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Background and Objectives: Atrial fibrillation (AF) is a common complication of cardiac surgery. c-Src has been implicated in atrial remodeling in chronic AF, but its role in the early postoperative setting remains unclear. We, therefore, investigated whether baseline c-Src expression in atrial tissue is associated with the subsequent development of postoperative AF (PoAF). The aim of the present work was the evaluation of atrial c-Src expression and activity in patients subjected to open heart surgery who were previously free from AF and to check if changes to the initial level of this protein predispose to the development of postoperative AF (PoAF). Materials and Methods: Forty-two patients without previous AF history we enrolled. Patients with an AF episode during postoperative in-hospital follow-up were assigned to the PoAF group, while the rest (in sinus rhythm—SR) constituted the control group. Samples of the right atrial appendage were harvested before the introduction of the extracorporeal circulation. The expression of c-Src and phospho-c-Src(Tyr416), as well as upstream regulators of c-Src kinase, STAT3, ERK1/2, PDGFRα, and PDGFRβ, was assessed using Western blot. Results: AF occurred in 14 subjects. Expression of c-Src and phospho-c-Src was significantly higher in the PoAF group than in the SR group (c-Src: 1.65×, p = 0.037, and phospho-c-Src: 2.75×, p = 0.003). In addition, in the right atrium of PoAF patients, there was significantly elevated expression of STAT3, ERK1/2, and PDGF receptors, which may facilitate activation of c-Src kinase in patients with PoAF. Conclusions: Our preliminary findings suggest that c-Src expression and activity may contribute to atrial vulnerability and could represent a molecular target for future therapeutic interventions to prevent PoAF.

The significance of interleukin 6 (IL-6) in long-term reference memory was tested in the Morris water maze (MWM) in 4-month-old C57BL/6J IL-6-deficient (IL-6 KO) and control mice. Three-day learning measured by escape latency time to find the hidden platform was comparable in both genotypes. In a single probe trial performed 7 days later, without the platform, latency to the platform site and path length to the target place were significantly shorter (p < 0.05 and p < 0.02, respectively), and platform-site crossovers more frequent (p < 0.05) in IL-6 KO mice. The swimming speed in IL-6 KO mice was significantly lower during learning (p = 0.0025) but not in the probe trial. Lack of differences between genotypes in a hole-board and in an elevated plus maze indicates that the observed effects were memory specific. The facilitatory effect of IL-6 deficiency on long-term reference memory in MWM indicates that IL-6 plays a role in consolidation process.

The significance of plasminogen activation during the tympanic membrane (TM) healing is known mainly from studies performed on knock-out mice. In the previous study, we reported activation of genes coding proteins of plasminogen activation and inhibition system in rat’s TM perforation healing. The aim of the present study was the evaluation of protein products expressed by these genes and their tissue distribution using Western blotting and immunofluorescent method, respectively, during 10-day observation period after injury. Otomicroscopical and histological evaluation were employed to assess the healing process. The expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) were significantly upregulated in the proliferation phase, with subsequent gradual attenuation during remodeling phase of healing process, when keratinocyte migration was weakening. The expression of plasminogen activator inhibitor type 1 (PAI-1) also showed the highest levels during the proliferation phase. The increase of tissue plasminogen activator (tPA) expression was observed during the whole observation period, with the highest activity during the remodeling phase. Immunofluorescence of these proteins was present mainly in migrating epithelium. Our study found that plasminogen activation (uPA, uPAR, tPA) and inhibitory (PAI-1) molecules form a well-structured regulatory system of the epithelial migration that is critical to the healing of TM after its perforation.

Chronic peripheral elevation of interleukin 6 (IL-6) in humans is associated with cognitive deficits. 4- and 24-month-old IL-6-deficient C57BL/6J (IL-6KO) and reference wild-type (WT) mice were tested in an object recognition test. Discrimination ratios and recognition indexes were significantly lower in 4-month-old IL-6KO and in 24-month-old WT mice vs 4-month-old WT animals. Their discrimination ratios had negative values and recognition indexes were below 50% indicating inability to differentiate the novel from the familiar object after 1-hour delay. In 24-month-old IL-6KO mice recognition index reached 53.17% indicating that their recognition memory was not worsened with age in comparison with younger IL-6-deficient animals. Results of holeboard and elevated plus maze indicated that this effect was memory specific. Inborn IL-6 deficiency attenuated recognition memory in 4-month-old mice and did not altered recognition memory in aged animals. IL-6 signalling may constitute a target for development of the protection against memory disturbances connected with IL-6 overexpression.

