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The NOAEL equivalent for the cumulative body burden of cadmium: focus on proteinuria as an endpoint
No full textThe risk of developing chronic kidney disease (CKD), signified by a decrease in the estimated glomerular filtration rate (eGFR), has been linked to long-term exposure to low levels of the metal pollutant cadmium (Cd). Proteinuria is a hallmark of CKD and predicts continued progressive functional decline of the kidney. The aim of this study was to use the extent of proteinuria for Cd health risk assessment. Data were from 405 apparently healthy Thai nationals, of whom 12.6% had an eGFR below 60 mL/min/1.73 m2 (low eGFR), and 16.3% and 13.5% had moderate and severe proteinuria. Urinary excretion of Cd (ECd) and urinary total protein (Epro) were measured and normalized to both creatinine clearance (Ccr) and creatinine excretion (Ecr). We found that the risk of having a low eGFR [prevalence odds ratio (POR) = 12.2, P < 0.001] and severe proteinuria [POR = 10.4, P = 0.001) were increased markedly for every ten-fold increase in ECd/Ccr. However, when ECd was normalized to Ecr, the association between eGFR and ECd was found to be insignificant due to non-differential errors introduced by the Ecr-normalization. Respective benchmark dose limit (BMDL) values of ECd/Ecr that increased protein excretion by 5% and 10% were 0.0536 and 0.1140 µg/g creatinine. The ECd/Ecr at which 5% of the population had Cd-related proteinuria was 1.86 µg/g creatinine, respectively. For the first time, a urinary Cd excretion rate of 0.0536 µg/g creatinine has been derived as a Cd exposure level that produces negligible kidney damage
Acid base equilibria of olopatadine in aqueous media
No full textThe protolytic equilibria of raloxifene were investigated in the presence of differently charged
and/or polar micelles (CTAB, TX-100, Brij 35). The ionization constants were determined
potentiometrically at a constant ionic strength (0.1 M NaCl) and temperature 25°C. In a relation to
the pKa values previously determined in surfactant-free media, the presence of micelles caused a
shift from -3.03 pKa to +3.12 pKa units. Significant changes in distribution of equilibrium forms at
biopharmaceutically important pH values suggest on potential consideration of interactions between
raloxifene and molecules present under the physiological conditions.17th International Conference on Fundamental and Applied Aspects of Physical Chemistry, September 23-27, 2024 Belgrade, Serbi
Comparison of the advia 2120 and mek-1305 analyzers based on the results of haematology parameters
No full textSvako uvođenje nove metode ili novog analizatora u
rutinski rad laboratorije zahteva prethodnu verifikaciju koja se često sprovodi poređenjem njihovih rezultata sa rezultatima dobijenim prethodno korišćenom
metodom ili analizatorom. U ovu svrhu koristi se
provera odstupanja od ukupne dozvoljene greške
(TEa) ili različiti statistički testovi poput t-testa parova,
linearne regresione analize, Passing and Bablok
regresije ili Blad-Altman grafika. Svaki od ovih testova
ima prednosti i nedostatke, a ispravan izbor testa u
velikoj meri presu|uje rezultate verifikacije. TEa je
procenat dozvoljenog odstupanja koji se izvodi iz
biološke varijacije i za određeni parametar i koji
uzima u obzir bias i nepreciznost i osetljiv je na sistematsku i slučajnu grešku. Passing and Bablok
regresija omogućava proveru slaganja između dve
grupe podataka koji nisu normalno distribuirani i
njeni rezultati ukazuju na prisustvo sistematske
greške dajući uvid u to da li je ona konstantna ili procentualna. U ovom radu smo ispitivali slaganje rezultata dobijenih na dva hematološka analizatora
računajući odstupanje od TEa i koristeći Passing-Bablok analizu. Hematološki parametri, broj leukocita (WBC), broj eritrocita (RBC), koncentracija
hemoglobina (HGB), vrednost hematokrita (HCT) i
broj trombocita (PLT) određivani su upotrebom dva
hematološka analizatora, Advia 2120 (Siemens,
Minhen, Nemačka) i MEK-1305 (Nihon Kohden,
Tokio, Japan). Za svaki parametar je računato odstupanje od TEa vrednosti koje su preuzete iz Westgardove baze Desirable Biological Variation Database i primenjena je Passing and Bablok regresiona analiza
upotrebom softvera MedCalc (Medcalc Software Ltd,
Osten, Belgija). Passing-Bablok analiza je pokazala
zadovoljavajuću linearnost definisanu kao p>0,05 za
CUSUM test, i odsustvo konstantne greške za sve
parametre. Proporcionalna greška je bila prisutna za
WBC i HCT pri čemu rezultati WBC između dve
metode nisu pokazali značajno odstupanje od TEa
(TEa4,1%).
