Obesity prevalence is becoming a serious global health and economic issue and is a major risk factor for concomitant diseases that worsen the quality and duration of life. Therefore, the urgency of ...the development of novel therapies is of a particular importance. A previous study of ours revealed that the natural pterocarpan, maackiain (MACK), significantly inhibits adipogenic differentiation in human adipocytes through a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent mechanism. Considering the observed anti-adipogenic potential of MACK, we aimed to further elucidate the molecular mechanisms that drive its biological activity in a
obesity model. Therefore, in the current study, the anti-obesogenic effect of MACK (25, 50, and 100 μM) was compared to orlistat (ORST, 12 μM) as a reference drug. Additionally, the hybrid combination between the ORST (12 μM) and MACK (100 μM) was assessed for suspected synergistic interaction. Mechanistically, the observed anti-obesogenic effect of MACK was mediated through the upregulation of the key metabolic regulators, namely, the nuclear hormone receptor 49 (
) that is a functional homologue of the mammalian PPARs and the AMP-activated protein kinase (aak-2/AMPK) in
. Collectively, our investigation indicates that MACK has the potential to limit lipid accumulation and control obesity that deserves future developments.
Obesity is a persistent and continuously expanding social health concern. Excessive fat mass accumulation is associated with increased risk of chronic diseases including diabetes, atherosclerosis, ...non-alcoholic steatohepatitis, reproductive dysfunctions and certain types of cancer.
Alchemilla monticola
Opiz. is a perennial plant of the Rosaceae family traditionally used to treat inflammatory conditions and as a component of weight loss herbal mixtures. In the search for bioactive leads with potential anti-adipogenic effect from
A. monticola
extract (ALM), we have employed nuclear magnetic resonance (NMR) based metabolomics to obtain data for the phytochemical profile of the extract. Further, molecular docking simulation was performed against key adipogenic targets for selected pure compounds, present in the ALM extract. Evaluation of the biological activity was done in human adipocytes exposed to ALM (5, 10 and 25 μg/ml), pure astragalin (AST) or quercitrin (QUE) both at the concentrations of 5, 10 and 25 μM. Investigation of the molecular pathways involved was performed through real-time quantitative PCR and Western blot analyses. According to the docking predictions strong putative affinity was revealed for both AST and QUE towards peroxisome proliferator-activated receptor gamma (PPARγ) and phosphoinositide 3-kinase (PI3K). Assessment of the intracellular lipid accumulation revealed anti-adipogenic activity of ALM. Correspondingly, the expression of the adipogenic genes CCAAT/enhancer-binding protein alpha (
CEBPA
) and
PPARG
was downregulated upon ALM and AST treatment. The Western blotting results exposed protein kinase B (AKT), PI3K and PPARγ as targets for the inhibitory effect of ALM and AST on adipogenesis. Collectively, we provide a broader insight of the phytochemical composition of
A. monticola
. Additionally, we demonstrate the anti-adipogenic effect of ALM and its active compound AST in human adipocytes. Furthermore, PI3K/AKT signaling pathway is identified to mediate the ALM anti-adipogenic action. Hence, the ALM extract and its secondary metabolite AST are worth further exploration as potentially active agents in obesity management.
Context. Age, metallicity, and spatial distribution of globular clusters (GCs) provide a powerful tool for reconstructing major star-formation episodes in galaxies. IKN is a faint dwarf spheroidal ...(dSph) in the M 81 group of galaxies. It contains five old GCs, which makes it the galaxy with the highest known specific frequency (SN = 126). Aims. We estimate the photometric age, metallicity, and spatial distribution of the poorly studied IKN GCs. We search SDSS for GC candidates beyond the HST/ACS field of view, which covers half of IKN. Methods. To break the age-metallicity degeneracy in the colour, we used WHT/LIRIS KS-band photometry and derived photometric ages and metallicities by comparison with SSP models in the V,I,Ks colour space. Results. IKN GCs’ VIKs colours are consistent with old ages (≥8 Gyr) and a metallicity distribution with a higher mean than is typical for such a dSph (Fe/H ≃ -1.4-0.2+0.6 dex). Their photometric mass range (0.5 < ℳGC< 4 × 105 M⊙) implies an unusually high mass ratio between GCs and field stars, of 10.6%. Mixture model analysis of the RGB field stars’ metallicity suggests that 72% of the stars may have formed together with the GCs. Using the most massive GC−SFR relation, we calculated a star formation rate (SFR) of ~10 M⊙/yr during its formation epoch. We note that the more massive GCs are closer to the galaxy photometric centre. IKN GCs also appear spatially aligned along a line close to the major axis of the IKN and nearly orthogonal to the plane of spatial distribution of galaxies in the M 81 group. We identify one new IKN GC candidate based on colour and the PSF analysis of the SDSS data. Conclusions. The evidence of i) broad and high metallicity distribution of the field IKN RGB stars and its GCs, ii) high fraction, and iii) spatial alignment of IKN GCs supports a scenario for tidally triggered, complex IKN’s star formation history in the context of interactions with galaxies in the M 81 group.
