The examination of inflammatory, oxidative stress and lipid status parameters in sarcoidosis patients

Sarkoidoza je inflamatorno oboljenje ismatra se da genetska predispozicija organizma i specifiĉni agensi iz spoljašnje sredine igraju znaĉajnu ulogu u prekomernoj aktivaciji imunskog sistema koji se nalazi u osnovi oboljenja. MeĊu agensima iz spoljašnje sredine, mikobakterijski antigeni imaju najveći znaĉaj. Novije publikacije govore o postojanju mikobakterijskog antigena - katalaza-peroksidaza (mKatG) u sarkoidnim granulomima. Smatra se da ovaj antigen dovodi do stimulacije imunskog odgovora i tako doprinosi inicijaciji oboljenja. Imunološki odgovor zapoĉinje akumulacijom aktiviranih T pomoćniĉkih (“helper”) limfocitai makrofaga na mestima inflamacije. Usled kompleksnih interakcija T limfocita i makrofaga, formira se sarkoidni granulom. Granulomi su sastavljeni od visoko-diferentovanih mononuklearnih fagocita i limfocita. Aktivirane ćelije imunskog sistema produkuju razliĉite proinflamatorne medijatore meĊu kojima su znaĉajni interleukin (IL) -2, IL-12, IL-15, faktor nekroze tumora α (TNF α), angiotenzin konvertujući enzim (ACE). C-reaktivni protein (CRP) kao inflamatorni marker se takoĊe povećano sintetiše u jetri kao odgovor na povećanu produkciju proinflamatornih citokina, ali nije dokazano da on moţe da posluţi kao koristan marker za procenu aktivnosti bolesti. U kliniĉkoj dijagnozi granulomatoznih oboljenja izdvojio se ACE, ali su utvrĊeni nedostaci i ovog parametra. Noviji radovi naglašavaju znaĉaj serumskog amiloida A (SAA) kao vaţnog markera granulomatozne inflamacije jer, osim što predstavlja deo granuloma, on reguliše njegovo formiranje, ali utiĉe i na produkciju citokina. Sinteza SAA se povećava u jetri i oslobaĊa se zajedno sa CRP-om pod uticajem IL-1 i IL-6. Sarkoidoza se prema toku moţe podeliti na akutnu ili hroniĉnu, a manifestacije mogu da budu plućne i/ili vanplućne. Akutna bolest je ograniĉenog toka, sa ĉestim spontanim remisijama dok hroniĉna perzistira i praćena je progresijom oboljenja. Pored pluća, mogu biti zahvaćeni srce, oĉi, nervni system, mišići, kostii drugi organi. Vanplućna manifestacija koja uglavnom ukljuĉuje i plućno tkivo predstavlja teţi oblik od iskljuĉivo plućne manifestacije. Poznato je da se u inflamatornim stanjima povećava nivo oksidativnog stresa i smanjuje nivo antioksidativne zaštite. Inflamatorne ćelije pojaĉano stvaraju superoksid anjon radikal (O2.-) koji se konvertuje do vodonik-peroksida (H2O2). Dejstvom oksidanasa na lipidne molekule najpre se generišu lipidni hidroperoksidi, dok u krajnjem stadijumu lipidne peroksidacije nastaje malondialdehid (MDA)...Sarcoidosis is an inflammatory disease and it has been considered that genetic predisposition and specific environmental agents play significant role in the excessive activation of the immune system that is major characteristic of the disease. Among environmental agents, mycobacterial antigens are thought to be most important. Recent publications reported the presence of mycobacterial antigen catalase-peroxidase (mKatG) in sarcoid granulomas. This antigen leads to immune response stimulation contributing to disease onset. Immune response begins with accumulation of T helper lymphocytes and macrophages at the sites of inflammation. Complex interactions between lymphocytes and macrophages contribute to granuloma formation. Granulomas consist of highly-differentiated mononuclear phagocytes and lymphocytes. Activated cells of immune system produce different proinflammatory mediators such as interleukin (IL) -2, IL-12, IL-15, tumor necrosis factor α (TNFα), angiotensin converting enzyme (ACE). C-reactive protein (CRP) is synthesized in the liver and its production is increased as a response to proinflammatory cytokines, but the significance of CRP as a useful marker of disease activity has not been proved. ACE became important in clinical diagnosis of granulomatous diseases, but this marker also has its disadvantages. Recent reports pointed out the significance of serum amyloid A (SAA), suggesting it as an important marker of granulomatous inflammation, because it regulates granuloma formation and influences the cytokines production. IL-1 and IL-6 stimulate the increased production of SAA in the liver and its release into the bloodstream together with CRP. According to disease course, sarcoidosis can be acute or chronic, with disease manifestations on lungs and/or other tissues. Acute disease has limited course and spontaneous remissions often occur, while chronic disease persists and isusually progressive. Besides lungs, other tissues/organs that can be affected are: heart, eyes, nervous system, muscles, bones and others. Combined pulmonary and extrapulmonary manifestations are more severe forms than isolated pulmonary form. It is well established that, in inflammatory conditions, the levels of oxidative stress increase and the levels antioxidative defence decrease. Inflammatory cells produce superoxide anion radical (O2.-) that is dismutated into hydrogen peroxide (H2O2). Oxidants lead to damage of lipids generating lipid hydroperoxides and further oxidative modification leads to malondialdehyde (MDA) formation..

