Influence of cadmium and lead on bioelements homeostasis and oxidative stress parameters in patients with breast, prostate and testis cancer

Kadmijum (Cd) i olovo (Pb) su neesencijalni metali prirodno prisutni u životnoj sredini, ali je razvojindustrije značajno povećao njihovu koncentraciju u vazduhu, vodi i hrani. Iako se poslednjih godinabeleži pad njihovih koncentracija u životnoj sredini, istraživanja nedvosmisleno potvrđuju da iizloženost niskim dozama može dovesti do oštećenja različitih organskih sistema, te i endokrinog, štoih čini značajnim faktorom u pojavi/razvoju hormon zavisnih karcinoma, poput karcinoma dojke,prostate i testisa. S tim u vezi, pri proceni toksičnih efekata Cd i Pb potrebno je razmotriti potencijalniuticaj istovremene izloženosti jer je realni scenario da je čovek izložen smeši toksičnih supstanci, a datoksični efekti smeše mogu biti kvalitativno i kvantitativno drugačiji u odnosu na efekte pojedinačnihsupstanci. Stoga je ova studija imala cilj da ispita potencijalnu ulogu Cd i Pb kao faktora rizika uetiologiji karcinoma dojke, prostate i testisa ispitivanjem oksidativnog statusa, profila bioelemenata inivoa polnih hormona kod pacijenata obolelih od ovih karcinoma, te da utvrdi eventualni prediktivnipotencijal pojedinačnih parametra za nastanak karcinoma dojke, prostate i testisa.Retrospektivnoj case control studiji prethodila je in vivo studija na mužjacima Wistar pacova koji suakutno bili izloženi Cd i/ili Pb sa ciljem da se u uslovima istovremene izloženosti ispita distribucijametala, kao i da se utvrde toksični efekti metala i njihova priroda i intenzitet na krv i krvotvorneorgane, jetru, bubrege, prostatu i testise evaluacijom parametara oksidativnog statusa i ispitivanjeminterakcija sa bioelementima, bakrom (Cu) i cinkom (Zn).Case control studija je obuhvatila 55 pacijentkinja sa karcinomom dojke, 41 pacijenta sa karcinomomprostate i 52 pacijenta sa karcinomom testisa, dok su u kontrolnu grupu bile uključene zdrave žene(41), odnosno zdravi muškarci (61). Značajno više koncentracije Cd, odnosno niže Pb u tumorskomtkivu dojke u odnosu na okolno zdravo tkivo utvrđene su kod pacijentkinja sa karcinomom dojke, doksu estrogen receptor pozitivne karcinome dojke karakterisale više koncentracije oba toksična metala utumorskim tkivima u odnosu na negativnu ekspresiju receptora. Pacijente sa karcinomima prostate itestisa karakterisale su značajno više koncentracije Cd u krvi u odnosu na zdrave ispitanike, a pokazanaje i značajna akumulacija oba toksična metala u tumorskom tkivu prostate i testisa. Značajan odds ratiopokazan je za Cd u tkivu izmenjene strukture dojke (1,02), Cd u krvi pacijenata sa karcinomomprostate (1,18) i karcinomom testisa (1,98).Eksperimentalna in vivo studija utvrdila je hepato- i nefrotoksične efekte Cd i Pb, sa izraženijemefektom nakon akutne ekspozicije smeši. Oba toksična metala pokazala su sposobnost prolaska krv-testis barijere, međutim akutna izloženost nije značajno narušila homeostazu testosterona niti izmenilamorfološku strukturu prostate i testisa mužjaka pacova. Case control studija prepoznala je višekoncentracije Cd, ali ne i Pb značajnim prediktorom za nastanak karcinoma i potvrdila je narušenuhomeostazu oksidativnog statusa, redistribuciju Cu i Zn kao i disbalans polnih hormona kao važnemehanizme toksičnosti koji se nalaze u osnovi toksičnih efekata Cd i Pb kod obolelih od karcinomadojke, prostate i testisa.Cadmium (Cd) and lead (Pb) are non-essential metals naturally present in the environment, but theindustry development significantly increased their levels in air, water and food. Regardless theirdecreased environmental levels in recent decades, research unequivocally confirms that exposure tolow levels of Cd and Pb can damage numerous organs, including endocrine system. Furthermore, bothof them have been recognized as significant factor in the occurrence/development of hormone-dependent cancers, such as breast, prostate and testis cancer. In this regard, it is necessary to considerthe potential impact of simultaneous Cd and Pb exposure because the more realistic scenario is thathumans are exposed to a mixture of toxic substances, and that the toxic effects of the mixture may bequalitatively and quantitatively different from the effects of individual substances. Therefore, the casecontrol study aimed to determine the potential implication of Cd and Pb in the etiology of breast,prostate and testis cancer by examining oxidative status, bioelement profiles and sex hormone levels,and to establish the parameters, significant for breast, prostate and testis cancer prediction.In vivo study with male Wistar rats acutely treated by Cd and/or Pb, conducted prior the retrospectivecase control study, aimed to investigate metals distribution as well the toxic metals effects and todetermine the nature and intensity of Cd and Pb co-exposure effects on blood, liver, kidney, prostateand testis by evaluating oxidative status parameters and examining interactions with bioelements,copper (Cu) and zinc (Zn).The case control study encompassed 55 breast, 41 prostate and 52 testis cancer patients, while controlgroups were represented by 41 healthy women and 61 healthy men. Significantly higher Cd levels, butlower Pb in breast tumor tissue compared to surrounding healthy tissue was established in patients,while estrogen receptor positive breast cancer characterized by higher levels of both toxic metals intumor tissues compared to negative receptor expression. Notably higher blood Cd levels weredocumented in prostate and testicular cancers patients in relation to healthy subjects, and a significantaccumulation of both toxic metals in prostate and testis tumor tissue was shown. Thy study recognizeda significant odds ratio for Cd in breast cancer tissue (1.02), Cd in blood of prostate (1.18) and testiscancer patients (1.98).The in vivo study showed Cd and Pb hepatotoxic and nephrotoxic effects, with more pronounced effectafter mixture exposure. Regardless ability to cross the blood-testis barrier Cd and Pb did notsignificantly disturb testosterone homeostasis neither morphological structure of prostate and testis.Case control study recognized higher Cd levels in breast cancer tissue as well in blood of prostate andtestis cancer patients, but no Pb levels as significant factor in cancer prediction and confirmed oxidativestress, Cu and Zn redistribution as well impaired sex hormones homeostasis as pivotal mechanisms ofCd and Pb toxicity in breast, prostate and testis cancer pathology

