Melatonin blocks the activation of estrogen receptor for DNA binding.

The present study shows that melatonin prevents, within the first cell cycle, the estradiol-induced growth of synchronized MCF7 breast cancer cells. By using nuclear extracts of these cells, we first examined the binding of estradiol-estrogen receptor complexes to estrogen-responsive elements and found that the addition of estradiol to whole cells activates the binding of the estrogen receptor to DNA whereas melatonin blocks this interaction. By contrast, melatonin neither affects the binding of estradiol to its receptor nor the receptor nuclear localization. Moreover, we also show that addition of estradiol to nuclear extracts stimulates the binding of estrogen receptor to DNA, but this activation is also prevented by melatonin. The inhibitory effect caused by melatonin is saturable at nanomolar concentrations and does not appear to be mediated by RZR nuclear receptors. The effect is also specific, since indol derivatives do not cause significant inhibition. Furthermore, we provide evidence that melatonin does not interact with the estrogen receptor in the absence of estradiol. Together, these results demonstrate that melatonin interferes with the activation of estrogen receptor by estradiol. The effect of melatonin suggests the presence of a receptor that, upon melatonin addition, destabilizes the binding of the estradiol-estrogen receptor complex to the estrogen responsive element.     

Some of the amino acid chemistry going on in the Laboratory of Amino Acids, Peptides and Proteins

Some of the chemistry of amino acids going on in our laboratory (Laboratoire des Amino acides Peptides et Protéines) is described as well as some mass spectrometry methodology for their characterization particularly on solid supports. Several aspects are presented including: (i) the stereoselective synthesis of natural and unnatural amino acids using 2-hydroxypinan-3-one as chiral auxiliary; (ii) the stereoselective synthesis of natural and unnatural amino acids by deracemization of alpha-amino acids via their ketene derivatives; (iii) the synthesis of alpha-aryl-alpha-amino acids via reaction of organometallics with a glycine cation; (iv) the diastereoselective synthesis of glycosyl-alpha-amino acids; (v) the synthesis of beta-amino acids using alpha-aminopyrrolidinopiperazinediones as chiral templates; (vi) the reactivity of urethane-N-protected N-carboxyanhydrides. To characterize natural and non natural amino acids through their immonium ions by mass spectrometry, some methodology is also described.     

Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2α phosphorylation and chemoresistance in colon cancer

Aberrant activation of endoplasmic reticulum (ER) stress by extrinsic and intrinsic factors contributes to tumorigenesis and resistance to chemotherapies in various cancer types. Our previous studies have shown that the downregulation of PHLPP, a novel family of Ser/Thr protein phosphatases, promotes tumor initiation, and progression. Here we investigated the functional interaction between the ER stress and PHLPP expression in colon cancer. We found that induction of ER stress significantly decreased the expression of PHLPP proteins through a proteasome-dependent mechanism. Knockdown of PHLPP increased the phosphorylation of eIF2α as well as the expression of autophagy-associated genes downstream of the eIF2α/ATF4 signaling pathway. In addition, results from immunoprecipitation experiments showed that PHLPP interacted with eIF2α and this interaction was enhanced by ER stress. Functionally, knockdown of PHLPP improved cell survival under ER stress conditions, whereas overexpression of a degradation-resistant mutant PHLPP1 had the opposite effect. Taken together, our studies identified ER stress as a novel mechanism that triggers PHLPP downregulation; and PHLPP-loss promotes chemoresistance by upregulating the eIF2α/ATF4 signaling axis in colon cancer cells.Subject terms: Biochemistry, Cancer     

Involving society in science: Reflections on meaningful and impactful stakeholder engagement in fundamental research

Open Science calls for transparent science and involvement of various stakeholders. Here are examples of and advice for meaningful stakeholder engagement. Subject Categories: Economics, Law & Politics, History & Philosophy of Science

The concepts of Open Science and Responsible Research and Innovation call for a more transparent and collaborative science, and more participation of citizens. The way to achieve this is through cooperation with different actors or “stakeholders”: individuals or organizations who can contribute to, or benefit from research, regardless of whether they are researchers themselves or not. Examples include funding agencies, citizens associations, patients, and policy makers (https://aquas.gencat.cat/web/.content/minisite/aquas/publicacions/2018/how_measure_engagement_research_saris1_aquas2018.pdf). Such cooperation is even more relevant in the current, challenging times—even apart from a global pandemic—when pseudo‐science, fake news, nihilist attitudes, and ideologies too often threaten social and technological progress enabled by science. Stakeholder engagement in research can inform and empower citizens, help render research more socially acceptable, and enable policies grounded on evidence‐based knowledge. Beyond, stakeholder engagement is also beneficial to researchers and to research itself. In a recent survey, the majority of scientists reported benefits from public engagement (Burns et al, 2021). This can include increased mutual trust and mutual learning, improved social relevance of research, and improved adoption of results and knowledge (Cottrell et al, 2014). Finally, stakeholder engagement is often regarded as an important factor to sustain public investment in the life sciences (Burns et al, 2021).

Stakeholder engagement in research can inform and empower citizens, help render research more socially acceptable and enable policies grounded on evidence‐based knowledge

Here, we discuss different levels of stakeholder engagement by way of example, presenting various activities organized by European research institutions. Based on these experiences, we propose ten reflection points that we believe should be considered by the institutions, the scientists, and the funding agencies to achieve meaningful and impactful stakeholder engagement.     

Endothelin-1-induced nociception

Intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of morphine to mice antagonized the abdominal constriction induced by an i.p. injection of endothelin-1 (ET-1; 0.1 mg/kg). The ED50 values (95% confidence intervals) were 39.3 (16.5-80.2) ng and 1.5 (0.8-4.9) ng, respectively. The antagonism of ET-1-induced abdominal constriction by morphine was blocked by naloxone (1.0 mg/kg, s.c.) or by 24 h pretreatment with beta-funaltrexamine (beta-FNA; 8.84 micrograms, i.c.v.). These results demonstrate for the first time that the stimulus resulting from an i.p. injection of ET-1 is transmitted via ascending (pain) pathways that are subject to attenuation by opioid (mu) receptor activation. Hence, ET-1-induced abdominal constriction is a new pain model which, given the other pharmacology of ET-1, might represent a unique model with potential specific utility for anginal or other visceral pain.     

Editorial: Software survey section

Editorial: Software survey section     

Editorial: Software survey section

Editorial: Software survey section     

Solution- and solid-phase synthesis and anti-HIV activity of maslinic acid derivatives containing amino acids and peptides

Maslinic acid (1) has been coupled at C-28 with several α- and ω-amino acids by using solution- and solid-phase synthetic procedures. Twelve derivatives (2–13) with a single amino acid residue were prepared in solution phase, whereas a dipeptide (14), a tripeptide (15), and a series of conjugate dipeptides (16–24) were synthesized in solid phase. The anti-HIV activity of these compounds was assessed on MT-2 cells infected with viral clones carrying the luciferase gene as a reporter. While in maslinic acid (1) were present both cytotoxic and antiviral activities, only the derivatives 13 and 24 showed anti-HIV-1 activity and therefore represent a novel class of anti-HIV-1 compounds.