Cancer cells are hallmarked by high proliferation and imbalanced redox consumption and signaling. Various oncogenic pathways such as proliferation and evading cell death converge on redox-dependent ...signaling processes. Nrf2 is a key regulator in these redox-dependent events and operates in cytoprotection, drug metabolism and malignant progression in cancer cells. Here, we show that patients with primary malignant brain tumors (glioblastomas, WHO °IV gliomas, GBM) have a devastating outcome and overall reduced survival when Nrf2 levels are upregulated. Nrf2 overexpression or Keap1 knockdown in glioma cells accelerate proliferation and oncogenic transformation. Further, activation of the Nrf2-Keap1 signaling upregulates xCT (aka SLC7A11 or system X
) and amplifies glutamate secretion thereby impacting on the tumor microenvironment. Moreover, both fostered Nrf2 expression and conversely Keap1 inhibition promote resistance to ferroptosis. Altogether, the Nrf2-Keap1 pathway operates as a switch for malignancy in gliomas promoting cell proliferation and resistance to cell death processes such as ferroptosis. Our data demonstrate that the Nrf2-Keap1 pathway is critical for cancer cell growth and operates on xCT. Nrf2 presents the Achilles' heel of cancer cells and thus provides a valid therapeutic target for sensitizing cancer for chemotherapeutics.
Applying the process of superheated atomization (flash atomization) finely dispersed sprays with moderate droplet velocities can be obtained, without the necessity of high pressure or an additional ...gas phase. In this paper occurring evaporation phenomena inside a nozzle capillary and their impact on the generated spray are analyzed. Evaporation is enhanced for increasing superheating. An intensified evaporation induces a considerably extended spray and smaller droplet sizes are generated. Furthermore a reduced mass flux and decreased velocity of the droplets are to be expected. By increasing the amount of vapor spray pulsation, triggered by bubble bursting, is increased. This is shown in acoustic measurements, which also demonstrate a simple way to monitor, or even control the atomization of superheated liquids.
Thyroid hormones and their metabolites are active regulators of gene expression, mitochondrial function and various other physiological actions in different organs and tissues. These actions are ...mediated by a spatio-temporal regulation of thyroid hormones and metabolites within a target cell. This spatio-temporal resolution as well as classical and non-classical actions of thyroid hormones and metabolites is accomplished and regulated on multiple levels as uptake, local activation and signaling of thyroid hormones. In this review, we will give an overview of the systems involved in regulating the presence and activity of thyroid hormones and their metabolites within the brain, specifically in neurons. While a wealth of data on thyroxin (T4) and 3,5,3’-triiodothyronine (T3) in the brain has been generated, research into the presence of action of other thyroid hormone metabolites is still sparse and requires further investigations.
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•TH and their metabolites are present within the brain.•TH and their metabolites control various actions in the brain, specifically in neurons.•Transporters, deiodinases, and (non-) nuclear receptors mediate spatio-temporal regulations.
Four large community-randomized trials examining universal testing and treatment (UTT) to reduce HIV transmission were conducted between 2012-2018 in Botswana, Kenya, Uganda, Zambia and South Africa. ...In 2014, the UNAIDS 90-90-90 targets were adopted as a useful metric to monitor coverage. We systematically review the approaches used by the trials to measure intervention delivery, and estimate coverage against the 90-90-90 targets. We aim to provide in-depth understanding of the background contexts and complexities that affect estimation of population-level coverage related to the 90-90-90 targets.
Estimates were based predominantly on "process" data obtained during delivery of the interventions which included a combination of home-based and community-based services. Cascade coverage data included routine electronic health records, self-reported data, survey data, and active ascertainment of HIV viral load measurements in the field.
The estimated total adult populations of trial intervention communities included in this study ranged from 4,290 (TasP) to 142,250 (Zambian PopART Arm-B). The estimated total numbers of PLHIV ranged from 1,283 (TasP) to 20,541 (Zambian PopART Arm-B). By the end of intervention delivery, the first-90 target (knowledge of HIV status among all PLHIV) was met by all the trials (89.2%-94.0%). Three of the four trials also achieved the second- and third-90 targets, and viral suppression in BCPP and SEARCH exceeded the UNAIDS target of 73%, while viral suppression in the Zambian PopART Arm-A and B communities was within a small margin (~ 3%) of the target.
All four UTT trials aimed to implement wide-scale testing and treatment for HIV prevention at population level and showed substantial increases in testing and treatment for HIV in the intervention communities. This study has not uncovered any one estimation approach which is superior, rather that several approaches are available and researchers or policy makers seeking to measure coverage should reflect on background contexts and complexities that affect estimation of population-level coverage in their specific settings. All four trials surpassed UNAIDS targets for universal testing in their intervention communities ahead of the 2020 milestone. All but one of the trials also achieved the 90-90 targets for treatment and viral suppression. UTT is a realistic option to achieve 95-95-95 by 2030 and fast-track the end of the HIV epidemic.
