Metabolic and electrochemical mechanisms of dimeric naphthoquinones cytotoxicity in breast cancer cells

Cancer cells reprogram their metabolism due to genetic alteration to compensate for increased energy demand and enhanced anabolism, cell proliferation, and protection from oxidative damage. Here, we assessed the cytotoxicity of three dimeric naphthoquinones against the glycolytic MCF-7 versus the oxidative MDA-453 breast carcinoma cell lines. Dimeric naphthoquinones 1 and 2 impaired MDA-453, but not MCF-7, cell growth at IC(50)=15 μM. Significant increase in reactive oxygen species, decrease in oxygen consumption and ATP production were observed in MDA-453 cells but not in MCF-7 cell. These findings suggest that oxidative stress and mitochondrial dysfunction are mechanisms by which these agents exert their cytotoxic effects. Cyclic voltammetry and semi-empirical molecular orbital calculations further characterized the electrochemical behavior of these compounds. These results also suggest that dimeric naphthoquinones may be used to selectively target cancer cells that depend on oxidative phosphorylation for energy production and macromolecular synthesis.     

Phosphatase Complex Pph3/Psy2 Is Involved in Regulation of Efficient Non-Homologous End-Joining Pathway in the Yeast Saccharomyces cerevisiae

One of the main mechanisms for double stranded DNA break (DSB) repair is through the non-homologous end-joining (NHEJ) pathway. Using plasmid and chromosomal repair assays, we showed that deletion mutant strains for interacting proteins Pph3p and Psy2p had reduced efficiencies in NHEJ. We further observed that this activity of Pph3p and Psy2p appeared linked to cell cycle Rad53p and Chk1p checkpoint proteins. Pph3/Psy2 is a phosphatase complex, which regulates recovery from the Rad53p DNA damage checkpoint. Overexpression of Chk1p checkpoint protein in a parallel pathway to Rad53p compensated for the deletion of PPH3 or PSY2 in a chromosomal repair assay. Double mutant strains Δpph3/Δchk1 and Δpsy2/Δchk1 showed additional reductions in the efficiency of plasmid repair, compared to both single deletions which is in agreement with the activity of Pph3p and Psy2p in a parallel pathway to Chk1p. Genetic interaction analyses also supported a role for Pph3p and Psy2p in DNA damage repair, the NHEJ pathway, as well as cell cycle progression. Collectively, we report that the activity of Pph3p and Psy2p further connects NHEJ repair to cell cycle progression.     

Effects of chronic renal failure on caveolin-1, guanylate cyclase and AKT protein expression

Chronic renal failure (CRF) has been documented to cause oxidative stress and alter nitric oxide (NO) metabolism. However, the effect of CRF on proteins related to NO bioactivity has not been investigated. The present study was designed to test the hypothesis that CRF would induce changes in caveolin-1 (Cav-1), soluble guanylate cyclase (sGC) and Akt, three proteins important in regulating NO synthase (NOS) functionality. Male Sprague-Dawley rats were randomized to CRF via 5/6 nephrectomy or sham-operated control groups. After 6 weeks, body weight, blood pressure, creatinine clearance, plasma creatinine, urinary cyclic guanosine monophosphate (cGMP) and immunodetectable levels of Cav-1, sGC and Akt were determined in the renal, aorta, heart and liver tissues from both groups. CRF resulted in marked decreases in body weight and creatinine clearance, and elevation of blood pressure and plasma creatinine. An apparent upregulation of sGC protein abundance in renal tissue was noted, with no change in aorta, heart and liver. This was accompanied by a reduction in urinary cGMP levels, indicative of sGC dysfunction. Cav-1 protein abundance was increased in aortic, liver and renal tissues. In contrast, CRF depressed Akt abundance in aorta, heart and liver tissues. These data document that CRF is characterized by alteration in the abundance of proteins regulating NO function in hepatic, vascular, cardiac and renal tissues, and a decrease in cGMP, which contributes to hypertension and changes in NO bioactivity previously noted in this model.     

