Browsing by Author "Sudar-Milovanovic, Emina (23570110000)"

Apoptosis may contribute to a significant proportion of neuron death following acute brain ischemia (ABI), but the underlying mechanisms are still not fully understood. Brain ischemia may lead to stroke, which is one of the main causes of long-term morbidity and mortality in both developed and developing countries. Therefore, stroke prevention and treatment is clinically important. There are two important separate areas of the brain during ABI: the ischemic core and the ischemic penumbra. The ischemic core of the brain experiences a sudden reduction of blood flow, just minutes after ischemic attack with irreversible injury and subsequent cell death. On the other hand, apoptosis within the ischemic penumbra may occur after several hours or days, while necrosis starts in the first hours after the onset of ABI in the ischemic core. ABI is characterized by key molecular events that initiate apoptosis in many cells, such as overproduction of free radicals, Ca2+ overload and excitotoxicity. These changes in cellular homeostasis may trigger either necrosis or apoptosis, which often depends on cell type, cell age, and location in the brain. Apoptosis results in DNA fragmentation, degradation of cytoskeletal and nuclear proteins, cross-linking of proteins, formation of apoptotic bodies, expression of ligands for phagocytic cell receptors and finally uptake by phagocytic cells. This review focuses on recent findings based on animal and human studies regarding the apoptotic mechanisms of neuronal death following ABI and the development of potential neuroprotective agents that reduce morbidity. The effects of statins on stroke prevention and treatment as well as on apoptotic mediators are also considered. © 2017 Bentham Science Publishers.

The diabetes pandemic demands solutions for proper glycemic control and prevention of future chronic complications that could result in organ failure or comorbidities. In this regard, we now know that patients diagnosed with diabetes require individual management plans. Thus, new treatment management strategies have been designed to allow clinicians to tailor the most appropriate therapy for diabetes patients individually. These treatment management plans extend beyond defining the appropriate medications for patients; they provide a directive toward some acute and chronic complications that should be screened for, as they are historically known to occur with diabetes. Observing any of the complications or comorbidities requires the patient medication regimen to be adapted accordingly. This chapter describes such modern treatment plans for the two primary forms of diabetes, type 1 and type 2, based on both basic and clinical studies, later incorporated in various diabetes management guidelines and outlines expected future trends. © Springer Nature Switzerland AG 2020.

The diabetes pandemic demands solutions for proper glycemic control and prevention of future chronic complications that could result in organ failure or comorbidities. In this regard, we now know that patients diagnosed with diabetes require individual management plans. Thus, new treatment management strategies have been designed to allow clinicians to tailor the most appropriate therapy for diabetes patients individually. These treatment management plans extend beyond defining the appropriate medications for patients; they provide a directive toward some acute and chronic complications that should be screened for, as they are historically known to occur with diabetes. Observing any of the complications or comorbidities requires the patient medication regimen to be adapted accordingly. This chapter describes such modern treatment plans for the two primary forms of diabetes, type 1 and type 2, based on both basic and clinical studies, later incorporated in various diabetes management guidelines and outlines expected future trends. © Springer Nature Switzerland AG 2020.

