Deletion of SIRT1 in perivascular adipose tissue accelerates obesity-induced endothelial dysfunction

Conference Theme: Tomorrow’s medicines: pharmacology, patients and populationsINTRODUCTION: Perivascular adipose tissue (PVAT) exhibits brown adipose features and its dysfunction is implicated in cardiovascular diseases. SIRT1 is key to adipocyte phenotypes and metabolism. AIMS: In the present study, we aim to investigate the role of SIRT1 within PVAT in modulating obesity-evoked endothelial dysfunction. Methods. Wild type (WT) and adipocyte-specific SIRT1 knockout mice (AKO) were fed with standard chow or westernized diet for 12 weeks. Endothelium-dependent relaxation (EDR) in aortic rings with or without PVAT was assessed by wire myograph. DHE staining was …published_or_final_versio

Repurposing of statins via inhalation to treat lung inflammatory conditions

© 2018 Elsevier B.V. Despite many therapeutic advancements over the past decade, the continued rise in chronic inflammatory lung diseases incidence has driven the need to identify and develop new therapeutic strategies, with superior efficacy to treat these diseases. Statins are one class of drug that could potentially be repurposed as an alternative treatment for chronic lung diseases. They are currently used to treat hypercholesterolemia by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, that catalyses the rate limiting step in the mevalonate biosynthesis pathway, a key intermediate in cholesterol metabolism. Recent research has identified statins to have other protective pleiotropic properties including anti-inflammatory, anti-oxidant, muco-inhibitory effects that may be beneficial for the treatment of chronic inflammatory lung diseases. However, clinical studies have yielded conflicting results. This review will summarise some of the current evidences for statins pleiotropic effects that could be applied for the treatment of chronic inflammatory lung diseases, their mechanisms of actions, and the potential to repurpose statins as an inhaled therapy, including a detailed discussion on their different physical-chemical properties and how these characteristics could ultimately affect treatment efficacies. The repurposing of statins from conventional anti-cholesterol oral therapy to inhaled anti-inflammatory formulation is promising, as it provides direct delivery to the airways, reduced risk of side effects, increased bioavailability and tailored physical-chemical properties for enhanced efficacy

Optimization of RPMI 2650 Cells as a Model for Nasal Mucosa

In the past few years, a human nasal epithelial cell line derived from septum carcinoma (RPMI 2650) has been proposed as a potential in vitro model for screening nasally delivered drugs. However, these studies have left some unanswered questions in terms of the validation of the in vitro model. In particular, no clear agreement was found with respect to several parameters, such as the seeding density, the time for switching cell culture from liquid covered culture (LCC) to air liquid interface (ALI) conditions, or the day at which cell cultures have to be used for transport experiments, when these cells are cultured in vitro. Hence, the aim of this study was to expand on the previous in vitro cell models to better define the fundamental parameters to be used as a tool for studying drug deposition and transport through the nasal mucosa

How Do Mechanics Guide Fibroblast Activity? Complex Disruptions during Emphysema Shape Cellular Responses and Limit Research.

The emphysema death toll has steadily risen over recent decades, causing the disease to become the third most common cause of death worldwide in 2019. Emphysema is currently incurable and could be due to a genetic condition (Alpha-1 antitrypsin deficiency) or exposure to pollutants/irritants, such as cigarette smoke or poorly ventilated cooking fires. Despite the growing burden of emphysema, the mechanisms behind emphysematous pathogenesis and progression are not fully understood by the scientific literature. A key aspect of emphysematous progression is the destruction of the lung parenchyma extracellular matrix (ECM), causing a drastic shift in the mechanical properties of the lung (known as mechanobiology). The mechanical properties of the lung such as the stiffness of the parenchyma (measured as the elastic modulus) and the stretch forces required for inhalation and exhalation are both reduced in emphysema. Fibroblasts function to maintain the structural and mechanical integrity of the lung parenchyma, yet, in the context of emphysema, these fibroblasts appear incapable of repairing the ECM, allowing emphysema to progress. This relationship between the disturbances in the mechanical cues experienced by an emphysematous lung and fibroblast behaviour is constantly overlooked and consequently understudied, thus warranting further research. Interestingly, the failure of current research models to integrate the altered mechanical environment of an emphysematous lung may be limiting our understanding of emphysematous pathogenesis and progression, potentially disrupting the development of novel treatments. This review will focus on the significance of emphysematous lung mechanobiology to fibroblast activity and current research limitations by examining: (1) the impact of mechanical cues on fibroblast activity and the cell cycle, (2) the potential role of mechanical cues in the diminished activity of emphysematous fibroblasts and, finally, (3) the limitations of current emphysematous lung research models and treatments as a result of the overlooked emphysematous mechanical environment

