Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells

Pharmacological allosteric agonists (calcimimetics) of the extracellular calcium-sensing receptor (CaSR) have substantial gastro-intestinal side effects and induce the expression of inflammatory markers in colon cancer cells. Here, we compared the effects of both CaSR-specific (R enantiomers) and -unspecific (S enantiomers) enantiomers of a calcimimetic (NPS 568) and a calcilytic (allosteric CaSR antagonists; NPS 2143) to prove that these effects are indeed mediated via the CaSR, rather than via off-target effects, e.g., on β-adrenoceptors or calcium channels, of these drugs. The unspecific S enantiomer of NPS 2143 and NPS S-2143 was prepared using synthetic chemistry and characterized using crystallography. NPS S-2143 was then tested in HEK-293 cells stably transfected with the human CaSR (HEK-CaSR), where it did not inhibit CaSR-mediated intracellular Ca2+ signals, as expected. HT29 colon cancer cells transfected with the CaSR were treated with both enantiomers of NPS 568 and NPS 2143 alone or in combination, and the expression of CaSR and the pro-inflammatory cytokine interleukin 8 (IL-8) was measured by RT-qPCR and ELISA. Only the CaSR-selective enantiomers of the calcimimetic NPS 568 and NPS 2143 were able to modulate CaSR and IL-8 expression. We proved that pro-inflammatory effects in colon cancer cells are indeed mediated through CaSR activation. The non-CaSR selective enantiomer NPS S-2143 will be a valuable tool for investigations in CaSR-mediated processes

Determination of Diagnostic Reference Levels (DRLs) in General Radiographyin Latin America

The International Atomic Energy Agency (IAEA) through the International Action Plan on Radiation Protection of Patients and the International Commission on Radiological Protection have for some time carried out important efforts to assure that in the medical applications of the ionising radiations, the optimisation of radiological protection of patients is fundamental, to such a point that the IAEA includes it directly as a requirement for these practices (in its International Basic Safety Standards for Protection against Ionising Radiation and for the Safety of Radiation Sources (BSS)-GSR Part 1, 2011). For this reason, among the objectives of Regional Project RLA/9/057 and Regional Project RLA/9/067, the intention was to establish the dose references in conventional radiology for Latin America, for the purposes of determining whether these doses comply with the requirements of the BSS and to tend to improve practices, in order to minimise the dose received by the patients.Fil: Blanco, Susana Alicia Ana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Belgrano. Facultad de Ingenieria; ArgentinaFil: Mora, Patricia. Centro de Investigación en Ciencias Atómicas, Nucleares y Moleculares; Costa RicaFil: Almonte, Narkiss. Comisión Nacional de Energía. Dirección Nuclear; República DominicanaFil: Benavente, Tony. Instituto Peruano de Energía Nuclear; PerúFil: Benson, Nadja. Ministerio de Salud. Dirección General de Salud; Reino UnidoFil: Blanco, Daniel. Universidad de la República. Centro de Investigaciones Nucleares; UruguayFil: Cárdenas, Juan. Centro de Protección e Higiene de las Radiaciones; CubaFil: Defaz Gómez, Yolanda. Hospital Oncológico SOLCA Nucleo de Quito; EcuadorFil: Edding, Oscar. Instituto de Salud Pública; ChileFil: Escobar, Carolina. Ministerio de Salud Pública y Acción Social. Unidad Reguladora de Radiaciones Ionizantes; El SalvadorFil: Fonseca, María. Hospital Nacional Roosevelt; GuatemalaFil: Gamarra, Mirta. Ministerio de Salud Pública y Bienestar Social; ParaguayFil: García Aguilar, Juan. Instituto Nacional de Investigaciones Nucleares; MéxicoFil: Khoury, Helen Jamil. Universidade Federal de Pernambuco; BrasilFil: Quintero, Ana Rosa. Hospital Oncológico "Dr Luis Razetti"; VenezuelaFil: Roas Zuniga, Norma. Universidad Nacional Autónoma de Nicaragua; NicaraguaFil: Zaire, Edgar. Instituto Boliviano de Ciencia y Tecnología Nuclear; BoliviaFil: Nader, Alejandro. International Atomic Energy Agency; Austri

Resolving issues with environmental impact assessment of marine renewable energy installations

Growing concerns about climate change and energy security have fueled a rapid increase in the development of marine renewable energy installations (MREIs). The potential ecological consequences of increased use of these devices emphasizes the need for high quality environmental impact assessment (EIA). We demonstrate that these processes are hampered severely, primarily because ambiguities in the legislation and lack of clear implementation guidance are such that they do not ensure robust assessment of the significance of impacts and cumulative effects. We highlight why the regulatory framework leads to conceptual ambiguities and propose changes which, for the most part, do not require major adjustments to standard practice. We emphasize the importance of determining the degree of confidence in impacts to permit the likelihood as well as magnitude of impacts to be quantified and propose ways in which assessment of population-level impacts could be incorporated into the EIA process. Overall, however, we argue that, instead of trying to ascertain which particular developments are responsible for tipping an already heavily degraded marine environment into an undesirable state, emphasis should be placed on better strategic assessment.Publisher PDFPeer reviewe

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Resolving issues with environmental impact assessment of marine renewable energy installations

Growing concerns about climate change and energy security have fueled a rapid increase in the development of marine renewable energy installations (MREIs). The potential ecological consequences of increased use of these devices emphasizes the need for high quality environmental impact assessment (EIA). We demonstrate that these processes are hampered severely, primarily because ambiguities in the legislation and lack of clear implementation guidance are such that they do not ensure robust assessment of the significance of impacts and cumulative effects. We highlight why the regulatory framework leads to conceptual ambiguities and propose changes which, for the most part, do not require major adjustments to standard practice. We emphasize the importance of determining the degree of confidence in impacts to permit the likelihood as well as magnitude of impacts to be quantified and propose ways in which assessment of population-level impacts could be incorporated into the EIA process. Overall, however, we argue that, instead of trying to ascertain which particular developments are responsible for tipping an already heavily degraded marine environment into an undesirable state, emphasis should be placed on better strategic assessment