Reduced global longitudinal and radial strain with normal left ventricular ejection fraction late after effective repair of aortic coarctation: a CMR feature tracking study

We sought to determine whether global and regional left ventricular (LV) strain parameters were altered in repaired coarctation of the aorta (COA) with normal LV ejection fraction (EF) when compared with healthy adult controls, and whether such alterations were related to LV hypertrophy (LVH). We identified 81 patients after COA repair (31 female, age 25 ± 8.5 years) with inclusion criteria at follow-up CMR of: age ≥13 years, time post-repair ≥10 years, no aortic valve disease, LV-EF >50 %). LV deformation indices derived using CMR-feature tracking and volumetric EF were compared between COA patients and normal controls (n = 20, 10 female, age 37 ± 7 years), and between COA with versus without LVH. In repaired COA versus controls, LV-EF (%) was 62 ± 7.2 versus 58 ± 3.0 (p = 0.01), and LV mass (g/m²) 66 ± 16.8 versus 57.7 ± 6.0 (p = 0.0001). LV global longitudinal strain (GLS) was decreased to ?17.0 ± 4.7 % in COA (?20 ± 5 % in controls, p = 0.02), and global radial strain (GRS) reduced to 40 ± 15 % (50 ± 12.4 % in controls, p = 0.003). The global circumferential strain (GCS) was preserved in COA at ?23 ± 4.7 % (?24.6 ± 2.4 % in controls, p = 0.14). Regionally, LS decrease was marked in the basal segments (septal, p = 0.005, lateral, p = 0.013). In COA with LVH (n = 45, mass 76.3 ± 12.8 g/m²) versus without LVH (n = 36, mass 52.2 ± 10 g/m²), GLS was more markedly decreased (?15.7 ± 4.8 vs. ?18.5 ± 4.2 %, p = 0.016, but GRS and GCS were similar (p = 0.49 and 0.27). In post-repair COA with normal LV-EF, GLS and GRS are reduced whilst GCS is preserved. GLS reduction is more pronounced in the presence of LVH. GLS may qualify as indicator of early LV dysfunction.     

Comparison of chronic ethanol and chronic intermittent ethanol treatments on the expression of GABA(A) and NMDA receptor subunits.

We examined the mRNA and protein levels of GABA(A) and NMDA receptor (NMDAR) subunits in cultured mouse cortical neurons following exposure to chronic ethanol (CE) or chronic intermittent ethanol (CIE), and after 5 days of withdrawal. With respect to GABA(A) receptor mRNA, both treatments decreased the levels of alpha1 and alpha2 subunits, and increased the level of alpha4. However, only CE treatment caused parallel changes in the protein levels; alpha2 and alpha4 protein levels did not change after CIE. Both treatments did not alter beta2 and beta3 mRNA levels, but they increased beta2/3 protein levels. The gamma2 subunit mRNA levels decreased with both treatments, but protein levels did not change. Most of the changes returned to control levels after withdrawal, except for the gamma2 subunit protein, which was lower than controls. In the case of NMDAR subunit, both treatments greatly increased the levels of NR2B mRNA, but barely altered NR1 mRNA and polypeptide levels. CIE treatment caused a relatively higher increase in NR2B protein, and this was the only sustained increase after long-term withdrawal. Taken together, our results show that CIE regimen has less pronounced effects on GABA(A) receptor expression, but increases NR2B expression more dramatically than CE treatment in cultured cortical neurons. These differential effects on subunit expression may result in altered receptor structure and function as a result of ethanol exposure.     

H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase

It has been suggested that phosphorylation of the histone variant H2AX after ultraviolet light (UV) irradiation is triggered by DNA double-strand breaks induced as replication forks collide with UV-induced bulky lesions. More recently, it has been shown that UV-induced H2AX phosphorylation can also occur outside of S-phase, but the mechanism for this replication-independent induction is not well understood. In this study, we show that H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is induced in all phases of the cell cycle. Accumulation of DNA repair intermediates by inhibition of DNA repair synthesis resulted in a marked increase of H2AX phosphorylation in repair proficient but not repair-deficient xeroderma pigmentosum-A cells. Using chemical inhibitors of the PI(3)-like kinase family of protein kinases as well as ataxia telangiectasia mutated and Rad-3 related (ATR)-deficient Seckel syndrome cells and ataxia telangiectasia mutated-deficient ataxia telangiectasia cells, we show that the H2AX phosphorylation induced by accumulation of repair intermediates is mediated primarily by the ATR kinase. We suggest a model for UV light-induced phosphorylation of H2AX where in addition to replication blockage, DNA repair intermediates trigger H2AX phosphorylation via the ATR kinase.     

