Mitochondrial unfolded protein response, mitophagy and other mitochondrial quality control mechanisms in heart disease and aged heart

Mitochondria are involved in crucial homeostatic processes in the cell: the production of adenosine triphosphate and reactive oxygen species, and the release of pro-apoptotic molecules. Thus, cell survival depends on the maintenance of proper mitochondrial function by mitochondrial quality control. The most important mitochondrial quality control mechanisms are mitochondrial unfolded protein response, mitophagy, biogenesis, and fusion-fission dynamics. This review deals with mitochondrial quality control in heart diseases, especially myocardial infarction and heart failure. Some previous studies have demonstrated that the activation of mitochondrial quality control mechanisms may be beneficial for the heart, while others have shown that it may lead to heart damage. Our aim was to describe the mechanisms by which mitochondrial quality control contributes to heart protection or damage and to provide evidence that may resolve the seemingly contradictory results from the previous studies

Current knowledge on the genetic background of developmental dysplasia of the hip and the histomorphological status of the cartilage

Developmental dysplasia of the hip (DDH) represents a morphological abnormality characterized by the incongruity of femoral head and acetabulum. It ranges from mild dysplastic changes to complete dislocation. DDH has been associated with several hereditary and environmental risk factors, which could explain the incidence variability among different countries. Numerous genes may be involved in the disease etiology and progression. However, there are controversies in the literature regarding some of these genes. DDH-induced secondary osteoarthritis (OA) is characterized by changes in the macromolecule content of the cartilage and the expression of cartilage degradation markers. In addition, it exhibits a pattern of specific histological changes, with several reported differences between primary and DDH-induced secondary OA. The articular cartilage of patients with DDH shows specific radiological characteristics, including changes visible already in infancy, but also at pre-arthritic stages, early stages of OA, and in fully developed DDH-induced secondary OA. Although DDH has been extensively researched in different disease stages, the etiology of the disorder still remains uncertain. This review focuses on the current knowledge on the histomorphological status of the cartilage and the genetic background of DDH

Učinak pentadekapeptida BPC 157 na ishemijsko/reperfuzijske ozljede u mozgu štakora [The effect of pentadecapeptide BPC 157 on ischemic/reperfusion injuries in rat brain]

Introduction. Ischemic/reperfusion injuries are the basis of cardiovascular insult (CVI) while pentadecapeptide BPC 157, is already been proven to affect vessel integrity, it is a mediator of Robert's cytoprotection, it has beneficial effects on various injuries and interacts with the NO system, making it a promising agent for cerebral ischemic/reperfusion injuries. ----- Materials and methods. The effect of BPC 157 was examined using an animal model of bilateral carotid artery occlusion (BCAO), in Wistar rats. After an occlusion of 20 min, the rats were randomly divided into groups, treated group was administered BPC 157 (10μg/kg) while the control group was given saline (1ml, 0.9%NaCl), and depending on the group the animals received an agonist and/or antagonist of NO system (L-arginine and/or L-NAME). After 24 hours, the neurological assessment was performed using the Morris water maze test, inlined beam walk test and lateral push test and tissue samples were taken for pathohistological and RT-qPCR gene expression analysis. ----- Results. The neurological assessment showed that BPC 157 has beneficial effects on the neurological outcome, while the pathohistological analysis and gene expression analysis further confirmed the beneficial effects of BPC 157. ----- Conclusion. This experiment has revealed the beneficial effect of BPC 157 and thereby opened the possibility of using BPC 157 as a therapeutical agent in ischemic/reperfusion injuries

A randomized, double-blind, efficacy and safety study of PF-05280586 (a Rituximab biosimilar) compared with Rituximab reference product (MabThera®) in subjects with previously untreated CD20-positive, low-tumor-burden follicular lymphoma (LTB-FL)

