Small-molecule modulators of mitochondrial channels as chemotherapeutic agents

Ion channels residing in the inner (IMM) and outer (OMM) mitochondrial membranes are emerging as noteworthy pharmacological targets in oncology. While these aspects have not been investigated for all of them, a role in cancer growth and/or metastasis and/or drug resistance has been shown at least for the IMM-residing Ca2+ uniporter complex and K+- selective mtKV1.3, mtIKCa, mtSKCa and mtTASK-3, and for the OMM Voltage-Dependent Anion Channel (mitochondrial porin). A special case is that of the Mitochondrial Permeability Transition Pore, a large pore which forms in the IMM of severely stressed cells, and which may be exploited to precipitate the death of cancerous cells. Here we briefly discuss the oncological relevance of mitochondria and their channels, and summarize the methods that can be adopted to selectively target these intracellular organelles. We then present an updated list of known mitochondrial channels, and review the pharmacology of those with proven relevance for cancer

Quercetin prevents progression of disease in elastase/LPS-exposed mice by negatively regulating MMP expression

Abstract Background Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, emphysema and irreversible airflow limitation. These changes are thought to be due to oxidative stress and an imbalance of proteases and antiproteases. Quercetin, a plant flavonoid, is a potent antioxidant and anti-inflammatory agent. We hypothesized that quercetin reduces lung inflammation and improves lung function in elastase/lipopolysaccharide (LPS)-exposed mice which show typical features of COPD, including airways inflammation, goblet cell metaplasia, and emphysema. Methods Mice treated with elastase and LPS once a week for 4 weeks were subsequently administered 0.5 mg of quercetin dihydrate or 50% propylene glycol (vehicle) by gavage for 10 days. Lungs were examined for elastance, oxidative stress, inflammation, and matrix metalloproteinase (MMP) activity. Effects of quercetin on MMP transcription and activity were examined in LPS-exposed murine macrophages. Results Quercetin-treated, elastase/LPS-exposed mice showed improved elastic recoil and decreased alveolar chord length compared to vehicle-treated controls. Quercetin-treated mice showed decreased levels of thiobarbituric acid reactive substances, a measure of lipid peroxidation caused by oxidative stress. Quercetin also reduced lung inflammation, goblet cell metaplasia, and mRNA expression of pro-inflammatory cytokines and muc5AC. Quercetin treatment decreased the expression and activity of MMP9 and MMP12 in vivo and in vitro, while increasing expression of the histone deacetylase Sirt-1 and suppressing MMP promoter H4 acetylation. Finally, co-treatment with the Sirt-1 inhibitor sirtinol blocked the effects of quercetin on the lung phenotype. Conclusions Quercetin prevents progression of emphysema in elastase/LPS-treated mice by reducing oxidative stress, lung inflammation and expression of MMP9 and MMP12.http://deepblue.lib.umich.edu/bitstream/2027.42/78260/1/1465-9921-11-131.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78260/2/1465-9921-11-131.pdfPeer Reviewe

Interactive 3D Digital Models for Anatomy and Medical Education

This chapter explores the creation and use of interactive, three-dimensional (3D), digital models for anatomy and medical education. Firstly, it looks back over the history and development of virtual 3D anatomy resources before outlining some of the current means of their creation; including photogrammetry, CT and surface scanning, and digital modelling, outlining advantages and disadvantages for each. Various means of distribution are explored, including; virtual learning environments, websites, interactive PDF’s, virtual and augmented reality, bespoke applications, and 3D printing, with a particular focus on the level of interactivity each method offers. Finally, and perhaps most importantly, the use of such models for education is discussed. Questions addressed include; How can such models best be used to enhance student learning? How can they be used in the classroom? How can they be used for selfdirected study? As well as exploring if they could one day replace human specimens, and how they complement the rise of online and e-learning

