Significance of p57(Kip2) down-regulation in oncogenesis of bladder carcinoma: an immunohistochemical study

AIMS AND BACKGROUND: Cyclin-dependent kinase inhibitors have important roles in the oncogenesis of various tumors including urothelial cancer. The aim of this study was to establish the importance of p57(Kip2), a unique cyclin-dependent kinase inhibitor, in the oncogenesis of bladder carcinoma. This article also focused on another cyclin-dependent kinase inhibitor, p27(Kip1), and telomerase enzyme and examined the relationship between these proteins. MATERIAL AND METHODS: Thirty-one patients with urothelial carcinomas of the bladder and 7 cases with normal urinary bladder mucosa were included in the study. Immunohistochemical study was performed by monoclonal antibodies of p27(Kip1), p57(Kip2), and the telomerase subunit (hTERT). All immunohistochemical preparations were evaluated by an immunohistochemical histological score. RESULTS: p57(Kip2) and p27Kip1) expression were seen in all of the cases of normal mucosa. In carcinoma cases, 8 of 31 (25.8%) showed p57(Kip2) nuclear positivity and 20 of 31 (64.5%) expressed nuclear p27(Kip1). HSCOREs of carcinoma cases showed lower scores of nuclear p57(Kip2) and p27(Kip1) than normal mucosa, but only HSCOREs of nuclear p57(Kip2) (P = 0.001) showed statistical significance. Despite unknown significance, cytoplasmic p57(Kip2) and p27(Kip1) were also evaluated. Immunohistochemical analysis showed that carcinomas expressed higher HSCOREs of hTERT than normal mucosa, and there was a significant difference (P = 0.026) between muscle invasive carcinomas and normal mucosa. CONCLUSIONS: The data showed that p57(Kip2) down-regulation along with p27(Kip1) is a well-established feature of urothelial carcinoma. Probably, this down-regulation of cyclin-dependent kinase inhibitors supports the proliferation phase of oncogenesis. In the study, we also showed that hTERT expression was up-regulated in higher stages of urothelial carcinoma.     

Alteration of iron homeostasis following chronic exposure to manganese in rats

Recent studies suggest that manganese-induced neurodegenerative toxicity may be partly due to its action on aconitase, which participates in cellular iron regulation and mitochondrial energy production. This study was performed to investigate whether chronic manganese exposure in rats influenced the homeostasis of iron in blood and cerebrospinal fluid (CSF). Groups of 8–10 rats received intraperitoneal injections of MnCl₂ at the dose of 6 mg Mn/kg/day or equal volume of saline for 30 days. Concentrations of manganese and iron in plasma and CSF were determined by atomic absorption spectrophotometry. Rats exposed to manganese showed a greatly elevated manganese concentration in both plasma and CSF. The magnitude of increase in CSF manganese (11-fold) was equivalent to that of plasma (10-fold). Chronic manganese exposure resulted in a 32% decrease in plasma iron (p<0.01) and no changes in plasma total iron binding capacity (TIBC). However, it increased CSF iron by 3-fold as compared to the controls (p<0.01). Northern blot analyses of whole brain homogenates revealed a 34% increase in the expression of glutamine synthetase (p<0.05) with unchanged metallothionein-I in manganese-intoxicated rats. When the cultured choroidal epithelial cells derived from rat choroid plexus were incubated with MnCl₂ (100 μM) for four days, the expression of transferrin receptor mRNA appeared to exceed by 50% that of control (p<0.002). The results indicate that chronic manganese exposure alters iron homeostasis possibly by expediting unidirectional influx of iron from the systemic circulation to cerebral compartment. The action appears likely to be mediated by manganese-facilitated iron transport at brain barrier systems.     

Spontaneous subarachnoidal hemorrhage in patients with Covid-19: case report

Journal of NeuroVirology - In this article, subarachnoidal hemorrhage developing in a case with Covid-19-related pneumonia was evaluated. In the presence of respiratory system infection signs such...     

Sodium L‐lactate differently affects brain‐derived neurothrophic factor,inducible nitric oxide synthase,and heat shock protein 70 kDa production in human astrocytes and SH‐SY5Y cultures

