Glucose Metabolism Disorders: Challenges and Opportunities for Diagnosis and Treatment

Alterations of glucose metabolism are recognized as one of the most important risk factors for the development and complications of cardiometabolic diseases [...]

Antioksidativna svojstva lipoproteina visoke gustine: više od kardiovaskularne zaštite

High-density lipoprotein (HDL) is the most complex lipoprotein particle, containing lipids and dozens of various functional proteins. Such sophisticated composition enables numerous activities of HDL; from the reverse cholesterol transport, to antioxidative, anti- inflammatory, anti-aggregation, antiadhesive, and vasodilatory effects. Accordingly, the significance of HDL goes far beyond its cardioprotective properties and novel research points towards its role in etiopathogenesis of various other diseases. Antioxidative properties of HDL are primarily attributed to the enzyme paraoxonase 1 (PON1), whose principal role is to protect low-density lipoprotein (LDL) and cell membranes against harmful effects of reactive oxygen species (1). PON1 is located on HDL particles and its activity largely depends on HDL structure. Our investigations have shown that PON1 is not equally distributed across the entire population of serum HDL subfractions. Namely, our results suggest that the allocation of PON1 on specific HDL subclasses changes in pathophysiological conditions, such as chronic kidney disease, polycystic ovary syndrome, or hypertension in pregnancy. Similarly, a shift in HDL subclasses distribution toward smaller, dysfunctional particles is reported in diabetes, metabolic syndrome, obstructive sleep apnea, sarcoidosis, but also in malignant diseases, such as colorectal cancer. In parallel, antioxidative defense mechanisms were diminished in all these categories of patients, which was evident as decreased PON1 activity and rise of oxidative stress. Structural modifications of HDL particles affect their functions, thus antioxidative capability of PON1 depends on qualitative properties of its lipoprotein carrier. Such complex interaction is highly significant for the initiation and progression of numerous diseases.Lipoprotein visoke gustine (high‐density lipoprotein, HDL) je najkompleksnija lipoproteinska čestica koja, pored lipidnih komponenti, sadrži i desetine različitih funkcionalnih proteina. Ovakav složen sastav omogućava brojne funkcije HDL; od reverznog transporta holesterola, do antioksidativnih, antiinflamatornih, antiagregacijskih, antiadhezivnih i vazodilatatornih svojstava. U skladu s tim, značaj HDL u mnogome prevazilazi kardioprotektivne efekte, a savremena otkrića ukazuju na ulogu ovih čestica u etiopatogenezi različitih oboljenja. Antioksidativna svojstva HDL prevashodno su vezana za enzim paraoksonazu 1 (PON1), čija je osnovna funkcija zaštita lipoproteina niske gustine (low‐density lipoprotein, LDL) i ćelijskih membrana od oksidativnih oštećenja (1). PON1 je locirana na HDL česticama i uočeno je da aktivnost ovog enzima u velikoj meri zavisi od strukture samog HDL. U našim istraživanjima pokazali smo da PON1 nije ravnomerno zastupljena na svim subfrakcijama HDL, te da se ova zastupljenost menja u različitim patofiziološkim stanjima, kao što su hronične bubrežne bolesti, sindrom policističnih jajnika, ili hipertenzija u trudnoći. Slično tome, pomeranje raspodele HDL subfrakcija ka manjim, disfunkcionalnim česticama uočeno je kod pedijatrijskih i odraslih pacijenata sa dijabetesom, metaboličkim sindromom, opstruktivnom apnejom u toku spavanja, sarkoidozom, ali i sa malignim bolestima, kao što je kolorektalni karcinom. Istovremeno, nivo antioksidativne zaštite kod ovih pacijenata je bio snižen, što je bilo vidljivo i kao smanjenje aktivnosti PON1, te sledstveno povećanje nivoa oksidativnog stresa. Strukturne modifikacije HDL čestica utiču na njihovu funkciju, pa tako i antioksidativni kapacitet enzima PON1 zavisi od kvalitativnih svojstava njegovog lipoproteinskog nosača. Ovakva složena interakcija između HDL i pridruženih funkcionalnih proteina značajna je za nastanak i progresiju brojnih oboljenja.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Hashimoto Thyroiditis and Dyslipidemia in Childhood: A Review

