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Chalcones constitute an important group of natural compounds abundant in fruits and comestible plants. They are a subject of increasing interest because of their biological activities, including anti-diabetic and anti-obesity effects. The simple chalcone structural scaffold can be modified at multiple sites with different chemical moieties. Here, we generated an artificial chalcone, i.e., 3,5-dimethyl-2,4,6-trimethoxychalcone (TriMetChalc), derived from 2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC). DMC is a major compound of Cleistocalyx operculatus, a plant widely used in Asia for its anti-hyperglycemic activity. Using ob/ob mice as an obesity model, we report that, after 3 weeks of per os administration, TriMetChalc modified food intake through the specific activation of brain structures dedicated to the regulation of energy balance. TriMetChalc also decreased weight gain, glucose intolerance, and hepatic steatosis. Moreover, through extensive liver lipidomic analysis, we identified TriMetChalc-induced modifications that could contribute to improving the liver status of the animals. Hence, TriMetChalc is a chalcone derivative capable of reducing food intake and the addition of glucose intolerance and hepatic steatosis in a mouse model of obesity. In light of these results, we believe that TriMetChalc action deserves to be more deeply evaluated over longer treatment periods and/or in combination with other chalcones with protective effects on the liver. [ABSTRACT FROM AUTHOR]

The cell catalysts calnexin (CNX) and protein-disulfide isomerase (PDI) cooperate in establishing the disulfide bonding of the H!V envelope (Env) glycoprotein. Following H!V binding to lymphocytes, cell-surface PDI also reduces Env to induce the fusogenic conformation. We sought to define the contact points between Env and these catalysts to illustrate their potential as therapeutic targets. In lysates of Env-expressing cells, 15% of the gp160 precursor, but not gp120, coprecipitated with CNX, whereas only 0.25% of gp160 and gp120 coprecipitated with PDI. Under in vitro conditions, which mimic the Env/PDI interaction during virus/cell contact, PDI readily associated with Env. The domains of Env interacting in cellulo with CNX or in vitro with PDI were then determined using anti-Env antibodies whose binding site was occluded by CNX or PDI. Antibodies against domains V1/V2, C2, and the C terminus of V3 did not bind CNX-associated Env, whereas those against Cl, V1/V2, and the CD4-binding domain did not react with PDI-associated Env. In addition, a mixture of the latter antibodies interfered with PDI-mediated Env reduction. Thus, Env interacts with intracellular CNX and extracellular PDI via discrete, largely nonoverlapping, regions. The sites of interaction explain the mode of action of compounds that target these two catalysts and may enable the design of further new competitive agents. [ABSTRACT FROM AUTHOR]