Cancer stem cell metabolism

Cancer is now viewed as a stem cell disease. There is still no consensus on the metabolic characteristics of cancer stem cells, with several studies indicating that they are mainly glycolytic and others pointing instead to mitochondrial metabolism as their principal source of energy. Cancer stem cells also seem to adapt their metabolism to microenvironmental changes by conveniently shifting energy production from one pathway to another, or by acquiring intermediate metabolic phenotypes. Determining the role of cancer stem cell metabolism in carcinogenesis has become a major focus in cancer research, and substantial efforts are conducted towards discovering clinical targets

Heterogeneity and standardization of Phase II metabolism in cultured cells

Caco-2 cells are widely used for transepithelial transport and metabolism studies. We analysed the metabolites produced from quercetin (Q) during transport of this flavonoid across Caco-2 monolayers and by plastic-adhering cells. We found that the pattern of Phase II metabolic activity varies markedly depending on the particular cell clone, age of the cell culture, and stressful treatment such as freezing/thawing. Prolonged culturing and stress cause a decrease of "detoxifying" conjugating activity. This can be re-established by growing the cells with a low concentration of the transport/metabolism substrate for a few days. We suggest this metabolism-activating procedure be used to make studies with these cells more readily comparable

Profile and Motivations of Registered Whole‐Body Donors in Turkey: Istanbul University Experience

Little is known regarding the profiles of whole body donors in Muslim majority countries where donation is scarce. Therefore, this study aims to profile registered donors in Turkey by means of a survey. The explored data could be used to improve ongoing campaign efforts and ethical practices such as commemoration services. Registered donors of the donation programs at the two faculties of medicine of Istanbul University were compared with the national population and a cluster analysis was performed to reveal any concealed sub-groups. Data from 188 respondents were analyzed. The majority of registered donors were married (42%), male (65.4%), aged over 50 years (76%), held a tertiary education degree (49.7%), and were irreligious (58.5%). Cluster analysis revealed two groups with significantly different educational levels, marital statuses, and religious choices. Regarding whether their bodies could be used for education or research, the majority (64.5%) of the respondents left the decision to the anatomy department. Similarly, 73.8% approved indefinite use of their organs, body parts and/or skeletons. The respondents were also willing to share their medical history (94.2%) and personal information (81.6%) if needed. Motivational themes for body donation including usefulness, impermanence, religion, awareness, and kinship were devised after a thematic analysis. Among the respondents, 56.5% were registered organ donors and 63.3% were frequent blood donors. The results of this study provide data that may help revising informed consent forms, developing and implementing thanksgiving ceremonies, and selecting additional targets for supporting body donation campaign activities such as organ and blood donation units

Absorption and metabolism of resveratrol carboxyesters and methanesulfonate by explanted reat intestinal segments

Model prodrugs of resveratrol carrying protecting substituents at the hydroxyls have been synthesised and tested. Resveratrol triacetate and resveratrol-tri-mPEG(1900) were formed by linking methyl groups or poly(ethylene glycol) chains, respectively, via carboxyester bonds. Resveratrol trimesylate, a molecule less susceptible to hydrolytic attack, was synthesised as well. This latter compound proved to be stable in vitro, while the carboxyester derivatives were slowly hydrolysed in solutions mimicking the gastric or intestinal environment, and rapidly converted to resveratrol in blood. In ex vivo permeation experiments with explanted intestinal segments, resveratrol and its triacetate derivative appeared in the basolateral compartment essentially as a mixture of Phase II metabolites. When the PEGylated derivative was provided on the apical side, unconjugated resveratrol accounted for about 50% of the compounds in the basolateral-side chamber. The same result was obtained by providing an equivalent physical mixture of resveratrol and PEG polymer, indicating that this behaviour is likely due to an adjuvating effect of PEG rather than to the covalent polymer conjugation. These observations suggest that the ester derivatives are rapidly hydrolysed at the intestinal surface or inside enterocytes, and are then processed as resveratrol. On the other hand, the mesylate was transported from the apical to the basolateral side without modification. It may thus be possible to enhance absorption and hinder metabolism of natural polyphenols by constructing pro-drugs incorporating bonds with appropriate resistance to enzymatic hydrolysis