Antioxidant and Anti-Inflammatory Activities of Flavanones from Glycyrrhiza glabra L. (licorice) Leaf Phytocomplexes: Identification of Licoflavanone as a Modulator of NF-kB/MAPK Pathway

Inflammation represents an adaptive response generated by injuries or harmful stimuli. Natural remedies represent an interesting alternative to traditional therapies, involving several biochemical pathways. Besides, the valorization of agrochemical wastes nowadays seems to be a feasible way to reduce the health spending and improve the accessibility at bioactive natural compounds. In this context, the chemical composition of three Glycyrrhiza glabra L. (licorice) leaf extracts, obtained through maceration or ultrasound-assisted method (fresh and dried leaves) was investigated. A guided fractionation obtained three main components: pinocembrin, glabranin and licoflavanone. All the extracts showed similar antioxidant properties, evaluated by 2,2'-diphenyl-1-picrylhydrazyl (DPPH) or 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) Diammonium Salt (ABTS) assay, while, among the isolated compounds, licoflavanone exhibited the best antioxidant activity. The anti-inflammatory activity of the extracts and the purified compounds was investigated in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. Extract C and licoflavanone showed a good anti-inflammatory activity without affecting cell viability, as they decreased nitrite levels even when used at 12.5 μg/mL (p < 0.005) and 50 μM concentration (p < 0.001), respectively. Interestingly, licoflavanone markedly decreased pro-inflammatory cytokines and cyclooxygenase 2/inducible nitric oxide synthase (COX-2/iNOS) expression levels (p < 0.001). A modulation of nuclear factor kappa B/mitogen-activated protein kinases (NF-kB/MAPK) pathway underlay such behavior, highlighting the potential of this natural compound as a new scaffold in anti-inflammatory drug research

Investigation of TNBC in vitro Antiproliferative Effects of Versatile Pirrolo[1,2-a]quinoxaline Compounds

he triple-negative breast cancer (TNBC) is characterized by a more aggressive nature and poorer prognosis, nowadays none pharmaceutical approach is still available. For this reason, the research of new active compounds and attractive targets represents an interesting field. In this context MDA- MB-231 cell line was selected to evaluate the antiproliferative effects of new [1,2-a]-pyrroloquinoxaline derivatives. The MTT assay revealed that the amine forms of synthesized molecules were more active compared to iminic ones at 72 h of incubation. The antiproliferative effect of the most promising compounds highlighted the formation of autophagic vacuoles

GPR120/FFAR4 Pharmacology: Focus on Agonists in Type 2 Diabetes Mellitus Drug Discovery

The G-protein coupled receptors (GPCRs) activated by free fatty acids (FFAs) have emerged as new and exciting drug targets, due to their plausible translation from pharmacology to medicines. This perspective aims to report recent research about GPR120/FFAR4 and its involvement in several diseases, including cancer, inflammatory conditions, and central nervous system disorders. The focus is to highlight the importance of GPR120 in Type 2 diabetes mellitus (T2DM). GPR120 agonists, useful in T2DM drug discovery, have been widely explored from a structure–activity relationship point of view. Since the identification of the first reported synthetic agonist TUG-891, the research has paved the way for the development of TUG-based molecules as well as new and different chemical entities. These molecules might represent the starting point for the future discovery of GPR120 agonists as antidiabetic drugs

Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels

Sesquiterpenes such as leucodin and the labdane-type diterpene manool are natural compounds endowed with remarkably in vitro vasorelaxant and in vivo hypotensive activities. Given their structural similarity with the sesquiterpene lactone (+)-sclareolide, this molecule was selected as a scaffold to develop novel vasoactive agents. Functional, electrophysiology, and molecular dynamics studies were performed. The opening of the five-member lactone ring in the (+)-sclareolide provided a series of labdane-based small molecules, promoting a significant in vitro vasorelaxant effect. Electrophysiology data identified 7 as a Ca(V)1.2 channel blocker and a K(Ca)1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the Ca(V)1.2 channel agonist Bay K 8644 suggested that 7 might interact with the dihydropyridine binding site. Docking and molecular dynamic simulations provided the molecular basis of the Ca(V)1.2 channel blockade and K(Ca)1.1 channel stimulation produced by 7. Finally, 7 reduced coronary perfusion pressure and heart rate, while prolonging conduction and refractoriness of the atrioventricular node, likely because of its Ca2+ antagonism. Taken together, these data indicate that the labdane scaffold represents a valuable starting point for the development of new vasorelaxant agents endowed with negative chronotropic properties and targeting key pathways involved in the pathophysiology of hypertension and ischemic cardiomyopathy. © 2022 by the authors