Sa druge strane, velika odstupanja od TEa su bila
prisutna i za RBC (TEa>4,4%) i PLT (TEa>13,4%),
dok Passing and Bablok analiza nije pokazala da postoji značajna razlika u rezultatima ovih parametara
između dve metode. Primenom Passing-Bablok ana lize pokazano je dobro slaganje u vrednostima parametara određivanih na dva različita hematološka
analizatora. Uzimajući u obzir da su za neke od parametara uočena veća odstupanja od TEa, preporučuje
se korišćenje oba načina provere prilikom verifikacije
novog analizatora.Every introduction of a new method or a new analyzer
to the routine work of a laboratory requires a previous
verification that is often carried out by comparing their
results with the results obtained by the previously used
method or analyzer. For this purpose, examining the
deviation of the allowable total error (TEa), or the dif-
ferent statistic tests such as paired t-test, linear regres-
sion analysis, Passing and Bablok regression or Blad-
Altman chart can be used. Each of these tests has its
advantages and setbacks, and the right choice of a
test decides the results of the verification to a signifi-
cant degree. TEa is the percent of allowed deviation
derived from the biological variance for a specific
parameter and it takes into account both bias and
unprecision, while it is sensitive to both systematic and
random error. Passing and Bablok regression allows
testing the agreement between the two groups of
data with non-normal distribution and its results point
to the presence of a systematic error, giving insight to
wheter it is constatnt or proportional. In this study we
examined the agreement between the results
obtained by two different haematology analyzers cal-
culating the deviation from TEa and using the Passing
and Bablok analysis. Haematology parameters, white
blood cell count (WBC), red blood cell count (RBC),
haemoglobin concentration (HGB), haematocrit value
(HCT), and platelet count (PLT) were assessed using
two haematology analyzers, Advia 2120 (Siemens,
Munich, Germany) i MEK-1305 (Nihon Kohden,
Tokyo, Japan). The calculation of the deviation from
TEa value taken from the Westgard Desirable Biological Variation Database and Passing and Bablok
regression analysis using MedCalc (Medcalc Software
Ltd, Osten, Belgium) were performed for each param-
eter. Passing and Bablok analysis showed satisfying
linearity defined as p>0.05 for CUSUM test, and the
absence of the constant error for all parameters. The
proportional error was present for WBC and HCT,
whereas the WBC results didn’t show significant devi-
ation from TEa (TEa<14.6%), while the HCT results
did (TEa>4.1%). On the other hand, great deviations
from TEa were present for both RBC (TEa>4.4%) and
PLT (TEa>13.4%), while Passing and Bablok analysis
showed no significant difference in the results
between the methods for these parameters. Using the
Passing and Bablok analysis showed a good agree-
ment in the values of the parameters measured on the
two different haematology analysers. Considering the
fact that the greater deviations from TEa were noticed
for a few parameters, the use of both these methods
for the verification of a new analyser is recommended.Međunarodni XXIII srpski kongres medicinske biohemije i laboratorijske medicine,16–18. septembar, 2024, Posterske sekcij
Integrative Framework for Developing Innovative SIRT2 Inhibitors
No full textSirtuin 2 inhibitors (SIRT2i) represent a promising class of potential drugs in the therapy of
age-related disorders, including malignant diseases. Recent studies demonstrated potential of
SIRT2i in advancing tumour immunotherapy by activating tumour-infiltrating lymphocytes. [1,2]
Some of the key obstacles in the development of new SIRT2 inhibitors include the complex
conformational dynamics of the sirtuin 2 (SIRT2) binding site, a lack of a clear correlation between
structure and activity, and insufficient exploration of the pharmacological context of SIRT2 inhibition.