Inflammatory mediators play an important role in development and progression of cardiovascular disease. Both adrenergic stimulation and high levels of interleukin-6 (IL-6) indicate an unfavorable outcome in patients with myocardial infarction or heart failure. Understanding the interaction between β-adrenergic stimulation and IL-6 in the myocardium may contribute to developing more effective treatments. The aim of this study was to verify the role of IL-6 in the effects of β-adrenergic stimulation in activating selected intracellular signaling pathways in mouse myocardium. Experiments were performed on 12-week-old male mice: 16 C57BL/6JIL6 (IL-6 KO) and 17 C57BL/6J (WT). Animals received intraperitoneal injections of isoproterenol (ISO, 50 mg/kg) or placebo (0.9% NaCl) once a day for 16 days. The phosphorylation of STAT3 (signal transducer and activator of transcription 3), ERK1/2 (extracellular-regulated kinases 1/2), Akt1/2/3, p-38, c-Raf and expression of SOCS3 (suppressor of cytokine signaling 3), PIAS1/3 (protein inhibitors of activated STAT) was assessed by western blotting in the myocardium 24 h after the last injection. Evaluation of gene expression downstream of these pathways was performed by real-time PCR. Chronic ISO treatment leads to increased fibrosis of the myocardium in mice lacking IL-6, which is accompanied by increased activity of ERK1/2, p38 and reduced expression of SOCS3. Administration of ISO in IL-6 KO animals intensified gene expression of proteins activated by MAPK/ERK (myc; CEBPB; BMP4; Fasn; Tank), while it reduced expression of genes repressed by ERK 1/2 (Wisp1, Wnt1). IL-6 plays an important role in regulating the activation of MAPK pathways in the mouse myocardium in response to chronic β-adrenergic stimulation.

This study investigates age-related neurodegeneration in the cerebellar cortex, emphasizing the role of IL-6 deficiency in preserving Purkinje cells. We found that apoptosis plays a minimal role in Purkinje cell loss by using 4-month- and 24-month-old wild-type (WT) and IL-6 knockout (IL-6KO) mice. At 24 months, WT mice exhibited severe Purkinje cell degeneration, including atrophic cell bodies, eosinophilic cytoplasm, pyknotic nuclei, mitochondrial disruption, and increased levels of lipofuscin-rich lysosomes. In contrast, IL-6KO mice showed fewer lysosomes, reduced mitochondrial damage, and less neuronal atrophy, indicating a neuroprotective effect. Lower p53 expression and decreased levels of its downstream effectors (p21, and Bax) in IL-6KO mice correlated with reduced cellular stress. Minimal changes in apoptotic markers (Bax and caspase-3) further reinforce the limited role of apoptosis. Neuroinflammation, marked by elevated GFAP, was prominent in aged WT mice but attenuated in IL-6KO mice. Reduced p53 accumulation, less severe neuroinflammation, and preserved metabolic homeostasis in IL-6KO mice correlated with improved Purkinje cell survival. These findings suggest that IL-6 accelerates neurodegeneration via p53-associated stress and inflammation, while IL-6 deficiency mitigates these effects. Targeting IL-6 signaling through anti-inflammatory strategies or IL-6 inhibition may offer a therapeutic approach for age-related neurodegenerative disorders.

Our earlier studies demonstrated slower age-related memory decline in IL-6-deficient than in control mice. Therefore, in the present study we evaluated the effect of IL-6 deficiency and aging on expression of p53, connected with accumulation of age-related cellular damages, in hippocampus of 4- and 24-month-old IL-6-deficient C57BL/6J (IL-6KO) and wild type control (WT) mice. The accumulation of p53 protein in hippocampus of aged IL-6KO mice was significantly lower than in aged WT ones, while p53 mRNA level was significantly higher in IL-6-deficient mice, what indicates that the effect was independent on p53 transcription. Presence of few apoptotic cells in hippocampal dentate gyrus and lack of changes in levels of pro-apoptotic Bax, antiapoptotic Bcl-2, as well as in p21 protein in aged animals of both genotypes, points to low transcriptional activity of p53, especially in aged WT mice. Because the amount of p53 protein did not correlate with the level of Mdm2 protein, its main negative regulator, other than Mdm2-dependent mechanism was involved in p53 build-up. Significantly higher mRNA levels of autophagy-associated genes: Pten, Tsc2, and Dram1 in IL-6KO mice, in conjunction with significantly lower amount of Bcl-2 protein in 4-month-old IL-6KO mice, suggests that lack of IL-6/STAT3/Bcl-2 signaling could account for better autophagy performance in these mice, preventing excessive accumulation of proteins. Taken together, attenuated p53 protein build-up, absence of enhanced apoptosis, and transcriptional up-regulation of autophagy-associated genes imply that IL-6 deficiency may protect hippocampus from age-related accumulation of cellular damages.

