Metallomics of benign and malignant diseases of the thyroid gland

Etiologija tiroidnih oboljenja je nedovoljno prouĉena i najnoviji literaturni podaci ukazuju da bi metali mogli da igraju kljuĉnu ulogu u patogenezi velikog broja poremećaja, ukljuĉujući i bolesti tiroidne ţlezde. S tim u vezi, cilj ove studije bio je da se odredi sadrţaj esencijalnih i toksiĉnih metala u zdravim tiroidnim tkivima (ZTT) i napravi komparativna analiza sa sadrţajem metala u tiroidnim tkivima sa dijagnostifikovanim benignim i malignim oboljenjima. Dodatni cilj studije bio je sagledavanje metalomike u zavisnosti od bioloških i kliniĉko-patoloških parametara, kao i pronalaţenje najznaĉajnijeg metala (ili njegovog odnosa sa drugim metalom) koji bi mogao da razdvoji ispitivane grupe i obezbedi informacije o molekulskoj osnovi patofizioloških promena ispitivane bolesti tiroidne ţlezde na tkivnom nivou. Uzorci tkiva za analizu metala sakupljeni su nakon operacije tiroidne ţlezde. U istraţivanju je uĉestvovalo 200 pacijenata, od toga 21 pacijent sa Hašimotovim tiroiditisom (HT), 62 pacijenta sa koloidnom strumom (KS), 36 pacijenata sa benignim tumorima (BT) i 81 pacijent sa malignim tumorima (70 sa papilarnim karcinomom, 8 sa folikularnim i troje sa medularnim karcinomom). Od svakog pacijenta sa dijagnostifikovanim tumorom uzorkovano je i ZTT sa najveće moguće udaljenosti od primarnog tumora, koji je bio jasno demarkiran (n = 117). U svakoj patologiji ispitan je sadrţaj metala u zavisnosti od pola, uzrasta, konzumiranja duvana i veliĉine tiroidnog nodusa. Metalomika papilarnog karcinoma tiroidne ţlezde dodatno je ispitana u zavisnosti od patohistološkog (PH) tipa tumora, prethodne istorije tiroidnog oboljenja u porodici, „TNM“ klasifikacije, prisustva invazije tiroidne kapsule, intratiroidne multicentriĉne diseminacije i retrosternalnog tiroidnog rasta. Uzorci tkiva razoreni su mikrotalasnom digestijom i koncentracija elemenata, mangana (Mn), nikla (Ni), bakra (Cu), cinka (Zn), arsena (As), selena (Se), kadmijuma (Cd), olova (Pb), torijuma (Th) i uranijuma (U) odreĊena je metodom induktivno spregnute plazme sa masenom spektrometrijom (ICP-MS). Za kvantifikaciju metala ĉije su koncentracije bile veće od 10 μg/L dodatno je primenjena metoda induktivno spregnute plazme sa optiĉkom emisionom spektrometrijom (ICP-OES). Za obradu dobijenih podataka primenjene su uni- i multivarijantne statistiĉke metode. PronaĊeno je da je sadrţaj selena u ZTT bio znaĉajno smanjen (i do 15 puta) u poreĊenju sa drugim populacionim grupama širom sveta, na osnovu ĉega bi mogla da se istakne deficijencija selena u ispitivanoj grupi srpske populacije. UtvrĊeno je da patološka tiroidna tkiva imaju znaĉajno izmenjen sadrţaj velikog broja metala u poreĊenju sa ZTT...The etiology of thyroid diseases is not very well clarified and the latest literature data indicated that metals could play a key role in the pathogenesis of a great number of disorders, including the thyroid gland diseases. In this regard, the aim of this study was to determine the content of toxic and essential metals in the healthy thyroid tissues (HTTs), as well as to compare the content of metals in tissues with diagnosed benign and malignant thyroid gland diseases. The further aim of this study was to investigate metallomics according to the biological-, clinical- and pathological-parameters, as well as to find the most significant metal (or its ratio to another metal) that could separate examined groups, as well as to provide additional information on the molecular basis of pathophysiological changes of the examined thyroid disease at the tissue’s level. Tissue samples for metal analysis were collected after thyroid surgery. The study included 200 patients, of which 21 patients with Hashimoto’s thyroiditis (HT), 62 patients with colloid goiter (CG), 36 patients with benign tumors (BTs) and 81 patients with malignant tumors (70 with papillary carcinoma, 8 with follicular and three with medullary thyroid carcinoma). HTT was sampled from each patient with diagnosed tumor from the greatest possible distance from the primary tumor, which was well demarked (n = 117). In each pathology, the content of metals was investigated according to sex, age, smoking habits and goiter size. Metallomics of the papillary thyroid carcinoma (PTC) was further examined based on the pathohistological (PH) type of tumor, previous history of any thyroid disease in the family, TNM classification, capsular invasion, intrathyroid dissemination, and the retrosternal thyroid growth. Tissue samples were decomposed by microwave digestion and the concentration of elements, manganese (Mn), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), cadmium (Cd), lead (Pb), thorium (Th) and uranium (U) was determined by inductively coupled plasma-mass spectrometry (ICP-MS). Inductively coupled plasma-optical emission spectrometry (ICP-OES) was additionally used to quantify metals with concentrations higher than 10 μg/L. Uni- and multivariate statistical methods were applied for data analysis. It was found that the content of selenium in the HTTs was significantly reduced (up to 15 times) compared to other population groups worldwide, which could highlight the deficiency of Se in the investigated group of Serbian population. It was estimated that pathological thyroid tissues had significantly altered metal’s content when compared to the HTTs. The most altered metal’s content was found in tissues of patients with the HT..