Redox homeostasis, oxidative stress and antioxidant system in health and disease: The possibility of modulation by antioxidants

Redox imbalance occurs when the factors of oxidative stress, known as prooxidants, outweigh the mechanisms of antioxidant protection. In a healthy state, homeostatic mechanisms ensure the balanced production of free radicals and a complete series of antioxidants responsible for their safe removal. The generation of free radicals is a part of physiological processes in a healthy organism, some of which act as specific signaling molecules, and their presence and activity are necessary in these processes. In various diseases such as cancer, cardiovascular disease, diabetes, autoimmune diseases, rheumatic diseases, systemic lupus, and skin diseases, the generation of free radicals overwhelms the protective mechanisms, leading to the development of "oxidative stress" that damages cells and tissues. To prevent the harmful effects of free radicals within cells, there exists a system of enzymatic antioxidant protection composed of superoxide dismutase (SOD), glutathione peroxidase (GSHPx), glutathione reductase (GR), glutaredoxin, reduced/oxidized glutathione (GSH/GSSG), and thioredoxin (TRX). The examples of non-enzymatic antioxidants are: antioxidant vitamins such as A, C and E, dihydrolypoic acid, metallothioneins, ceruloplasmin, coenzyme Q 10, urea, creatinine, etc. Redox balance is influenced by the circadian rhythm and external factors that constitute the "exposome", including dietary habits and lifestyle. Antioxidant supplementation has become increasingly popular for maintaining optimal body function. However, it is important to note that some antioxidants can exhibit prooxidant activity, emphasizing the need for controlled use. The relationship between the redox status of the body and the action of antioxidants enables the development of multidisciplinary research that connects biochemistry, molecular biology, nutritional science, natural product chemistry, and clinical practice

Oxidative status parameters in children with urinary tract infection

Introduction: Urinary tract infection (UTI) is one of the most common bacterial infectious diseases in children. The aim of this study was to determine the total prooxidant and antioxidant capacity of children with UTI, as well as changes of oxidative status parameters according to acute inflammation persistence and acute kidney injury (AKI) development. Materials and methods: The patients enrolled in the study comprised 50 Caucasian children (median age was 6 months) with UTI. Total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), inflammation marker C-reactive protein (CRP) and renal function parameters urea and creatinine were analyzed in patient's serums. Results: According to duration of inflammation during UTI, TAS values were significantly higher (0.99 vs. 0.58 mmol/L, P = 0.017) and OSI values were significantly lower (0.032 vs. 0.041 AU, P = 0.037) in the subjects with longer duration of inflammation than in the subjects with shorter duration of inflammation. We did not find significant difference in basal values of oxidative status parameters according to AKI development. Conclusions: OSI values could detect the simultaneous change of TAS and TOS due to change in the oxidative-antioxidant balance during the recovery of children with UTI. TAS and OSI as markers of oxidative stress during UTI are sensitive to accompanying inflammatory condition. Further investigations are needed to evaluate whether TAS, TOS and OSI could be used to monitor disease severity in children with UTI

