Simvastatin induces apoptosis by a Rho-dependent mechanism in cultured cardiac fibroblasts and myofibroblasts

Several clinical trials have shown the beneficial effects of statins in the prevention of coronary heart disease. Additionally, statins promote apoptosis in vascular smooth muscle cells, in renal tubular epithelial cells and also in a variety of cell lines; yet, the effects of statins on cardiac fibroblast and myofibroblast, primarily responsible for cardiac tissue healing are almost unknown. Here, we investigated the effects of simvastatin on cardiac fibroblast and myofibroblast viability and studied the molecular cell death mechanism triggered by simvastatin in both cell types.

Methods

Rat neonatal cardiac fibroblasts and myofibroblasts were treated with simvastatin (0.1-10 μM) up to 72 h. Cell viability and apoptosis were evaluated by trypan blue exclusion method and by flow cytometry, respectively. Caspase-3 activation and Rho protein levels and activity were also determined by Western blot and pull-down assay, respectively.

Results

Simvastatin induces caspase-dependent apoptosis of cardiac fibroblasts and myofibroblasts in a concentration- and time-dependent manner, with greater effects on fibroblasts than myofibroblasts. These effects were prevented by mevalonate, farnesylpyrophosphate and geranylgeranylpyrophosphate, but not squalene. These last results suggest that apoptosis was dependent on small GTPases of the Rho family rather than Ras.

Conclusion

Simvastatin triggered apoptosis of cardiac fibroblasts and myofibroblasts by a mechanism independent of cholesterol synthesis, but dependent of isoprenilation of Rho protein. Additionally, cardiac fibroblasts were more susceptible to simvastatin-induced apoptosis than cardiac myofibroblasts. Thus simvastatin could avoid adverse cardiac remodeling leading to a less fibrotic repair of the damaged tissues.     

Hypophosphatemic osteomalacia: a report of five cases and evaluation of bone markers

In this study, we analyzed the changes in biochemical markers of bone turnover in five patients with hypophosphatemic osteomalacia. The following bone markers were evaluated: among bone formation markers, total alkaline phosphatase (TAP), bone alkaline phosphatase (BAP), osteocalcin (bone Gla protein, BGP) and procollagen type I N propeptide (PINP); among bone resorption markers, serum C-terminal cross-linked telopeptide of type I collagen (s-CTx), urinary hydroxyproline (HYP), and N-terminal and and C-terminal cross-linked telopeptides of collagen (NTx and - and -CTx). In addition, the /-CTx ratio was evaluated. TAP and BAP were the markers with the highest increase in both frequency and magnitude. Conversely, BGP values were low in all patients. Collagen-related markers were slightly increased in nearly half of the patients. Among them, PINP showed the highest proportion of increased values. The /-CTx ratio was within normal values in all patients. In conclusion, TAP and BAP seem to be the best bone markers in the diagnostic evaluation of hypophosphatemic osteomalacia. In addition, their high values associated with low levels of BGP provide an even more reliable biochemical profile of this disorder, when associated with the classic mineral and skeletal homeostasis abnormalities.     

The effect of quercetin phase II metabolism on its MRP1 and MRP2 inhibiting potential

The present study characterises the effect of phase II metabolism, especially methylation and glucuronidation, of the model flavonoid quercetin on its capacity to inhibit human MRP1 and MRP2 activity in Sf9 inside-out vesicles. The results obtained reveal that 3'-O-methylation does not affect the MRP inhibitory potential of quercetin. However, 4'-O-methylation appeared to reduce the potential to inhibit both MRP1 and MRP2. In contrast, glucuronidation in general, and especially glucuronidation at the 7-hydroxylmoiety, resulting in 7-O-glucuronosyl quercetin, significantly increased the potential of quercetin to inhibit MRP1 and MRP2 mediated calcein transport with inhibition of MRP1 being generally more effective than that of MRP2. Overall, the results of this study reveal that the major phase II metabolites of quercetin are equally potent or even better inhibitors of human MRP1 and MRP2 than quercetin itself. This finding indicates that phase II metabolism of quercetin could enhance the potential use of quercetin- or flavonoids in general-as an inhibitor to overcome MRP-mediated multidrug resistance.     

Expression profiling of T-cell lymphomas differentiates peripheral and lymphoblastic lymphomas and defines survival related genes.