Mercury and Autism Spectrum Disorder: Exploring the Link through Comprehensive Review and Meta-Analysis

Mercury (Hg) is a non-essential trace metal with unique neurochemical properties and harmful effects on the central nervous system. In this study, we present a comprehensive review and meta-analysis of peer-reviewed research encompassing five crucial clinical matrices: hair, whole blood, plasma, red blood cells (RBCs), and urine. We assess the disparities in Hg levels between gender- and age-matched neurotypical children (controls) and children diagnosed with autism spectrum disorder (ASD) (cases). After applying rigorous selection criteria, we incorporated a total of 60 case-control studies into our meta-analysis. These studies comprised 25 investigations of Hg levels in hair (controls/cases: 1134/1361), 15 in whole blood (controls/cases: 1019/1345), 6 in plasma (controls/cases: 224/263), 5 in RBCs (controls/cases: 215/293), and 9 in urine (controls/cases: 399/623). This meta-analysis did not include the data of ASD children who received chelation therapy. Our meta-analysis revealed no statistically significant differences in Hg levels in hair and urine between ASD cases and controls. In whole blood, plasma, and RBCs, Hg levels were significantly higher in ASD cases compared to their neurotypical counterparts. This indicates that ASD children could exhibit reduced detoxification capacity for Hg and impaired mechanisms for Hg excretion from their bodies. This underscores the detrimental role of Hg in ASD and underscores the critical importance of monitoring Hg levels in ASD children, particularly in early childhood. These findings emphasize the pressing need for global initiatives aimed at minimizing Hg exposure, thus highlighting the critical intersection of human–environment interaction and neurodevelopment health

Multiformni glioblastom lokaliziran u motornom korteksu: specifičnosti u odnosu na gliome niskog stupnja iste lokalizacije - analiza serije od šezdeset bolesnika