[1,2] The main goal of this work was to establish a framework to support future rational design of
new SIRT2 inhibitors through the integration of molecular modelling, cheminformatics, and
bioinformatics approaches.
In the first phase of the framework development, a protocol for structure-based virtual
screening (SBVS) was established, relying on enhanced sampling of the conformational dynamics
of the SIRT2 binding site. Improved sampling was achieved through metadynamics simulations using
a set of collective variables derived from the time-independent component analysis. The application
of enhanced sampling identified, for the first time, the existence of the cryptic pocket within the SIRT2
binding site and demonstrated significant expansion of known chemical space of SIRT2i through
prospective screening study. [1] In the second phase of the framework development, a set of four
highly validated quantitative structure-activity relationship (QSAR) models were developed by
incorporating all SIRT2i data available to date. The models were trained on a large dataset
comprising a total of 1797 compounds, utilizing five leading machine learning algorithms. The models
were employed to create a tool for rational design of SIRT2 inhibitors, named SIRT2i_Predictor. [2]
In the third phase of framework development, leveraging the data on chemical sensitivity of
pancreatic adenocarcinoma cell lines, a bioinformatics protocol was developed to predict a
synergistic combinations of histone deacetylase inhibitors (including sirtuins) and other bioactive
molecules in order to prioritize targets for development of novel dual acting SIRT2i. [3]
The framework discovered novel SIRT2i from unexplored portions of chemical space, guided
the design and synthesis of novel SIRT2i, and identified potential targets for development of dualacting SIRT2i. Additionally, it demonstrated utility in repurposing studies by designing dual
SIRT2/AURKA and SIRT2/PD-L1 inhibitors as novel antineoplastic for advancing cancer
immunotherapeutic approaches
Environmental Cadmium Exposure Induces an Increase in Systolic Blood Pressure by Its Effect on GFR
No full textChronic exposure to the nephrotoxic metal pollutant, cadmium (Cd), has been associated with hypertension, but the mechanism by which it raises blood pressure is not understood. We hypothesize that exposure to Cd reduces the glomerular filtration rate (GFR), which in turn causes a rise in blood pressure. Data were collected from 447 Thai subjects with a mean age of 51.1 years, of which 48.8% had hypertension, 15.4% had diabetes, and 6.9% had an estimated GFR (eGFR) below 60 mL/min/1.73 m2 (low eGFR). More than half (58.8%) and 23.9% had moderate and severe tubular proteinuria, respectively. The mean blood and urinary Cd concentrations were 2.75 and 4.23 µg/L, respectively. Doubling of body burden of Cd increased the prevalence odds ratios (POR) for low eGFR and severe tubular proteinuria 41% and 48%, respectively. The POR for hypertension rose twofold in those with blood Cd levels of 0.61–1.69 µg/L or urinary Cd excretion levels ≥ 0.98 µg/g creatinine. In the hypertensive group, the eGFR was inversely associated with age (β = −0.517), the Cd excretion rate (β = −0.177), and diabetes (β = −0.175). By mediation analysis, an increase in SBP was attributable totally to the effect of Cd on GFR. Thus, blood pressure appeared to rise as GFR fell. This finding is consistent with the well-known role of the kidney in long-term blood pressure regulation, and explains a universally high prevalence of hypertension among patients with low eGFR
Antioxidants in the prevention and treatment of metabolic syndrome
No full textMetabolički sindrom predstavlja skup metaboličkih poremećaja, kao što su abdominalna gojaznost,
insulinska rezistencija, dislipidemija, steatoza i hipertenzija, koji povećavaju rizik od dijabetesa tipa 2 i
kardiovaskularnih bolesti. Etiologija metaboličkog sindroma je rezultat interakcija između genetskih,
bihejvioralnih, ekoloških i nutritivnih faktora rizika. Iako su mehanizmi kompleksni i nedovoljno
razjašnjeni, pretpostavlja se da oksidativni stres ima integrativnu ulogu u razvoju metaboličkog
sindroma, kao i njegovih komplikacija.
