Heteropolytungstates as potential antidiabetic agents: effect on hyperglycemia, and hepato- and nephrotoxicity evaluation in streptozotocin- induced diabetic rats

Полиоксометалати (ПОМ), поред антимикробног и антитуморског дејства, могу бити делотворни у снижавању хипергликемије код дијабетичких животиња...Polyoxometalates (POMs) have been found to exibit antimicrobial, anticancer, and antidiabetic activities..

Efekat deprivacije REM faze spavanja na aktivnost acetilholinesteraze i NA+/K+-ATPaze sinaptozoma mozga pacova u hipotiroidizmu

Hipotireoidizam i deprivacija REM spavanja prepoznati su kao mogući faktori rizika za nastanak neurodegenerativnih oboljenja, pre svega Alchajmerove bolesti (AB). Enzimi acetilholinesteraza (AchE) i Na+ /K+ -ATPaza imaju ulogu u taloženju amiloidnih plakova, tako da je njihova ukupna aktivnost u mozgu obolelog od AB snižena. Cilj istraživanja bio je utvrđivanje mogućeg efekta hipotireoidizma i deprivacije REM faze spavanja na aktivnost AchE i Na+ /K+ -ATPaze. Koristili smo eksperimentalni model hipotireoidizma izazvan propiltiouracilom. Nakon uvođenja u hipotiroidizam, eksperimentalna grupa životinja (n = 12) podeljena je u dve podrupe. Životinje iz prve podgrupe (n = 6) boravile su 72 h na maloj platformi, koja ne dozvoljava REM spavanje, jer usled atonije životinja upada u vodu i budi se. Drugoj podgrupi životinja (n = 6) omogućeno je spavanje. Nakon 72 h, životinje su žrtvovane, i u sinaptozomalnoj frakciji mozga pacova određivana je aktivnost AchE i Na+ /K+ -ATPaze spektrofotometrijski. Rezultati pokazuju da hipotireoidizam dovodi do snižene aktivnosti AchE i Na+ /K+ -ATPaze u odnosu na kontrolu (p ≤ 0,01), dok zajednički efekat hipotireoidizma i deprivacije REM spavanja dovodi do snižene aktivnosti AchE i Na+ /K+ -ATPaze u odnosu na kontrolu (n = 6, p ≤ 0,01), ali ne u odnosu na hipotiroidizam (p > 0,05). Na osnovu dobijenih rezultata možemo zaključiti da hipotireoidizam smanjuje aktivnost enzima AchE i Na+ /K+ -ATPaze, a da deprivacija REM faze spavanja dodatno ne smanjuje aktivnost ovih enzima u hipotireoidizmu, tako je mogući način delovanja hipotireoidizma kao faktora rizika za nastanak AB upravo sniženje aktivnosti ovih enzima.Četvrti srpski kongres o štitastoj žlezdi : Zbornik sažetaka : Septembar, 2017, Zlatibor