The verified presence of a glioblastoma multiforme (GBM ) tumor in the motor area of the brain, in a patient lacking preoperative neurological deficit, offers no certainty that the tumor can be radically removed without the possibility of causing postoperative motor deficit. We present a series of 60 patients hospitalized at the Clinical Department of Neurosurgery, Clinical Center of Serbia in Belgrade between October 2011 and February 2015, harboring tumors located within and in the vicinity of the motor zone of the brain. By using Karnofsky‘s index (KI), the pre- and postoperative conditions of the patients were evaluated. Regarding electrical stimulation of the motor cortex, significantly lower values of the electrical current intensity, frequency, and pulse wave duration (p<0.01) were needed for triggering motor response in case of GBM tumor compared to a slowly growing tumor (low-grade). Patients with low-grade gliomas (LGG) had statistically significantly higher KI values pre- and postoperatively than patients with GBM (p<0.01). Using electrical stimulation of the cortex, a higher grade of resection of LGG could be achieved as compared with the group presenting with GBM (c2=5.281; df=1; p<0.05). Our findings and review of the results reported by other authors underline the necessity of routine application of electrical stimulation of the cerebral cortex in order to identify the primary motor field (M1).Jasna prezentacija tumora mozga u području motorne zone kod bolesnika koji prijeoperacijski nisu imali slabost ekstremiteta nije jamstvo da se on može radikalno odstraniti bez poslijeoperacijskog neurološkog deficita. Prikazujemo niz od 60 ispitanika sa supratentorijalnim tumorima lokaliziranim u i oko motorne zone mozga, koji su hospitalizirani na Institutu za neurokirurgiju KCS u Beogradu u razdoblju od listopada 2011. do veljače 2015. godine. Procjena prije- i poslijeoperacijskog stanja bolesnika je vrednovana ljestvicom Karnofski indeksa (KI). Iz serije su isključeni bolesnici s recidivom tumora i bolesnici čiji je KI kod prijma bio manji od 70. Tijekom procedure elektrostimulacije motornog korteksa potrebne su značajno manje vrijednosti jačine struje, frekvencije i pulsnog vala (p<0,01) za izazivanje motornog odgovora u slučaju postojanja tipa tumora multiformnog glioblastoma (glioblastoma multiforme, GBM ) u odnosu na spororastuće gliome (niskog stupnja) mozga. Nađena je statistički značajna razlika u prije- i poslijeoperacijskim vrijednostima KI (F=48,856; df=1; p<0,01; Eta2=0,457), naime, bolesnici s gliomima niskog stupnja imali su statistički značajno veću vrijednost KI prije- i poslijeoperacijski u odnosu na vrijednosti KI kod skupine bolesnika s GBM (p<0,01). Uporabom elektrostimulacije korteksa postignut je veći stupanj radikalnosti kirurške resekcije glioma niskog stupnja u odnosu na skupinu bolesnika s GBM (c2=5,281; df=1; p<0,05). Kirurgija tumora lokaliziranih u motornom korteksu predstavlja izazov zbog pratećeg rizika od de novo nastanka motornog deficita. Naši rezultati kao i rezultati drugih autora pokazuju neophodnost rutinske primjene direktne elektrostimulacije moždane kore radi identifikacije primarnog motornog polja (M1)

Correction to: Redox Status and Antioxidative Cofactor Metals Influence Clinical and Pathological Characteristics of Papillary Thyroid Carcinoma and Colloid Goiter (Biological Trace Element Research, (2020), 197, 2, (349-359), 10.1007/s12011-019-01995-x)

Papillary thyroid carcinoma (PTC) is the endocrine neoplasm that occurs the most often worldwide, and its molecular pathophysiology is still not well characterized. Redox status is recognized as an important factor of carcinogenesis, but its influence on the PTC's clinical course needs to be better elucidated. The aim of this research was to determine the tissue redox status of 65 PTC and 45 colloid goiter (CG) patients together with antioxidative cofactor metal profiling. The malondialdehyde (MDA) concentration was used to access the prooxidation level, while antioxidant mechanisms were estimated by assaying the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). The antioxidative cofactor metals included quantification of Se, Cu, Zn, and Mn concentration. PTC tissues had normal prooxidation levels and increased GPx and GR activity. The activity of SOD has been significantly reduced in multicentric PTC dissemination and increased in smokers. SOD activity was directly dependent on MDA levels in CG tissues. CG patients with retrosternal goiter had reduced MDA concentration and SOD activity. Numerous correlations between redox parameters in PTC tissues reveal good co-activation of antioxidative mechanisms and cooperative response on prooxidation. PTC tissues had decreased Se levels and increased concentration of Cu and Mn in comparison to other tissues. MDA concentration and SOD activity were significant predictors of PTC's multicentric dissemination and for the existence of lymph node metastases, respectively. Particularly, the concentration of Cu predicted the retrosternal localization in CG patients. Significant findings presented in this study provide a possibility for development of novel prognostic molecular biomarkers of PTC and CG.The contribution corrects an equation from the paper: Rovcanin, B.; Stojsavljevic, A.; Kekic, D.; Gopcevic, K.; Manojlovic, D.; Jovanovic, M.; Knezevic, S.; Zivaljevic, V.; Diklic, A.; Paunovic, I. Redox Status and Antioxidative Cofactor Metals Influence Clinical and Pathological Characteristics of Papillary Thyroid Carcinoma and Colloid Goiter. Biol Trace Elem Res 2020, 197 (2), 349–359. [https://doi.org/10.1007/s12011-019-01995-x

Supplementary data for the article: Stojsavljević, A.; Trifković, J.; Rasić-Milutinović, Z.; Jovanović, D.; Bogdanović, G.; Mutić, J.; Manojlović, D. Determination of Toxic and Essential Trace Elements in Serum of Healthy and Hypothyroid Respondents by ICP-MS: A Chemometric Approach for Discrimination of Hypothyroidism. Journal of Trace Elements in Medicine and Biology 2018, 48, 134–140. https://doi.org/10.1016/j.jtemb.2018.03.020

