Role of angiotensin‐1 receptor blockade in cirrhotic liver resection

Background: The regeneration capacity of cirrhotic livers might be affected by angiotensin‐1 (AT1) receptors located on hepatic stellate cells (HSC). The effect of AT1 receptor blockade on microcirculation, fibrosis and liver regeneration was investigated. Materials and methods: In 112 Lewis rats, cirrhosis was induced by repetitive intraperitoneal injections of CCl₄. Six hours, 3, 7 and 14 days after partial hepatectomy or sham operation, rats were sacrificed for analysis. Animals were treated with either vehicle or 5 mg/kg body weight losartan pre‐operatively and once daily after surgery by gavage. Microcirculation and portal vein flow were investigated at 6 h. The degree of cirrhosis was assessed by Azan Heidenhein staining, activation of HSC by desmin staining, apoptosis by ssDNA detection and liver regeneration by Ki‐67 staining. Changes in expression of various genes important for liver regeneration and fibrosis were analysed at 6 h and 3 days. Haemodynamic parameters and liver enzymes were monitored. Results: Losartan treatment increased sinusoidal diameter, sinusoidal blood flow and portal vein flow after partial hepatectomy (P<0.05), but not after sham operation. AT1 receptor blockade resulted in increased apoptosis early after resection. HSC activation was reduced and after 7 days, a significantly lower degree of cirrhosis in resected animals was observed. Losartan increased the proliferation of hepatocytes at late time‐points and of non‐parenchymal cells early after partial hepatectomy (P<0.05). Tumour necrosis factor (TNF)‐α was significantly upregulated at 6 h and stem cell growth factor (SCF) was downregulated at 3 days (P<0.05). Conclusion: Losartan increased hepatic blood flow, reduced HSC activation and liver fibrosis, but interfered with hepatocyte proliferation after partial hepatectomy in cirrhotic livers.     

Increased subventricular zone-derived cortical neurogenesis after ischemic lesion

In adult rodents stroke enhances neurogenesis resulting in the addition of neurons to forebrain regions such as striatum or cortex where postnatal neurogenesis under normal conditions plays a negligible role. In the cortex, new neurons are generated either from local cortical precursors that are activated by stroke or from precursors residing in the subventricular zone (SVZ) of lateral ventricles that under normal conditions supply neuroblasts by and large only for the olfactory bulb. In this study we used 5HT3A-EGFP transgenic mice in which all neuroblasts originating in the SVZ are EGFP-labeled. We induced stroke in these mice and by combination of EGFP detection with BrdU injections we labeled all post-stroke-generated SVZ-derived neuroblasts. We showed an increase in SVZ-derived neuroblasts 14 and 35 days after stroke in the ipsilateral hemisphere. Post-stroke-generated SVZ-derived neuroblasts migrated to the cortex and survived for at least 35 days representing 2% of BrdU-positive cells in peri-infarct area where they differentiate into mature neurons. Thus, stroke enhances SVZ neurogenesis and attracts newborn neurons to the injury zone.     

Use of Naltrexone to Treat Opioid Addiction in a Country in Which Methadone and Buprenorphine Are Not Available

Opioid dependence is one of the most severe drug dependencies. Naltrexone is a medication that completely blocks the subjective and other effects of opioids and, when administered to detoxified opioid addicts and taken as directed, prevents relapse and helps maintain abstinence. The major problem with naltrexone is poor compliance, particularly in countries in which there is a treatment alternative based on substitution of illicit opioids such as heroin with orally administered opioid agonists (methadone) or partial agonist/antagonists (buprenorphine). In Russia, substitution therapy is forbidden by law, and naltrexone is the only available pharmacotherapy for heroin dependence. Due to the lack of alternatives to naltrexone and stronger family control of compliance (adherence), naltrexone is more effective for relapse prevention and abstinence stabilization in Russia than in Western countries. Long-acting, sustained-release formulations (injectable and implantable) seem particularly effective compared with oral formulations. This article summarizes the results of studies conducted in Russia during the past 10 years that demonstrate these points.     

7-azaindenoisoquinolines as topoisomerase I inhibitors and potential anticancer agents

A series of 7-azaindenoisoquinoline topoisomerase I (Top1) inhibitors have been prepared to investigate the effect of increased electron affinity of the aromatic system on the ability to stabilize the Top1-DNA cleavage complex. Ab initio calculations suggest that introduction of nitrogen into the aromatic system of the indenoisoquinolines would facilitate charge transfer complex formation with DNA, thus improving the π-π stacking interactions. The present study shows that 7-azaindenoisoquinolines demonstrate improved water solubility without any decrease in Top1 inhibitory activity or cytotoxicity. Analysis of the biological results reveals that smaller lactam ring substituents enable intercalation into both free DNA and Top1-DNA cleavage complex, whereas larger substituents only allow binding to the cleavage complex but not free DNA. Free DNA binding suppresses Top1-catalyzed DNA cleavage at high drug concentrations, whereas DNA cleavage and inhibition of religation occurs at low drug concentration.     

