Exploring the anti-proliferative activity of Pelargonium sidoides DC with in silico target identification and network pharmacology

Pelargonium sidoides DC (Geraniaceae) is a medicinal plant indigenous to Southern Africa that has been widely evaluated for its use in the treatment of upper respiratory tract infections. In recent studies, the anti-proliferative potential of P. sidoides was shown, and several phenolic compounds were identified as the bioactive compounds. Little, however, is known regarding their anti-proliferative protein targets. In this study, the anti-proliferative mechanisms of P. sidoides through in silico target identification and network pharmacology methodologies were evaluated. The protein targets of the 12 phenolic compounds were identified using the target identification server PharmMapper and the server for predicting Drug Repositioning and Adverse Reactions via the Chemical–Protein Interactome (DRAR-CPI). Protein–protein and protein–pathway interaction networks were subsequently constructed with Cytoscape 3.4.0 to evaluate potential mechanisms of action. A total of 142 potential human target proteins were identified with the in silico target identification servers, and 90 of these were found to be related to cancer. The protein interaction network was constructed from 86 proteins involved in 209 interactions with each other, and two protein clusters were observed. A pathway enrichment analysis identified over 80 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched with the protein targets and included several pathways specifically related to cancer as well as various signaling pathways that have been found to be dysregulated in cancer. These results indicate that the anti-proliferative activity of P. sidoides may be multifactorial and arises from the collective regulation of several interconnected cell signaling pathways.https://link.springer.com/journal/110302018-11-18hj2017AnatomyBiochemistr

Activity-guided isolation and identification of the major antioxidant and anticancer compounds from a commercial Pelargonium sidoides tincture

Extracts prepared from the roots of Pelargonium sidoides (DC) are commercially available for the treatment of respiratory related conditions. Recently, a commercial radix mother tincture of this plant was shown to have both antioxidant and anticancer effects especially related to the G0/G1 block in the Jurkat E6.1 cell line (unpublished results). Fractions were prepared by semi-preparative HPLC, and their antioxidant and anticancer activities were determined. The more hydrophilic fractions isolated namely F6-F12 were all found to have strong reducing capacities and were able to scavenge peroxyl radicals. In the human lung cell line, NCI-H460, significant cellular antioxidant effects were observed. Anticancer activity was evaluated in the NCI-pre-screen panel (NCI-H460, MCF-7 and SF-268) and the Jurkat E6.1 cell line. Fractions F7, F9 and F12 were found to inhibit the cell growth of these four cell-lines (p < 0.05), especially the Jurkat E6.1 cell line with the sulforhodamine B assay. Mass spectrometry analysis revealed that these active fractions contained several polyphenolic compounds such as gallic acid, trihydroxycoumarin, dihydroxycoumarin sulfates, proanthocyanidins and phenolic glycosides. A phenolic acid glycoside sulfate not previously shown in Pelargonium sidoides extracts was also isolated. In conclusion, the antioxidant and/or anticancer activity of the Pelargonium sidoides tincture may be attributed to the presence of these polyphenolics.National Research Foundation of South Africahttp://link.springer.com/journal/442016-11-30hb201

Anti-proliferative properties of commercial Pelargonium sidoides tincture, with cell-cycle G(0)/G(1) arrest and apoptosis in Jurkat leukaemia cells