Brojne studije su pokazale narušen oksidativno-stresni status kod osoba sa metaboličkim sindromom,
kao i inverznu povezanost dijetarnog unosa i/ili serumskih koncentracija dijetarnih antioksidanasa
sa rizikom od metaboličkog sindroma, ukazujući na značaj njihovog optimalnog unosa. Hrana
predstavlja izvor brojnih antioksidanasa, kao što su vitamini, minerali, provitamini (beta-karoten),
koenzimi (koenzim Q10, alfa-lipoinska kiselina), ali i fitohemikalija (karotenoida, polifenola i dr.),
čije se uloge u antioksidativnoj zaštiti organizma posljednjih godina intenzivno istražuju. Osim
direktnih antioksidativnih efekata, sastojci hrane i na indirektan način pružaju podršku endogenom
antioksidativnom zaštitnom sistemu, kao prekursori sinteze endogenih antioksidanasa, kofaktori
antioksidativnih enzima ili kao modulatori redoks-senzitivnih signalnih puteva. Posljednjih godina,
sve je veće interesovanje za efikasnost suplementacije izolovanim nutrijentima i biološki aktivnim
sastojcima sa antioksidativnim svojstvima u cilju prevencije ili u okviru terapije metaboličkog
sindroma. Međutim, samoinicijativna i nekontrolisana upotreba ovih proizvoda povezana je s rizicima
od neželjenih efektata, usljed prekomjernog i dugotrajnog unosa antioksidanasa, kao i potencijalnim
interakcijama sa farmakološkom terapijom.
Za uspješnu prevenciju i terapiju metaboličkog sindroma neophodan je multidisciplinarni pristup.
Uloga farmaceuta u ovim aktivnostima je višestruka i između ostalog uključuje i savjetovanje o
pravilnoj ishrani, kao i na dokazima zasnovane preporuke o racionalnoj i bezbjednoj upotrebi dodataka
ishrani sa antioksidativnim sastojcima.Metabolic syndrome is a constellation of metabolic disorders, such as abdominal obesity, insulin resi- stance, dyslipidemia, hepatic steatosis, and hypertension that increase the risk of type 2 diabetes and cardiovascular disease. Metabolic syndrome results from interactions between genetic, behavioral, environmental, and nutritional risk factors. Although the mechanisms are complex and insufficiently elucidated, it is assumed that oxidative stress plays an integrative role in the development of metabo- lic syndrome and its complications. Numerous studies have indicated an impaired oxidative stress status in patients with metabolic syn- drome, as well as an inversed association of dietary intake and serum concentrations of antioxidants with the risk of metabolic syndrome, indicating the importance of their optimal intake. Food is a so- urce of numerous antioxidants, such as vitamins, minerals, provitamins (beta-carotene), coenzymes (coenzyme Q10, alpha-lipoic acid), but also phytochemicals (carotenoids, polyphenols, etc.), whose roles in the antioxidant defense are intensively researched. In addition to direct antioxidant effects, foods’ bioactive compounds indirectly support the endogenous antioxidant defense system as pre- cursors of synthesizing endogenous antioxidants, cofactors of antioxidant enzymes, or modulators of redox-sensitive signaling pathways. In recent years, there has been increasing interest in the effects of antioxidant supplementation in the prevention or within the treatment of metabolic syndrome. Howe- ver, self-initiated and uncontrolled use of these products is associated with risk of unwanted effects due to excessive and long-term intake of antioxidants and potential interactions with pharmacological therapy. A multidisciplinary approach is necessary to prevent and treat metabolic syndrome successfully. The pharmacist’s role in these activities is multiple and, among others, includes counseling on healthy diet and evidence-based recommendations on the rational and safe use of antioxidant supplements
Assessment of the gluten content in fruit and vegetable foods for children
No full textRecent studies have shown that exposure to gluten during childhood, especially in infants with a
genetic predisposition, may increase the risk of developing gluten-related disorders such as celiac
disease. As the introduction of baby food is permitted for infants and young children from 4 months
of age, it is extremely important to monitor the safety and quality of this product group, including
testing for gluten content in order to provide appropriate nutritional recommendations and reduce
the risk of adverse health effects. Also, the possibility of cross-contamination during production
highlights the importance of testing the gluten content of baby foods, especially those labeled
