Quercetin (QCT) is flavonoid that possesses various biological functions including anti-oxidative and radical-scavenging activities. Moreover, QCT exerts some preventive actions in treatment of cardiovascular diseases. The aim of present study was to explore effects of prolonged administration of QCT on changes induced by repeated application of doxorubicin (DOX) in rat hearts. We focused on the ultrastructure of myocardium, matrix metalloproteinases (MMPs), biometric parameters, and apoptosis induction. Our aim was also to examine effects of QCT on ischemic tolerance in hearts exposed to chronic effects of DOX, and to determine possible mechanisms underlying effects of QCT. Our results showed that QCT prevented several negative chronic effects of DOX: (I) reversed DOX-induced blood pressure increase; (II) mediated improvement of deleterious effects of DOX on ultrastructure of left ventricle; (III) prevented DOX-induced effects on tissue MMP-2 activation; and (iv) reversed effects of DOX on apoptosis induction and superoxide dismutase inhibition. Moreover, we showed that rat hearts exposed to effects of QCT were more resistant to ischemia/reperfusion injury. Effects of QCT on modulation of ischemic tolerance were linked to Akt kinase activation and connexin-43 up-regulation. Taken together, these results demonstrate that prolonged treatment with QCT prevented negative chronic effects of DOX on blood pressure, cellular damage, MMP-2 activation, and apoptosis induction. Moreover, QCT influenced myocardial responses to acute ischemic stress. These facts bring new insights into mechanisms of QCT action on rat hearts exposed to the chronic effects of DOX.

Aim: To investigate the role of matrix metalloproteinases (MMPs) in the responses of rats to a prolonged doxorubicin (DOX) treatment. Methods: Male Wistar rats were used. DOX was administered by intraperitoneal injections of seven doses (cumulative dose was 15 mg/kg). Control animals were treated with saline. Tissue or plasma samples were collected at four and eight weeks after the application of the last dose. Protein levels were determined by immunoblot assay, and MMP activities were measured by gelatin zymography. Superoxide content was analyzed using a lucigenin chemiluminescence assay and superoxide dismutase (SOD) activities with a SOD assay kit. Qualitative structural alterations of the heart were characterized by transmission electron microscopy. Results: Systolic blood pressure was higher in DOX-treated rats as compared with the control rats at 8 weeks after treatment. In contrast, there were no differences in the heart rate between the control and DOX-treated rats. DOX treatment caused marked heterogeneous subcellular alterations of cardiomyocytes and structural disorganizations of the cardiac extracellular space. The effects of DOX were linked to a stimulation of plasma MMP-2 and MMP-9 activities that had already increased by 4 weeks after the end of the treatment. In the left ventricle, however, DOX only led to increased MMP-2 activation at 8 weeks after the end of treatment. These changes in tissue MMP-2 were connected with stimulation of Akt kinase activation, inhibition of SOD, an increase in superoxide levels, induction of iNOS protein expression and caspase-3 activation. Conclusion: Our results show that MMPs are involved in the chronic cardiotoxicity of DOX in rats. The data also suggest that reactive oxygen species (superoxide), NO production (iNOS) and the Akt kinase pathway can modulate MMP-2 activities in rat hearts influenced by DOX.

Aims: We aimed to evaluate the prevalence of irritable bowel syndrome (IBS), functional dyspepsia (FD), and their overlap syndrome (OS) in the Bulgarian population and to assess the risk factors associated with these disorders. Methods: We sent an internet-based survey to Bulgarian adults. The survey collected data on socio- demographic, behavioral and lifestyle characteristics, and diagnostic questions following the Rome IV criteria to assess IBS, FD and their overlap occurrence. Results: Data was collected from 1,896 individuals (mean age = 35.5 years, 18-65, SD=11.7), 73.1% females. The prevalence of IBS was 20% (14% were with predominant constipation, 32% with predominant diarrhea, 52% had IBS with mixed bowel habits, and 2% unclassified IBS). Gender (p=0.005), age (p<0.001), marital status (p=0.009), occupation (p=0.001), alcohol consumption (p=0.013), sexual problems (p<0.001), FD (p<0.001), and milk intolerance (p<0.001) were significantly associated with IBS. Females (p=0.032; OR: 1.50), patients with FD (p<0.001; OR: 104.98), sexual problems (p= 0.001; ОR: 1.55 ), and milk intolerance (p<0.001; OR: 2.22) are at a higher risk of having IBS. The prevalence of FD was 12.7% (39% had postprandial distress syndrome, 33% epigastric pain syndrome, and 28% had the overlapping variant). Patients with IBS (p<0.001; OR: 127.88) and milk intolerance (p<0.001) were significantly associated with FD prevalence. The prevalence of OS was 11.7%. Gender (p=0.013), milk intolerance (p<0.001, OR: 1.65), urinary (p=0.035) and sexual problems (p<0.001, ОR: 1.80) were associated with OS prevalence. Conclusion: This is the first study to estimate the prevalence of IBS, FD, and their OS and assess the behavioral and demographic risk factors associated with these disorders in the Bulgarian population. Our results are valuable in filling in the epidemiological data gap regarding IBS, FD, and OS in Eastern Europe.

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Abstract. Matrix metalloproteinases (MMPs) are enzymes that play an important role in degradation and remodeling of extracellular matrix and MMP-2 has been also shown as a primary mediator of the acute mechanical dysfunction of the heart immediately after ischemia/reperfusion (I/R). The aims of the study were to investigate the influence of I/R on MMP-2 and to study the effects of wortmannin on modulation of MMP-2 activities after cycle of short I/R procedures (ischemic preconditioning, IP). Wortmannin is a specific inhibitor of PI3K/Akt kinase pathway activation of which was found to play a role in infarct size limiting mechanisms in the rat heart. In the study isolated Langendorff-perfused rat hearts subjected to protocols of prolonged (test) I/R and/or IP were used. Wortmannin was infused before and during the reperfusion phase of IP. The levels and activation of proteins were determined by immunoblot assay. The MMP-2 activities were measured by zymography. We found that ischemia induced time-dependent activation of tissue pro-MMP-2. Strong activation occurred after 15 min ischemia, during prolonged ischemia and following reperfusion the activities of this form of MMP-2 declined. The specific activities of both 72 and 63 kDa forms of MMP-2 were increased in perfusates collected during reperfusion after 30 min ischemia and these activities peaked in the first minute of reperfusion. Cycle of short ischemia and reperfusion that led to increased cardiac tolerance against prolonged I/R reduced 72 kDa MMP-2 activities and induced also an activation of Akt kinase. The application of wortmannin was connected with inhibition of IP-mediated Akt kinase activation. Moreover, the actions of wortmannin were linked with modulation of MMP-2 activities. Our results suggest that MMP-2 may be involved in the responses of rat hearts to ischemia and point to possible relationship between Akt kinase and modulation of MMP-2 activities in rat hearts.