Influence of cadmium and lead on bioelements homeostasis and oxidative stress parameters in patients with breast, prostate and testis cancer

Kadmijum (Cd) i olovo (Pb) su neesencijalni metali prirodno prisutni u životnoj sredini, ali je razvoj industrije značajno povećao njihovu koncentraciju u vazduhu, vodi i hrani. Iako se poslednjih godina beleži pad njihovih koncentracija u životnoj sredini, istraživanja nedvosmisleno potvrđuju da i izloženost niskim dozama može dovesti do oštećenja različitih organskih sistema, te i endokrinog, što ih čini značajnim faktorom u pojavi/razvoju hormon zavisnih karcinoma, poput karcinoma dojke, prostate i testisa. S tim u vezi, pri proceni toksičnih efekata Cd i Pb potrebno je razmotriti potencijalni uticaj istovremene izloženosti jer je realni scenario da je čovek izložen smeši toksičnih supstanci, a da toksični efekti smeše mogu biti kvalitativno i kvantitativno drugačiji u odnosu na efekte pojedinačnih supstanci. Stoga je ova studija imala cilj da ispita potencijalnu ulogu Cd i Pb kao faktora rizika u etiologiji karcinoma dojke, prostate i testisa ispitivanjem oksidativnog statusa, profila bioelemenata i nivoa polnih hormona kod pacijenata obolelih od ovih karcinoma, te da utvrdi eventualni prediktivni potencijal pojedinačnih parametra za nastanak karcinoma dojke, prostate i testisa. Retrospektivnoj case control studiji prethodila je in vivo studija na mužjacima Wistar pacova koji su akutno bili izloženi Cd i/ili Pb sa ciljem da se u uslovima istovremene izloženosti ispita distribucija metala, kao i da se utvrde toksični efekti metala i njihova priroda i intenzitet na krv i krvotvorne organe, jetru, bubrege, prostatu i testise evaluacijom parametara oksidativnog statusa i ispitivanjem interakcija sa bioelementima, bakrom (Cu) i cinkom (Zn). Case control studija je obuhvatila 55 pacijentkinja sa karcinomom dojke, 41 pacijenta sa karcinomom prostate i 52 pacijenta sa karcinomom testisa, dok su u kontrolnu grupu bile uključene zdrave žene (41), odnosno zdravi muškarci (61). Značajno više koncentracije Cd, odnosno niže Pb u tumorskom tkivu dojke u odnosu na okolno zdravo tkivo utvrđene su kod pacijentkinja sa karcinomom dojke, dok su estrogen receptor pozitivne karcinome dojke karakterisale više koncentracije oba toksična metala u tumorskim tkivima u odnosu na negativnu ekspresiju receptora. Pacijente sa karcinomima prostate i testisa karakterisale su značajno više koncentracije Cd u krvi u odnosu na zdrave ispitanike, a pokazana je i značajna akumulacija oba toksična metala u tumorskom tkivu prostate i testisa. Značajan odds ratio pokazan je za Cd u tkivu izmenjene strukture dojke (1,02), Cd u krvi pacijenata sa karcinomom prostate (1,18) i karcinomom testisa (1,98). Eksperimentalna in vivo studija utvrdila je hepato- i nefrotoksične efekte Cd i Pb, sa izraženijem efektom nakon akutne ekspozicije smeši. Oba toksična metala pokazala su sposobnost prolaska krv- testis barijere, međutim akutna izloženost nije značajno narušila homeostazu testosterona niti izmenila morfološku strukturu prostate i testisa mužjaka pacova. Case control studija prepoznala je više koncentracije Cd, ali ne i Pb značajnim prediktorom za nastanak karcinoma i potvrdila je narušenu homeostazu oksidativnog statusa, redistribuciju Cu i Zn kao i disbalans polnih hormona kao važne mehanizme