Supplementary material for: [https://doi.org/10.1016/j.jtemb.2018.03.020]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2181]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3074

Association between oxidative stress biomarkers and concentrations of some metal ions in the blood of patients with brain tumors and hydrocephalus

Introduction Any substance that induces production of free radicals can be a potential cause of brain damage. The aim of our study was to investigate the relationship between some metal ions and oxidative stress biomarkers in the blood of patients with brain tumor and hydrocephalus. Material and methods Our study included 27 control subjects, 24 patients with brain tumor and 21 patients with hydrocephalus. The activities of superoxide dismutase (CuZn SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR), glutathione S-transferase (GST) and acetyl cholinesterase (AChE), as well as concentrations of reduced glutathione (GSH), lipid peroxides (TBARS) and sulfhydryl groups (SH) were analyzed in the plasma and red blood cells (RBCs) of patients. We also determined the concentrations of Mn, Ni, Co, Cu, Zn, As, Se, Cd, Hg and Fe. Results The higher activity of SOD and concentration of GSH in both investigated groups could indicate higher oxidative stress. We also observed decreased levels of SH groups in both groups of patients. In both groups of patients we detected decreased concentrations of Ni, Co, Zn and Fe (and Mn in brain tumor patients) and increased concentrations of As, Se and Cd in the blood. Interestingly, we observed a higher concentration of Cd in both plasma and RBCs of hydrocephalus patients compared to the patients with brain tumor. Conclusions There are strong correlations between some metal ion concentrations and certain oxidative stress biomarkers in the blood of patients, which supports our hypothesis, but the observed trend needs to be further investigated

Assessment of trace metal alterations in the blood, cerebrospinal fluid and tissue samples of patients with malignant brain tumors

The pathogenesis of malignant brain tumors (MBTs) should be better understood due to the evident association between prolonged exposure to metals and increased risk of MBTs. The present research aimed to find trace metals that could contribute to the pathogenesis of MBTs. Essential trace elements (Mn, Co, Zn, Cu, Se) and relevant toxic metals (Al, Ni, As, Sr, Cd, Ce, Pt, Pb, U) in the serum, cell fraction (CF), cerebrospinal fluid (CSF) and cancerous tissue (CT) samples of MBT patients were analyzed. The results were compared with sex- and age-matched control groups. For the first time, this research showed that elemental profiles of serum, CF, CSF and CT samples in MBT patients were significantly altered compared to the appropriate controls, as well as that higher contents of trace elements (particularly Mn, Se, and Pb) could be involved in the pathogenesis of MBTs. However, the most noticeable change found was the elevated U content, indicating its considerable role as a major cerebral discriminator of the presence/absence of MBTs. The U/Se ratio could be considered as an appropriate blood marker in diagnostic MBT evaluation. The reported results could contribute to better understanding of the poorly understood pathogenesis of MBTs. Furthermore, the reported results could highlight a molecular basis for the pathophysiological changes caused by the hazardous effects of trace metals on brain homeostasis

A first record of the antioxidant defense and selected trace elements in Salamandra salamandra larvae on Mt. Avala and Mt. Vršački Breg (Serbia)

We investigated the activities of superoxide dismutase (SOD), catalase (CAT), glutathioneperoxidase (GSH-Px), glutathione reductase (GR) and the phase II biotransformation enzyme glutathioneS-transferase (GST) in the whole body of fire salamander larvae (Salamandra salamandra) from twolocalities on Mt. Avala (AVS and ABP) and one locality on Mt. Vršački Breg (VSB), Serbia. We alsodetermined the total glutathione (GSH) and sulfhydryl group (SH) contents, as well as the concentrations ofmanganese (Mn), copper (Cu), zinc (Zn), selenium (Se), arsenic (As), cadmium (Cd), lead (Pb) and uranium(U). The obtained results show that animals from VSB had significantly lower weights and lengths thananimals from AVS and ABP. The activities of all investigated enzymes were significantly higher, while theSH content was significantly lower in animals from VSB compared to those from AVS and ABP. Nocorrelations between trace-element concentrations in water and animal tissue were observed. We concludedthat the obtained results were more likely a consequence of the combination of developmental differencesand the effects of different habitat conditions, environmental and anthropogenic influences than ofconcentrations of trace elements in the water alone

Zinc Deficiency, Plasma Fatty Acid Profile and Desaturase Activities in Hemodialysis Patients: Is Supplementation Necessary?