Aging is related to gradual increase of interleukin 6 (IL-6) plasma level that affects peroxisome proliferator-activated receptor (PPAR) expression. We evaluated age-related changes in cardiac expression of PPARα, its coactivator PGC-1α, and selected downstream proteins in mice with systemic IL-6 knockout (IL6KO). Male C57BL6/J wild-type (WT) and IL6KO mice were used at the age of 16–20 weeks (young) and 24–30 months (senescent). Echocardiography and electron microscopy were applied to assess the function and ultrastructure of the heart. Western blotting and quantitative real-time PCR were used to estimate protein and mRNA levels of selected genes. PPARα expression in the myocardium of young IL6KO animals is lower and remains unchanged with aging, whereas in WT mice it declines with age and in both senescent groups it is equal. We observed aging-related upregulation of PGC-1α and less pronounced decline of Sirt3 in IL6KO animals; the level of cytochrome C was significantly decreased in IL6KO group only, suggesting disturbed mitochondrial function, which was not sufficient to evoke obvious changes in cardiac performance and function assessed by echocardiography. IL-6 and aging are involved in regulation of PPARα and PGC-1α expression and may influence the mitochondrial function.

TNF[alpha] and PPAR[gamma] are important modulators of metabolism, inflammation, and atherosclerosis. Coronary artery disease is the leading cause of heart failure (HF). The aim of the study was to assess whether polymorphisms of the TNF[alpha] (- 308G>A) and PPARG2 (Pro12Ala) genes are associated with the risk of developing HF by patients with ischemic heart disease. Methods. 122 patients without HF (aged 63 [+ or -] 8.8 years, 85% males) with confirmed coronary artery disease qualified for coronary bypass grafting were enrolled in the study. After the procedure, they were screened for cardiac parameters. Those with elevated NT-proBNP or diminished left ventricular ejection fraction during follow-up were assigned to the HF group (n=78), and the remaining ones to the non-HF group (n=44). The TNF[alpha] -308G>A and PPARG2 Pro12Ala polymorphisms were detected using the TaqMan method. Results. The distributions of TNF[alpha] -308G>A and PPARG2 Pro12Ala did not differ between the HF and non-HF groups (-308G>A: 16% vs. 11.4% of alleles; Pro12Ala: 23.9% vs. 20.5% of alleles, respectively). IL-6 concentration in the plasma of TNF[alpha] A-allele carriers at months 1 and 12 after CABG was higher in the HF group compared to the non-HF group (1 month after CABG: 5.3 [+ or -] 3.4 vs. 3.1 [+ or -] 2.9, p<0.05; 12 months after CABG: 4.2 [+ or -] 3,9 vs. 1.4 [+ or -] 1.2, p<0.01, respectively). Both polymorphisms were not related to changes in the plasma TNF[alpha] concentration or other parameters related to HF. Conclusions. Our study did not reveal any correlation between the PPARG2 Pro12Ala and TNF[alpha] -308G>A polymorphisms and development of HF in patients with ischemic heart disease after coronary bypass grafting.

TNFα and PPARγ are important modulators of metabolism, inflammation, and atherosclerosis. Coronary artery disease is the leading cause of heart failure (HF). The aim of the study was to assess whether polymorphisms of the TNFα (-308G>A) and PPARG2 (Pro12Ala) genes are associated with the risk of developing HF by patients with ischemic heart disease. Methods. 122 patients without HF (aged 63 ± 8.8 years, 85% males) with confirmed coronary artery disease qualified for coronary bypass grafting were enrolled in the study. After the procedure, they were screened for cardiac parameters. Those with elevated NT-proBNP or diminished left ventricular ejection fraction during follow-up were assigned to the HF group (n=78), and the remaining ones to the non-HF group (n=44). The TNFα -308G>A and PPARG2 Pro12Ala polymorphisms were detected using the TaqMan method. Results. The distributions of TNFα -308G>A and PPARG2 Pro12Ala did not differ between the HF and non-HF groups (-308G>A: 16% vs. 11.4% of alleles; Pro12Ala: 23.9% vs. 20.5% of alleles, respectively). IL-6 concentration in the plasma of TNFα A-allele carriers at months 1 and 12 after CABG was higher in the HF group compared to the non-HF group (1 month after CABG: 5.3 ± 3.4 vs. 3.1 ± 2.9, p<0.05; 12 months after CABG: 4.2 ± 3,9 vs. 1.4 ± 1.2, p<0.01, respectively). Both polymorphisms were not related to changes in the plasma TNFα concentration or other parameters related to HF. Conclusions. Our study did not reveal any correlation between the PPARG2 Pro12Ala and TNFα -308G>A polymorphisms and development of HF in patients with ischemic heart disease after coronary bypass grafting.