CONTEXT : Pelargonium sidoides DC (Geraniaceae) is an important medicinal plant indigenous to South Africa and Lesotho. Previous studies have shown root extracts rich in polyphenolic compounds with antibacterial, antiviral and immunomodulatory activities. Little is known regarding the anticancer properties of Pelargonium sidoides extracts. OBJECTIVE : This study evaluates the anti-proliferative effects of a Pelargonium sidoides radix mother tincture (PST). MATERIALS AND METHODS : The PST was characterized by LC-MS/MS. Anti-proliferative activity was evaluated in the pre-screen panel of the National Cancer Institute (NCI-H460, MCF-7 and SF-268) and the Jurkat leukemia cell line at concentrations of 0-150 μg/mL. Effect on cell growth was determined with sulforhodamine B and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays after 72 h. Effect on cell cycle and apoptosis induction in Jurkat cells was determined by flow cytometry with propidium iodide and Annexin V: fluorescein isothiocyanate staining. RESULTS : Dihydroxycoumarin sulfates, gallic acid as well as gallocatechin dimers and trimers were characterized in PST by mass spectrometry. Moderate anti-proliferative effects with GI50 values between 40 and 80 μg/mL observed in the NCI-pre-screen panel. Strong activity observed with Jurkat cells with a GI50 of 6.2 μg/mL, significantly better than positive control 5-fluorouracil (GI50 of 9.7 μg/mL). The PST arrested Jurkat cells at G0/G1 phase of the cell cycle and increased the apoptotic cells from 9% to 21%, while the dead cells increased from 4% to 17%. CONCLUSION : We present evidence that Pelargonium sidoides has cancer cell type specific antiproliferative effects and may be a source of novel anticancer molecules.National Research Foundation of South Africa.http://www.tandfonline.com/loi/iphb202017-09-30hb2016AnatomyBiochemistr

Antioxidant and anti-inflammatory properties of Ilex guayusa tea preparations : a comparison to Camellia sinensis teas

Ilex guayusa tea preparations are now commercially available as Runa tea. Little is known regarding the antioxidant and anti-inflammatory bioactivities of this tea. The I. guayusa teas had a total polyphenolic content between 54.39 and 67.23 mg GAE/g dry mass and peroxyl radical scavenging capacities between 1773.41 and 2019 µmol TE/g dry mass, nearly half of that for the Camellia sinensis teas. The I. guayusa teas afforded 60-80% protection from oxidative stress in the Caco-2 cellular antioxidant assay, comparable to the C. sinensis teas. The anti-inflammatory activity in lipopolysaccharide-stimulated RAW 264.7 cells of I. guayusa teas was similarly comparable to the C. sinensis teas with nitric oxide production reduced by 10-30%. Major compounds identified by mass spectrometry were the phenolic mono- and dicaffeoylquinic acid derivatives. I. guayusa teas are a good source of dietary phenolic compounds with cellular antioxidant and anti-inflammatory properties.http://pubs.rsc.org/en/journals/journalissues/fo#!recentarticles&adv2018-12-13hj2017AnatomyBiochemistr

Evaluation of the anti-diabetic activity of some common herbs and spices : providing new insights with inverse virtual screening

Culinary herbs and spices are widely used as a traditional medicine in the treatment of diabetes and its complications, and there are several scientific studies in the literature supporting the use of these medicinal plants. However, there is often a lack of knowledge on the bioactive compounds of these herbs and spices and their mechanisms of action. The aim of this study was to use inverse virtual screening to provide insights into the bioactive compounds of common herbs and spices, and their potential molecular mechanisms of action in the treatment of diabetes. In this study, a library of over 2300 compounds derived from 30 common herbs and spices were screened in silico with the DIA-DB web server against 18 known diabetes drug targets. Over 900 compounds from the herbs and spices library were observed to have potential anti-diabetic activity and liquorice, hops, fennel, rosemary, and fenugreek were observed to be particularly enriched with potential anti-diabetic compounds. A large percentage of the compounds were observed to be potential polypharmacological agents regulating three or more anti-diabetic drug targets and included compounds such as achillin B from yarrow, asparasaponin I from fenugreek, bisdemethoxycurcumin from turmeric, carlinoside from lemongrass, cinnamtannin B1 from cinnamon, crocin from sa ron and glabridin from liquorice. The major targets identified for the herbs and spices compounds were dipeptidyl peptidase-4 (DPP4), intestinal maltase-glucoamylase (MGAM), liver receptor homolog-1 (NR5A2), pancreatic alpha-amylase (AM2A), peroxisome proliferator-activated receptor alpha (PPARA), protein tyrosine phosphatase non-receptor type 9 (PTPN9), and retinol binding protein-4 (RBP4) with over 250 compounds observed to be potential inhibitors of these particular protein targets. Only bay leaves, liquorice and thyme were found to contain compounds that could potentially regulate all 18 protein targets followed by black pepper, cumin, dill, hops and marjoram with 17 protein targets. In most cases more than one compound within a given plant could potentially regulate a particular protein target. It was observed that through this multi-compound-multi target regulation of these specific protein targets that the major anti-diabetic e ects of reduced hyperglycemia and hyperlipidemia of the herbs and spices could be explained. The results of this study, taken together with the known scientific literature, indicated that the anti-diabetic potential of common culinary herbs and spices was the result of the collective action of more than one bioactive compound regulating and restoring several dysregulated and interconnected diabetic biological processes.The National Research Foundation of South Africa, the Spanish Ministry of Economy and Competitiveness (CTQ2017-87974-R) and by the Fundación Séneca del Centro de Coordinación de la Investigación de la Región de Murcia under Project 20988/PI/18.http://www.mdpi.com/journal/moleculesam2020BiochemistryGeneticsMicrobiology and Plant Patholog