Izmenjena struktura i antioksidativni kapacitet lipoproteinskih čestica visoke gustine u preeklampsiji

Background/Aim. One of the complications that can oc- cur during pregnancy is the development of preeclampsia (PE). The main characteristics of this condition are high blood pressure and very often signs of kidney damage or other organ damage. The condition affects 5–7% of all pregnant women and is one of the main factors of maternal and perinatal morbidity and mortality worldwide. The aim of this study was to investigate the structural and functional modifications of high-density lipoprotein (HDL) particles during high-risk pregnancies (HRP) for PE development. Methods. The longitudinal prospective study included a to- tal of 91 pregnant women with a HRP for developing PE. Out of this total number, 71 women did not develop PE until delivery, and this group was designated as the group without PE (WPE). The rest of the 20 HRP women devel- oped PE before delivery and were designated as the PE group. The blood was sampled toward the end of each tri- mester and before the delivery. The distribution of HDL particles was determined by the vertical 3–31% polyacryla- mide gradient gel electrophoresis method. The antioxidative capacity of HDL particles was measured by the activity of the HDL-associated enzyme – paraoxonase 1 (PON1). PON1 activity was determined by the method of kinetic spectrophotometry from serum samples. Results. The re- sults have shown that the proportions of HDL 2b particles significantly increased in the 2nd trimester (p ˂ 0.05) and remained increased until the end of pregnancy in the WPE group. PON1 activity was significantly higher in the 3 rd tri- mester (p < 0.05) of the WPE group. In the PE group, we found that the proportions of HDL 3a particles significantly decreased in the 2 nd trimester (p < 0.05) and remained de- creased until the end of pregnancy. PON1 activity has not changed in the PE group during pregnancy. Conclusion. Dyslipidemia in pregnancy could be associated with differ- ent modifications of HDL particles. The adaptive pregnancy mechanisms expressed as a functional modification of HDL particles in pregnant women who develop PE seem inade- quate and, therefore, lose their atheroprotective role.Uvod/Cilj. Jedna od komplikacija koja se može javiti tokom trudnoće je razvoj preeklampsije (PE). Glavne karakteristike ovog stanja su visok krvni pritisak i vrlo često znaci oštećenja bubrega ili drugih organa. Ovo stanje pogađa 5–7% svih trudnica i jedan je od glavnih faktora morbiditeta i mortaliteta trudnica i fetusa ili novorođenčadi. Cilj ovog rada bio je ispitivanje strukturnih i funkcionalnih modifikacija lipoproteinskih čestica visoke gustine (high- density lipoprotein – HDL) u trudnoćama sa visokim rizikom (TVR) za razvoj PE. Metode. U longitudinalnoj prospektivnoj studiji učestvovala je ukupno 91 trudnica sa TVR od razvoja PE. Od ukupnog broja trudnica, kod njih 71, PE se nije razvila do kraja trudnoće i ova grupa je označena kao grupa bez PE (BPE). Kod preostalih 20 žena sa TVR se razvila PE do porođaja, i one su svrstane u grupu PE. Krv je uzimana za analizu na kraju svakog trimestra i pred porođaj. Raspodela HDL čestica je određivana metodom vertikalne elektroforeze u 3–31% gradijentu poliakrilamidnog gela. Antioksidativni kapacitet HDL čestica je određivan na osnovu aktivnosti enzima paraoksonaze 1 (PON1) vezanog za HDL. Aktivnost PON1 u serumu je određivana metodom kinetičke spektrofotometrije. Rezultati. Rezultati su pokazali da se udeo HDL 2b čestica značajno povećao u drugom trimestru (p < 0,05) i ostao je povećan do kraja trudnoće u grupi BPE. Aktivnost PON1 bila je značajno veća u trećem trimestru (p < 0,05) kod ove grupe trudnica. Udeo HDL 3a čestica se značajno smanjio u drugom trimestru u PE grupi trudnica (p < 0,05) i ostao je snižen do kraja trudno će. Aktivnost PON1 enzima u PE gripi se nije menjala u toku trudnoće. Zaključak. Dislipidemija u trudnoći može biti posledica različitih modifikacija HDL čestica. Strukturne i funkcionalne modifikacije HDL čestica, kao jedan od adaptivnih mehanizama, kod trudnica kod kojih se razvila PE, nisu adekvatne i kao takve gube svoju ateroprotektivnu ulogu