Background: Biosimilars are highly similar to the licensed biologic ("reference product"), with no clinically meaningful differences in safety, purity, or potency between the two products. ----- Objective: This comparative 52-week clinical study evaluated the efficacy, safety, immunogenicity, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-05280586 (Ruxience™ [a rituximab biosimilar]) versus rituximab reference product sourced from the EU (MabThera®; rituximab-EU). ----- Patients and methods: Subjects with CD20-positive, low-tumor-burden follicular lymphoma (LTB-FL) and an Eastern Cooperative Oncology Group performance status 0-1 were randomized (1:1) to PF-05280586 or rituximab-EU (375 mg/m2 intravenously [once weekly for 4 weeks at days 1, 8, 15, and 22]), stratified using the Follicular Lymphoma International Prognostic Index 2 classification. The primary endpoint was overall response rate (ORR) at week 26 (percentage of subjects achieving complete response [CR] or partial response [PR]). Therapeutic equivalence was concluded if the two-sided 95% confidence interval (CI) for the difference in ORR between groups was within the prespecified margin (± 16%). Secondary endpoints included progression-free survival (PFS), CR rate, safety, immunogenicity, PK, and PD. ----- Results: A total of 394 subjects were randomized: PF-05280586 (n = 196) or rituximab-EU (n = 198). ORR at week 26 was 75.5% (PF-05280586) versus 70.7% (rituximab-EU), for a difference of 4.66%; 95% CI (- 4.16 to 13.47), which was entirely within the prespecified equivalence margin. Rates of CR were 29.3% (PF-05280586) versus 31.0% (rituximab-EU). Estimated 1-year PFS rates were 78.2% (95% CI 70.2-84.2) and 83.0% (95% CI 75.0-88.6) for PF-05280586 and rituximab-EU, respectively. Safety, immunogenicity, and mean serum concentrations were similar between groups. ----- Conclusions: The efficacy, safety, immunogenicity, PK, and PD of PF-05280586 and rituximab-EU were similar up to week 52 in subjects with previously untreated CD20-positive LTB-FL

Aktivnost eritrocitne glutation S-transferaze u djece oboljele od HenochSchönleinove purpure [Erythrocyte glutathione S-transferase activity in children with Henoch-Schönlein purpura]

Introduction: Henoch-Schönlein purpura (HSP) is the most common vasculitis of the childhood. Among all possible symptoms / complications, nephritis (HSPN) is the main and almost only cause of morbidity and mortality in HSP. The aim of this study was to investigate the value of erythrocyte glutathione S-transferase (eGST) activity as an early predictor of nephritis in HSP. ----- Subjects and methods: Ninety-seven children with HSP were enrolled into the study. The control group consisted of 52 children without clinical and laboratory signs of inflammation. In all patients e-GST activity was determined spectrometrically from the whole blood samples, after incubation with a commercial GST assay at the time of enrolment and twice more in regular intervals during follow up period of six months. In children from the control group e-GST activity was determined at the time of enrolment. ----- Results: At the beginning of the disease the e-GST activity values were significantly higher in the group of patients with HSPN compared to the group of HSP patients without nephritis: median (interquartile range) 5,70 U/gHb (4,38-7,50 U/gHb) compared to 3,10 U/gHb (2,20-4,20 U/gHb); P˂0,001. Similar results were obtained after the comparison of the patients with HSPN and control group: 5,70 U/gHb (4,38-7,50 U/gHb) vs. 3,13 U/gHb (1,91-4,20 U/gHb); P˂0,001. There were no statistically significant differences between the group of HSP patients without nephritis and a control group (P=0,837). During the follow up period of six months, a significant decrease of e-GST activity was observed in the HSPN patients, but it was still significantly higher compared to the group of HSP patients without nephritis (P˂0,001 / P˂0,001). In the ROC analysis of the e-GST activity determination value in the prediction of HSP nephritis, at the e-GST values >4,1 U/gHb a significant area under the curve (AUC) of 91.1% (P < 0.001) and sensitivity of 90.5% and specificity of 72.7% was found at the beginning of the study. The sensitivity of the nephritis detection tests decreased, and the specificity increased during the follow up period. No significant correlation between e-GST activity and severity of skin changes, or used therapy was found. Among the routine laboratory tests, a consistent, statistically significant, positive correlation was found only between e-GST activity and the number of erythrocytes per mm3 in urine samples. ----- Conclusion: e-GST activity is a reliable, independent marker of early nephritis risk assessment in children with HSP. As a sensitive and specific, feasible and inexpensive laboratory test, it has potential practical utility in the diagnostic algorithm and monitoring of the children with HSP