The present study analyzed the in vitro effects induced by sodium L‐lactate on human astrocytes and the SH‐SY5Y cell line, when added at concentrations of 5, 10, and 25 mmol/liter. Expression of brain‐derived neurotrophic factor (BDNF), inducible nitric oxide synthase (iNOS), and heat shock protein 70 kDa (HSP70) was evaluated by Western blot analysis. Cell viability with MTT, release of nitric oxide (NO) through the Griess reaction, and production of BDNF by enzyme‐linked immunoassay was determined. Data indicate that, in SH‐SY5Y as well as in cortical astrocytes, after 4 hr sodium L‐lactate increases the expression and release of BDNF, iNOS, and NO; after 24 hr, it turns is ineffective for the production of the neurotrophin in SH‐SY5Y and not in astrocytes, but the expression of iNOS and release of NO appear to be further increased compared with those after 4 hr. Sodium L‐lactate influences differently the expression of HSP70 in SH‐SY5Y compared with astrocytes. We propose, based on these findings, that sodium L‐lactate affects the expression of BDNF in SH‐SY5Y and astrocytes in a different manner: high levels of iNOS and NO expressed in SH‐SY5Y have a profound inhibitory effect on the release of BDNF related to a more limited production of HSP70 by SH‐SY5Y. In conclusion, the results demonstrate differences in the responses of SH‐SY5Y and astrocytes to stimulation by high levels of sodium L‐lactate. Sodium L‐lactate differently and dose and time dependently influences the expression and release of BDNF, iNOS, NO, and HSP70 depending on the cell type. © 2012 Wiley Periodicals, Inc.     

Early neurodevelopmental assessment in Duchenne muscular dystrophy

The aim of this study was to assess neurodevelopmental profile in young boys affected by Duchenne muscular dystrophy and to establish the correlation between neurodevelopmental findings, and the type and site of mutations. A structured neurodevelopmental assessment (Griffiths Scale of Mental Development) was performed in 81 DMD boys before the age of four years (range: 7–47 months). The mean total DQ was 87 (SD 15.3). Borderline DQ (between 70 and 84) was found in 32% and DQ below 70 in 12.3% of the patients. Children with mutations upstream or in exon 44 had higher DQ than those with mutations downstream exon 44 which are associated with involvement of dystrophin isoforms expressed at high levels in brain. The difference was significant for total and individual subscale DQ with the exception of the locomotor subscale. Items, such as ability to run fast, or getting up from the floor consistently failed in all children, irrespective of the age or of the site of mutation. Our results help to understand the possible different mechanisms underlying the various aspects of neurodevelopmental delay, suggesting that the involvement of brain dystrophin isoforms may cause a delay in the maturation of coordination and dexterity.     

Transforming growth factor-beta1 induces apoptosis in vascular endothelial cells by activation of mitogen-activated protein kinase

BACKGROUND: Vascular endothelial cell apoptosis is central in atherosclerosis and intimal hyperplasia. Transforming growth factor (TGF)-beta1 induces endothelial cell apoptosis through unidentified mechanism(s). Although TGF-beta1 signals through the Smad proteins, in some nonendothelial cell types it also activates the mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 MAPK [p38(MAPK)]). p38(MAPK) relays apoptotic signals in several cell types. We hypothesized that TGF-beta1 activates endothelial cell MAPKs and induces apoptosis through p38(MAPK) activation. METHODS: Human umbilical vein or bovine capillary endothelial cells were incubated with TGF-beta1 for 0.5 to 12 hours. MAPK activation was characterized by Western blotting with antibodies to phosphorylated extracellular signal-regulated kinase 1/2, p38(MAPK), or c-Jun N-terminal kinases 1/2. To study apoptosis, extracts of cells incubated with TGF-beta1 for 6 hours with or without MAPK inhibitors were characterized by Western blotting analysis of poly (ADP-Ribose) polymerase degradation. RESULTS: TGF-beta1 induced p38(MAPK), extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase 1/2 activation and increased apoptosis. Inhibition of p38(MAPK) significantly reduced TGF-beta1-induced apoptosis. In contrast, inhibition of other signaling pathways was ineffective. CONCLUSIONS: TGF-beta1 induces endothelial cell apoptosis through p38(MAPK) activation. Because TGF-beta1 is upregulated in vascular remodeling, p38(MAPK) is a potential target to prevent endothelial cell apoptosis during this process.     

Are Mean Platelet Volume and Platelet Distribution Width Useful Parameters in Children With Acute Rheumatic Carditis?

Rheumatic fever (RF) is an inflammatory disease caused by autoimmune response to a preceding group A streptococcal infection. Mean platelet volume (MPV) reflects the platelet size and the rate of platelet production in bone marrow, and it may be used as an indicator of platelet activation and severity of inflammation. Fifty-three consecutive patients diagnosed with acute rheumatic carditis and 53 control subjects were enrolled into this study. Leukocyte and platelet counts were significantly higher in patients with acute carditis before treatment compared with controls, whereas MPV and platelet distribution width (PDW) values were not significantly different between groups. Platelet counts, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) values were decreased significantly in patients with RF after treatment. There was not a significant difference in terms of platelet count between the controls and the patient group after treatment. ESR was found to be correlated with CRP in patients before and after treatment. In conclusion, the results of our study showed that MPV and PDW levels do not change during acute rheumatic carditis before and after treatment.