Cholesterol Metabolic Profiling of HDL in Women with Late-Onset Preeclampsia

A specific feature of dyslipidemia in pregnancy is increased high-density lipoprotein (HDL) cholesterol concentration, which is probably associated with maternal endothelium protection. However, preeclampsia is most often associated with low HDL cholesterol, and the mechanisms behind this change are scarcely explored. We aimed to investigate changes in HDL metabolism in risky pregnancies and those complicated by late-onset preeclampsia. We analyze cholesterol synthesis (cholesterol precursors: desmosterol, 7-dehydrocholesterol, and lathosterol) and absorption markers (phytosterols: campesterol and β-sitosterol) within HDL particles (NCSHDL), the activities of principal modulators of HDL cholesterol’s content, and major HDL functional proteins levels in mid and late pregnancy. On the basis of the pregnancy outcome, participants were classified into the risk group (RG) (70 women) and the preeclampsia group (PG) (20 women). HDL cholesterol was lower in PG in the second trimester compared to RG (p < 0.05) and followed by lower levels of cholesterol absorption markers (p < 0.001 for campesterolHDL and p < 0.05 for β-sitosterolHDL). Lowering of HDL cholesterol between trimesters in RG (p < 0.05) was accompanied by a decrease in HDL phytosterol content (p < 0.001), apolipoprotein A-I (apoA-I) concentration (p < 0.05), and paraoxonase 1 (PON1) (p < 0.001), lecithin–cholesterol acyltransferase (LCAT) (p < 0.05), and cholesterol ester transfer protein (CETP) activities (p < 0.05). These longitudinal changes were absent in PG. Development of late-onset preeclampsia is preceded by the appearance of lower HDL cholesterol and NCSHDL in the second trimester. We propose that reduced capacity for intestinal HDL synthesis, decreased LCAT activity, and impaired capacity for HDL-mediated cholesterol efflux could be the contributing mechanisms resulting in lower HDL cholesterol

Pulmonary function, oxidative stress and inflammatory markers in severe COPD exacerbation

Background: Oxidative stress and inflammation play an important role in the pathogenesis of chronic: obstructive pulmonary disease (COPD). Objective: Pulmonary function, oxidative stress parameters and inflammatory markers were measured in 74 patients with severe COPD exacerbation and 41 healthy subjects. In patients all parameters were assessed at two time points: Firstly, one day after admission and secondly, after 7-10 days when they were clinically stable enough to be discharged. Patients were divided in two groups according the presence of ischemic heart disease (IHD): IHD positive (IHD+) patients and IHD negative (IHD-) patients. Methods and Results: During hospitalisation O(2)(center dot-), malondialdehyde (MDA), advanced oxidation protein products (AOPP) and total oxidant status (TOS) increased and were higher at discharge compared with admission and the control group. Superoxide dismutase (SOD) activity was significantly lower in COPD patients at both time points compared with the control group. Total antioxidant status (TAS) was significantly lower and the prooxidant-antioxidant balance (PAB) was higher at both time points in COPD patients compared with the control group. High sensitive C-reactive protein (hsCRP) and also the neutrophil count were significantly higher at admission compared with discharge. Paraoxonase 1 (PON1) enzymatic activities in COPD patients did not differ compared with the control group. IHD+ COPD patients had significantly lower PON1 activity but higher PAB levels and hsCRP concentrations, compared with IHD- COPD patients. Conclusion: The oxidant/antioxidant imbalance was significantly pronounced in patients with COPD exacerbation for at least 24 hours following their admission and when they were clinically stable enough to be discharged. Increased oxidative stress, elevated systemic inflammation and decreased antioxidant defence were common in end-stage disease and particularly COPD patients with ischemic heart disease