This study aimed at examining the early effects of hyperbaric oxygen therapy (HBOT) on inducible nitric oxide synthase (iNOS) activity/expression in lymphocytes of type 1 diabetes mellitus (T1DM) patients. A group of 19 patients (mean age: 63 ± 2.1) with T1DM and with the peripheral arterial disease were included in this study. Patients were exposed to 10 sessions of HBOT in the duration of 1 h to 100% oxygen inhalation at 2.4 ATA. Blood samples were collected for the plasma C-reactive protein (CRP), plasma free fatty acid (FFA), serum nitrite/nitrate, and serum arginase activity measurements. Expression of iNOS and phosphorylation of p65 subunit of nuclear factor-κB (NFκB-p65), extracellular-regulated kinases 1/2 (ERK1/2), and protein kinase B (Akt) were examined in lymphocyte lysates by Western blot. After exposure to HBOT, plasma CRP and FFA were significantly decreased (p < 0 001). Protein expression of iNOS and serum nitrite/nitrate levels were decreased (p < 0 01), while serum arginase activity was increased (p < 0 05) versus before exposure to HBOT. Increased phosphorylation of NFκB-p65 at Ser536 (p < 0 05) and decreased level of NFκB-p65 protein (p < 0 001) in lymphocytes of T1DM patients were observed after HBOT. Decreased phosphorylation of ERK1/2 (p < 0 05) and Akt (p < 0 05) was detected after HBOT. Our results indicate that exposure to HBO decreased iNOS activity/expression via decreasing phosphorylation of ERK1/2 and Akt followed by decreased activity of NFκB. © 2019 Ivana Resanovic et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This study aimed at examining the early effects of hyperbaric oxygen therapy (HBOT) on inducible nitric oxide synthase (iNOS) activity/expression in lymphocytes of type 1 diabetes mellitus (T1DM) patients. A group of 19 patients (mean age: 63 ± 2.1) with T1DM and with the peripheral arterial disease were included in this study. Patients were exposed to 10 sessions of HBOT in the duration of 1 h to 100% oxygen inhalation at 2.4 ATA. Blood samples were collected for the plasma C-reactive protein (CRP), plasma free fatty acid (FFA), serum nitrite/nitrate, and serum arginase activity measurements. Expression of iNOS and phosphorylation of p65 subunit of nuclear factor-κB (NFκB-p65), extracellular-regulated kinases 1/2 (ERK1/2), and protein kinase B (Akt) were examined in lymphocyte lysates by Western blot. After exposure to HBOT, plasma CRP and FFA were significantly decreased (p < 0 001). Protein expression of iNOS and serum nitrite/nitrate levels were decreased (p < 0 01), while serum arginase activity was increased (p < 0 05) versus before exposure to HBOT. Increased phosphorylation of NFκB-p65 at Ser536 (p < 0 05) and decreased level of NFκB-p65 protein (p < 0 001) in lymphocytes of T1DM patients were observed after HBOT. Decreased phosphorylation of ERK1/2 (p < 0 05) and Akt (p < 0 05) was detected after HBOT. Our results indicate that exposure to HBO decreased iNOS activity/expression via decreasing phosphorylation of ERK1/2 and Akt followed by decreased activity of NFκB. © 2019 Ivana Resanovic et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is associated with inflammation and subsequent increase in cardiovascular risk. Because of its widespread presence and distribution, invasive diagnostic procedures (i.e., liver biopsy) are reserved for a limited number of subjects. With liver ultrasound, Fatty liver index (FLI) and fibrosis-4 (FIB-4) scores non-invasively assess liver steatosis and fibrosis. We aimed to evaluate the changes in inflammatory markers and FLI/FIB-4 scores in non-obese metformin-treated type 2 diabetes patients (T2DM) with NAFLD. Methods: All subjects underwent abdominal ultrasound aiming for NAFLD stratification (grade 1 to 3 according to its severity). Metabolic parameters (morning glycaemia, HbA1C, lipids, liver function tests), serum inflammatory markers (C-reactive protein, ferritin, and nitric oxide) and FLI/-FIB-4 were calculated. Results: FLI score and ultrasound NAFLD grades were found to correlate (p<0.05). We observed a significant correlation between the levels of ferritin and C-reactive protein (CRP) (p<0.05), and the FLI (p<0.05). Body weight (BW) (p<0.05), waist circumference (WC) (p<0.05), the levels of HbA1c (p<0.05), transferrin (p<0.05), insulin (p<0.05), and FLI score (p<0.05) significantly dif-fered between groups as defined by the severity of NAFLD. Conclusion: This pilot study suggests that the serum inflammatory markers at the average normal values point to the sufficiency of metformin-single therapy in inflammation control in non-obese T2DM patients with NAFLD. © 2022 Bentham Science Publishers.

Introduction: Follicular and serum vitamin D are considered potential markers of the oocyte and embryos' quality and predictors of in vitro fertilization (IVF) outcomes. Methods: This retrospective cross-sectional study correlated vitamin D in sera and follicular fluid of women with unexplained infertility mutually and with IVF outcomes. ELISA was used for measuring vitamin D. Results: The results show positive correlation only between follicular and serum levels of vitamin D (Rho = 0.615, p = 0.025), and between follicular levels of vitamin D and the percentage of embryo fragmentation (Rho = 0.544; p = 0.036). Conclusions: The results suggest that serum and follicular fluid vitamin D measurements could be complementary tools to the routine assessment of embryos. © 2021 Termedia & Banach.