PACAP-38 (P38) is a pleiotropic peptide that exerts multiple peripheral and central actions, including neurotrophic, neuroprotective and anti-inflammatory actions. Previous studies have suggested an improvement of memory in rats that have received a single systemic injection of P38. In a therapeutic perspective, we used an analog, acetyl-[Ala 15 , Ala 20 ]PACAP-38-propylamide (ALG), to improve both stability and affinity for PAC1 receptors vs. endogen PACAP. We investigated the effect of P38 and ALG on memory consolidation using a spatial novelty detection (SND) task in which rats had to memorize a configuration of objects to identify that, during a test session, a familiar object has been moved to a new location. Rats received an intravenous injection of P38 or ALG after the last training session. In Experiment 1, P38 (30 µg/kg) improved spatial memory consolidation allowing detection of novelty vs. saline injection. In Experiment 2, we confirmed this effect and showed that P38 restored the performance similar to what was found using non-injected rats. This suggests that, contrary to ALG, P38 exerted a promesiant rather than an anxiety-related effect whereas ALG did not show similar action. We also examined whether P38 effect involved an interaction with NR2B-containing NMDA receptors (NMDARs) by administrating ifenprodil (IFE; a selective NR2B-containing NMDAR antagonist) alone or in combination with P38 or ALG. The results suggested that P38 action on memory involved NR2B-containing NMDARs. Lastly, brain-derived neutrophic factor (BDNF) modulation appeared to be not related to the behavioral performance in the SND task. Overall, the results indicate that P38 exerted a beneficial effect on memory consolidation in a non-associative task, whereas ALG did not have this action., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We compared the effects of single intraveinous injection of pituitary adenylate cyclase-activating polypeptide-38 (P38) to those of its analog, acetyl-[Ala 15 , Ala 20 ]PACAP-38-propylamide (P38-alg) on spatial memory in the Morris water maze (MWM) using a weak massed-learning procedure, post-training brain derived neurotrophic factor (BDNF) and post-training oxidative stress biomarker assays in male Wistar rats. Acquisition of the MWM task following P38 (30 μg/kg) and P38-alg (30 μg/kg) treatments was similar to control group (Saline: 0.9% NaCl) and there was no interaction between treatments and performance. However, in the probe test, P38-treated group showed a specific interest for the target quadrant whereas the two other groups exhibited less focused place searching behavior. Moreover, P38 had an anxiogenic effect as measured by the distribution of swimming at the periphery of the pool. The swimming test resulted in a decrease in BDNF contents in the hippocampus. P38 but not P38-alg treatment restored BDNF expression. In terms of oxidative stress, both P38 and P38-alg treatments had antioxidative effects. The activity of antioxidative enzymes in the neocortex was increased. However only P38 reduced the levels of carbonylated proteins (CP). These data show that P38 and P38-alg have different behavioral and neurobiological effects. Thus, P38-alg and other analogs with specific functional profiles, inducing beneficial central effects (e.g. neuroprotection) while minimizing undesired peripheral effects may be useful for potential therapeutical use., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The capacity of the surface glycoproteins of enveloped viruses to mediate virus/cell binding and membrane fusion requires a proper thiol/disulfide balance. Chemical manipulation of their redox state using reducing agents or free sulfhydryl reagents affects virus/cell interaction. Conversely, natural thiol/disulfide rearrangements often occur during the cell interaction to trigger fusogenicity, hence the virus entry. We examined the relationship between the redox state of the 20 cysteine residues of the SARS-CoV (severe acute respiratory syndrome coronavirus) Spike glycoprotein S1 subdomain and its functional properties. Mature S1 exhibited approximately 4 unpaired cysteines, and chemically reduced S1 displaying up to approximately 6 additional unpaired cysteines still bound ACE2 and enabled fusion. In addition, virus/cell membrane fusion occurred in the presence of sulfhydryl-blocking reagents and oxidoreductase inhibitors. Thus, in contrast to various viruses including HIV (human immunodeficiency virus) examined in parallel, the functions of the SARS-CoV Spike glycoprotein exhibit a significant and surprising independence of redox state, which may contribute to the wide host range of the virus. These data suggest clues for molecularly engineering vaccine immunogens.

1-Deoxynojirimycin (DNM) is a saccharide decoy that inhibits cellular alpha-glucosidase I-II activity. Treatment by DNM of human immunodeficiency virus (HIV)-infected lymphocyte cultures inhibits virus spread. The functional properties of the membrane-associated Env glycoprotein (Env) modified in the presence of DNM remain unclear because previous reports on this subject have essentially used recombinant soluble Envs whose properties differ notably from those of Env anchored on the surface of the virus. To model virus-associated Env synthesized in the presence of DNM, native Env was expressed at the surface of mammalian cells treated with DNM. As expected, its glycosylation pattern was altered in the presence of the inhibitor. Env was found able to bind CD4, whereas its ability to induce membrane fusion was abolished. The immunoreactivity of regions involved in interactions of Env with CXCR4 (V1, V2, C2, and V3) was modified and Env displayed altered interaction with this coreceptor. These results are consistent with the inhibition by DNM of virus entry at the Env/coreceptor interaction step. Finally, preliminary data indicate that suboptimal concentrations of DNM and natural or synthetic CXCR4 ligands used in combination potently inhibit the Env-mediated membrane fusion process. Altogether, our results suggest that DNM and its analogs deserve further investigation as anti-HIV agents in combination with experimental compounds targeting CXCR4 to inhibit each partner of this crucial step of HIV entry.