Antidiabetic Activities of an LC/MS Fingerprinted Aqueous Extract of Fagonia cretica L. in Preclinical Models

Diabetes mellitus is a chronic disease and one of the most important public health challenges facing mankind. Fagonia cretica is a medicinal plant used widely in the Punjab in Pakistan. A recent survey has demonstrated that traditional healers and herbalists frequently use this plant to treat diabetes. In the current study, the traditional medicine was prepared as a tea, and the profile of the main metabolites present in the traditional medicine was analysed via LC/MS/MS. The extract was shown to contain a number of phenolic glycosides including quercetin-3-O-rutinoside, kaempferol-3-O-rutinoside, kaempferol-3-O-glycoside, kaempferol-3(6′-malonylglucoside), isorhamnetin-3-O-rutinoside, and isorhamnetin 3-(6″-malonylglucoside) in addition to two unidentified sulphonated saponins. The traditional medicine inhibits α-glucosidase in vitro with an IC50 of 4.62 µg/mL. The hypoglycaemic effect of the traditional medicine was evaluated in normoglycaemic and streptozotocin-treated diabetic rats, using glibenclamide as an internal control. The preparation (250 or 500 mg/kg body weight) was administered once a day for 21 consecutive days. The dose of 500 mg/kg was effective in the management of the disease, causing a 45 % decrease in the plasma glucose level at the end of the experimental period. Histological analysis of pancreatic sections confirmed that streptozotocin/nictotinamide treatment caused destruction of pancreatic islet cells, while pancreatic sections from the treatment groups showed that both the extract and glibenclamide partially prevented this deterioration. The mechanism of this protective effect is unclear. However, such a finding suggests that ingestion of the tea could confer additional benefits and should be investigated further

Crataegus Extract WS®1442 Stimulates Cardiomyogenesis and Angiogenesis From Stem Cells: A Possible New Pharmacology for Hawthorn?

Extracts from the leaves and flowers of Crataegus spp. (i.e., hawthorn species) have been traditionally used with documented preclinical and clinical activities in cardiovascular medicine. Based on reported positive effects on heart muscle after ischemic injury and the overall cardioprotective profile, the present study addressed potential contributions of Crataegus extracts to cardiopoietic differentiation from stem cells. The quantified Crataegus extract WS®1442 stimulated cardiomyogenesis from murine and human embryonic stem cells (ESCs). Mechanistically, this effect was found to be induced by promoting differentiation of cardiovascular progenitor cell populations but not by proliferation. Bioassay-guided fractionation, phytochemical and analytical profiling suggested high-molecular weight ingredients as the active principle with at least part of the activity due to oligomeric procyanidines (OPCs) with a degree of polymerization between 3 and 6 (DP3–6). Transcriptome profiling in mESCs suggested two main, plausible mechanisms: These were early, stress-associated cellular events along with the modulation of distinct developmental pathways, including the upregulation of brain-derived neurotrophic factor (BDNF) and retinoic acid as well as the inhibition of transforming growth factor β/bone morphogenetic protein (TGFβ/BMP) and fibroblast growth factor (FGF) signaling. In addition, WS®1442 stimulated angiogenesis ex vivo in Sca-1+ progenitor cells from adult mice hearts. These in vitro data provide evidence for a differentiation promoting activity of WS®1442 on distinct cardiovascular stem/progenitor cells that could be valuable for therapeutic heart regeneration after myocardial infarction. However, the in vivo relevance of this new pharmacological activity of Crataegus spp. remains to be investigated and active ingredients from bioactive fractions will have to be further characterized

Covalent Modification of Human Serum Albumin by the Natural Sesquiterpene Lactone Parthenolide

The reactivity of parthenolide (PRT), a natural sesquiterpene lactone from Tanacetum parthenium (Asteraceae), with human serum albumin (HSA) was studied by UHPLC/+ESI-QqTOF MS analysis after tryptic digestion of albumin samples after incubation with this compound. It was found that the single free cysteine residue, C34, of HSA (0.6 mM) reacted readily with PRT when incubated at approximately 13-fold excess of PRT (8 mM). Time-course studies with PRT and its 11β,13-dihydro derivative at equimolar ratios of the reactants revealed that PRT under the chosen conditions reacts preferably with C34 and does so exclusively via its α-methylene-γ-lactone moiety, while the epoxide structure is not involved in the reaction

Occurrence of Benzoic Acid Esters as Putative Catabolites of Prunasin in Senescent Leaves of <i>Prunus laurocerasus</i>

<i>Prunus laurocerasus</i> is an evergreen shrub containing large quantities of the cyanogenic glycoside prunasin (<b>1</b>) in its leaves, which decomposes to prunasin amide (<b>2</b>) or glucose-1-benzoate (<b>4</b>) when the leaves become chlorotic as a result of senescence or pseudosenescence. This study was aimed at the systematic identification of senescence-associated metabolites to contribute further insight into the catabolism of <b>1</b>. LC-ESIMS profiles of senescent and green leaves were analyzed by principal component analysis. In senescent leaves, the concentrations of 36 compounds were increased significantly including several benzoic acid derivatives, of which prunasin amide-6′-benzoate (<b>5</b>) and prunasin acid-6′-benzoate (<b>6</b>) were isolated and identified. The observed metabolic changes were also induced by treatment of <i>P. laurocerasus</i> shrubs with exogenous ethylene. The data presented support an oxidative catabolism of <b>1</b> without release of hydrogen cyanide and the remobilization of its nitrogen in the course of senescence. The results are discussed in the context of functional diversification and drug discovery, where senescent plant material represents a widely unexplored source for the discovery of natural products

