenesis. During its developmental cycle, the mammary gland displays many of the properties associated with breast cancer. An early first full-term pregnancy may have a protective effect. Rodent models are useful for investigating potential breast carcinogens. The purpose of this review is to help recognizing histological appearance of the epithelium and the stroma of the normal mammary gland in rats, and throughout its development in relation to tumorigenic potential.

The use of lectins identified with specific antibodies in lectin histochemistry of NZB/W F1 mouse kidney

Summary The affinity of Helix pomatia , peanut, Pisum sativum , soy bean, and wheat germ agglutinins to various nephron parts of NZB/W F 1 mice was different and is assumed to be age dependent. The affinity of Pisum sativum agglutinin to basal membranes of small renal vessels increased with the age of NZB/W F 1 mice. The wheat germ agglutinin bound to structures with alkaline phosphatase activity.

Histological evaluation of rat mammary tumours after treatment with retinoic acid analogues — phytol, TTNPB and vitamin D3 analogue seocalcitol

The effects of retinoic acid analogue — phytol (precursor of retinoic X receptors ligand), TTNPB (retinoic acid receptor agonist) and seocalcitol (EB1089, analogue of vitamin D3) in mammary tumours of Sprague-Dawley rats induced with 1-methyl-1-nitrosourea (MNU) were investigated. Treatment with phytol, TTNPB and seocalcitol may have some protective and therapeutical effects on malignant processes. Treatment with these components in combination of TTNPB and phytol or seocalcitol and phytol inhibited progression of MNU-induced tumours of the rat mammary gland, and also induced decrease of tumour burden and volume in comparison with treated control group. Treatment of rats with the above compounds had no effect on malignity and invasiveness of carcinomas.

Determination of selective biochemical parameters in pregnant and lactating nice after stobadine administration

The effect of oral administration of stobadine, a cardioprotective drug, was studied on the basis of determination of selective biochemical parameters in pregnant and lactating rats. Stobadine was administered orally at a dose of 50 mg/kg from day 15 of gestation until day 21 of lactation. We determined creatinine and urea in serum, acidity, protein, glucose, ketones, bilirubin, urobilinogen, blood, and creatinine in urine from females on days 15 and 20 of gestation and 7, 14, and 21 of lactation. In the biochemical parameters investigated no significant differences between control and experimental animals were recorded on any of the days studied. Histopathological examination of kidney tissue did not reveal kidney damage after stobadine administration.