c-Src inhibition improves cardiovascular function but not remodeling or fibrosis in Ang II-induced hypertension

c-Src plays an important role in angiotensin II (Ang II) signaling. Whether this member of the Src family kinases is involved in the development of Ang II–induced hypertension and associated cardiovascular damage in vivo remains unknown. Here, we studied Ang II–infused (400 ng/kg/min) mice in which c-Src was partially deleted (c-Src+/−) and in wild-type (WT, c-Src+/+) mice treated with a c-Src inhibitor (CGP077675; 25 mg/kg/d). Ang II increased blood pressure and induced endothelial dysfunction in WT mice, responses that were ameliorated in c-Src+/− and CGP077675-treated mice. Vascular wall thickness and cross-sectional area were similarly increased by Ang II in WT and c-Src+/− mice. CGP077675 further increased cross-sectional area in hypertensive mice. Cardiac dysfunction (ejection fraction and fractional shortening) in Ang II–infused WT mice was normalized in c-Src+/− mice. Increased oxidative stress (plasma thiobarbituric acid–reactive substances, hydrogen peroxide, and vascular superoxide generation) in Ang II–infused WT mice was attenuated in c-Src–deficient and CGP077675-treated mice. Hyperactivation of vascular c-Src, ERK1/2 (extracellular signal–regulated kinase 1/2), and JNK (c-Jun N-terminal kinase) in hypertensive mice was normalized in CGP077675-treated and c-Src+/− mice. Vascular fibronectin was increased by Ang II in all groups and further augmented by CGP077675. Cardiac fibrosis and inflammation induced by Ang II were amplified in c-Src+/− and CGP-treated mice. Our data indicate that although c-Src downregulation attenuates development of hypertension, improves endothelial and cardiac function, reduces oxidative stress, and normalizes vascular signaling, it has little beneficial effect on fibrosis. These findings suggest a divergent role for c-Src in Ang II–dependent hypertension, where c-Src may be more important in regulating redox-sensitive cardiac and vascular function than fibrosis and remodeling

Differential renal effects of candesartan at high-and ultra-high doses in diabetic mice: potential role of ACE2/AT2R/Mas

High doses of Ang II receptor (AT1R) blockers (ARBs) are renoprotective in diabetes. Underlying mechanisms remain unclear. We evaluated whether high/ultra-high doses of candesartan (ARB) up-regulate angiotensin-converting enzyme 2 (ACE2)/Ang II type 2 receptor (AT2R)/Mas receptor [protective axis of the of the renin–angiotensin system (RAS)] in diabetic mice. Systolic blood pressure (SBP), albuminuria and expression/activity of RAS components were assessed in diabetic db/db and control db/+ mice treated with increasing candesartan doses (intermediate, 1 mg/kg/d; high, 5 mg/kg/d; ultra-high, 25 and 75 mg/kg/d; 4 weeks). Lower doses candesartan did not influence SBP, but ultra-high doses reduced SBP in both groups. Plasma glucose and albuminuria were increased in db/db compared with db/+ mice. In diabetic mice treated with intermediate dose candesartan, renal tubular damage and albuminuria were ameliorated and expression of ACE2, AT2R and Mas and activity of ACE2 were increased, effects associated with reduced ERK1/2 phosphorylation, decreased fibrosis and renal protection. Ultra-high doses did not influence the ACE2/AT2R/Mas axis and promoted renal injury with increased renal ERK1/2 activation and exaggerated fibronectin expression in db/db mice. Our study demonstrates dose-related effects of candesartan in diabetic nephropathy: intermediate–high dose candesartan is renoprotective, whereas ultra-high dose candesartan induces renal damage. Molecular processes associated with these effects involve differential modulation of the ACE2/AT2R/Mas axis: intermediate–high dose candesartan up-regulating RAS protective components and attenuating pro-fibrotic processes, and ultra-high doses having opposite effects. These findings suggest novel mechanisms through the protective RAS axis, whereby candesartan may ameliorate diabetic nephropathy. Our findings also highlight potential injurious renal effects of ultra-high dose candesartan in diabetes

POESIA, CRÍTICA E TRADUÇÃO: ENTREVISTA COM RONALD AUGUSTO

Entrevista com o poeta, músico, ensaísta e crítico literário sul-riograndense Ronald Augusto, que reflete a respeito das traduções e críticas que sua obra tem recebido, terminando por uma discussão das possibilidades da crítica como uma forma de tradução (e da tradução como uma forma de crítica)