Background: Desaturation and elongation are critical processes in endogenous metabolic fatty acid pathways. Zinc (Zn) is a cofactor for desaturases and elongases enzymes. There is limited evidence regarding the relationships between biomarkers of Zn status, nutritional intake, plasma phospholipid fatty acid profile and clinical outcomes among patients undergoing hemodialysis (HD). Objective: To examine the relationships between dietary and serum levels of Zn and Cu/Zn ratio and to explore associations of these micronutrients with PUFA profile and estimated desaturase and elongase enzyme activities in serum phospholipids among HD patients. Methods: This study included 40 adult patients undergoing hemodialysis treatment. Repeated 24-h recalls were applied for dietary intake assessment. Serum concentration of Zn and Cu were determined using inductively coupled plasma mass spectrometry and fatty acid composition by gas-liquid chromatography. Desaturase and elongase activities were calculated from product-precursor fatty acid ratios. Results: Inadequate dietary Zn intake was found in 55% of HD patients. They all had serum Zn concentration below the reference value of 60 μg/dL (mean 38.8 ± 7.72 μg/dL). Adequate zinc intake was accompanied with significantly higher intake of energy, total fats, SFA, MUFA and proteins. There was no correlation between Zn serum status and Zn intake estimates. Serum Cu/Zn ratio was high, (2.76 ± 0.68), directly and significantly associated with HD period, CRP, BMI, VFA, and inversely with Kt/V, albumin, iron, and iPTH. The n-6/n-3 ratio in plasma phospholipids was elevated (12.25 ± 3.45) and patients with inadequate Zn intake had lower n-3 PUFA intake and status compared to those with adequate intake. Serum Zn concentrations were inversely correlated with linoleic/dihomo-γ-linolenic acid ratio (LA/DGLA) (p = 0.037), related to D6-desaturase activity (p = 0.033) and directly with DGLA relative abundances (p = 0.024). Cu status was inversely associated with EPA level (p = 0.03) and estimates of elongase activity (p = 0.001). Furthermore, positive relationship was found between the Cu/Zn ratio and determined elongase value (p = 0.01). Conclusion: Findings of this study underpin the high prevalence of Zn deficiency and inadequate n-3 PUFA intake and status among subjects undergoing HD. The results obtained indicate that the assessment of Zn status should be a standard parameter of nutritional status screening in HD patients while emphasizing the importance of Cu/Zn determination. Although further research is warranted, Zn and-n-3 PUFA supplementation in HD patients might be beneficial for the prevention and attenuation of adverse health outcomes

The Effects of BSA-Stabilized Selenium Nanoparticles and Sodium Selenite Supplementation on the Structure, Oxidative Stress Parameters and Selenium Redox Biology in Rat Placenta

The chemical element selenium (Se) is a nonmetal that is in trace amounts indispensable for normal cellular functioning. During pregnancy, a low Se status can increase the risk of oxidative stress. However, elevated concentrations of Se in the body can also cause oxidative stress. This study aimed to compare the effects of BSA-stabilized Se nanoparticles (SeNPs, Se0) (BSA-bovine serum albumin) and inorganic sodium selenite (NaSe, Se+4) supplementation on the histological structure of the placenta, oxidative stress parameters and the total placental Se concentration of Wistar rats during pregnancy. Pregnant females were randomized into four groups: (i) intact controls; (ii) controls that were dosed by daily oral gavage with 8.6% bovine serum albumin (BSA) and 0.125 M vit C; (iii) the SeNP group that was administered 0.5 mg of SeNPs stabilized with 8.6% BSA and 0.125 M vit C/kg bw/day by oral gavage dosing; (iv) the NaSe group, gavage dosed with 0.5 mg Na2SeO3/kg bw/day. The treatment of pregnant females started on gestational day one, lasted until day 20, and on day 21 of gestation, the fetuses with the placenta were removed from the uterus. Our findings show that the mode of action of equivalent concentrations of Se in SeNPs and NaSe depended on its redox state and chemical structure. Administration of SeNPs (Se0) increased fetal lethality and induced changes in the antioxidative defense parameters in the placenta. The accumulation of Se in the placenta was highest in SeNP-treated animals. All obtained data indicate an increased bioavailability of Se in its organic nano form and Se0 redox state in comparison to its inorganic sodium selenite form and Se+4 redox state