Biochemical and hematological parameters in the 1st trimester of pregnancy

The 1st trimester of pregnancy is accompanied with changes in different biochemical and hematological parameters. Analyses scheduled to be performed in the 1st trimester are complete blood count, blood group, Rh factor and the double test. Many experts also suggest the determination of lipid status parameters as a routine analysis in the early pregnancy. Reliable data about maternal and fetal health can be obtained by the assessment of the above-mentioned parameters. They may be helpful in assessing the risk for pregnancy complication development and/or perinatal adverse outcomes

Biohemijski i hematološki parametri u prvom trimestru trudnoće

The 1st trimester of pregnancy is accompanied with changes in different biochemical and hematological parameters. Analyses scheduled to be performed in the 1st trimester are complete blood count, blood group, Rh factor and the double test. Many experts also suggest the determination of lipid status parameters as a routine analysis in the early pregnancy. Reliable data about maternal and fetal health can be obtained by the assessment of the above-mentioned parameters. They may be helpful in assessing the risk for pregnancy complication development and/or perinatal adverse outcomes.Prvi trimestar trudnoće praćen je promenama različitih biohemijskih i hematoloških parametara. Analize koje se rade u 1. trimestru su kompletna krvna slika, krvna grupa, Rh faktor i tzv. „double“ test. Mnogi stručnjaci predlažu određivanje parametara lipidnog statusa kao rutinsku analizu u ranoj trudnoći. Procenom gore navedenih parametara mogu se dobiti pouzdani podaci o zdravlju majke i fetusa, a mogu da posluže i za procenu rizika za razvoj komplikacija u trudnoći i/ili perinatalnih neželjenih ishoda

Matriks metaloproteinaze-9 i tkivni inhibitori matriks metaloproteinaza-1 kod pacijenata sa sarkoidozom