DIA-DB : a database and web server for the prediction of diabetes drugs

The DIA-DB is a web server for the prediction of diabetes drugs that uses two different and complementary approaches: (a) comparison by shape similarity against a curated database of approved antidiabetic drugs and experimental small molecules and (b) inverse virtual screening of the input molecules chosen by the users against a set of therapeutic protein targets identified as key elements in diabetes. As a proof of concept DIA-DB was successfully applied in an integral workflow for the identification of the antidiabetic chemical profile in a complex crude plant extract. To this end, we conducted the extraction and LC-MS based chemical profile analysis of Sclerocarya birrea and subsequently utilized this data as input for our server. The server is open to all users, registration is not necessary, and a detailed report with the results of the prediction is sent to the user by email once calculations are completed. This is a novel public domain database and web server specific for diabetes drugs and can be accessed online through http://bio-hpc.eu/software/dia-db/.http://pubs.acs.org/journal/jcics1/about.htmlhj2021BiochemistryGeneticsMicrobiology and Plant Patholog

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer

Exploring African Medicinal Plants for Potential Anti-Diabetic Compounds with the DIA-DB Inverse Virtual Screening Web Server

Medicinal plants containing complex mixtures of several compounds with various potential beneficial biological effects are attractive treatment interventions for a complex multi-faceted disease like diabetes. In this study, compounds identified from African medicinal plants were evaluated for their potential anti-diabetic activity. A total of 867 compounds identified from over 300 medicinal plants were screened in silico with the DIA-DB web server (http://bio-hpc.eu/software/dia-db/) against 17 known anti-diabetic drug targets. Four hundred and thirty compounds were identified as potential inhibitors, with 184 plants being identified as the sources of these compounds. The plants Argemone ochroleuca, Clivia miniata, Crinum bulbispermum, Danais fragans, Dioscorea dregeana, Dodonaea angustifolia, Eucomis autumnalis, Gnidia kraussiana, Melianthus comosus, Mondia whitei, Pelargonium sidoides, Typha capensis, Vinca minor, Voacanga africana, and Xysmalobium undulatum were identified as new sources rich in compounds with a potential anti-diabetic activity. The major targets identified for the natural compounds were aldose reductase, hydroxysteroid 11-beta dehydrogenase 1, dipeptidyl peptidase 4, and peroxisome proliferator-activated receptor delta. More than 30% of the compounds had five or more potential targets. A hierarchical clustering analysis coupled with a maximum common substructure analysis revealed the importance of the flavonoid backbone for predicting potential activity against aldose reductase and hydroxysteroid 11-beta dehydrogenase 1. Filtering with physiochemical and the absorption, distribution, metabolism, excretion and toxicity (ADMET) descriptors identified 28 compounds with favorable ADMET properties. The six compounds&#8212;crotofoline A, erythraline, henningsiine, nauclefidine, vinburnine, and voaphylline&#8212;were identified as novel potential multi-targeted anti-diabetic compounds, with favorable ADMET properties for further drug development