Hashimoto autoimmune thyroiditis (AIT) is the most common cause of acquired hypothyroidism in the pediatric population. Development of AIT is mediated mainly by cellular immune response directed toward thyroid autoantigens, leading to inflammation and impaired function of thyroid gland. Both thyroid dysfunction and inflammation affect the metabolism of plasma lipoproteins. The alterations in lipid profile worsen with the advancement of hypothyroidism, ranging from discrete changes in euthyroid AIT patients, to atherogenic dyslipidemia in the overt hypothyroidism. In this review, characteristics of dyslipidemia in pediatric AIT patients, and the consequences in respect to the risk for cardiovascular disease (CVD) development are discussed. Additionally, benefit of L-thyroxine treatment on serum lipid profile in pediatric AIT patients is addressed. Finally, potential usefulness of novel lipid biomarkers, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), non-cholesterol sterols, low-density lipoprotein particle size and number, and high-density lipoprotein structure and functionality in AIT patients is also covered. Further longitudinal studies are needed in order to elucidate the long-term cardiovascular outcomes of dyslipidemia in pediatric patients with Hashimoto AIT.articl

Indirect reference intervals for haematological parameters in capillary blood of pre-school children

Introduction: Indirect estimation of reference intervals (RIs) is straightforward and inexpensive procedure for determination of intra-laboratory RIs. We applied the indirect approach to assess RIs for haematological parameters in capillary blood of pre-school children, using results stored in our laboratory database. Materials and methods: We extracted data from laboratory information system, for the results obtained by automatic haematology analyser in capillary blood of 154 boys and 146 girls during pre-school medical examination. Data distribution was tested, and logarithmic transformation was applied if needed. Reference intervals were calculated by the nonparametric percentile method. Results: Reference intervals were calculated for: RBC count (4.2-5.4 x1012/L), haemoglobin (114-146 g/L), MCH (25.0-29.4 pg), MCHC (321-368 g/L), RDW-SD (36.1-43.5 fL), WBC count (4.5-12.3 x109/L), neutrophils count (1.7-6.9 x109/L) and percentage (29.0-69.0%), lymphocytes count (1.6-4.4 x109/L) and percentage (21.9-60.7%), PLT (165-459 x109/L), MPV (8.1-11.4 fL) and PDW (9.2-14.4%). Gender specific RIs were calculated for mo-nocytes count (male (M): 0.2-1.6 x109/L; female (F): 0.1-1.4 x109/L) and percentage (M: 2.5-18.3%; F: 1.8-16.7%), haematocrit (M: 0.34-0.42 L/L; F: 0.34-0.43 L/L), MCV (M: 73.4-84.6 fL; F: 75.5-84.2 fL) and RDW (M: 12.1-14.3%; F: 11.7-13.9%), due to observed gender differences in these parameters (P = 0.031, 0.028, 0.020, 0.012 and 0.001; respectively). Estimated RIs markedly varied from the literature based RIs that are used in the labora-tory. Conclusions: Indirect method employed in this study enables straightforward assessment of RIs in pre-school children. Herein derived RIs differed from the literature-based ones, indicating the need for intra-laboratory determination of RIs for specific populations and sample types

A New Look at Novel Cardiovascular Risk Biomarkers: The Role of Atherogenic Lipoproteins and Innovative Antidiabetic Therapies

The presence of residual cardiovascular disease (CVD) risk is a current dilemma in clinical practice; indeed, despite optimal management and treatment, a considerable proportion of patients still undergo major CV events. Novel lipoprotein biomarkers are suggested as possible targets for improving the outcomes of patients at higher risk for CVD, and their impact on major CV events and mortality have previously been investigated. Innovative antidiabetic therapies have recently shown a significant reduction in atherogenic lipoproteins, beyond their effects on glucose parameters; it has also been suggested that such anti-atherogenic effect may represent a valuable mechanistic explanation for the cardiovascular benefit of, at least, some of the novel antidiabetic agents, such as glucagon-like peptide-1 receptor agonists. This emphasizes the need for further research in the field in order to clearly assess the effects of innovative treatments on different novel biomarkers, including atherogenic lipoproteins, such as small dense low-density lipoprotein (LDL), lipoprotein(a) (Lp(a)) and dysfunctional high-density lipoprotein (HDL). The current article discusses the clinical importance of novel lipid biomarkers for better management of patients in order to overcome residual cardiovascular risk