Coronary artery disease (CAD) and myocardial infarction (MI) are recognized as leading causes of mortality in developed countries. Although typically associated with behavioral risk factors, such as smoking, sedentary lifestyle, and poor dietary habits, such vascular phenotypes have also long been recognized as being related to genetic background. We review the currently available data concerning genetic markers for CAD in English and non-English articles with English abstracts published between 2003 and 2018. As genetic testing is increasingly available, it may be possible to identify adequate genetic markers representing the risk profile and to use them in a clinical setting. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.

Background: Overexpression of inducible nitric oxide synthase (iNOS) is a key link between high-fat (HF) diet induced obesity and cardiovascular disease. Oestradiol has cardioprotective effects that may be mediated through reduction of iNOS activity/expression. Methods: In the present study, female Wistar rats were fed a standard diet or a HF diet (42% fat) for 10 weeks. iNOS gene and protein expressions were measured in heart tissue. HF-fed rats exhibited a significant increase in cardiac iNOS mRNA by 695% (p<0.05), iNOS protein level by 248% (p<0.01), without changes in nitrate/nitrite levels. Expression of CD36 protein in plasma membranes was increased by 37% (p<0.05), while the concentration of free fatty acids (FFA) was reduced by 25% (p<0.01) in HF-fed rats. Expression of the p50 subunit of nuclear factor-ΚB (NFΚB-p50) in heart was increased by 77% (p<0.01) in HF-fed rats. Expression of protein kinase B (Akt) and extracellular signalregulated kinases 1/2 (ERK1/2) were unchanged between the groups. There was a significant increase in the ratio of phospho-Akt/total Akt but not for phospho-ERK1/2/total ERK1/2 in HF-fed rats. Estrogen receptor-α levels (by 50%; p<0.05) and serum oestradiol concentrations (by 35%; p<0.05) were shown to be significantly reduced in HF-fed rats. Results and Conclusion: Our results revealed that a HF diet led to increased iNOS expression, most likely via a mechanism involving Akt and NFΚB-p50 proteins. Decreased levels of oestradiol and ERΚ protein in the HF-fed group, in combination with increased iNOS levels are consistent with the hypothesis that oestradiol has a cardioprotective effect through its ability to regulate iNOS expression. © 2017 Bentham Science Publishers.

Background: Oestradiol is an important regulatory factor with several positive effects on the cardiovascular (CV) system. We evaluated the molecular mechanism of the in vivo effects of oestradiol on the regulation of cardiac inducible nitric oxide (NO) synthase (iNOS) expression and activity. Methods: Male Wistar rats were treated with oestradiol (40 mg/kg, intraperitoneally) and after 24 h the animals were sacrificed. The concentrations of NO and L-Arginine (L-Arg) were determined spectro-photometrically. For protein expressions of iNOS, p65 subunit of nuclear factor-κB (NFκB-p65), Ras homolog gene family-member A (RhoA), angiotensin II receptor type 1 (AT1R), insulin receptor substrate 1 (IRS-1), p85, p110 and protein kinase B (Akt), Western blot method was used. Co-immunoprecipitation was used for measuring the association of IRS-1 with the p85 subunit of phos-phatidylinositol-3-kinase (PI3K). The expression of iNOS messenger ribonucleic acid (mRNA) was measured with the quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of the tissue was used to detect localization and expression of iNOS in heart tissue. Results: Oestradiol treatment reduced L-Arg concentration (p<0.01), iNOS mRNA (p<0.01) and protein (p<0.001) expression, level of RhoA (p<0.05) and AT1R (p<0.001) protein. In contrast, plasma NO (p<0.05), Akt phosphorylation at Thr308 (p<0.05) and protein level of p85 (p<0.001) increased after oestradiol treatment. Conclusion: Our results suggest that oestradiol in vivo regulates cardiac iNOS expression via the PI3K/Akt signaling pathway, through attenuation of RhoA and AT1R. © 2019 Bentham Science Publishers.

