Engineering zinc oxide hybrid selenium nanoparticles for synergetic anti-tuberculosis treatment by combining Mycobacterium tuberculosis killings and host cell immunological inhibition

IntroductionAs a deadly disease induced by Mycobacterium tuberculosis (Mtb), tuberculosis remains one of the top killers among infectious diseases. The low intracellular Mtb killing efficiency of current antibiotics introduced the long duration anti-TB therapy in clinic with strong side effects and increased drug-resistant mutants. Therefore, the exploration of novel anti-TB agents with potent anti-TB efficiency becomes one of the most urgent issues for TB therapies. MethodsHere, we firstly introduced a novel method for the preparation of zinc oxide-selenium nanoparticles (ZnO-Se NPs) by the hybridization of zinc oxide and selenium to combine the anti-TB activities of zinc oxide nanoparticles and selenium nanoparticles. We characterized the ZnO-Se NPs by dynamic laser light scattering and transmission electron microscopy, and then tested the inhibition effects of ZnO-Se NPs on extracellular Mtb by colony-forming units (CFU) counting, bacterial ATP analysis, bacterial membrane potential analysis and scanning electron microscopy imaging. We also analyzed the effects of ZnO-Se NPs on the ROS production, mitochondrial membrane potential, apoptosis, autophagy, polarization and PI3K/Akt/mTOR signaling pathway of Mtb infected THP-1 macrophages. At last, we also tested the effects of ZnO-Se NPs on intracellular Mtb in THP-1 cells by colony-forming units (CFU) counting. ResultsThe obtained spherical core-shell ZnO-Se NPs with average diameters of 90 nm showed strong killing effects against extracellular Mtb, including BCG and the virulent H37Rv, by disrupting the ATP production, increasing the intracellular ROS level and destroying the membrane structures. More importantly, ZnO-Se NPs could also inhibit intracellular Mtb growth by promoting M1 polarization to increase the production of antiseptic nitric oxide and also promote apoptosis and autophagy of Mtb infected macrophages by increasing the intracellular ROS, disrupting mitochondria membrane potential and inhibiting PI3K/Akt/mTOR signaling pathway. DiscussionThese ZnO-Se NPs with synergetic anti-TB efficiency by combining the Mtb killing effects and host cell immunological inhibition effects were expected to serve as novel anti-TB agents for the development of more effective anti-TB strategy

In Silico Resources to Assist in the Development and Evaluation of Physiologically-Based Kinetic Models

Since their inception in pharmaceutical applications, physiologically-based kinetic (PBK) models are increasingly being used across a range of sectors, such as safety assessment of cosmetics, food additives, consumer goods, pesticides and other chemicals. Such models can be used to construct organ-level concentration-time profiles of xenobiotics. These models are essential in determining the overall internal exposure to a chemical and hence its ability to elicit a biological response. There are a multitude of in silico resources available to assist in the construction and evaluation of PBK models. An overview of these resources is presented herein, encompassing all attributes required for PBK modelling. These include predictive tools and databases for physico-chemical properties and absorption, distribution, metabolism and elimination (ADME) related properties. Data sources for existing PBK models, bespoke PBK software and generic software that can assist in model development are also identified. On-going efforts to harmonise approaches to PBK model construction, evaluation and reporting that would help increase the uptake and acceptance of these models are also discussed

Life Cycle Assessment (LCA) of BEV’s Environmental Benefits for Meeting the Challenge of ICExit (Internal Combustion Engine Exit)

Based on necessary literature review, LC (Life Cycle) emissions, in particular LCCO2 (Life Cycle CO2) emissions, of BEVs (Battery Electric Vehicles) have been assessed and compared with the most efficient ICEVs (Internal Combustion Engine Vehicles), such as non-plug-in HEVs (Hybrid Electric Vehicles) and diesel cars. By considering CO2 emissions from vehicle production, vehicle recycle and the entire process of energy flow (from the mining of the energy source to a vehicle being driven), LCCO2 emission models of BEVs and ICEVs were built. For comparing between BEVs and ICEVs in terms of their LC emissions, a new measure named SRPR (Square Root of Power and Range) has been proposed for correctly reflecting the powertrain’s main performance. Results show that, although BEVs have much lower ECR (Energy Consumption Rate) than non-plug-in HEV and diesel cars, their LCCO2 are very variable, and are very dependent on LCCO2 of power generation mix of specific country. In some countries where thermal power generation, in particular coal power generation, is still dominant, BEVs’ LCCO2 are apparently higher than ICEVs. If a country would like to have their BEVs operating lower LCCO2 than ICEVs, the overall average LCCO2 from their power generation mix should be at least at the level about 320 g/kWh. As a case study, by analysing the power generation development trend and the BEV development trend in China, it suggests that their aim for developing BEVs to have lower LCCO2 than ICEVs in next two or three decades would be very difficult to meet. If they like to put priority on the reduction of LCCO2 of ground vehicles, BEVs could not be widely promoted in China until they made their power generation clean enough, probably at least in next 20 even 30 years. Finally, BEVs’ other LC pollutant emissions, such as NOx (Nitrogen Oxides), PM (Particulate Matters), SOx (Sulfur Oxides) would not be a very serious problem if those thermal power generations are equipped with adequate exhaust aftertreatment for removing those pollutant emissions

SOD3 is secreted by adipocytes and mitigates high-fat diet-induced obesity, inflammation and insulin resistance

Aims: To study the expression and regulatory role of SOD3 in adipocytes and adipose tissue. Results: SOD3 expression was determined in various tissues of adult C57BL/6J mice, human adipose tissue and epididymal (eWAT), subcutaneous (sWAT) and brown (BAT) adipose tissue of high-fat diet (HFD)-induced obese mice. SOD3 expression and release were evaluated in adipocytes differentiated from primary human preadipocytes and murine bone marrow-derived mesenchymal stem cells. The regulatory role for SOD3 was determined by SOD3 lentivirus knockdown in human adipocytes and global SOD3 KO mice. SOD3 was expressed at high levels in white adipose tissue and adipocytes were the main cells expressing SOD3 in adipose tissue. SOD3 expression was significantly elevated in adipose tissue of HFD-fed mice. Moreover, SOD3 expression and release were markedly increased in differentiated human adipocytes and adipocytes differentiated from mouse bone marrow-derived mesenchymal stem cells compared to undifferentiated cells. In addition, SOD3 silencing in human adipocytes increased expression of genes involved in metabolic pathways such as PPARγ and SEEBP1c and promoted the accumulation of triglyceride. Finally, global SOD3 KO mice were more obese and insulin resistant with enlarged adipose tissue and increased triglyceride accumulation. Innovation: Our data showed that SOD3 is secreted from adipocytes and regulates lipid metabolism in adipose tissue. This important discovery may open up new avenues of research for the cytoprotective role of SOD3 in obesity and its associated metabolic disorders. Conclusion: SOD3 is a protective factor secreted by adipocytes in response to HFD-induced obesity and regulates adipose tissue lipid metabolism