Razvoj novih antidijabetičkih lekova na bazi polioksometalatnih nanoklastera

Zahvaljujući brojnim istraživanjima koja su ispitivala biološka svojstva strukturno različitih polioksometalata, došlo se do zapažanja da ova kompleksna neorganska jedinjenja, pored antimikrobnog i antitumorskog delovanja, mogu biti delotvorna u snižavanju hiperglikemije kod pacova sa eksperimentalno izazvanim dijabetesom. Stoga, cilj ove studije je bio da se ispitaju antidijabetički potencijal i mogući toksični efekti dva polioksovolframata:(NH4 )14[NaP5 W30O110]·31H2 O, {NaP5 W30} i K14[AgP5 W30O110]·22H2 O·6KCl, {AgP5 W30}. U cilju realizacije postavljenog cilja, korišćena su tri eksperimentalna modela: (1) antihiperglikemijska screening studija u kojoj je ispitivan uticaj jednokratne intraperitonealne primene {NaP5 W30} i {AgP5 W30} (5, 10 i 20 mg/kg) na snižavanje hiperglikemije kod dijabetičkih pacova, (2) akutna peroralna toksikološka studija koja je istraživala hepato- i nefrotoksične efekte odabranih heteropolivolframata kod zdravih pacova i (3) studija posvećena rasvetljavanju mogućih mehanizama antidijabetičkog delovanja heteropolivolframata. Rezultati screening studije su pokazali da su oba ispitivana heteropolivolframata efikasna u snižavanju hiperglikemije, s tim što se {NaP5 W30}, u odnosu na {AgP5 W30}, pokazao kao moćniji antihiperglikemijski agens. Rezultati biohemijskih parametara funkcije i patohistološka analiza jetre i bubrege korišćenjem konvencionalne svetlosne i transmisione elektronske mikroskopije pokazuju da dvonedeljna primena {NaP5 W30} i {AgP5 W30} (20 mg/kg) izaziva blagi do umereni stepen hepato- i nefrotoksičnosti kod zdravih životinja. U poslednjem eksperimentalnom protokolu, pokazano je da tronedeljna peroralna primena {NaP5 W30} (20 mg/kg) povećava koncentraciju insulina u serumu dijabetičkih pacova, što može biti jedan od mehanizama njegovog antidijabetičkog delovanja. Takođe, pokazano je da {NaP5 W30} ispoljava hepato-, nefro-, kardio- i neuroprotektivno dejstvo kod dijabetičkih pacova, što je procenjeno na osnovu analize: (1) relativne mase organa, (2) biohemijskih parametara funkcije, (3) parametara oksidativnog stresa u homogenatu tkiva, (4) aktivnosti acetilholinesteraze, Na+ /K+-ATPaze i ecto-ATPaza u sinaptozomima i (5) patohistoloških promena u tkivima korišćenjem konvencionalne svetlosne i transmisione elektronske mikroskopije. Stoga, {NaP5 W30} i {AgP5 W30} mogu se smatrati mogućim neinsulinskim lekovima-kandidatima u terapiji dijabetesa tipa 2, koji bi se podvrgli daljim pretkliničkim istraživanjima.Simpozijum „Stremljenja i novine u medicini“ Medicinskog fakulteta u Beogradu, Beograd, 04-08. decembra, 2023

Heteropolytungstates as potential antidiabetic agents: effect on hyperglycemia, and hepato- and nephrotoxicity evaluation in streptozotocin- induced diabetic rats

Полиоксометалати (ПОМ), поред антимикробног и антитуморског дејства, могу бити делотворни у снижавању хипергликемије код дијабетичких животиња...Polyoxometalates (POMs) have been found to exibit antimicrobial, anticancer, and antidiabetic activities..