Nasal tip sutures part I: the evolution

Suture techniques for reshaping the nasal tip have been in use for many decades. However, the past two decades have been the most influential in the advancement of the procedures commonly used today. This report details the origin of the major tip suture techniques and tracks their evolution through the years. The early techniques in tip rhinoplasty share a basic principle: the sacrifice of lateral crus integrity to augment the middle and medial crural cartilage to gain tip projection and height. These techniques often disrupt the support mechanisms of the tip lobule, leading to undesirable postoperative results, including supratip fullness, tip asymmetry, tip drop, and an overoperated appearance. Modern nasal tip surgery is founded on the philosophy that suture placement does not simply secure partially excised sections of alar cartilage; rather it aims to directly reshape and reposition the various nasal tip components. The principal suturing methods available in the repertoire of today's rhinoplasty surgeon are the medial crural suture, the middle crura suture, the interdomal suture, the transdomal suture, the lateral crura suture, the medial crura anchor suture, the tip rotation suture, the medial crura footplate suture, and the lateral crura convexity control suture. This report acknowledges past contributions to nasal tip surgery and looks at the recent evolution of techniques commonly used today.     

Lpaatδ/Agpat4 deficiency impairs maximal force contractility in soleus and alters fibre type in extensor digitorum longus muscle

Lysophosphatidic acid acyltransferase (LPAAT) δ/acylglycerophosphate acyltransferase 4 is a mitochondrial enzyme and one of five homologues that catalyze the acyl-CoA-dependent synthesis of phosphatidic acid (PA) from lysophosphatidic acid. We studied skeletal muscle LPAATδ and found highest levels in soleus, a red oxidative fibre-type that is rich in mitochondria, and lower levels in extensor digitorum longus (EDL) (white glycolytic) and gastrocnemius (mixed fibre-type). Using Lpaatδ-deficient mice, we found no change in soleus or EDL mass, or in treadmill time-to-exhaustion compared to wildtype littermates. There was, however, a significant reduction in the proportion of type I and type IIA fibres in EDL but, surprisingly, not soleus, where these fibre-types predominate. Also unexpectedly, there was no impairment in force generation by EDL, but a significant reduction by soleus. Oxidative phosphorylation and activity of complexes I, I?+?II, III, and IV in soleus mitochondria was unchanged and therefore could not explain this effect. However, pyruvate dehydrogenase activity was significantly reduced in Lpaatδ^?/? soleus and EDL. Analysis of cellular lipids indicated no difference in soleus triacylglycerol, but specific elevations in soleus PA and phosphatidylethanolamine levels, likely due to a compensatory upregulation of Lpaatβ and Lpaatε in Lpaatδ^?/? mice. An anabolic effect for PA as an activator of skeletal muscle mTOR has been reported, but we found no change in serine 2448 phosphorylation, indicating reduced soleus force generation is unlikely due to the loss of mTOR activation by a specific pool of LPAATδ-derived PA. Our results identify an important role for LPAATδ in soleus and EDL.     

Spiral blood flow in aorta–renal bifurcation models

The presence of a spiral arterial blood flow pattern in humans has been widely accepted. It is believed that this spiral component of the blood flow alters arterial haemodynamics in both positive and negative ways. The purpose of this study was to determine the effect of spiral flow on haemodynamic changes in aorta–renal bifurcations. In this regard, a computational fluid dynamics analysis of pulsatile blood flow was performed in two idealised models of aorta–renal bifurcations with and without flow diverter. The results show that the spirality effect causes a substantial variation in blood velocity distribution, while causing only slight changes in fluid shear stress patterns. The dominant observed effect of spiral flow is on turbulent kinetic energy and flow recirculation zones. As spiral flow intensity increases, the rate of turbulent kinetic energy production decreases, reducing the region of potential damage to red blood cells and endothelial cells. Furthermore, the recirculation zones which form on the cranial sides of the aorta and renal artery shrink in size in the presence of spirality effect; this may lower the rate of atherosclerosis development and progression in the aorta–renal bifurcation. These results indicate that the spiral nature of blood flow has atheroprotective effects in renal arteries and should be taken into consideration in analyses of the aorta and renal arteries.     