toksičnosti koji se nalaze u osnovi toksičnih efekata Cd i Pb kod obolelih od karcinoma dojke, prostate i testisa.Cadmium (Cd) and lead (Pb) are non-essential metals naturally present in the environment, but the industry development significantly increased their levels in air, water and food. Regardless their decreased environmental levels in recent decades, research unequivocally confirms that exposure to low levels of Cd and Pb can damage numerous organs, including endocrine system. Furthermore, both of them have been recognized as significant factor in the occurrence/development of hormone- dependent cancers, such as breast, prostate and testis cancer. In this regard, it is necessary to consider the potential impact of simultaneous Cd and Pb exposure because the more realistic scenario is that humans are exposed to a mixture of toxic substances, and that the toxic effects of the mixture may be qualitatively and quantitatively different from the effects of individual substances. Therefore, the case control study aimed to determine the potential implication of Cd and Pb in the etiology of breast, prostate and testis cancer by examining oxidative status, bioelement profiles and sex hormone levels, and to establish the parameters, significant for breast, prostate and testis cancer prediction. In vivo study with male Wistar rats acutely treated by Cd and/or Pb, conducted prior the retrospective case control study, aimed to investigate metals distribution as well the toxic metals effects and to determine the nature and intensity of Cd and Pb co-exposure effects on blood, liver, kidney, prostate and testis by evaluating oxidative status parameters and examining interactions with bioelements, copper (Cu) and zinc (Zn). The case control study encompassed 55 breast, 41 prostate and 52 testis cancer patients, while control groups were represented by 41 healthy women and 61 healthy men. Significantly higher Cd levels, but lower Pb in breast tumor tissue compared to surrounding healthy tissue was established in patients, while estrogen receptor positive breast cancer characterized by higher levels of both toxic metals in tumor tissues compared to negative receptor expression. Notably higher blood Cd levels were documented in prostate and testicular cancers patients in relation to healthy subjects, and a significant accumulation of both toxic metals in prostate and testis tumor tissue was shown. Thy study recognized a significant odds ratio for Cd in breast cancer tissue (1.02), Cd in blood of prostate (1.18) and testis cancer patients (1.98). The in vivo study showed Cd and Pb hepatotoxic and nephrotoxic effects, with more pronounced effect after mixture exposure. Regardless ability to cross the blood-testis barrier Cd and Pb did not significantly disturb testosterone homeostasis neither morphological structure of prostate and testis. Case control study recognized higher Cd levels in breast cancer tissue as well in blood of prostate and testis cancer patients, but no Pb levels as significant factor in cancer prediction and confirmed oxidative stress, Cu and Zn redistribution as well impaired sex hormones homeostasis as pivotal mechanisms of Cd and Pb toxicity in breast, prostate and testis cancer pathology

Evaluation of glassionomer cement application for permanent binding of prosthetic dentures

