Given a passage, construct a question on the basis of the information present in the passage. Construct the question in such a way that (i) it is unambiguous, (ii) it is answerable from the passage, (iii) its answer is unique (iv) it answer uses text phrases from the passage. Avoid creating questions that (i) can't be answered correctly without actually understanding the passage and (ii) uses the same words or phrases given in the passage.
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Question: Angiotensin II (Ang II) signaling has been implicated in cardiac arrhythmogenesis, which involves induction of reactive oxygen species (ROS). It was shown that Ang II can activate Ca/Calmodulin kinase II (CaMKII) by oxidation via a NADPH oxidase 2 (NOX2)-dependent pathway leading to increased arrhythmic afterdepolarizations. Interestingly, cAMP-dependent protein kinase A (PKA) which regulates similar targets as CaMKII has recently been shown to be redox-sensitive as well.', 'This study aims to investigate the distinct molecular mechanisms underlying Ang II-related cardiac arrhythmias with an emphasis on the individual contribution of PKA vs. CaMKII.', 'Isolated ventricular cardiac myocytes from rats and mice were used. Ang II exposure resulted in increased NOX2-dependent ROS generation assessed by expression of redox-sensitive GFP and in myocytes loaded with ROS indicator MitoSOX. Whole cell patch clamp measurements showed that Ang II significantly increased peak Ca and Na current (ICa and INa) possibly by enhancing steady-state activation of ICa and INa. These effects were absent in myocytes lacking functional NOX2 (gp91phox(-/-)). In parallel experiments using PKA inhibitor H89, the Ang II effects on peak INa and ICa were also absent. In contrast, genetic knockout of CaMKIIδ (CaMKIIδ(-/-)) did not influence the Ang II-dependent increase in peak ICa and INa. On the other hand, Ang II enhanced INa inactivation, increased late INa and induced diastolic SR (sarcoplasmic reticulum) Ca leak (confocal Ca spark measurements) in a CaMKIIδ-, but not PKA-dependent manner. Surprisingly, only the increase in diastolic SR Ca leak was absent in gp91phox(-/-)myocytes suggesting that Ang II regulates INa inactivation in a manner dependent on CaMKII- but not on NOX2. Finally, we show that Ang II increased the propensity for cellular arrhythmias, for which PKA and CaMKII contribute, both dependent on NOX2.

Answer: Does nADPH oxidase 2 mediate angiotensin II-dependent cellular arrhythmias via PKA and CaMKII?


Question: Granulocyte-colony stimulating factor (G-CSF) is used for the mobilization of bone marrow and endothelial progenitor cells, though G-CSF-induced inflammation may cause endothelial dysfunction. We examined the effects of G-CSF on endothelium, C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-alpha) and anti-inflammatory cytokines namely interleukin 10 (IL-10).', 'We studied 60 women with breast cancer, who were randomized to either subcutaneous G-CSF (5 microg/kg), o.d. for 5 days after adjuvant chemotherapy (n = 40) or placebo (n = 20).', 'We measured flow-mediated dilatation (FMD%) of the brachial artery by ultrasonography, CRP, TNF-alpha, IL-10 and the ratio TNF-alpha/ IL-10 blood levels before, 2-h and 5-days after the G-CSF or placebo treatment.', 'There was a greater increase of FMD, IL-10 and reduction of TNF-alpha/ IL-10, 2 h and 5 days after the G-CSF treatment compared to placebo. Although, CRP and TNF-alpha were higher, TNF-alpha/IL-10 was lower at the end of G-CSF treatment compared to placebo. Improvement of FMD was related to changes of IL-10 and TNF-alpha/IL-10.

Answer: Is treatment with granulocyte colony stimulating factor associated with improvement in endothelial function?


Question: Pirfenidone (5 methyl-1-phenyl-2(1H)-pyridone) is a novel anti-fibrotic agent, which has been shown to decrease collagen deposition in a variety of animal models in vivo, and recently in hepatic fibrosis also. At cellular level, we have recently demonstrated that pirfenidone is able to inhibit proliferation of hepatic stellate cells induced by platelet-derived growth factor, as well as collagen type I accumulation and alpha1(I) procollagen mRNA expression.', 'To evaluate if pirfenidone maintains its anti-fibrotic properties also when administered after the induction of hepatic damage and to further investigate the molecular mechanisms leading to the anti-fibrotic effect of pirfenidone.', 'Rats treated with dimethylnitrosamine (10 mg/kg) for 5 weeks received a liquid diet containing 0.5% pirfenidone starting from the third week. Pirfenidone treatment reduced the degree of liver injury, as determined by alanine aminotransferase values and necro-inflammatory score, which was associated with reduced hepatic stellate cells proliferation and collagen deposition. Treatment with dimethylnitrosamine increased transcripts levels for transforming growth factorbeta1, procollagen alpha1(I), tissue inhibitors of metalloproteinase-1 and matrix metalloproteinase-2 by 7-, 7-, 4- and 15-fold, respectively. Pirfenidone administration downregulated elevated levels of those transcripts by 50-60%, and this was associated with a 70% reduction in collagen deposition.

Answer:
Is the anti-fibrotic effect of pirfenidone in rat liver fibrosis mediated by downregulation of procollagen alpha1 ( I ) , TIMP-1 and MMP-2?