Priprema biološkog materijala i validacija bioanalitičkih HPLC metoda za ispitivanje lekova i njihovih metabolite

Purification of biological matrix prior to HPLC analysis has been complex procedure and source of great variability of analytical results. The most used biological matrixes used for analysis are plasma, serum, urine and saliva and it has been advisable to use the simplest procedure for purification of these samples. Biological matrixes are complex and variability of its content is the main problem in development of bioanalytical methods. Namely, plasma and urine samples contain large number of endogenous compounds in concentrations much larger than concentration of investigated analyte. The concentrations of investigated analytes are often in very low concentrations and its structure can be very similar to structure of some endogenous compounds. Due to this problem, purification and concentration of biomatrix is one of the most important steps in development of bioanalytical methods. For bioanalytical methods the most important parameters are reliability and repeatability of the analytical results. Validation of bioanalytical chromatographic methods can be conducted according to The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Food and Drug Administration (FDA) and European Medicines Agency (EMA). During the validation process selectivity, limit of detection (LOD), lower limits of quantification (LLOQ), range, linearity, precision, accuracy, stability and efficacy of biological sample purification have to be investigated.Priprema biološkog materijala pre HPLC analize predstavlja kompleksnu proceduru koja je obično izvor velike varijabilnosti dobijenih analitičkih rezultata. Najčešće analizirane telesne tečnosti jesu plazma, serum, urin i saliva, i poželjno je primeniti što jednostavniju proceduru pri pripremi navedenih uzoraka. Kompleksnost i varijabilnost sastava biološkog materijala predstavlja jedan od glavnih problema u razvoju bioanalitičkih metoda. Plazma i urin sadrže veliki broj endogenih komponenata prisutnih u koncentracijama koje su obično veće od koncentacije samog leka i/ili njegovih metabolita. Osim što se lekovi i/ili njihovi metaboliti često nalaze u malim koncentracijama, njihova struktura može biti slična strukturi nekih endogenih komponenata. Imajući ovo u vidu, prečišćavanje i koncentrisanje biološkog materijala je jedan od najvažnijih koraka u razvoju bioanalitičke metode. Bez obzira sa kojim se uzorcima biološkog materijala radi, važno je voditi računa da se tokom analize dobiju pouzdani i ponovljivi rezultati. Validacija bioanalitičkih hromatografskih metoda izvodi se prema preporukama The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) regulative, Food and Drug Administration (FDA) i European Medicines Agency (EMA). U okviru postupka validacije ispituje se selektivnost, donja granica detekcije (LD), donja granica određivanja (eng. lower limits of quantification, LLOQ), opseg, linearnost, preciznost, tačnost, stabilnost i efikasnost postupka prečišćavanja uzoraka biološkog materijala

Atherosclerosis Development and Progression: The Role of Atherogenic Small, Dense LDL

Atherosclerosis is responsible for large cardiovascular mortality in many countries globally. It has been shown over the last decades that the reduction of atherosclerotic progression is a critical factor for preventing future cardiovascular events. Low-density lipoproteins (LDL) have been successfully targeted, and their reduction is one of the key preventing measures in patients with atherosclerotic disease. LDL particles are pivotal for the formation and progression of atherosclerotic plaques; yet, they are quite heterogeneous, and smaller, denser LDL species are the most atherogenic. These particles have greater arterial entry and retention, higher susceptibility to oxidation, as well as reduced affinity for the LDL receptor. Increased proportion of small, dense LDL particles is an integral part of the atherogenic lipoprotein phenotype, the most common form of dyslipidemia associated with insulin resistance. Recent data suggest that both genetic and epigenetic factors might induce expression of this specific lipid pattern. In addition, a typical finding of increased small, dense LDL particles was confirmed in different categories of patients with elevated cardiovascular risk. Small, dense LDL is an independent risk factor for cardiovascular diseases, which emphasizes the clinical importance of both the quality and the quantity of LDL. An effective management of atherosclerotic disease should take into account the presence of small, dense LDL in order to prevent cardiovascular complications