Oxidative stress in conjunction with glutathione depletion has been linked with various acute and chronic degenerative disorders, yet the molecular mechanisms have remained unclear. In contrast to ...the belief that oxygen radicals are detrimental to cells and tissues by unspecific oxidation of essential biomolecules, we now demonstrate that oxidative stress is sensed and transduced by glutathione peroxidase 4 (GPx4) into a-yet-unrecognized cell-death pathway. Inducible GPx4 inactivation in mice and cells revealed 12/15-lipoxygenase-derived lipid peroxidation as specific downstream event, triggering apoptosis-inducing factor (AIF)-mediated cell death. Cell death could be entirely prevented either by α-tocopherol (α-Toc), 12/15-lipoxygenase inhibitors, or siRNA-mediated AIF silencing. Accordingly, 12/15-lipoxygenase-deficient cells were highly resistant to glutathione depletion. Neuron-specific GPx4 depletion caused neurodegeneration in vivo and ex vivo, highlighting the importance of this pathway in neuronal cells. Since oxidative stress is common in the etiology of many human disorders, the identified pathway reveals promising targets for future therapies.
Integrated Room Automation (IRA) for office buildings deals with the automated control of blinds, electric lighting, heating, cooling, and ventilation of a room or building zone. Model Predictive ...Control (MPC) presents a promising method to achieve energy savings thanks to improved control. This paper presents the development and validation of an intermediate complexity, integrated building and building equipment model suitable for application within MPC. A resistance-capacitance (RC) modeling approach was chosen. The result is a 12th order multiple-input-multiple-output bilinear model for the coupled simulation of the thermal, light and air quality dynamics of a single room. It includes the subsystems mechanical and natural ventilation, radiator and floor heating, cooling ceiling and thermally activated building system. For computational efficiency and compatibility with MPC, several approximations and a reduction of complexity were necessary. The resulting behaviors were validated against detailed building and system simulations. The model was found to deliver accurate and reliable results. It can be flexibly configured to represent typical building types and variants of technical systems. Furthermore, it is sufficiently efficient to support large-scale sensitivity studies. Finally, the model is ready for adaptation and integration into commercial algorithms for the control of real buildings.
Transport of thyroid hormone in brain Wirth, Eva K; Schweizer, Ulrich; Köhrle, Josef
Frontiers in endocrinology (Lausanne),
01/2014, Letnik:
5
Journal Article
Recenzirano
Odprti dostop
Thyroid hormone (TH) transport into the brain is not only pivotal for development and differentiation, but also for maintenance and regulation of adult central nervous system (CNS) function. In this ...review, we highlight some key factors and structures regulating TH uptake and distribution. Serum TH binding proteins play a major role for the availability of TH since only free hormone concentrations may dictate cellular uptake. One of these proteins, transthyretin is also present in the cerebrospinal fluid (CSF) after being secreted by the choroid plexus. Entry routes into the brain like the blood-brain-barrier (BBB) and the blood-CSF-barrier will be explicated regarding fetal and adult status. Recently identified TH transmembrane transporters (THTT) like monocarboxylate transporter 8 (Mct8) play a major role in uptake of TH across the BBB but as well in transport between cells like astrocytes and neurons within the brain. Species differences in transporter expression will be presented and interference of TH transport by endogenous and exogenous compounds including endocrine disruptors and drugs will be discussed.
Thyroid hormones, their metabolites, and synthetic analogues are potential anti-steatotic drug candidates considering that subclinical and manifest hypothyroidism is associated with hepatic lipid ...accumulation, non-alcoholic fatty liver disease, and its pandemic sequelae. Thyromimetically active compounds stimulate hepatic lipogenesis, fatty acid beta-oxidation, cholesterol metabolism, and metabolic pathways of glucose homeostasis. Many of these effects are mediated by T3 receptor β1-dependent modulation of transcription. However, rapid non-canonical mitochondrial effects have also been reported, especially for the metabolite 3,5-diiodothyronine (3,5-T2), which does not elicit the full spectrum of “thyromimetic” actions inherent to T3. Most preclinical studies in rodent models of obesity and first human clinical trials are promising with respect to the antisteatotic hepatic effects, but potent agents exhibit unwanted thyromimetic effects on the heart and/or suppress feedback regulation of the hypothalamus-pituitary-thyroid-periphery axis and the fine-tuned thyroid hormone system. This narrative review focuses on 3,5-T2 effects on hepatic lipid and glucose metabolism and (non-)canonical mechanisms of action including its mitochondrial targets. Various high fat diet animal models with distinct thyroid hormone status indicate species- and dose-dependent efficiency of 3,5-T2 and its synthetic analogue TRC150094. No convincing evidence has been presented for their clinical use in the prevention or treatment of obesity and related metabolic conditions.
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