The modern trend in sunscreen products is towards the development of UV filters with multi-functional properties, to provide a broad shielding against ultraviolet radiation, antioxidant activity, and ...the prevention of skin cancer. Additionally, they should also be safe for humans as well as the environment. The benzimidazole heterocycle is a suitable platform for the development of such multifunctional molecules with potential application in cosmetic formulations, due to their ability to act as both UV protectors and reactive pharmacophores. This review presents for the first time the progress in the synthesis and optimization of benzimidazole compounds as UV sunscreen filters. The modifications to the substitution pattern of the lead compound and structure–activity relationships are discussed, as well as the synthetic approaches for the preparation of 2-substituted benzimidazoles. These aggregated data will be useful in future in the development of modern benzimidazole-based sunscreen.
Powassan virus (POWV) is an emerging tick borne flavivirus (TBFV) that causes severe neuroinvasive disease. Currently, there are no approved treatments or vaccines to combat POWV infection. Here, we ...generated and characterized a nanoparticle immunogen displaying domain III (EDIII) of the POWV E glycoprotein. Immunization with POWV EDIII presented on nanoparticles resulted in significantly higher serum neutralizing titers against POWV than immunization with monomeric POWV EDIII. Furthermore, passive transfer of EDIII-reactive sera protected against POWV challenge in vivo. We isolated and characterized a panel of EDIII-specific monoclonal antibodies (mAbs) and identified several that potently inhibit POWV infection and engage distinct epitopes within the lateral ridge and C-C' loop of the EDIII. By creating a subunit-based nanoparticle immunogen with vaccine potential that elicits antibodies with protective activity against POWV infection, our findings enhance our understanding of the molecular determinants of antibody-mediated neutralization of TBFVs.
Obesity is a global health burden for which we do not yet have effective treatments for prevention or therapy. Plants are an invaluable source of bioactive leads possessing anti-adipogenic potential. ...Ethnopharmacological use of Ononis spinosa L. roots (OSR) for treatment of obesity and metabolic disorders requires а scientific rationale. The current study examined the anti-adipogenic capacity of OSR and its secondary metabolites ononin (ONON) and maackiain (MACK) in human adipocytes as an in vitro model of obesity. Both ONON and MACK diminished lipid accumulation during adipocyte differentiation. Molecular docking analysis exposed the potential interactions between MACK or ONON and target regulatory adipogenic proteins. Furthermore, results from an RT-qPCR analysis disclosed significant upregulation of AMPK by MACK and ONON treatment. In addition, ONON increased SIRT1, PI3K and ACC mRNA expression, while MACK notably downregulated CEBPA, AKT, SREBP1, ACC and ADIPOQ. The protein level of PI3K, C/EBPα, PPARγ and adiponectin was reduced upon MACK treatment in a concentration-dependent manner. Similarly, ONON suppressed PI3K, PPARγ and adiponectin protein abundance. Finally, our study provides evidence that ONON exerts anti-adipogenic effect by upregulation of SIRT1 and inhibition of PI3K, PPARγ and adiponectin, while MACK induced strong inhibitory effect on adipogenesis via hampering PI3K, PPARγ/C/EBPα signaling and anti-lipogenic effect through downregulation of SREBP1 and ACC. Even though OSR does not hamper adipogenic differentiation, it could be exploited as a source of natural leads with anti-adipogenic potential. The multidirectional mechanism of action of MACK warrant further validation in the context of in vivo obesity models.
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•Ononis spinosa root extract did not obstruct adipogenesis.•Secondary metabolites from Ononis spinosa hampered adipocyte differentiation.•Ononin inhibited adipogenesis through SIRT1/PPARγ and PI3K signaling.•Maackiain inhibited adipo- and lipogenesis via PI3K/PPARγ and SREBP1 inhibition.