Fixed dentures are created in order to rehabilitate the function of orofacial system, to correct disordered interdental relation, as well as the relation between jaws and to do esthetic correction. Binding of fixed dentures to the teeth carriers is done with a layer of binding biomaterials from the group of dental cements. Cement as the choice of dental biomaterials has to be the best cement for the most frequent, routine management for these type of works and most frequently used materials – metal, acrylate, ceramics. Cement must be safe to use with patients. Ideally, it must have longtime advantages such as to be for various uses, to find the right balance between results and simplicity of application, which are the most important for routine management. There are many types of cement. In this study, Zn-phosphate and glassionomer cement were used. In modern dental technology, production of cement is well developed and the most concerns are about non-toxicity, biocompatibility, bioinertion, biofunction. In some cases acidic balance disorder of saliva medium can bring to release of low doses of heavy metal ions after the reaction of cement and heavy metal ions from dental compounds. In this study, the best results were achieved with glassionomer cement, because the lowest percent of released heavy metal ions in saliva medium was noticed after cementing of fixed dentures by glassionomer cement. Because of its characteristics, glassionomer cement can be the choice material for permanent cementing of fixed prosthetic dentures

The fungistatic activity of organic selenium and its application to the production of cultivated mushrooms agaricus bisporus and pleurotus spp.

The activity of organic selenium against pathogenic molds and its use as a potential selenium source in the production of enriched mushrooms were examined. The effect of commercial selenized yeast on mycelia growth was examined using a method with mycelia disks and a well diffusion method. For mushroom enrichment, different concentrations of selenium were added to a growth substrate. The results presented in this paper suggest that the most suitable concentration of selenized yeast that inhibits the growth of the mycopathogenic molds is 70-100 mg/kg of selenium. With the addition of this concentration to the substrate, mushroom fruit bodies will uptake a high level of selenium, about 100 mu g/g for Pleurotus spp., and 200 mu/g for Agaricus bisporus in dry weight of the mushroom. Thereby a double effect in the cultivation of mushrooms is achieved

The importance of combined NGS and MLPA genetic tests for differential diagnosis of maturity onset diabetes of the young

Introduction: Maturity onset diabetes of the young (MODY) is a rare form of monogenic diabetes. Being clinically and genetically heterogeneous, it is often misdiagnosed as type 1 or type 2 diabetes, leading to inappropriate therapy. MODY is caused by a single gene mutation. Thirteen genes, defining 13 subtypes, have been identified to cause MODY. A correct diagnosis is important for the right therapy, prognosis, and genetic counselling. Material and methods: Twenty-nine unrelated paediatric patients clinically suspected of having MODY diabetes were analysed using TruSight One panel for next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) assay. Results: In this study we identified variants in MODY genes in 22 out of 29 patients (75.9%). Using two genetic tests, NGS and MLPA, we detected both single nucleotide variants and large deletions in patients. Most of the patients harboured a variant in the GCK gene (11/22), followed by HNF1B (5/22). The rest of the variants were found in the NEUROD1 and HNF1A genes. We identified one novel variant in the GCK gene: c.596T gt C, p.Val199Ala. The applied genetic tests excluded the suspected diagnosis of MODY in two patients and revealed variants in other genes possibly associated with the patient's clinical phenotype. Conclusions: In our group of MODY patients most variants were found in the GCK gene, followed by variants in HNF1B, NEUROD1, and HNF1A genes. The combined NGS and MLPA-based genetic tests presented a comprehensive approach for analysing patients with suspected MODY diabetes and provided a successful differential diagnosis of MODY subtypes

Bezbednost primene lekova koji se koriste u terapiji HIV infekcije

Human immunodeficiency virus (HIV), isolated in 1983 by Paster Institute researches, has been recognised as the cause of million fatalies in 21st century. Initial monotherapy failed to show promising results, however, with the development of highly active antiretroviral therapy new era of HIV treatment has started. This new approach resulted in extended life time, reduced development of virus resistance as well as morbidity and mortality of HIV patients. Antiretroviral therapy is longlife and connected with serious adverse and toxic effects. Mitochondrial toxicity can be manifested as periferal lipoathrophy, hepatic steatosis, lactic acidosis, neuropathy and miopathy. Metabolic features associated with lipodystrophy include hypertriglyceridaemia, hypercholesterolaemia, insuline resistance and abnormal glucose tolerance. Hepatotoxicity, nephrotoxicity, osteopenia, rash and gastrointestinal symptoms can also occur during antiretroviral therapy. The aim od this work was to present the most important adverse and toxic effects of drugs used in HIV therapy.Virus humane imunodeficijencije, izolovan zahvaljujući istraživačima Paster Instituta 1983. godine, uzročnik je milionskih žrtava u XXI veku. Kako inicijalna monoterapija nije uspela da pokaže zavidne rezultate, razvojem visoko aktivne antiretrovirusne terapije započeta je nova era HIV terapije. Nov pristup lečenju produžio je životni vek obolelih, smanjio pojavu rezistencija kao i stopu morbiditeta i mortaliteta obolelih. Antiretrovirusna terapija je doživotna i nosi sa sobom ozbiljne neželjene i toksične efekte. Mitohondrijska toksičnost može se ispoljiti kao periferna lipoatrofija, hepatična steatoza, laktična acidoza, neuropatija i miopatija. Metabolički poremaćaji udruženi sa lipodistrofijom uključuju hipertrigliceridemiju, hiperholestirolemiju, insulinsku rezistenciju i abnormalnu glukoznu toleranciju. Hepatotoksičnost, nefrotoksičnost, ostepenija, pojava raša i smetnje na nivou gastroinestinalnog trakta takođe se mogu javiti pri primeni antiretrovirusne terapije. Cilj ovoga rada je bio da da prikaz najznačajnijih neželjenih i toksičnih efekata lekova koji se koriste u terapiji HIV-a

