Daphnanes diterpenes from the latex of Hura crepitans L. and their PKCζ-dependent anti-proliferative activity on colorectal cancer cells.

Hura crepitans L. (Euphorbiaceae) is a thorn-covered tree widespread in South America, Africa and Asia which produces an irritating milky latex containing numerous secondary metabolites, notably daphnane-type diterpenes known as Protein Kinase C activators. Fractionation of a dichloromethane extract of the latex led to the isolation of five new daphnane diterpenes (1-5), along with two known analogs (6-7) including huratoxin. Huratoxin (6) and 4',5'-epoxyhuratoxin (4) were found to exhibit significant and selective cell growth inhibition against colorectal cancer cell line Caco-2 and primary colorectal cancer cells cultured as colonoids. The underlying mechanism of 4 and 6 was further investigated revealing the involvement of PKCζ in the cytostatic activity.

Anti-Aging Potential of a Rosa centifolia Stem Extract with Focus on Phytochemical Composition by Bioguided Fractionation.

Agricultural practices generate huge amounts of by-products, often simply discarded as waste that must be processed at some cost. The natural by-products revalorisation as raw material to produce high-added value ingredients for various industrial sectors may pave the way towards more sustainable industrial practices, via an optimised utilisation of natural resources. Integrating the circular economy precepts to production systems is considered to be a more and more promising management solution to significantly reduce the environmental impact of economic activities. This article discusses the valorisation of Rosa centifolia stem to produce a natural extract with cosmetic anti-aging potential. To do so, the cosmetic potential of 30 extracts obtained by maceration of agricultural by-products in a hydroalcoholic solvent was evaluated: their activities, as well as their inhibitory activities of specific enzymes were assessed in vitro to identify those that could be used effectively as anti-ageing actives while meeting the consumer's expectations in terms of sustainability, naturality, transparency and traceability.[1] A hydroalcoholic extract of R. centifolia stem revealed itself particularly promising due to its valuable anti-hyaluronidase and antioxidant activities, and its interesting anti-elastase and anti-inflammatory potential. The bio-guided fractionation of this extract allows the characterisation of three major compounds, e. g., isoquercitrin, quercitrin and euscaphic acid, never identified in R. centifolia previously.

Bioactive Isocedrenes from Perezia multiflora.

Four isocedrenes (1:  - 4: ), including one new compound (2: ), were isolated from an ethanolic extract of the aerial parts of Perezia multiflora by bioactivity-guided fractionation. For compounds 1: and 3: , a revised stereochemical assignment is proposed based on molecular modeling studies using DFT-NMR calculations. Antiparasitic activity of the four compounds was evaluated using an in vitro culture of Plasmodium falciparum and axenic amastigotes of Leishmania infantum. IC50 values ranged from 0.81 to 16.1 µM (P. falciparum) and 0.16 to 2.03 µM (L. infantum). Toxicity was evaluated against J774A.1 mouse macrophages or human macrophages generated from THP-1 monocytic cells (IC50 values ranging from 0.16 to 2.64 µM). Compound 4: exhibited weak selectivity against P. falciparum with a selectivity index (SI = CC50/IC50) of 3. No selectivity was observed for compounds 1:  - 3: against both parasites.

Daphnanes diterpenes from the latex of Hura crepitans L. And activity against human colorectal cancer cells Caco-2.

Hura crepitans (Euphorbiaceae) is a tree from South America that produces an irritant latex used as a fish poison. A bio-guided fractionation of an ethanolic extract of the latex led to the isolation and structural identification of three known daphnane-type diterpenes (1-3) including huratoxin (1), together with two new analogs (4, 5). Compound 1 was found to exhibit significant and selective cell growth inhibition against the colorectal cancer cell line Caco-2, with morphological modifications suggesting formations mimicking the intestinal crypt architecture. The underlying mechanism of 1 was further investigated, in comparison with 12-O-tetradecanoylphorbol-13-acetate (TPA), revealing two different mechanisms.

How Histone Deacetylase Inhibitors Alter the Secondary Metabolites of Botryosphaeria mamane, an Endophytic Fungus Isolated from Bixa orellana.

Fungi are talented organisms able to produce several natural products with a wide range of structural and pharmacological activities. The conventional fungal cultivation used in laboratories is too poor to mimic the natural habitats of fungi, and this can partially explain why most of the genes responsible for the production of metabolites are transcriptionally silenced. The use of Histone Deacetylase inhibitors (HDACis) to perturb fungal secondary biosynthetic machinery has proven to be an effective approach for discovering new fungal natural products. The present study relates the effects of suberoylanilide hydroxamic acid (SAHA) and sodium valproate (VS) on the metabolome of Botryosphaeria mamane, an endophytic fungus isolated from Bixa orellana L. UHPLC/HR-MS analysis, integrated with four metabolomics tools: MS-DIAL, MS-FINDER, MetaboAnalyst and GNPS molecular networking, was established. This study highlighted that SAHA and VS changed metabolites in B. mamane, causing upregulation and downregulation of metabolites production. In addition, twelve compounds were detected in the extracts as metabolites structurally correlated to SAHA, indicating its important reactivity in the medium or its metabolism by the fungus. An addition of SAHA induced the production of eight metabolites while VS induced only two metabolites undetected in the control strain. This result illustrates the importance of adding HDACis to a fungal culture in order to induce metabolite production.

Profiling of Hura crepitans L. latex by ultra-high-performance liquid chromatography/atmospheric pressure chemical ionisation linear ion trap Orbitrap mass spectrometry.

INTRODUCTION: The phytochemistry of the latex of Hura crepitans L. (Euphorbiaceae), a widespread tree in the Amazonian forest having many uses, is little known. Only huratoxin, a daphnane diterpene orthoester, has been described despite the high pharmacological potential of this kind of compounds. Glucosphingolipids (cerebrosides) are also known to be distributed in Euphorbiaceae latexes. OBJECTIVE: To tentatively identify daphnanes diterpenes and cerebrosides in the latex of H. crepitans. METHODS: An ethanolic extract of the lyophilised latex of H. crepitans was analysed by ultra-high-performance liquid chromatography (UHPLC) coupled with positive and negative atmospheric pressure chemical ionisation high-resolution mass spectrometry (APCI-HRMS) method using a quadrupole/linear ion trap/Orbitrap (LTQ-Orbitrap). Tandem mass spectrometry (MS/MS) spectra were recorded by two different fragmentation modes: collision induced dissociation (CID) and higher-energy collisional dissociation (HCD). RESULTS: The analysis of CID- and HCD-MS/MS spectra allowed to propose fragmentation patterns for daphnane esters and cerebrosides and highlight diagnostic ions in positive and negative ion modes. A total of 34 compounds including 24 daphnane esters and 10 cerebrosides have been tentatively annotated. Among them, 17 daphnane diterpenes bearing one or two acyl chains are new compounds and the cerebrosides are described in the genus Hura for the first time. CONCLUSION: This study revealed the chemical constituents of the latex of H. crepitans and particularly its richness and chemical diversity in daphnane diterpenes, more frequently encountered in the species of Thymelaeaceae.