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

Obstructive sleep apnea and cardiometabolic risk

Opstruktivna apneja u snu (OSA) je hronično progresivno oboljenje sa visokom prevalencom u populaciji koje, bez pravovremene dijagnoze i terapije, može dovesti do značajnih posledica po kvalitet života pacijenata. OSA je čest komorbiditet kod pacijenata sa metaboličkim sindromom (MS) i kardiovaskularnim bolestima (KVB) i predstavlja važan faktor rizika za nastanak ovih oboljenja, a prisustvo nelečenog, teškog oblika OSA povezano je sa porastom ukupnog i mortaliteta usled koronarnih događaja. Brojne studije su ukazale na vezu između MS i OSA, te je ovaj fenomen opisan kao poseban poremećaj - sindrom Z. Istraživanje uzročno-posledične veze između OSA i KVB je u velikoj meri otežano kompleksnom prirodom samog oboljenja. Smatra se da je kardiometabolički rizik u OSA udružen sa arterijskom hipertenzijom, insulinskom rezistencijom, endotelnom disfunkcijom, inflamacijom, dislipidemijom i oksidativnim stresom. Lečenje OSA se danas najefikasnije sprovodi neinvazivnom ventilacijom, pomoću uređaja koji obezbeđuje pozitivan pritisak u gornjim disajnim putevima (eng. continuous positive airway pressure, CPAP) i na taj način sprečava pojavu apneja tokom spavanja. Rezultati kliničkih studija su pokazali da CPAP terapija značajno poboljšava hemodinamske parametre, reguliše hipertenziju, povećava osetljivost na insulin i koriguje dislipidemiju. Buduća istraživanja bi trebalo da rasvetle da li je apneja u snu faktor rizika za KVB per se ili je ta veza posledica šireg patofiziološkog procesa, čiji je deo i OSA.Obstructive sleep apnea (OSA) is a chronic, progressive disorder with a high prevalence in the population. Without timely diagnosis and therapy OSA can significantly affect the quality of life of the patients. OSA is a common co-morbidity in patients with metabolic syndrome (MS) and cardiovascular disease (CVD) and is an important risk factor for their development. The presence of untreated, severe OSA is associated with an increase in total and cardiovascular mortality. Numerous studies have pointed to the relationship between MS and OSA, and this phenomenon was described as syndrome Z. Investigation of the causal relationship between OSA and CVD has been greatly confounded by the complex nature of the disease itself. Cardiometabolic risk in OSA is associated with arterial hypertension, insulin resistance, endothelial dysfunction, inflammation, dyslipidemia, and oxidative stress. The treatment of OSA is now most effectively performed by continuous positive airway pressure (CPAP), a type of non-invasive ventilation which prevents the onset of sleep apnea. The results of clinical studies have shown that CPAP therapy significantly improves haemodynamic parameters, regulates hypertension, increases insulin sensitivity, and corrects dyslipidemia. Future investigations should clarify whether sleep apnea is a risk factor for CVD per se or is a consequence of a broader pathophysiological process, of which OSA is part

Obesity and dyslipidemia

Obesity, a pandemic of the modern world, is intimately associated with dyslipidemia, which is mainly driven by the effects of insulin resistance and pro-inflammatory adipokines. However, recent evidence suggests that obesity-induced dyslipidemia is not a unique pathophysiological entity, but rather has distinct characteristics depending on many individual factors. In line with that, in a subgroup of metabolically healthy obese (MHO) individuals, dyslipidemia is less prominent or even absent. In this review, we will address the main characteristics of dyslipidemia and mechanisms that induce its development in obesity. The fields, which should be further investigated to expand our knowledge on obesity-related dyslipidemia and potentially yield new strategies for prevention and management of cardiometabolic risk, will be highlighted. Also, we will discuss recent findings on novel lipid biomarkers in obesity, in particular proprotein convertase subtilisin/kexin type 9 (PCSK9), as the key molecule that regulates metabolism of low-density lipoproteins (LDL), and sphingosine-1-phosphate (S1P), as one of the most important mediators of high-density lipoprotein (HDL) partides function. Special attention will be given to microRNAs and their potential use as biomarkers of obesity-associated dyslipidemia