Crosstalk between Glycogen-Selective Autophagy, Autophagy and Apoptosis as a Road towards Modifier Gene Discovery and New Therapeutic Strategies for Glycogen Storage Diseases

Glycogen storage diseases (GSDs) are rare metabolic monogenic disorders characterized by an excessive accumulation of glycogen in the cell. However, monogenic disorders are not simple regarding genotype-phenotype correlation. Genes outside the major disease-causing locus could have modulatory effect on GSDs, and thus explain the genotype-phenotype inconsistencies observed in these patients. Nowadays, when the sequencing of all clinically relevant genes, whole human exomes, and even whole human genomes is fast, easily available and affordable, we have a scientific obligation to holistically analyze data and draw smarter connections between genotype and phenotype. Recently, the importance of glycogen-selective autophagy for the pathophysiology of disorders of glycogen metabolism have been described. Therefore, in this manuscript, we review the potential role of genes involved in glycogen-selective autophagy as modifiers of GSDs. Given the small number of genes associated with glycogen-selective autophagy, we also include genes, transcription factors, and non-coding RNAs involved in autophagy. A cross-link with apoptosis is addressed. All these genes could be analyzed in GSD patients with unusual discrepancies between genotype and phenotype in order to discover genetic variants potentially modifying their phenotype. The discovery of modifier genes related to glycogen-selective autophagy and autophagy will start a new chapter in understanding of GSDs and enable the usage of autophagy-inducing drugs for the treatment of this group of rare-disease patients

Novel silver(I) compounds with 1-adamantanamine

In this work, three novel silver(I) complexes with an almost completely rigid and bulky monodentate ligand, 1-adamantanamine, were synthesized. The aliphatic amine, 1-adamantanamine, is the sole electron donor ligand in these complexes. In addition to spectroscopic characterization, the basic biological activities of the new compounds were investigated and their minimum inhibitory concentrations were determined. The antifungal and antibacterial activities indicate that these compounds could potentially be applied as new therapeutics

Environmental Exposure to Metals, Parameters of Oxidative Stress in Blood and Prostate Cancer: Results from Two Cohorts

We studied the potential role of exposure to various metal(oid)s (As, Cd, Cr, Hg, Ni, and Pb) in prostate cancer. Two cohorts were established: the Croatian cohort, consisting of 62 cases and 30 controls, and the Serbian cohort, consisting of 41 cases and 61 controls. Blood/serum samples were collected. Levels of investigated metal(oid)s, various parameters of oxidative stress, and prostate-specific antigen (PSA) were determined in collected samples. A comparison of the measured parameters between 103 prostate cancer patients and 91 control men from both Croatian and Serbian cohorts showed significantly higher blood Hg, SOD, and GPx levels and significantly lower serum SH levels in prostate cancer patients than in controls. Correlation analyses revealed the significant relationship between certain parameters of oxidative stress and the concentrations of the measured metal(loid)s, pointing to the possible role of metal(oid)-induced oxidative stress imbalance. Furthermore, a significant inverse relationship was found between the blood Pb and the serum PSA in prostate cancer patients, but when the model was adjusted for the impacts of remaining parameters, no significant association between the serum PSA and the measured parameters was found. The results of the overall study indicate a substantial contribution of the measured metal(loid)s to the imbalance of the oxidant/antioxidant system. Although somewhat conflicting, the results of the present study point to the possible role of investigated metal(oid)s in prostate cancer, especially for Hg, since the obtained relationship was observed for both cohorts, followed by the disturbances in oxidative stress status, which were found to be correlated with Hg levels. Nevertheless, further studies in larger cohorts are warranted to explain and confirm the obtained results