GLP-1 Mediates Regulation of Colonic ACE2 Expression by the Bile Acid Receptor GPBAR1 in Inflammation

Background & Aims: ACE2, a carboxypeptidase that generates Ang-(1-7) from Ang II, is highly expressed in the lung, small intestine and colon. GPBAR1, is a G protein bile acid receptor that promotes the release of the insulinotropic factor glucagon-like peptide (GLP)-1 and attenuates intestinal inflammation. Methods: We investigated the expression of ACE2, GLP-1 and GPBAR1 in two cohorts of Crohn’s disease (CD) patients and three mouse models of colitis and Gpbar1−/− mice. Activation of GPBAR1 in these models and in vitro was achieved by BAR501, a selective GPBAR1 agonist. Results: In IBD patients, ACE2 mRNA expression was regulated in a site-specific manner in response to inflammation. While expression of ileal ACE2 mRNA was reduced, the colon expression was induced. Colon expression of ACE2 mRNA in IBD correlated with expression of TNF-α and GPBAR1. A positive correlation occurred between GCG and GPBAR1 in human samples and animal models of colitis. In these models, ACE2 mRNA expression was further upregulated by GPABR1 agonism and reversed by exendin-3, a GLP-1 receptor antagonist. In in vitro studies, liraglutide, a GLP-1 analogue, increased the expression of ACE2 in colon epithelial cells/macrophages co-cultures. Conclusions: ACE2 mRNA expression in the colon of IBD patients and rodent models of colitis is regulated in a TNF-α-and GLP-1-dependent manner. We have identified a GPBAR1/GLP-1 mechanism as a positive modulator of ACE2

BMJ Open

ObjectivesThe raising unit price of cigarette has been shown to be one of the most effective ways of reducing cigarette consumption and increasing rates of successful quitting. However, researchers have shown that price-sensitive smokers have used a variety of strategies to mitigate the effect of the rising price of cigarettes on their smoking habits. In particular, 23\ue2\u20ac\u201c34% of adult smokers in the US use cheaper brands, and 18\ue2\u20ac\u201c55% use coupons or promotions. Little is known about the discount use by type of brands. As such, the main purpose of this analysis is to evaluate the uses and price discount effects of these price-related discounts by manufacturers and major brands.SettingAn analysis based on the cross-sectional 2009\ue2\u20ac\u201c2010 National Adult Tobacco Survey (NATS).Participants11\ue2\u20ac\u2026766 current smokers aged 18 or above in the USA.Primary outcome measuresPrice-related discount was defined as smokers who used coupons, rebates, buy-one-get-one-free, two-for-one or any other special promotions for their last cigarettes purchase.ResultsThe use of price-related discounts and associated price impact vary widely by cigarette manufacturer and brand. Approximately one of three Camel, one of four Marlboro and one of eight Newport smokers used price-related discounts on their latest cigarette purchases. The average price reductions of discounts offered by Philip Morris (PM) or R.J. Reynolds (RJR) were around 29 cents per pack while that of Lorillard (Newport only) was 24 cents per pack. Cigarette brands that provided significant per pack price reductions include: PM Marlboro (28 cents), RJR brand Camel (41 cents), Doral (50 cents), Kool (73 cents) and Salem (80 cents), and Lorillard Newport (24 cents).ConclusionsPolicies that decrease price-minimisation strategies will benefit public health

Discovery of a AHR pelargonidin agonist that counter-regulates Ace2 expression and attenuates ACE2-SARS-CoV-2 interaction

The severe acute respiratory syndrome (SARS)-CoV-2 is the pathogenetic agent of Corona Virus Induced Disease (COVID)19. The virus enters the human cells after binding to the angiotensin converting enzyme (ACE)2 receptor in target tissues. ACE2 expression is induced in response to inflammation. The colon expression of ACE2 is upregulated in patients with inflammatory bowel disease (IBD), highlighting a potential risk of intestinal inflammation in promoting viral entry in the human body. Because mechanisms that regulate ACE2 expression in the intestine are poorly understood and there is a need of anti-SARS-CoV-2 therapies, we have settled to investigate whether natural flavonoids might regulate the expression of Ace2 in intestinal models of inflammation. The results of these studies demonstrated that pelargonidin activates the Aryl hydrocarbon Receptor (AHR) in vitro and reverses intestinal inflammation caused by chronic exposure to high fat diet or to the intestinal braking-barrier agent TNBS in a AhR-dependent manner. In these two models, development of colon inflammation associated with upregulation of Ace2 mRNA expression. Colon levels of Ace2 mRNA were directly correlated with Tnf-α mRNA levels. Molecular docking studies suggested that pelargonidin binds a fatty acid binding pocket on the receptor binding domain of SARS-CoV-2 Spike protein. In vitro studies demonstrated that pelargonidin significantly reduces the binding of SARS-CoV-2 Spike protein to ACE2 and reduces the SARS-CoV-2 replication in a concentration-dependent manner. In summary, we have provided evidence that a natural flavonoid might hold potential in reducing intestinal inflammation and ACE2 induction in the inflamed colon in a AhR-dependent manner