“gluten-free”. The aim of this work was to investigate the gluten content in fruit and vegetable baby
food for infants and young children labeled "gluten-free". The ELISA method was used to
determine the gluten content. 19 samples of baby food for infants on the market of the Republic of
Srpska were analyzed, of which 12 samples were fruit porridges, 3 porridges from a combination of
fruit and vegetables and 4 fruit porridges with the addition of rice. All samples were labeled as
"gluten-free", which implies that the gluten content in the product must be less than 20 mg/kg,
which was verified. Considering that the presence of gluten can have potentially negative effects on
the health of infants and young children, especially if there is a hypersensitivity to gluten or a
predisposition to develop one, it is very important to regularly check the safety of food for
children. The tests carried out have shown that the products intended for infants and young children
on the Republic of Srpska market are safe to consume
Translational research on cognitive impairment in chronic kidney disease
No full textCognitive decline is common in patients with acute or chronic kidney disease. Several areas of brain function can be affected, includ-
ing short- and long-term memory, attention and inhibitory control, sleep, mood, eating control and motor function. Cognitive decline
in kidney disease shares risk factors with cognitive dysfunction in people without kidney disease, such as diabetes, high blood pres-
sure, sedentary lifestyle and unhealthy diet. However, additional kidney-specific risk factors may contribute, such as uremic toxins,
electrolyte imbalances, chronic inflammation, acid–base disorders or endocrine dysregulation. Traditional and kidney-specific risk
factors may interact to cause damage to the blood–brain barrier, induce vascular damage in the brain and cause neurotoxicity or
neuroinflammation. Here, we discuss recent insights into the pathomechanisms of cognitive decline from animal models and novel
avenues for prevention and therapy. We focus on a several areas that influence cognition: blood–brain barrier disruption, the role of
skeletal muscle, physical activity and the endocrine factor irisin, and the emerging therapeutic role of sodium-glucose cotransporter
2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists. Taken together, these studies demonstrate the importance
of animal models in providing a mechanistic understanding of this complex condition and their potential to explain the mechanisms
of novel therapies
Pedijatrijski nefrotski sindrom: međusobna interakcija oksidativnog stresa i inflamacije
Get PDFBackground: The pathophysiological mechanisms crucial in
the development of nephrotic syndrome (NS) in the pediatric population are still not fully understood. This study
aimed to investigate the relationship between hypertension, oxidative stress, and inflammation in pediatric
patients during the acute phase of the disease.
Methods: The study included 33 children, aged 2 to 9
years, with nephrotic syndrome. Blood samples were collected during the acute phase and remission. Parameters of
oxidative status were determined, including total oxidative
status (TOS), advanced oxidation protein products (AOPP),
prooxidant-antioxidant balance (PAB), sulfhydryl groups (-
SH), paraoxonase 1 (PON1), and total antioxidant status
(TAS) in serum, measured spectrophotometrically. Inflam-
matory parameters such as pentraxin 3 (PTX3), leptin,
programmed cell death ligand 1 (PD-L1), and E-cadherin
were determined using enzyme-linked immunosorbent
assay (ELISA).
Results: Patients with nephrotic syndrome and hypertension had significantly higher levels of advanced oxidation
protein products and total antioxidant status (p=0.029 and
p=0.003, respectively). During the acute phase of the dis-
ease, lower activity of sulfhydryl groups and paraoxonase 1
was observed compared to remission (p<0.001, for both). Pentraxin 3 levels were higher, while leptin levels were
lower during the acute phase (p<0.001, for both).
Pentraxin 3 correlated with advanced oxidation protein
products and total antioxidant status during the acute
phase but not in remission (r s =0.42, p=0.027 and
r s =0.43, p=0.025, respectively). A negative correlation
between Advanced oxidation protein products and leptin
was observed during the acute phase, which disappeared
in remission (rs=-0.42, p=0.028).