Mantonico and Pecorello Grape Seed Extracts: Chemical Characterization and Evaluation of In Vitro Wound-Healing and Anti-Inflammatory Activities

The winemaking process produces a huge number of pomaces that generally are used for energy purposes. Further valuable applications such as health-promoting properties are still under investigation. The seeds of the white berries of Mantonico and Pecorello cv. were extracted in a Soxhlet apparatus, using n-hexane and chloroform as solvents. Extracts were characterized by NMR and GC-MS analyses. They were assayed in vitro as wound healing and anti-inflammatory agents in HaCaT and RAW 264.7 cell lines, respectively. n-hexane Mantonico extract resulted in the most interesting wound healing sample, while n-hexane Pecorello, containing a good number of carotenoids, resulted in a good anti-inflammatory candidate. These preliminary findings underlined the benefit of grape seed extracts valorization due to their health-promoting propertie

Serinol-Based Benzoic Acid Esters as New Scaffolds for the Development of Adenovirus Infection Inhibitors: Design, Synthesis, and In Vitro Biological Evaluation

Over the years, human adenovirus (HAdV) has progressively been recognized as a significant viral pathogen. Traditionally associated with self-limited respiratory, gastrointestinal, and conjunctival infections, mainly in immunocompromised patients, HAdV is currently considered to be a pathogen presenting significant morbidity and mortality in both immunosuppressed and otherwise healthy individuals. Currently available therapeutic options are limited because of their lack of effectivity and related side effects. In this context, there is an urgent need to develop effective anti-HAdV drugs with suitable therapeutic indexes. In this work, we identified new serinol-derived benzoic acid esters as novel scaffolds for the inhibition of HAdV infections. A set of 38 compounds were designed and synthesized, and their antiviral activity and cytotoxicity were evaluated. Four compounds (13, 14, 27, and 32) inhibited HAdV infection at low micromolar concentrations (2.82–5.35 μM). Their half maximal inhibitory concentration (IC50) values were lower compared to that of cidofovir, the current drug of choice. All compounds significantly reduced the HAdV DNA replication process, while they did not block any step of the viral entry. Our results showed that compounds 13, 14, and 32 seem to be targeting the expression of the E1A early gene. Moreover, all four derivatives demonstrated a significant inhibition of human cytomegalovirus (HCMV) DNA replication. This new scaffold may represent a potential tool useful for the development of effective anti-HAdV drugs.This work has been supported by Ministerio de Ciencia, Innovación y Universidades, Plan Estatal 2017-2020 Retos-Proyectos I+D+i (PID2019-104767RB-I00), Ministerio de Economı́a y Competitividad, Plan Estatal 2013-2016 Retos-Proyectos I + D + i (CTQ2016-78580-C2-2-R) and by Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economia, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009), cofinanced by European Development Regional Fund “A way to achieve Europe”, the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (PI17/01055; PI18/01191) and Proyectos de Desarrollo Tecnológico en Salud (DTS17/00130), the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT), and the program “Nicolás Monardes” (C-0059-2018), Servicio Andaluz de Salud, Junta de Andalucía. M.V.-H. also thanks Ministerio de Economı́a y Competitividad, Plan Estatal 2013-2016 Excelencia I+D+i (CTQ2016-78703-P)