Vanadium compounds: New potential antidiabetic drugs

Glavni ciljevi u lečenju osoba sa dijabetesom su ostvarenje individualnih glikemijskih ciljeva i prevencija komplikacija. Današnja savremena terapija dijabetesa, uz izuzetne uspehe, ima i određena ograničenja kao što su: paranteralni put primene leka, smanjenje efikasnosti leka nakon početnog poboljšanja glikemije, nedostupnost novijih lekova u nerazvijenim zemljama ili nepristupačnost leka zbog visoke cene. Zbog toga postoji stalna potreba za razvojem antihipeglikemijskih lekova jeftinijih i lakših za primenu, sa većom efikasnošću i manje toksičnim. U tom cilju, znatan broj studija ispitivao je uticaj neorganskih i organskih jedinjenja vanadijuma u snižavanju vrednosti hiperglikemije. Pokazano je da neorganska jedinjenja vanadijuma nakon peroralne primene imaju jako nizak stepen apsorpcije, tako da su visoke doze u snižavanju hiperglikemije izazivale ozbiljne neželjene efekte kod ispitanika. S druge strane, organsko jedinjenje vanadijuma bis(etilmaltolat)oksovanadijum(IV) došlo je do faze 2 kliničke studije ispitivanja antidijabetičke efikasnosti i bezbednosti, ali je studija prekinuta zbog nefrotoksičnog neželjenog efekta. Poslednjih nekoliko godina velika pažnja je posvećena istraživanju antidijabetičke aktivnosti polioksovanadata, ali su podaci o toksičnom potencijalu ovih jedinjenja još uvek nedovoljni. Iako je antidijabetička aktivnost odavno dokazana, tačni mehanizmi dejstva jedinjenja vanadijuma još uvek nisu u potpunosti razjašnjeni. U literaturi se navodi da jedinjenja vanadijuma mogu delovati na: sekreciju insulina, osetljivost ciljnih tkiva na insulin, stvaranje glukoze u jetri ili obim apsorpcije glukoze u digestivnom traktu. U zaključku, uprkos obećavajućim rezultatima dobijenim u istraživanjima na životinjama i ljudima, za sada još uvek nije otkriveno jedinjenje vanadijuma delotvorno u snižavanju hiperglikemije, uz istovremeno prihvatljivu bezbednost i sigurnost. Zbog toga je u budućnosti potrebno ulagati u pronalaženje novih jedinjenja vanadijuma, čije koristi će biti veće u odnosu na rizike.The general goals of diabetes treatment are to maintain optimal individualized glycemic targets and to prevent complications. Today, there are significant barriers to successful diabetes therapy, such as parenteral drug administration, decreased therapeutic efficacy after an initial improvement in glycemia, inaccessibility of new medicines in lower-income countries, and high drug prices. Accordingly, significant research attention has been devoted to the development of a cheap and comfortable antidiabetic agent, which demonstrates success in lowering blood glucose levels as well as fewer toxicity properties. In recent years, the effects of inorganic and organic vanadium compounds have been investigated in diabetes treatment. These studies have found the low bioavailability of orally administered inorganic vanadium salts; thus, effective doses to reduce blood glucose levels to normal may cause serious adverse events. In addition, the only study with an organo-vanadium compound (bis(maltolato)oxovanadium(IV)), which has reached Phase IIa clinical trial, was terminated after three months due to renal complications. Moreover, despite a growing interest in polyoxovanadates for treating diabetes in the last few years, the toxic potentials of these compounds are still unknown. However, the precise mechanism of their antidiabetic actions remains unclear. A broad spectrum of possible mechanisms and hypotheses, such as enhancement of insulin secretion and enhanced sensitivity to insulin, as well as suppression of hepatic glucose production and decrease of intestinal glucose absorption, have been presented. In conclusion, besides the promising results obtained in animal and human studies, no vanadium compound has successfully reduced blood glucose with acceptable safety and tolerability. More studies of vanadium benefit-risk could lead to a new era in vanadium biomedicine

Morphological, fractal, and textural features for the blood cell classification: the case of acute myeloid leukemia

Microscopic examination of stained peripheral blood smears is, nowadays, an indispensable tool in the evaluation of patients with hematological and non-hematological diseases. While a rapid automated quantification of the regular blood cells is available, recognition and counting of immature white blood cells (WBC) still relies mostly on the microscopic examination of blood smears by an experienced observer. Recently, there are efforts to improve the prediction by various machine learning approaches. An open dataset collection including the recently digitalized single-cell images for 200 patients, from peripheral blood smears at 100 × magnification, was used. We studied different morphological, fractal, and textural descriptors for WBC classification, with an aim to indicate the most reliable parameters for the recognition of certain cell types. Structural properties of both the mature and non-mature leukocytes obtained from (i) acute myeloid leukemia patients, or (ii) non-malignant controls, were studied in depth, with a sample size of about 25 WBC per group. We quantified structural and textural differences and, based on the statistical ranges of parameters for different WBC types, selected eight features for classification: Cell area, Nucleus-to-cell ratio, Nucleus solidity, Fractal dimension, Correlation, Contrast, Homogeneity, and Energy. Classification Precision of up to 100% (80% on average) was achieved

Toxicity evaluation of two biologically active polyoxotungstates

Introduction. Polyoxometalates (POMs) are negatively charged inorganic aggregates that possess potential antibacterial, anticancer, antidiabetic and antiviral effects. Although toxicity evaluation of drug candidates is necessary, reports of relevant toxicological studies of these compounds are relatively rare. Aims. Since our preliminary results demonstrated biological activities of the donut-shaped POM {NaP5W30} (POM1) and the Ag + -containing derivative POM {AgP5W30} (POM2), the aim of present study was to evaluate their toxicological effects in vivo, using Wistar albino rats as an experimental model. Methods. Animals (n = 6 per group) were orally treated with investigated POMs in daily doses of 20 mg/kg body weight for 14 days when the rats were sacrificed and blood samples were collected. The biochemical markers of renal (serum concentrations of urea - SUr and creatinine - SCr) and liver function (serum concentrations of total protein–TP and albumin - Alb, serum activities of aspartate aminotransferase - AST and alanine transaminase - ALT) were determined spectrophotometrically. Results. The POM1 and POM2 were induced statistically significant increasing of SUr (in: mmol/L) (7.95 ± 0.35 and 6.83 ± 0.26 vs. 4.97 ± 0.47; p 0.05). Conclusion. Obtained results suggested that both investigated POMs induce kidney injury as well as synthetic dysfunction of liver. Thus, their potential clinical application would require a more complex toxicological study.Abstracts of the 8th International Congress of Pathophysiolog