The Standard Model in Strong Fields: Electroweak Radiative Corrections for Highly Charged Ions

Electroweak radiative corrections to the matrix elements $<ns_{1/2}|{\hat H}_{PNC}|n'p_{1/2}>$ are calculated for highly charged hydrogenlike ions. These matrix elements constitute the basis for the description of the most parity nonconserving (PNC) processes in atomic physics. The operator ${\hat H}_{PNC}$ represents the parity nonconserving relativistic effective atomic Hamiltonian at the tree level. The deviation of these calculations from the calculations valid for the momentum transfer $q^{2}=0$ demonstrates the effect of the strong field, characterized by the momentum transfer $q^{2}=m_{e}^{2}$ ($m_{e}$ is the electron mass). This allows for a test of the Standard Model in the presence of strong fields in experiments with highly charged ions.Comment: 27 LaTex page

Biological and clinical implications of cancer stem cells in primary brain tumors

Despite therapeutic advances, glioblastoma multiforme (GBM) remains a lethal disease. The infiltrative nature of this disease and the presence of a cellular population resistant to current medical treatments account for the poor prognosis of these patients. Growing evidence indicates the existence of a fraction of cancer cells sharing the functional properties of adult stem cells, including self-renewal and a greater ability to escape chemo-radiotherapy-induced death stimuli. Therefore, these cells are commonly defined as cancer stem cells (GBM-SCs). The initial GBM-SC concept has been challenged, and refined according to the emerging molecular taxonomy of GBM. This allowed to postulate the existence of multiple CSC types, each one driving a given molecular entity. Furthermore, it is becoming increasingly clear that GBM-SCs thrive through a dynamic and bidirectional interaction with the surrounding microenvironment. In this article, we discuss recent advances in GBM-SC biology, mechanisms through which these cells adapt to hostile conditions, pharmacological strategies for selectively killing GBM-SCs, and how novel CSC-associated endpoints have been investigated in the clinical setting

Kinetics and growth modes of quasi-2d silver branched electrodeposits produced in the presence of a supporting electrolyte

Quasi-2d silver electrodeposits were grown electrochemically at constant potential from aqueous Ag+ ion-containing solutions in the presence of a supporting electrolyte, at room temperature, using a three-electrode quasi-2d circular electrochemical cell. Open branching and dense radial branching patterns were distinguished on the centimetre scale, and growth mode transitions could be observed during the process. Branching patterns exhibited a mass fractal behaviour with a mass fractal dimension increasing from that expected for a DLA-like pattern to that of a dense branching pattern as either the cathodic overpotential (ηc) or the Ag+ ion concentration in the solution (c) was increased. The electrodeposition current increased with time exhibiting different regimes depending on whether an open branching or a dense radial branching growth mode prevailed. When the electrodeposition time exceeded a certain critical value, the radial growth rate of electrodeposits (vr) approached a vr α ηcc relationship. The experimental morphologies and growth kinetics were reproduced by Monte Carlo simulations of a growth model in which depositing particles follow a biased random walk.Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicada

Growth of three-dimensional silver fractal electrodeposits under damped free convection

Quasispherical three-dimensional Ag electrodeposits grown at constant potential and damped free convection exhibit a quasi-isotropic radial growth up to a critical radius rc≃0.3 cm and a mass fractal dimension DM=2.5. For r≫rc, DM→3. The product vrη’ is nearly constant, vr being the radial growth velocity, and η’ the apparent medium viscosity. It appears that vr is determined by the Laplacian field operating between cathode and anode.Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicada

Unexpected detection of SARS-CoV-2 antibodies in the prepandemic period in Italy

There are no robust data on the real onset of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and spread in the prepandemic period worldwide. We investigated the presence of SARS-CoV-2 receptor-binding domain (RBD)–specific antibodies in blood samples of 959 asymptomatic individuals enrolled in a prospective lung cancer screening trial between September 2019 and March 2020 to track the date of onset, frequency, and temporal and geographic variations across the Italian regions. SARS-CoV-2 RBD-specific antibodies were detected in 111 of 959 (11.6%) individuals, starting from September 2019 (14%), with a cluster of positive cases (&gt;30%) in the second week of February 2020 and the highest number (53.2%) in Lombardy. This study shows an unexpected very early circulation of SARS-CoV-2 among asymptomatic individuals in Italy several months before the first patient was identified, and clarifies the onset and spread of the coronavirus disease 2019 (COVID-19) pandemic. Finding SARS-CoV-2 antibodies in asymptomatic people before the COVID-19 outbreak in Italy may reshape the history of pandemic