Matrix metaloproteinases (MMPs) and their specific inhibitors - tissue inhibitors of matrix metalloproteinases (TIMPs) play an important role in pulmonary extracellular matrix destruction. Sarcoidosis is an inflammatory disease affecting multiple organs. It has been reported that MMP-9 and TIMP-1 levels were increased in bronchoalveolar lavage fluid and induced sputum of sarcoidosis patients. The aim of our study was to evaluate MMP-9, TIMP-1 and MMP-9/TIMP-1 complex concentrations and MMP-9/TIMP-1 ratio in sarcoidosis patients, their relationship with inflammatory markers and their ability do predict the existence of disease. We included 101 sarcoidosis patients and 50 healthy subjects. Serum samples were analyzed. Besides routine biochemical parameters, high-sensitive C-reactive protein (hsCRP), serum amyloid A (SAA), MMP-9, TIMP-1 and MMP-9/TIMP-1 complex concentrations were measured. MMP-9 (P lt 0.05), hsCRP, SAA and TIMP-1 (P lt 0.001) concentrations were significantly increased in patients whereas MMP-9/TIMP-1 complex was higher in patients, but with marginal significance. In sarcoidosis, TIMP-1 correlated significantly positively with inflammatory parameters (P lt 0.05). Uni-variate analysis showed that MMP-9, TIMP-1, hsCRP and SAA had the ability to predict the existence of sarcoidosis. In the model consisted of MMP- 9, TIMP-1, hsCRP and SAA, only SAA remained significant predictor of disease (P lt 0.01). Results showed the significance of MMP-9 and TIMP-1 in sarcoidosis.Matriks metaloproteinaze (MMP) i tkivni inhibitori matriks metaloproteinaza (TIMP) imaju značajnu ulogu u destrukciji plućnog ekstracelularnog matriksa. Sarkoidoza je inflamatorno oboljenje koje zahvata različite organe. Utvrđeno je da su koncentracije MMP-9 i TIMP-1 povećane u bronhoalveolarnom lavatu i sputumu pacijenata sa sarkoidozom. Cilj naše studije je bio da se odrede koncentracije MMP-9, TIMP-1 i MMP-9/TIMP-1 kompleksa, MMP- 9/TIMP-1 odnosa u sarkoidozi, njihova povezanost sa parametrima inflamacije, kao i njihov potencijal za predviđanje postojanja bolesti. Ispitivanjem su obuhvaćeni 101 pacijent sa sarkoidozom i 50 zdravih ispitanika. Analizirani su uzorci seruma. Pored rutinskih biohemijskih parametara, merene su koncentracije visoko-osetljivog C-reaktivnog proteina (hsCRP), serumskog amiloida A (SAA), MMP-9, TIMP-1 i MMP-9/TIMP-1 kompleksa. MMP-9 (P lt 0,05), hsCRP, SAA i TIMP-1 (P lt 0,001) su bili značajno veći kod pacijenata dok je koncentracija MMP-9/TIMP-1 kompleksa bila veća, ali sa graničnom značajnošću. U sarkoidozi, TIMP-1 je značajno pozitivno korelirao sa inflamatornim parametrima (P lt 0,05). Uni-varijantna analiza je pokazala da su MMP-9, TIMP-1, hsCRP i SAA imali značajan potencijal za predviđanje postojanja bolesti. U modelu koji je sadržao MMP-9, TIMP-1, hsCRP i SAA, samo SAA je ostao značajan u ovom predviđanju (P lt 0,01). Rezultati pokazuju značaj MMP-9 i TIMP-1 u sarkoidozi

Effects of Gestational Diabetes Mellitus on Cholesterol Metabolism in Women with High-Risk Pregnancies: Possible Implications for Neonatal Outcome

Metabolic disorders in pregnancy, particularly gestational diabetes mellitus (GDM), are associated with an increased risk for adverse pregnancy outcome and long-term cardiometabolic health of mother and child. This study analyzed changes of serum cholesterol synthesis and absorption markers during the course of high-risk pregnancies, with respect to the development of GDM. Possible associations of maternal lipid biomarkers with neonatal characteristics were also investigated. The study included 63 women with high risk for development of pregnancy complications. Size and proportions of small low-density (LDL) and high-density lipoprotein (HDL) particles were assessed across trimesters (T1–T3), as well as concentrations of cholesterol synthesis (lathosterol, desmosterol) and absorption markers (campesterol, β-sitosterol). During the study, 15 women developed GDM, while 48 had no complications (non-GDM). As compared to the non-GDM group, women with GDM had significantly higher triglycerides in each trimester, while having a lower HDL-C level in T3. In addition, they had significantly lower levels of β-sitosterol in T3 (p < 0.05). Cholesterol synthesis markers increased across trimesters in both groups. A decrease in serum β-sitosterol levels during the course of pregnancies affected by GDM was observed. The prevalence of small-sized HDL decreased in non-GDM, while in the GDM group remained unchanged across trimesters. Newborn’s size in the non-GDM group was significantly higher (p < 0.01) and inversely associated with proportions of both small, dense LDL and HDL particles (p < 0.05) in maternal plasma in T1. In conclusion, high-risk pregnancies affected by GDM are characterized by altered cholesterol absorption and HDL maturation. Advanced lipid testing may indicate disturbed lipid homeostasis in GDM