Conclusions: Results of this study show that hypertension
influences oxidative stress markers, and decreased antioxi-
dant capacity may contribute to nephrotic syndrome devel-
opment. Pentraxin 3 appears as a potential disease activity
marker, indicating a dynamic connection between inflam-
mation and oxidative stress. Leptin may also play a role in
oxidative stress in nephrotic syndrome.Uvod: Patofiziološki mehanizmi ključni u razvoju nefrotskog sindroma (NS) u pedijatrijskoj populaciji još uvek nisu u potpunosti razjašnjeni. Ova studija ima za cilj proučavanje sinergističkog delovanja oksidativnog stresa i inflamacije u patogenezi NS. Takođe, jedan od ciljeva ove studije je i ispitivanje veze hipertenzije sa stepenom oksidativnog stresa i inflama - cije kod pacijenata u akutnoj fazi bolesti. Metode: U studiju je uključeno 33 dece sa NS uzrasta od 2 do 9 godina. Uzorci krvi su prikupljeni tokom akutne faze i remisije. Od parametara oksidativnog statusa određivani su: totalni oksidativni status (TOS), uznapredovali proizvodi oksidacije proteina (AOPP), balans prooksidans-antioksidans (PAB), sulfhidrilne grupe (-SH), paraoksonaza 1 (PON1) i ukupan antioksidativni status (TAS) u serumu su mereni spektrofometrijski, a od parametara inflamacije su pentraksin 3 (PTX3), leptin, ligand programirane smrti ćelije 1 (PD-L1) i E-kadherin određivani metodom enzimskog imunosorbentnog testa (ELISA). Rezultati: Pacijenti sa NS i hipertenzijom imali su značajno više nivoe AOPP i TOS (p=0.029 i p=0.003, respektivno). U akutnoj fazi bolesti su uočene nižu aktivnost -SH i PON1 u poređenju sa remisijom (p<0.001, za oba). Nivoi PTX 3 su bili viši, dok su nivoi leptina bili niži tokom akutne faze (p<0.001, za oba). PTX 3 je korelirao sa AOPP i TAS u akutnoj fazi, ali ne i u remisiji (rs=0.42, p=0.027 i rs=0.43, p=0.025,respektivno). U akutnooj fazi utvrđena je negativna korelacija između AOPP i leptina, koja je nestala u remisiji (rs=-0.42, p=0.028). Zaključak: Rezultati ove studije ukazuju da hipertenzija utiče na markere oksidativnog stresa, a smanjeni antioksidativni kapacitet može doprineti razvoju NS. PTX3 se pojavljuje kao potencijalni marker aktivnosti bolesti, što ukazuje na dinamičku vezu između inflamacije i oksidativnog stresa. Leptin može igrati ulogu u oksidativnom stresu u NS
Nutritional Value, Phytochemical Composition and Biological Activities of Lycium barbarum L. fruits from Serbia
No full textCultivation of goji berries (GB), fruits of Lycium barbarum L. (Solanaceae), is expanding worldwide, including in Europe. In this study, a comparative analysis of the nutritional value, chemical composition and in vitro biological activities of GB from different locations in Serbia was performed. Proximate compositions were evaluated according to standard methods. Minerals were assessed by inductively coupled plasma techniques, while fatty acids, sterols, and phenolic profiles were analyzed by gas- and liquid chromatography-based techniques coupled with flame-ionization, mass spectrometry, or diode array detection. The total content of phenolics, flavonoids, carotenoids, and polysaccharides was assessed using spectrophotometric methods. Methanol extracts from GB were examined for their antioxidant, enzyme inhibitory (α-amylase, α-glucosidase, acetylcholinesterase and tyrosinase) and antibacterial activities. Despite significant variations among samples from different locations, the results confirmed that GB are a valuable source of dietary fiber and protein and are characterized by favorable fatty acid profiles. Phytochemical analysis revealed that β-sitosterol, Δ5-avenasterol, and 24-methyldesmosterol are the predominant sterols and caffeic acid, gallic acid, quercetin and rutin are the main phenols. All GB samples showed both antioxidant and mild antimicrobial activity. A dose-dependent anti-enzymatic activity (IC50 ranging 1.68–6.88 mg/mL) was demonstrated. The results support further promotion of GB cultivation in Serbia and further investigations on their potential applications in various industries