We performed an ab initio next-generation risk assessment (NGRA) for a fragrance ingredient, benzyl salicylate (BSal), to demonstrate how cosmetic ingredients can be evaluated for systemic toxicity endpoints based on non-animal approaches. New approach methodologies (NAMs) used to predict the internal exposure included skin absorption assays, hepatocyte metabolism, and physiologically based pharmacokinetic (PBPK) modeling, and potential toxicodynamic effects were assessed using pharmacology profiling, ToxProfiler cell stress assay, transcriptomics in HepG2 and MCF-7 cells, ReproTracker developmental and reproductive toxicology (DART) assays, and cytotoxicity assays in human kidney cells. The outcome of the NGRA was compared to that of the traditional risk assessment approach based on animal data. The identification of the toxicologically critical entity was a critical step that directed the workflow and the selection of chemicals for PBPK modeling and testing in bioassays. The traditional risk assessment and NGRA identified salicylic acid (SA) as the "toxdriver." A deterministic PBPK model for a single-day application of 1.54 g face cream containing 0.5% BSal estimated the C max for BSal (1 nM) to be much lower than that of its major in vitro metabolite, SA (93.2 nM). Therefore, SA was tested using toxicodynamics bioassays. The lowest points of departure (PoDs) were obtained from the toxicogenomics assays. The interpretation of these results by two companies and methods were similar (SA only results in significant gene deregulation in HepG2 cells), but PoD differed (213 μM and 10.6 µM). A probabilistic PBPK model for repeated applications of the face cream estimated the highest C max of SA to be 630 nM. The resulting margins of internal exposure (MoIE) using the PoDs were 338 and 16, which were more conservative than those derived from external exposure and in vivo PoDs (margin of safety values were 9,705). In conclusion, both traditional and ab initio NGRA approaches concluded that the daily application of BSal in a cosmetic leave-on face cream at 0.5% is safe for humans. The processing and interpretation of toxicogenomics data can lead to different PoDs, which can subsequently affect the calculation of the MoIE. This case study supports the use of NAMs in a tiered NGRA ab initio approach.

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Privileged structures have been widely used as an effective template in medicinal chemistry for drug discovery. Chalcone is a common simple scaffold found in many naturally occurring compounds. Many chalcone derivatives have also been prepared due to their convenient synthesis. These natural products and synthetic compounds have shown numerous interesting biological activities with clinical potentials against various diseases. This review aims to highlight the recent evidence of chalcone as a privileged scaffold in medicinal chemistry. Multiple aspects of chalcone will be summarized herein, including the isolation of novel chalcone derivatives, the development of new synthetic methodologies, the evaluation of their biological properties, and the exploration of the mechanisms of action as well as target identification. This review is expected to be a comprehensive, authoritative, and critical review of the chalcone template to the chemistry community.

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The objectives of this study were to investigate the mechanisms of action and to evaluate the potential application of Desmos chinensis extracts for controlling rice sheath blight. The dichloromethane extract from D. chinensis demonstrated high antifungal activity against Rhizoctonia solani. The extract was shown to have anti-R. solani activity with minimum inhibitory concentration (MIC) and minimum fungicidal concentration values ranging from 31.2 to 62.5μgmL−1 and from 62.5 to 500μgmL−1, respectively. Bioautography on thin-layer chromatography plates demonstrated antifungal activity of the extract with an Rf value of 0.33. A total of 7 compounds, 2 benzoate esters (benzyl benzoate and benzyl 2-hydroxybenzoate), 2 sesquiterpenoids (α-eudesmol and β-eudesmol), 1 aromatic alcohol (benzyl alcohol), 1 aromatic ketone (acetophenone) and 1 diterpenoid (phytol), were detected and identified using gas chromatography–mass spectrometry analysis. Electron micrographs confirmed the effects of the extract on morphological and ultrastructural alterations in the treated fungal cells. The micrographs of the mycelia treated with the extract at 4MIC illustrated aberrant morphology such as shrinkage, partial distortion and globular structures of different sizes along the surface of the mycelia. Damaging membranous structures including disruption of the cell membrane, partial loss of nuclear membranes, and depletion of hyphal cytoplasm and membranous organelles were observed. Foliar application of D. chinensis extract at a concentration of 2mgmL−1 on rice markedly decreased sheath blight severity. It was concluded that the application of D. chinensis extract can be used as a botanical fungicide to control rice sheath blight.

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Seven flavonoids have been isolated from the aerial parts of Halostachys caspica C. A. Mey. (Chenopodiaceae) for the first time. By means of physicochemical and spectrometric analysis, they were identified as luteolin (1), chrysin (2), chrysin 7-O-β-D-glucopyranoside (3), quercetin (4), quercetin 3-O-β-D-glucopyranoside (5), isorhamentin-3-O-β-D-glucopyranoside (6), and isorhamentin-3-O-β-D-rutinoside (7). All flavonoids were evaluated to show a broad antimicrobial spectrum of activity on microorganisms including seven bacterial and one fungal species as well as pronounced antioxidant activity. Among them, the aglycones with relatively low polarity had stronger bioactivity than their glycosides. The results suggested that the isolated flavonoids could be used for future development of antimicrobial and antioxidant agents, and also provided additional data for supporting the use of H. caspica as forage.

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The drugs cyclosporine A (CsA) and tacrolimus (FK506) revolutionized organ transplantation. Both compounds are still widely used in the clinic as well as for basic research, even though they have dramatic side effects and modulate other pathways than calcineurin-NFATc, too. To answer the major open question - whether the adverse side effects are secondary to the actions of the drugs on the calcineurin-NFATc pathway - alternative inhibitors were developed. Ideal inhibitors should discriminate between the inhibition of (i) calcineurin and peptidyl-prolyl cis-trans isomerases (PPIases; the matchmaker proteins of CsA and FK506), (ii) calcineurin and the other Ser/Thr protein phosphatases, and (iii) NFATc and other transcription factors. In this review we summarize the current knowledge about novel inhibitors, synthesized or identified in the last decades, and focus on their mode of action, specificity, and biological effects.

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Ülke: Malaya

Taxon: Desmos chinensis

Referans: Burkill,1966

Kaynak: James A. Duke

Ülke: Malaya

Taxon: Desmos chinensis

Referans: Burkill,1966

Kaynak: James A. Duke

Ülke: Malaya

Taxon: Desmos chinensis

Referans: Burkill,1966

Kaynak: James A. Duke