Molecular Mechanisms of Membrane Deformation by I-BAR Domain Proteins

Conclusions: These data define I-BAR domain as a functional member of the BAR domain superfamily and unravel the mechanisms by which I-BAR domains deform membranes to induce filopodia in cells. Furthermore, our work reveals unexpected divergence in the mechanisms by which evolutionarily distinct groups of I-BAR domains interact with PI(4,5)P(2)-rich membranes

Working with the homeless: The case of a non-profit organisation in Shanghai

This article addresses a two-pronged objective, namely to bring to the fore a much neglected social issue of homelessness, and to explore the dynamics of state-society relations in contemporary China, through a case study of a non-profit organisation (NPO) working with the homeless in Shanghai. It shows that the largely invisible homelessness in Chinese cities was substantially due to exclusionary institutions, such as the combined household registration and 'detention and deportation' systems. Official policy has become much more supportive since 2003 when the latter was replaced with government-run shelters, but we argue that the NPO case demonstrates the potential for enhanced longer-term support and enabling active citizenship for homeless people. By analysing the ways in which the NPO offers services through collaboration and partnership with the public (and private) actors, we also argue that the transformations in postreform China and the changes within the state and civil society have significantly blurred their boundaries, rendering state-society relations much more complex, dynamic, fluid and mutually embedded

Sequence variation in TgROP7 gene among Toxoplasma gondii isolates from different hosts and geographical regions

Toxoplasma gondii can infect a wide range of hosts including mammals and birds, causing toxoplasmosis which is one of the most common parasitic zoonoses worldwide. The present study examined sequence variation in rhoptry 7 (ROP7) gene among different T. gondii isolates from different hosts and geographical localities. Phylogenetic analysis of the examined T. gondii isolates was conducted using the maximum likelihood (ML) method. Sequence analysis revealed that 60 nucleotide positions were variable in the ROP7 gene sequences among the 19 examined T. gondii isolates, corresponding to sequence variations of 0 to 1.7%, which occurred at the first, second and third codons. Phylogenetic analysis indicated that sequence variation in ROP7 gene was low among the examined T. gondii isolates from different hosts and geographical localities, and that the ROP7 sequence was not suitable as genetic marker for the differentiation of T. gondii isolates. The results of the present study suggest that ROP7 gene may be a suitable vaccine candidate.Key words: Sequence variation, rhoptry 7 (ROP7) gene, Toxoplasma gondii, toxoplasmosis, phylogenetic analysis

Iron Age and Anglo-Saxon genomes from East England reveal British migration history

British population history has been shaped by a series of immigrations, including the early Anglo-Saxon migrations after 400 CE. It remains an open question how these events affected the genetic composition of the current British population. Here, we present whole-genome sequences from 10 individuals excavated close to Cambridge in the East of England, ranging from the late Iron Age to the middle Anglo-Saxon period. By analysing shared rare variants with hundreds of modern samples from Britain and Europe, we estimate that on average the contemporary East English population derives 38% of its ancestry from Anglo-Saxon migrations. We gain further insight with a new method, rarecoal, which infers population history and identifies fine-scale genetic ancestry from rare variants. Using rarecoal we find that the Anglo-Saxon samples are closely related to modern Dutch and Danish populations, while the Iron Age samples share ancestors with multiple Northern European populations including Britain

Gated Diffusion-controlled Reactions

The binding and active sites of proteins are often dynamically occluded by motion of the nearby polypeptide. A variety of theoretical and computational methods have been developed to predict rates of ligand binding and reactivity in such cases. Two general approaches exist, "protein centric" approaches that explicitly treat only the protein target, and more detailed dynamical simulation approaches in which target and ligand are both treated explicitly. This mini-review describes recent work in this area and some of the biological implications