Background: Oestradiol is an important regulatory factor with several positive effects on the cardiovascular (CV) system. We evaluated the molecular mechanism of the in vivo effects of oestradiol on the regulation of cardiac inducible nitric oxide (NO) synthase (iNOS) expression and activity. Methods: Male Wistar rats were treated with oestradiol (40 mg/kg, intraperitoneally) and after 24 h the animals were sacrificed. The concentrations of NO and L-Arginine (L-Arg) were determined spectro-photometrically. For protein expressions of iNOS, p65 subunit of nuclear factor-κB (NFκB-p65), Ras homolog gene family-member A (RhoA), angiotensin II receptor type 1 (AT1R), insulin receptor substrate 1 (IRS-1), p85, p110 and protein kinase B (Akt), Western blot method was used. Co-immunoprecipitation was used for measuring the association of IRS-1 with the p85 subunit of phos-phatidylinositol-3-kinase (PI3K). The expression of iNOS messenger ribonucleic acid (mRNA) was measured with the quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of the tissue was used to detect localization and expression of iNOS in heart tissue. Results: Oestradiol treatment reduced L-Arg concentration (p<0.01), iNOS mRNA (p<0.01) and protein (p<0.001) expression, level of RhoA (p<0.05) and AT1R (p<0.001) protein. In contrast, plasma NO (p<0.05), Akt phosphorylation at Thr308 (p<0.05) and protein level of p85 (p<0.001) increased after oestradiol treatment. Conclusion: Our results suggest that oestradiol in vivo regulates cardiac iNOS expression via the PI3K/Akt signaling pathway, through attenuation of RhoA and AT1R. © 2019 Bentham Science Publishers.

Subclinical hypothyroidism (SH) is characterized by a mildly elevated concentration of thyroid stimulating hormone (TSH) despite free thyroxine (FT4) and triiodothyronine (FT3) levels within the reference range. Numerous studies revealed SH to be an independent risk factor for cardiovascular disease (CVD), including atherosclerosis, congestive heart failure, coronary heart disease, ischemic heart disease and the associated mortality. The relationship between SH and CVD is well documented, but the molecular mechanism underlying this correlation remain unknown. Endothelial dysfunction has been recognized as an initial step leading to CVD in patients with SH. Changes in lipid profile, inflammation and/or oxidative stress contribute to the endothelial dysfunction in SH. Moreover, the progression of SH is characterized by significantly decreased nitrite and nitrate levels. Recent animal and clinical studies discussed in this review suggest that nitric oxide (NO) levels could be a reliable biomarker for cardiovascular risk in SH. Understanding the regulation of NO production by thyroid hormone may provide novel and useful knowledge regarding how endothelial dysfunction in SH is linked with CVD and help us to uncover new treatments for SH. We suggest that serum NO level may be an indicator for the introduction and dosage of levothyroxine (LT4) replacement therapy in SH patients. Future studies should focus on understanding the molecular mechanisms underlying the effects of NO in physiological as well as in pathophysiological conditions such as hypothyroidism and their clinical relevance. © 2016 Bentham Science Publishers.

Cardiometabolic diseases (CMD) are a direct consequence of modern living and contribute to the development of multisystem diseases such as cardiovascular diseases and diabetes mellitus (DM). CMD has reached epidemic proportions worldwide. A sodium pump (Na+/K+-ATPase) is found in most eukaryotic cells’ membrane and controls many essential cellular functions directly or indirectly. This ion transporter and its isoforms are important in the pathogenesis of some pathological processes, including CMD. The structure and function of Na+/K+-ATPase, its expression and distribution in tissues, and its interactions with known ligands such as cardiotonic steroids and other suspected endogenous regulators are discussed in this review. In addition, we reviewed recent literature data related to the involvement of Na+/K+-ATPase activity dysfunction in CMD, focusing on the Na+/K+-ATPase as a potential therapeutic target in CMD. Copyright © 2023 Obradovic, Sudar-Milovanovic, Gluvic, Banjac, Rizzo and Isenovic.