The estimated health impact of sodium reduction through food reformulation in Australia: A modeling study

BackgroundThe Australian Government recently established sodium targets for packaged foods to encourage voluntary reformulation to reduce population sodium consumption and related diseases. We modeled the health impact of Australia’s sodium reformulation targets and additional likely health gains if more ambitious, yet feasible sodium targets had been adopted instead.Methods and findingsUsing comparative risk assessment models, we estimated the averted deaths, incidence, and disability-adjusted life years (DALYs) from cardiovascular disease (CVD), chronic kidney disease (CKD) and stomach cancer after implementation of (a) Australia’s sodium targets (overall and by individual companies); (b) United Kingdom’s targets (that covers more product categories); and (c) an optimistic scenario (sales-weighted 25th percentile sodium content for each food category included in the UK program). We used nationally representative data to estimate pre- and post-intervention sodium intake, and other key data sources from the Global Burden of Disease study. Full compliance with the Australian government’s sodium targets could prevent approximately 510 deaths/year (95% UI, 335 to 757), corresponding to about 1% of CVD, CKD, and stomach cancer deaths, and prevent some 1,920 (1,274 to 2,600) new cases and 7,240 (5,138 to 10,008) DALYs/year attributable to these diseases. Over half (59%) of deaths prevented is attributed to reformulation by 5 market-dominant companies. Compliance with the UK and optimistic scenario could avert approximately an additional 660 (207 to 1,227) and 1,070 (511 to 1,856) deaths/year, respectively, compared to Australia’s targets. The main limitation of this study (like other modeling studies) is that it does not prove that sodium reformulation programs will prevent deaths and disease events; rather, it provides the best quantitative estimates and the corresponding uncertainty of the potential effect of the different programs to guide the design of policies.ConclusionsThere is significant potential to strengthen Australia’s sodium reformulation targets to improve its health impact. Promoting compliance by market-dominant food companies will be critical to achieving the potential health gains.

Kathy Trieu and colleagues model the estimated health impact of sodium reformulation targets in Australia.     

Haemodynamic analysis of femoral artery bifurcation models under different physiological flow waveforms

Thrombus in a femoral artery may form under stagnant flow conditions which vary depending on the local arterial waveform. Four different physiological flow waveforms – poor (blunt) monophasic, sharp monophasic, biphasic and triphasic – can exist in the femoral artery as a result of different levels of peripheral arterial disease progression. This study aims to examine the effect of different physiological waveforms on femoral artery haemodynamics. In this regard, a fluid–structure interaction analysis was carried out in idealised models of bifurcated common femoral artery. The results showed that recirculation zones occur in almost all flow waveforms; however, the sites at where these vortices are initiated, the size and structure of vortices are highly dependent on the type of flow waveform being used. It was shown that the reverse diastolic flow in biphasic and triphasic waveforms leads to the occurrence of a retrograde flow which aids in ‘washout’ of the disturbed flow regions. This may limit the likelihood of thrombus formation, indicating the antithrombotic role of retrograde flow in femoral arteries. Furthermore, our data revealed that the flow particles experience considerably higher residence time under blunt and sharp monophasic waveforms than under biphasic and triphasic waveforms. This confirms that the risk of atherothrombotic plaque initiation and development in femoral arteries is higher under blunt and sharp monophasic waveforms than under biphasic and triphasic flow waveforms.     

TGF-β1 receptor blockade attenuates unilateral ureteral obstruction-induced renal fibrosis in C57BL/6 mice through attenuating Smad and MAPK pathways

Journal of Molecular Histology - Renal fibrosis is characterized by accumulation of extracellular matrix components and collagen deposition. TGF-β1 acts as a master switch promoting renal...