Detection of anti-correlation of hot and cold baryons in galaxy clusters

The largest clusters of galaxies in the Universe contain vast amounts of dark matter, plus baryonic matter in two principal phases, a majority hot gas component and a minority cold stellar phase comprising stars, compact objects, and low-temperature gas. Hydrodynamic simulations indicate that the highest-mass systems retain the cosmic fraction of baryons, a natural consequence of which is anti-correlation between the masses of hot gas and stars within dark matter halos of fixed total mass. We report observational detection of this anti-correlation based on 4 elements of a 9 x 9-element covariance matrix for nine cluster properties, measured from multi-wavelength observations of 41 clusters from the Local Cluster Substructure Survey. These clusters were selected using explicit and quantitative selection rules that were then encoded in our hierarchical Bayesian model. Our detection of anti-correlation is consistent with predictions from contemporary hydrodynamic cosmological simulations that were not tuned to reproduce this signal.Peer reviewe

LoCuSS : scaling relations between galaxy cluster mass, gas, and stellar content

We present a simultaneous analysis of galaxy cluster scaling relations between weak-lensing mass and multiple cluster observables, across a wide range of wavelengths, that probe both gas and stellar content. Our new hierarchical Bayesian model simultaneously considers the selection variable alongside all other observables in order to explicitly model intrinsic property covariance and account for selection effects. We apply this method to a sample of 41 clusters at 0.15 <z <0.30, with a well-defined selection criteria based on RASS X-ray luminosity, and observations from Chandra/XMM, SZA, Planck, UKIRT, SUSS, and Subaru. These clusters have well-constrained weak-lensing mass measurements based on Subaru/SuprimeCam observations, which serve as the reference masses in our model. We present 30 scaling relation parameters for 10 properties. All relations probing the intracluster gas are slightly shallower than self-similar predictions, in moderate tension with prior measurements, and the stellar fraction decreases with mass. K-band luminosity has the lowest intrinsic scatter with a 95th percentile of 0.16, while the lowest scatter gas probe is gas mass with a fractional intrinsic scatter of 0.16 +/- 0.03. We find no distinction between the core-excised X-ray or high-resolution Sunyaev-Zel'dovich relations of clusters of different central entropy, but find with modest significance that higher entropy clusters have higher stellar fractions than their lower entropy counterparts. We also report posterior mass estimates from our likelihood model.Peer reviewe

Ejecta Evolution Following a Planned Impact into an Asteroid: The First Five Weeks

The impact of the DART spacecraft into Dimorphos, moon of the asteroid Didymos, changed Dimorphos' orbit substantially, largely from the ejection of material. We present results from twelve Earth-based facilities involved in a world-wide campaign to monitor the brightness and morphology of the ejecta in the first 35 days after impact. After an initial brightening of ~1.4 magnitudes, we find consistent dimming rates of 0.11-0.12 magnitudes/day in the first week, and 0.08-0.09 magnitudes/day over the entire study period. The system returned to its pre-impact brightness 24.3-25.3 days after impact through the primary ejecta tail remained. The dimming paused briefly eight days after impact, near in time to the appearance of the second tail. This was likely due to a secondary release of material after re-impact of a boulder released in the initial impact, through movement of the primary ejecta through the aperture likely played a role.Comment: 16 pages, 5 Figures, accepted in the Astrophysical Journal Letters (ApJL) on October 16, 202

Ejecta Evolution Following a Planned Impact into an Asteroid: The First Five Weeks

The impact of the Double Asteroid Redirection Test spacecraft into Dimorphos, moon of the asteroid Didymos, changed Dimorphos’s orbit substantially, largely from the ejection of material. We present results from 12 Earth-based facilities involved in a world-wide campaign to monitor the brightness and morphology of the ejecta in the first 35 days after impact. After an initial brightening of ∼1.4 mag, we find consistent dimming rates of 0.11–0.12 mag day−1 in the first week, and 0.08–0.09 mag day−1 over the entire study period. The system returned to its pre-impact brightness 24.3–25.3 days after impact though the primary ejecta tail remained. The dimming paused briefly eight days after impact, near in time to the appearance of the second tail. This was likely due to a secondary release of material after re-impact of a boulder released in the initial impact, though movement of the primary ejecta through the aperture likely played a role