Bioassay-Guided Fractionation of a Leaf Extract from Combretum mucronatum with Anthelmintic Activity: Oligomeric Procyanidins as the Active Principle

Combretum mucronatum Schumach. &amp; Thonn. is a medicinal plant widely used in West African traditional medicine for wound healing and the treatment of helminth infections. The present study aimed at a phytochemical characterization of a hydroalcoholic leaf extract of this plant and the identification of the anthelmintic compounds by bioassay-guided fractionation. An EtOH-H2O (1:1) extract from defatted leaves was partitioned between EtOAc and H2O. Further fractionation was performed by fast centrifugal partition chromatography, RP18-MPLC and HPLC. Epicatechin (1), oligomeric proanthocyanidins (OPC) 2 to 10 (mainly procyanidins) and flavonoids 11 to 13 were identified as main components of the extract. The hydroalcoholic extract, fractions and purified compounds were tested in vitro for their anthelmintic activity using the model nematode Caenorhabditis elegans. The bioassay-guided fractionation led to the identification of OPCs as the active compounds with a dose-dependent anthelmintic activity ranging from 1 to 1000 μM. Using OPC-clusters with a defined degree of polymerization (DP) revealed that a DP ≥ 3 is necessary for an anthelmintic activity, whereas a DP &gt; 4 does not lead to a further increased inhibitory effect against the helminths. In summary, the findings rationalize the traditional use of C. mucronatum and provide further insight into the anthelmintic activity of condensed tannins

PLS-prediction and confirmation of hydrojuglone glucoside as the antitrypanosomal constituent of "Juglans spp."

Naphthoquinones (NQs) occur naturally in a large variety of plants. Several NQs are highly active against protozoans, amongst them the causative pathogens of neglected tropical diseases such as human African trypanosomiasis (sleeping sickness), Chagas disease and leishmaniasis. Prominent NQ-producing plants can be found among Juglans spp. (Juglandaceae) with juglone derivatives as known constituents. In this study, 36 highly variable extracts were prepared from different plant parts of J. regia, J. cinerea and J. nigra. For all extracts, antiprotozoal activity was determined against the protozoans Trypanosoma cruzi, T. brucei rhodesiense and Leishmania donovani. In addition, an LC-MS fingerprint was recorded for each extract. With each extract's fingerprint and the data on in vitro growth inhibitory activity against T. brucei rhodesiense a Partial Least Squares (PLS) regression model was calculated in order to obtain an indication of compounds responsible for the differences in bioactivity between the 36 extracts. By means of PLS, hydrojuglone glucoside was predicted as an active compound against T. brucei and consequently isolated and tested in vitro. In fact, the pure compound showed activity against T. brucei at a significantly lower cytotoxicity towards mammalian cells than established antiprotozoal NQs such as lapachol

Erratum: Antidiabetic Activities of an LC/MS Fingerprinted Aqueous Extract of Fagonia Cretica L. In Preclinical Models

Diabetes mellitus is a chronic disease and one of the most important public health challenges facing mankind. Fagonia cretica is a medicinal plant used widely in the Punjab in Pakistan. A recent survey has demonstrated that traditional healers and herbalists frequently use this plant to treat diabetes. In the current study the traditional medicine was prepared as a tea and the profile of the main metabolites present in the TM, was analysed via LC/MS/MS. The extract was shown to contain a number of phenolic glycosides including quercetin-3-O-rutinoside, kaempferol-3-rutnoside, kaempferol-3-O-glycoside, kaempferol-3(6\u27-malonylglucoside), isorhamnetin-3-O-rutinoside, and isorhamnetin 3-(6\u27\u27-malonyglucoside) in addtional to two unidenntified sulphonated saponins. The traditional medicine inhibits α-glucosidase in vitro with an IC50 of 4.62 µg/ml. The hypoglycaemic effect of the traditional medicine was evaluated in normoglycaemic and streptozotocin-treated diabetic rats, using glibenclamide as internal control. The preparation (250 or 500 mg/kg body weight) was administered once a Day for 21consecutive Days. The dose of 500 mg/kg was effective in the management of the disease causing a 45% decrease in plasma glucose level at the end of the experimental period. Histological analysis of pancreatic sections confirmed that streptozotocin/nictotinamide treatment caused destruction of pancreatic islet cells while pancreatic sections from treatment groups showed that both the extract and glibenclamide partially prevented this deterioration. The mechanism of this protective effect is unclear. However, such a finding suggests that ingestion of the tea could confer additional benefits and should be investigated further