PURPOSE: T-Cell lymphomas constitute heterogeneous and aggressive tumors in which pathogenic alterations remain largely unknown. Expression profiling has demonstrated to be a useful tool for molecular classification of tumors. EXPERIMENTAL DESIGN: Using DNA microarrays (CNIO-OncoChip) containing 6386 cancer-related genes, we established the expression profiling of T-cell lymphomas and compared them to normal lymphocytes and lymph nodes. RESULTS: We found significant differences between the peripheral and lymphoblastic T-cell lymphomas, which include a deregulation of nuclear factor-kappaB signaling pathway. We also identify differentially expressed genes between peripheral T-cell lymphoma tumors and normal T lymphocytes or reactive lymph nodes, which could represent candidate tumor markers of these lymphomas. Additionally, a close relationship between genes associated to survival and those that differentiate among the stages of disease and responses to therapy was found. CONCLUSIONS: Our results reflect the value of gene expression profiling to gain insight about the molecular alterations involved in the pathogenesis of T-cell lymphomas.     

The angiotensin II type 2 receptor: What is its clinical significance?

Angiotensin (Ang) II exerts its important physiologic functions through two distinct receptor subtypes, the type 1 (AT1) and type 2 (AT2) receptors. AT1 and AT2 receptors have demonstrated counterregulatory interactions in the cardiovascular and renal systems. The cross-talk between AT1 and AT2 receptors has been suggested to participate in regulating blood pressure, cardiovascular growth, fibrosis, and remodeling, as well as renal blood flow, growth, fibrosis, and sodium excretion. The AT1 receptor is distributed ubiquitously and abundantly in adult tissues, whereas expression of the AT2 receptor is high in the fetus but low in adult tissues. However, mounting evidence indicates that AT2 receptor cardiovascular expression increases in response to injury and AT1 receptor blocker therapy. This article reviews recent experimental and clinical data elucidating the role of the AT2 receptor in cardiovascular and renal homeostasis.     

Ultrasound diagnosis of ruptured hydatid cyst of the liver with biliary obstruction

Communication between a hydatid cyst of the liver and biliary tract results in a clinical picture of obstructive jaundice because of occupation of the extrahepatic biliary tract by intracystic material. Five cases of this complication are presented. Ultrasound criteria for diagnosis are analyzed, based on previous publications as well as our own experience.     

Familial Ehlers-Danlos Syndrome Type II: Abnormal Fibrillogenesis of Dermal Collagen

We examined a father and son affected by Ehlers-Danlos syndrome type II. Both patients had micrognathia together with ligament and skin hyperlaxity. The son exhibited complete cleft palate. Ultrastructural studies revealed abnormal collagen fibrils in the dermis of both patients. In the child the most striking alterations consisted of lateral fusion of an enormous number of collagen fibrils giving rise to huge polymorphic collagen masses. In the father's dermis the great majority of collagen fibrils appeared normal; however, lateral fusion of fibrils together with local abnormal collagen aggregation were occasionally seen. In both patients the dermal elastic network was well developed and elastic fibers appeared normal.     

Characterising the KMP-11 and HSP-70 recombinant antigens' humoral immune response profile in chagasic patients

Background  

Antigen specificity and IgG subclass could be significant in the natural history of Chagas' disease. The relationship between the different stages of human Chagas' disease and the profiles of total IgG and its subclasses were thus analysed here; they were directed against a crude T. cruzi extract and three recombinant antigens: the T. cruzi kinetoplastid membrane protein-11 (rKMP-11), an internal fragment of the T. cruzi HSP-70 protein_192-433, and the entire Trypanosoma rangeli HSP-70 protein.     

Positive emotion following a stroke.

OBJECTIVE: Interest in exploring the positive emotional health of adults has increased. The current study investigated the positive emotion of adults with stroke at discharge from in-patient medical rehabilitation and 3 months post-discharge. DESIGN: A longitudinal study in which information was collected during in-patient medical rehabilitation stay and 3 months post-discharge. SUBJECTS: The study included 856 persons with stroke aged 55 years or older. RESULTS: Mean age for the sample was 72.5 years, 78.7% of subjects were non-Hispanic white and 51.9% were women. Mean length of hospital stay was 20.2 days. More than one-third of patients reported higher positive emotion over the 3-month follow-up, while 29.7% reported lower positive emotion. In addition to discharge positive emotion, 4 factors, including depression, level of education and motor and cognition functional status score, significantly predicted lower depression at 3-month follow-up. CONCLUSION: A large percentage of adults reported high positive emotion in the initial months following a stroke. This finding adds to work on stroke recovery and indicates the emotional resilience of adults when faced with a health challenge. Understanding the role of positive emotion in persons living with stroke may provide insight into long-term recovery.