Protein Kinase C-α and Arginase I Mediate Pneumolysin-Induced Pulmonary Endothelial Hyperpermeability

Antibiotics-induced release of the pore-forming virulence factor pneumolysin (PLY) in patients with pneumococcal pneumonia results in its presence days after lungs are sterile and is a major factor responsible for the induction of permeability edema. Here we sought to identify major mechanisms mediating PLY-induced endothelial dysfunction. We evaluated PLY-induced endothelial hyperpermeability in human lung microvascular endothelial cells (HL-MVECs) and human lung pulmonary artery endothelial cells in vitro and in mice instilled intratracheally with PLY. PLY increases permeability in endothelial monolayers by reducing stable and dynamic microtubule content and modulating VE-cadherin expression. These events, dependent upon an increased calcium influx, are preceded by protein kinase C (PKC)-α activation, perturbation of the RhoA/Rac1 balance, and an increase in myosin light chain phosphorylation. At later time points, PLY treatment increases the expression and activity of arginase in HL-MVECs. Arginase inhibition abrogates and suppresses PLY-induced endothelial barrier dysfunction by restoring NO generation. Consequently, a specific PKC-α inhibitor and the TNF-derived tonoplast intrinsic protein peptide, which blunts PLY-induced PKC-α activation, are able to prevent activation of arginase in HL-MVECs and to reduce PLY-induced endothelial hyperpermeability in mice. Arginase I (AI)(+/-)/arginase II (AII)(-/-) C57BL/6 mice, displaying a significantly reduced arginase I expression in the lungs, are significantly less sensitive to PLY-induced capillary leak than their wild-type or AI(+/+)/AII(-/-) counterparts, indicating an important role for arginase I in PLY-induced endothelial hyperpermeability. These results identify PKC-α and arginase I as potential upstream and downstream therapeutic targets in PLY-induced pulmonary endothelial dysfunction.     

Complex genetic, photothermal, and photoacoustic analysis of nanoparticle-plant interactions

Understanding the nature of interactions between engineered nanomaterials and plants is crucial in comprehending the impact of nanotechnology on the environment and agriculture with a focus on toxicity concerns, plant disease treatment, and genetic engineering. To date, little progress has been made in studying nanoparticle-plant interactions at single nanoparticle and genetic levels. Here, we introduce an advanced platform integrating genetic, Raman, photothermal, and photoacoustic methods. Using this approach, we discovered that multiwall carbon nanotubes induce previously unknown changes in gene expression in tomato leaves and roots, particularly, up-regulation of the stress-related genes, including those induced by pathogens and the water-channel LeAqp2 gene. A nano-bubble amplified photothermal/photoacoustic imaging, spectroscopy, and burning technique demonstrated the detection of multiwall carbon nanotubes in roots, leaves, and fruits down to the single nanoparticle and cell level. Thus, our integrated platform allows the study of nanoparticles' impact on plants with higher sensitivity and specificity, compared to existing assays.     

Customized Planning of Augmentation Mammaplasty with Silicon Implants Using Three-Dimensional Optical Body Scans and Biomechanical Modeling of Soft Tissue Outcome

The aesthetic results of augmentation mammaplasty are essentially determined by the size and the shape of the implant as well as its position on the chest. To achieve successful aesthetic results, customized surgery planning based on a reliable visual concept of the prospective surgery outcome and quantitative methods for assessment of three-dimensional (3D) breast shape could be of considerable additional value. This report evaluates a novel method for customized planning and quantitative optimization of breast augmentation based on 3D optical body scanning of the patient’s breast and computational modeling of soft tissue mechanics. This method allows a 3D photo-realistic appearance of postsurgery breasts to be simulated for different surgical scenarios. It also allows the result of a virtual simulation to be implemented using measurements derived from a computationally predicted breast model. A series of clinical studies are presented that demonstrate the feasibility and accuracy of the proposed approach for customized 3D planning of breast augmentation, including direct comparison between simulated and postsurgery results. Our experimental results show that for 89% of the breast surface, the average difference between the simulated and postsurgery breast models amounts to less than 1 mm. The presented method for customized planning of augmentation mammaplasty enables realistic prediction and quantitative optimization of postsurgery breast appearance. Based on individual 3D data and physical modeling, the described approach enables more accurate and reliable predictions of surgery outcomes than conventionally used photos of prior patients, drawings, or ad hoc data manipulation. Moreover, it provides precise quantitative data for bridging the gap between virtual simulation and real surgery.