The synthetic 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a potent activator of the erythroid 2-p45-derived factor 2, Nrf2, a leucine-zipper regulator of the ...antioxidant response. Herein, we investigated the effect of CDDO-Me on neutrophil function in a murine model of joint damage. Collagenase-induced osteoarthritis (CIOA) was initiated by the intra-articular injection of collagenase in the knee-joint cavity of Balb/c mice. CDDO-Me was administrated intra-articularly twice a week starting at day 7 post-CIOA, and its effect was evaluated at day 14. Neutrophils in blood and bone marrow (BM), cell apoptosis, necrosis, expression of C-X-C chemokine receptor 4 (CXCR4), beta-galactosidase (β-Gal), and Nrf2 levels were measured by flow cytometry. In vitro, CDDO-Me promoted cell survival, reduced cell necrosis, and increased Nrf2 levels by 1.6 times. It decreased surface CXCR4 expression and reduced the frequency of senescent β-Gal+CXCR4+ neutrophils by three times. In vivo, the degree of knee-joint damage in CIOA was correlated with upregulated CXCR4 on CD11b+ neutrophils. CDDO-Me improved the disease histological score, increased the levels of Nrf2, and downregulated surface CXCR4 on mature BM cells. Our data suggest that CDDO-Me may act as a potent regulator of neutrophil senescence during the progression of knee-joint damage.
Abstract
This paper presents a study of noise pollution in the cabin of a passenger car in the context of various types of road. The purpose of the study is to understand how the type of road surface ...can influence the levels of noise inside the car. Sound pressure levels were measured on the A-scale of a sound level meter for 3 types of road surface - crushed stone pavement, asphalt, and cobblestone. The study was conducted at varying speeds of the car within the range of 10-60 km/h. Due to limitations of homogeneous road conditions, a duration of 10 seconds was chosen for each measurement. The sound level meter was placed at a selected measuring point, close to the driver’s head. On the data collected in the above-mentioned way, various regression models have been developed to assess the impact of speed and type of road surface on the noise level. It was found that the noise level increases with the roughness of the road surface, and the resulting risks were analysed.
Most known SARS-CoV-2 neutralizing antibodies (nAbs), including those approved by the FDA for emergency use, inhibit viral infection by targeting the receptor-binding domain (RBD) of the spike (S) ...protein. Variants of concern (VOC) carrying mutations in the RBD or other regions of S reduce the effectiveness of many nAbs and vaccines by evading neutralization. Therefore, therapies that are less susceptible to resistance are urgently needed. Here, we characterized the memory B-cell repertoire of COVID-19 convalescent donors and analyzed their RBD and non-RBD nAbs. We found that many of the non-RBD-targeting nAbs were specific to the N-terminal domain (NTD). Using neutralization assays with authentic SARS-CoV-2 and a recombinant vesicular stomatitis virus carrying SARS-CoV-2 S protein (rVSV-SARS2), we defined a panel of potent RBD and NTD nAbs. Next, we used a combination of neutralization-escape rVSV-SARS2 mutants and a yeast display library of RBD mutants to map their epitopes. The most potent RBD nAb competed with hACE2 binding and targeted an epitope that includes residue F490. The most potent NTD nAb epitope included Y145, K150, and W152. As seen with some of the natural VOC, the neutralization potencies of COVID-19 convalescent-phase sera were reduced by 4- to 16-fold against rVSV-SARS2 bearing Y145D, K150E, or W152R spike mutations. Moreover, we found that combining RBD and NTD nAbs did not enhance their neutralization potential. Notably, the same combination of RBD and NTD nAbs limited the development of neutralization-escape mutants
, suggesting such a strategy may have higher efficacy and utility for mitigating the emergence of VOC.
The U.S. FDA has issued emergency use authorizations (EUAs) for multiple investigational monoclonal antibody (MAb) therapies for the treatment of mild to moderate COVID-19. These MAb therapeutics are solely targeting the receptor-binding domain of the SARS-CoV-2 spike protein. However, the N-terminal domain of the spike protein also carries crucial neutralizing epitopes. Here, we show that key mutations in the N-terminal domain can reduce the neutralizing capacity of convalescent-phase COVID-19 sera. We report that a combination of two neutralizing antibodies targeting the receptor-binding and N-terminal domains may be beneficial to combat the emergence of virus variants.
The pH and water content in organic solvents are some of the most important parameters that play a key role in chemical laboratories, clinical analysis, food processing, biomedical and environmental ...monitoring, and life sciences. Herein we are reporting on the design, synthesis and sensor activity of a novel 4-amido-1,8-naphthalimide ratiometric fluorescent pH probe based on excimer-monomer switching mechanism. The fluorescence chemosensing behavior of the synthesized compound was studied in solvents of different polarity and the results obtained clearly demonstrates the great opportunity of the novel probe selectively to determine pH in aqueous solutions and water content in organic environment.
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