Biodegradable drug-eluting stents: Targeting urothelial tumors of upper urinary tract

INTRODUCTION & OBJECTIVES: Urothelial tumors of upper urinary tract are ranked among the most common types of cancers worldwide. The current standard therapy to prevent recurrence is intravesical Bacillus Calmetteâ Guerin (BCG) immunotherapy, but it presents several disadvantages such as BCG failure and intolerance. Another way is to use chemotherapy, which is generally better tolerated that BCG. In this case, drugs such as epirubicin, doxorubicin, paclitaxel and gemcitabine are used. Nevertheless, intravesical chemotherapy only prevents recurrence in the short-term. These failings can be partially attributed to the short residence time and low bioavailability of the drug within the upper urinary tract and the cancer cells, resulting in a need for frequent drug instillation. To avoid these problems, biodegradable ureteral stents impregnated by supercritical fluid CO2 (SCF) with each of the four anti-cancer drugs were produced. MATERIAL & METHODS: Four formulations with different concentrations of gelatin and alginate and crosslink agent were tested and bismuth was added to confer radiopaque properties to the stent. The preliminary in vivo validation studies in female domestic pigs was conducted at the University of Minho, Braga, after formal approval by the institutionâ s review board and in accordance with its internal ethical protocol for animal experiments. Paclitaxel, epirubicin, doxorubicin and gemcitabine were impregnated in the stents and the release kinetics was measured in artificial urine solution (AUS) for 9 days by UV spectroscopy in a microplate reader. The anti-tumoral effect of the developed stents in transitional cell carcinoma (TCC) and HUVEC primary cells, used as control, was evaluated. RESULTS: The in vivo validation of this second-generation of ureteral stents performed was herein demonstrated. Biodegradable ureteral stents were placed in the ureters of a female pigs, following the normal surgical procedure. The animals remained asymptomatic, with normal urine flow. The in vitro release study in AUS of the stent impregnated showed a higher release in the first 72h for the four anti-cancer drugs impregnated after this time the plateau was achieved and the stent degraded after 9 days. The direct and indirect contact of the anti-cancer biodegradable stents with the TCC and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the TCC cell line after 72h and no killing effect in the HUVEC cells. CONCLUSIONS: The use of biodegradable ureteral stent in urology clinical practice not only reduce the stent-related symptoms but also open new treatment therapyâ s, like in urothelial tumors of upper urinary tract. Furthermore, we have demonstrated the clinical validation in vivo pig model. This study has thus shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the TCC cell line, with no toxicity observed in the control, non-cancerous cells.The direct and indirect contact of the anti-cancer biodegradable stents with the TCC and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the TCC cell line after 72h and no killing effect in the HUVEC cells. This study has thus shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the TCC cell line, with no toxicity observed in the control, non-cancerous cells

Targeting urothelial tumors of upper urinary tract with drug-eluting stents impregnated by supercritical fluids

Urothelial tumors of upper urinary tract are ranked among the most common types of cancers worldwide and it has been considered as one of the more expensive to treat due of its long-term propensity of recurrence. The current standard therapy to prevent recurrence is intravesical Bacillus Calmette–Guerin (BCG) immunotherapy, but it presents several disadvantages such as BCG failure and intolerance. Another way is to use chemotherapy, that has been reported to be generally better tolerated that BCG. In this case, drugs such as epirubicin, doxorubicin, paclitaxel and gemcitabine are used. Nevertheless, intravesical chemotherapy only prevents recurrence in the short-term[1], [2]. These failings can be partially attributed to the short residence time and low penetration of the drug within the upper urinary tract and the cancer cells, resulting in a need for frequent drug instillation [3]. To avoid these problems, biodegradable ureteral stents impregnated by supercritical fluid CO2 (SCF) with each of the four anti-cancer drugs were produced (figure 1). Four types of drug-eluting biodegradable stents were studied, impregnated with paclitaxel, epirubicin, doxorubicin and gemcitabine. The release kinetics of the impregnated drugs from the anti-cancer drug-eluting stents was measured in artificial urine solution (AUS) for 9 days. The in vitro drugs release from the impregnated biodegradable ureteral stents was analyzed using a microplate reader. The in vitro release study in AUS showed a higher release in the first 72h for the four anti-cancer drugs impregnated after this time the plateau was achieved and the stent degrades after 9 days. Regarding the amount of impregnated drugs by SCF the gemcitabine showed higher amount (109 μg) and the lower amount was obtained for paclitaxel (67 ng). The diffusion coefficient and the impregnation yield were calculated. The anti-tumoral effect of the developed stents in transitional cell carcinoma (TCC) - T24 cell lines was evaluated. T24 cell line was exposed to graded concentrations (0.01 to 2000 ng/ml) of the four drugs for both 4 and 72 hours to determine the sensitivities to each drug (IC50). Toxicity as a result of both direct and indirect contact of the cell lines with the different material conditions of biodegradable stent were studied. The four anti-cancer drugs showed a concentrationdependent inhibitory effect on the T24 and HUVEC cell lines with IC50’s for paclitaxel of 7.30ng and 501.50ng, respectively. The T24 cell line shows to be more sensitive than HUVEC cell line for all the anti-cancer drugs tested. The direct and indirect contact of the anti-cancer biodegradable stents with the T24 and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the T24 cell line after 72h and no killing effect in the HUVEC cells. Finally, this study has shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the T24 cell lines, with no toxicity observed in the control, non-cancerous cells.Luso­- American Foundation's Grant for Internships in the University of California, Berkeley, 2015/CON5/CAN8; FCT PhD Grant (SFRH/BD/97203/2013); European Union's Seventh Framework Programme (FP7/2007­2013) under grant agreement n° REGPOT­CT2012­316331­ POLARIS; Project “Novel smart and biomimetic materials for innovative regenerative medicine approaches (Ref.: RL1 ­ ABMR ­ NORTE­01­0124­FEDER­000016)” cofinanced by North Portugal Regional Operational Programme (ON.2 – O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF

Utility of Pacemaker With Sleep Apnea Monitor to Predict Left Ventricular Overload and Acute Decompensated Heart Failure

Pacemakers with sleep apnea monitor (SAM) provide an easy tool to assess obstructive sleep apnea over long periods of time. The link between respiratory disturbances at night and the incidence of acute decompensated heart failure (ADHF) is not well established. We aimed at (1) determining the ability of SAM pacemakers to evaluate the extent of left ventricular overload and (2) assess the impact of respiratory disturbances at night on the occurrence of ADHF over 1-year of follow-up. We conducted a single-center prospective study. Consecutive patients with SAM pacemakers were comprehensively assessed. SAM automatically computes a respiratory disturbance index (RDI, apneas/hypopneas per hour - AH/h) in the previous night and the percentage of nights with RDI >20 AH/h in the previous 6 months. Thirty-seven patients were included (79.3 ± 11.2 years, 46% males). A high RDI in the previous night and a higher %nights with increased RDI were associated with increased NT-proBNP values (p = 0.008 and p = 0.013, respectively) and were the sole predictors of increased noninvasive pulmonary capillary wedge pressures (PCWP) in the morning of assessment (p = 0.031 and p = 0.044, respectively). Receiver operating characteristic curve analysis revealed an area under the curve of 0.804 (95% confidence interval 0.656 to 0.953, p = 0.002) for %nights with RDI >20 AH/h in the prediction of high PCWP. Patients with >12.5% of nights with RDI >20AH/h tended to have more ADHF during follow-up (log-rank p = 0.067). In conclusion, a high burden of apneas/hypopneas at night is associated with elevated NT-proBNP and PCWP values and an increased risk of ADHF over 1 year. These patients might benefit from early tailored clinical management

Polypodium leucotomos targets multiple aspects of oral carcinogenesis and it is a potential antitumor phytotherapy against tongue cancer growth

Peer reviewe

Potential application for antimicrobial and antileukemic therapy of a flavonoid-rich fraction of Camellia sinensis

The antimicrobial and antileukemic effect of a purified fraction of flavonoids from the leaves of Camellia sinensis was evaluated. An extraction yield of 9.77 mg.g-1 total flavonoids was recovered through a pressurized liquid extraction associated with solid-phase extraction. This fraction was tested against pathogenic microorganisms (Staphylococcus, Salmonella, and Enterococcus), considering the minimum inhibitory concentration. In addition, the human monocyte cell line THP-1, derived from a patient with acute monocytic leukemia, was used for the antitumor assay. The results show that the flavonoid-rich fraction obtained by coupling a Pressurized Liquids Extraction in-line with a Solid Phase Extraction (PLE-SPE) has a high antimicrobial effect and resulted in cell cycle blockage G0 / G1, increased DNA fragmentation, and altered leukemic cell morphology. These results suggest that a flavonoid-rich fraction obtained from Camellia sinensis can be applied as potential adjuvants in chemotherapy treatment to mitigate the side effects caused by chemotherapy or even as a supplement to cancer therapy9 página