Combined effects of hypothyroidism and REM sleep deprivation on Na+/K+-ATPase activity in rat brain

Seventh Congress of Serbian Neuroscience Society : October 25-27, 2017, Belgrade

The simultaneous action of acute paradoxical sleep deprivation and hypothyroidism modulates synaptosomal ATPases and acetylcholinesterase activities in rat brain

Background: Thyroid dysfunctions as well as sleep abnormalities are usually followed by neurological, psychiatric and/or behavioral disorders. On the other hand, changes in the brain adenosine triphosphatases (ATPases) and acetylcholinesterase (AChE) activities show significant importance in pathogenetic pathways in the evolution of numerous neuropsychiatric diseases. Methods: This study aimed to evaluate the in vivo simultaneous effects of hypothyroidism and paradoxical sleep deprivation for 72 h on synaptosomalATPases and AChE activities of whole rat brains. In order to induce hypothyroidism, 6-n-propyl-2-thiouracil was administrated in drinking water during 21 days. The modified multiple platform method was used to induce paradoxical sleep deprivation. The AChE and ATPases activities were measured using spectrophotometric methods. Results: Hypothyroidism significantly increased the activity of Na+/K+-ATPase compared to other groups, while at the same time significantly decreased AChE activity compared to the CT and SD groups. Paradoxical sleep deprivation significantly increased AChE activity compared to other groups. The simultaneous effect of hypothyroidism and sleep deprivation reduced the activity of all three enzymes (for Na+/K+-ATPase between HT/SD and HT group p < 0.0001, SD group p < 0.001,CT group p = 0.013; for ecto-ATPases between HT/SD and HT group p = 0.0034, SD group p = 0.0001, CT group p = 0.0007; for AChE between HT/SD and HT group p < 0.05, SD group p < 0.0001, CT group p < 0.0001). Conclusions: The effect of simultaneous existence of hypothyroidism and paradoxical sleep deprivation reduces the activity of the Na+/K+-ATPase, ecto-ATPases, and AChE, what is different from individual effect of hypothyroidism and paradoxical sleep deprivation itself. This knowledge could help in the choice of appropriate therapy in such condition. © 2023 Elsevier B.V

Modulation of rat synaptosomal ATPases and acetylcholinesterase activities induced by chronic exposure to the static magnetic field

Purpose: It is considered that exposure to static magnetic fields (SMF) may have both detrimental and therapeutic effect, but the mechanism of SMF influence on the living organisms is not well understood. Since the adenosine triphosphatases (ATPases) and acetylcholinesterase (AChE) are involved in both physiological and pathological processes, the modulation of Na+/K+-ATPase, ecto-ATPases and AChE activities, as well as oxidative stress responses were followed in synaptosomes isolated from rats after chronic exposure toward differently oriented SMF. Material and methods: Wistar albino rats were randomly divided into three experimental groups (six animals per group): Up and Down group - exposed to upward and downward oriented SMF, respectively, and Control group. After 50 days, the rats were sacrificed, and synaptosomes were isolated from the whole rat brain and used for testing the enzyme activities and oxidative stress parameters. Results: Chronic exposure to 1 mT SMF significantly increased ATPases, AChE activities, and malondialdehyde (MDA) level in both exposed groups, compared to control values. The significant decrease in synaptosomal catalase activity (1.48 ± 0.17 U/mg protein) induced by exposure to the downward oriented field, compared to those obtained for Control group (2.60 ± 0.29 U/mg protein), and Up group (2.72 ± 0.21 U/mg protein). Conclusions: It could be concluded that chronic exposure to differently oriented SMF increases ATPases and AChE activities in rat synaptosomes. Since brain ATPases and AChE have important roles in the pathogenesis of several neurological diseases, SMF influence on the activity of these enzymes may have potential therapeutic importance. © 2018, Copyright © 2018 Taylor & Francis Group, LLC