Acetylsalicylic acid-induced oxidative stress, cell cycle arrest, apoptosis and mitochondrial dysfunction in human hepatoma HepG2 cells

It is widely accepted that non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, reduce the risk of cancer. The anti-cancer and anti-inflammatory effects of NSAIDs are associated with the inhibition of prostaglandin synthesis and cyclooxygenase-2 activity. Several other mechanisms which contribute to the anti-cancer effect of these drugs in different cancer models both in vivo and in vitro are also presumed to be involved. The precise molecular mechanism, however, is still not clear. We investigated, therefore, the effects of acetylsalicylic acid (ASA, aspirin) on multiple cellular and functional targets, including mitochondrial bioenergetics, using human hepatoma HepG2 cancer cells in culture. Our results demonstrate that ASA induced G0/G1 cell cycle arrest and apoptosis in HepG2 cells. ASA increased the production of reactive oxygen species, reduced the cellular glutathione (GSH) pool and inhibited the activities of the mitochondrial respiratory enzyme complexes, NADH-ubiquinone oxidoreductase (complex I), cytochrome c oxidase (complex IV) and the mitochondrial matrix enzyme, aconitase. Apoptosis was triggered by alteration in mitochondrial permeability transition, inhibition of ATP synthesis, decreased expression of the anti-apoptotic protein Bcl-2, release of cytochrome c and activation of pro-apoptotic caspase-3 and the DNA repairing enzyme, poly (-ADP-ribose) polymerase (PARP). These findings strongly suggest that ASA-induced toxicity in human hepatoma HepG2 cells is mediated by increased metabolic and oxidative stress, accompanied by mitochondrial dysfunction which result in apoptosis.     

Enhanced bioavailability of exemestane via proliposomes based transdermal delivery

Exemestane, a novel steroidal aromatase inactivator used in the treatment of advanced breast cancer has limited bioavailability (42%) due to poor solubility, extensive first-pass metabolism, and also the absorption is dependent on formulation type and food. The present study is aimed to evaluate the feasibility of proliposomes for transdermal delivery of exemestane. The prepared proliposomes were characterized for size, zeta potential, and entrapment efficiency. The size of the vesicles was found to be between 440 and 700 nm with high entrapment efficiency for the formulation containing greater amounts of phosphatidylcholine. Differential scanning calorimetry and Fourier transform infrared studies were performed to understand the phase transition behavior and mechanism for skin permeation, respectively. The drug release across cellophane membrane follows zero-order kinetics by diffusion. Ex vivo permeation enhancement assessed from flux, permeability coefficient, and enhancement ratio were significantly higher for proliposome gels compared with control. A significant improvement in the bioavailability (2.4-fold) was observed from optimized proliposome gel compared with control (oral suspension). The stability data reveal that the formulations are more stable when stored at 4°C. In conclusion, proliposomal gels offer potential and prove to be efficient carriers for improved and sustained transdermal delivery of exemestane.     

Differential activity of NO synthase inhibitors as chemopreventive agents in a primary rat tracheal epithelial cell transformation system

A model to study the effectiveness of potential chemopreventive agents that inhibit neoplastic process by different mechanisms has been used to test the efficacy of seven nitric oxide synthase (NOS) inhibitors. Five selective inducible NOS (iNOS) inhibitors: S-methyl isothiourea (S-MITU), S-2-aminoethyl isothiourea (S-2-AEITU), S-ethyl isothiourea (S-EITU), aminoguanidine (AG), 2-amino-4-methyl pyridine (2-AMP), and two non selective general NOS inhibitors: l-N(6)-(1-iminoethyl) lysine (IEL) and N(omega)-nitro-l-arginine (NNLA), were tested for efficacy against a carcinogen, benzo[a]pyrene (B[a]P)-induced primary rat tracheal epithelial (RTE) cell transformation assay. RTE cells were treated with B[a]P alone or with five nontoxic concentrations of an NOS inhibitor and the resulting foci at the end of 30 days were scored for inhibition of transformation. The results indicate that all three isothiourea compounds inhibited B[a]P-induced RTE foci in a dose-dependent manner. S-AEITU was the most effective inhibitor with an IC(50) (the molar concentration that inhibits transformation by 50%) of 9.1 microM and 100% inhibition at the highest dose tested (30 microM). However, both S-EITU and S-MITU showed a maximum percent inhibition of 81% and 100% at 1 mM with an IC(50) of 84 and 110 microM, respectively. 2-AMP did not show any dose-dependent response, but was highly effective (57% inhibition) at an intermediate dose of 30 microM and an IC(50) of 25 microM. Similar to thiourea compounds, AG exhibited good dose-dependent inhibition with a maximum inhibition of 86% at 1 mM. NNLA and IEL were negative in this assay. Based on the IC(50) values, NOS inhibitors were rated for efficacy from high to low as follows: S-2-AEITU<2-AMP相似文献   

DNA synthesis is blocked by cigarette tar-induced DNA single-strand breaks

DNA single-strand breaks are caused by aqueous extracts of cigarettetar, due to the reduction of oxygen to superoxide by tar andthe subsequent production of hydroxyl radicals. The action ofDNA metabolism enzymes on these single-strand breaks has beenstudied to probe the consequences of these lesions for DNA repair.Our results demonstrate that cigarette tar-induced nicks areblocked at the 3' terminus since they are totally incapableof activating DNA for DNA synthesis by Escherichia coli DNApolymerase I. The 3' termini of these tar-induced nicks areactivated, however, for DNA synthesis by E. coli exonucleaseIII or by the 3' phosphatase activity of T4 polynucleotide kinase.Because of the inability of tar-induced lesions to support DNAsynthesis, they probably require a multi-step process for repairin vivo. As a consequence, the overall likelihood of mutationis increased due to the possibility for error at each step ofthe repair process.     

Effectiveness of tocotrienol-rich fraction combined with tamoxifen in the management of women with early breast cancer: a pilot clinical trial

Introduction  

Basic research has indicated that tocotrienols have potent antiproliferative and proapoptotic effects that would be expected to reduce the effect of breast cancer.