LEPTIN: FROM APPETITE SUPPRESSION TO AUTOIMMUNITY

The hormone leptin is released by adipocytes accordingly to current energy stores to suppress appetite. Apart from this, leptin acts as a proinflammatory cytokine and strongly stimulates  inflammation. Immune-modulating properties are partly achieved by affecting T-cell maturation, polarization, and viability. Leptin rises inflammatory cells count, increases proinflammatory cytokine secretion, and impairs regulatory T-lymphocytes differentiation. Leptin secretion and signalization disturbances have recently started to be observed in the context of autoimmunity.  In this review, we discuss signaling pathways affected by the satiety hormone, its effect on T-lymphocyte maturation, differentiation and polarization, and relation to other immune-modulating agents. In the end, we highlight the rising evidence connecting hyperleptinemia state which is almost always related to obesity, with autoimmune disorders and take a brief overview of possible mechanisms behind leptin’s potency to induce self-reactivity

Apolipoprotein E and matrix remodeling – a link to neurodegeneration in Alzheimer's disease

Summary. Apolipoprotein E (APOE) is a glycoprotein primarily produced by astrocytes and microglia. It plays a crucial role in complexing with amyloid β (Aβ) to accelerate its clearance. APOE genotyping holds great importance in determining whether an individual carries the APOE ε2/ε3/ε4 allele and the corresponding APOE2/E3/E4 protein isoform. Carrying the APOE ε4 allele has been associated with an increased risk of Aβ accumulation, amyloid plaque formation, and late-onset Alzheimer's disease (LOAD). The identification of novel biomarkers that indicate the earliest pathophysiological processes involved in Alzheimer's disease (AD) and the analysis of their diagnostic value in patients, especially through less invasive and cost-effective procedures that can visualize AD in a minimally invasive manner, are the focuses of numerous researchers. Matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs), and activators play a significant role in extracellular matrix remodeling, disruption of blood-brain barrier integrity, prolonged neuroinflammation, and Aβ clearance. These biomarkers are showing promise as potential blood-based diagnostic markers for patients with AD. In this context, we will discuss the possible mechanisms underlying the interrelation between APOE ε4 carrier status, matrix remodeling enzymes, and neurodegeneration in AD. Additionally, we will explore the diagnostic accuracy of these biomarkers in AD dementia patients based on the results obtained by our research group

THE INFLUENCE OF THE APOEε4 ALLELE ON PRO-INFLAMMATORY CYTOKINE LEVELS IN THE CEREBROSPINAL FLUID OF PATIENTS WITH ALZHEIMER’S DISEASE

Single nucleotide polymorphisms (SNPs) rs429358 and rs7412, the most commonly investigated variants in the apolipoprotein E gene (APOE) are crucial for APOEε4 carrier status determination. However, their association with inflammatory cytokine levels in patients with dementia due to Alzheimer’s disease (AD) remains unclear. This study aimed to investigate the influence of the APOEε4 allele on pro-inflammatory cytokine levels in the cerebrospinal fluid of patients with AD dementia. The research was conducted on 36 patients with probable dementia due to AD. APOE rs429358 and rs7412 were analyzed using the Real-Time PCR method with allele-specific TaqMan assays, followed by the analysis of APOEε4 allele carrier status. Patients carrying at least one APOEε4 allele were assigned as APOEε4+. Core biomarkers (Aβ42/40 ratio, t-Tau, p-Tau levels), as well as pro-inflammatory cytokine (Tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b)) levels, were determined in the patient’s cerebrospinal fluid (CSF) using Enzyme-linked Immunosorbent Assay (ELISA). Seventeen patients (47.22%) were assigned as APOEε4+. CSF TNF-α levels were significantly higher in APOEε4+ AD dementia patients in comparison to APOEε4- patients (p<0.001), while no significant differences in IL-1b levels between these two groups were obtained. Correlation analysis showed that TNF-α negatively correlated with the Aβ42/40 ratio (p=0.033), while positive correlation with t-Tau and p-Tau was observed (p=0.001, p=0.015, respectively). These findings highlight the potential significance of TNF-α in the context of APOEε4 positivity and its implications in AD pathology

MOLECULAR MECHANISMS OF ISCHEMIC-REPERFUSION INJURY DURING LIVER RESECTION FOR COLORECTAL CANCER METASTASES- STUDY PROTOCOL

Bleeding during liver resection is a significant threat to the clinical outcome. Portal triad occlusion with complete ischemia of the liver flow of hepatoduodenal ligament is a well-documented, safe and useful way to reduce this problem. Although the technique is efficient in limiting blood loss, there is still controversy concerning potential disadvantages and subsequent reperfusion liver injury. A prospective analysis will include at least 30 patients 18-75 years old, who are undergoing liver resection due to metastases of the colorectal carcinoma. After signing the informed consent, the parameters will be analyzed in three phases, pre-, intra- and postoperatively. During surgery (indicated by a surgical/oncological team of doctors not related to our study) liver tissue samples will be taken of the “healthy liver” (not involved in the tumor process) in which after tissue homogenization, analysis of parameters will be done responsible for the development of liver injury. This research will not affect the clinical practice, course and outcome of the treatment in patients who are included. The study may be useful for future patients who will undergo liver resections. The application of modern research methods with scientific validity of statistical processing of data and the use of appropriate literature, significant data will be obtained about the character, i.e. intensity of damage of the liver tissue in patients undergoing liver resections

POPULATION PHARMACOKINETICS OF 2-OXO-CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROME

The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of 2-oxo-clopidogrel in patients with acute coronary syndrome (ACS). Population pharmacokinetic analysis was performed by using 72 plasma concentrations from the same number of patients (mean age of 60.82±10.76 years; total body weight (TBW) of 73.63±9.67 kg) with ACS using non-linear mixed-effect modeling (NONMEM). Validation of the final PPK model was carried out through the bootstrap analysis with 200 runs and it was used to estimate the predictive performance of the pharmacokinetic model. The typical mean value for 2-oxo-clopidogrel clearance (CL), estimated by the base model (without covariates), in our population was 39.2 l h−1.The value of aspartate transaminase and co-medication with digoxin were determinants of a derived population model. The final regression model for the clearance of 2-oxo-clopidogrel was the following: CL (lh-1) = 1.7 + 1.31*AST + 115*DIGOXIN. The derived PK model describes the clearance of 2-oxo-clopidogrel in patients with ACS, showing that the value of aspartate transaminase and co-medication with digoxin are the most important covariate. This finding will provide the basis for future PK studies

Tumor necrosis factor alpha gene polymorphism in Serbian patients with sarcoidosis

Introduction. Sarcoidosis is a multisystemic disease of unknown etiology. Genetic factors play a considerable role in the onset of the disease. Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine which plays an important role in the pathogenesis of the disease and the formation of granuloma by regulating cellular proliferation and apoptosis. Objective. The aim of this study was to investigate the role of TNF-α-308 G/A polymorphism in the development of sarcoidosis and to evaluate the association between the aforementioned type of polymorphism and the clinical course of the disease. Methods. Seventy patients with sarcoidosis and 50 healthy volunteers were genotyped for the TNF-α-308G/A polymorphism. Polymorphism variants were examined by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) on the DNA isolated from blood leukocytes. Results. There were no significant differences in TNF-α-308A allele frequency distribution between sarcoidosis patients and the control group, but the TNF-α-308A allele was observed significantly more frequently in the sarcoidosis patients with Löfgren’s syndrome when compared with non-Löfgren’s patients. Conclusion. We have found that the TNF-α-308A variant is associated with Löfgren’s syndrome in Serbian patients with sarcoidosis