Chlorinated Withanolides from Withania somnifera

A chlorinated withanolide, 6α-chloro-5β,17α-dihydroxywithaferin A (1), and nine known withanolides, 6α-chloro-5β-hydroxywithaferin A (2), (22R)-5β-formyl-6β,27-dihydroxy-1-oxo-4-norwith-24-enolide, withaferin A, 2,3-dihydrowithaferin A, 3-methoxy-2,3-dihydrowithaferin A, 2,3-didehydrosomnifericin, withanone, withanoside IV and withanoside X, were isolated from Withania somnifera (Solanaceae). All structures were elucidated on the basis of spectroscopic methods (IR, HRESIMS, 1D/2D NMR). X-ray crystallography confirmed the absolute configuration of 1

SARS-CoV-2/COVID-19: - Mortalitätsauswertungen – während der Pandemie – in Deutschland und seinen Bundesländern für 2020

Seitdem die Weltgesundheitsorganisation am 11. März 2020 den Ausbruch des neuartigen Coronavirus zu einer globalen Pandemie erklärt hat, kam es auch in Deutschland durch SARS-CoV-2-Infektionen zu zum Teil schweren und tödlichen Verläufen. Diese Dissertationsarbeit hat empirisch geprüft, welche Veränderungen der Sterblichkeit bei Männern und Frauen unterschiedlichen Alters in Deutschland und seinen Bundesländern (BL) im Zusammenhang mit der COVID-19-Pandemie im Jahr 2020 beobachtet werden konnten. Dazu wurden bereits während des Jahres 1 (2020) der SARS-CoV-2/COVID-19-Pandemie ohne Präzedenz standardisierte Mortalitätsratios (SMRs) für Deutschland und seine 16 BL im Vergleich zu den Vorjahren 2016-2019 bestimmt und ausgewertet. Besonderes Augenmerk lag dabei auf der Betrachtung und Suche nach Unterschieden zwischen bestimmten Altersklassen (<65, ≥65 Jahre und total) sowie zwischen den Geschlechtern (männlich, weiblich und total). Die Datengrundlage dieser Dissertation bildeten Sterbefallzahlen für das Jahr 2020, die am 29.01.2021 vom statistischen Bundesamt online publiziert und mit Stata 14 ausgewertet wurden. Zwei mathematische Ansätze (Annahme einer Normalverteilung (NV) und Annahme einer lognormalen Verteilung (LNV)) wurden für die Statistik gewählt. Ergebnisse dieser Arbeit zeigen wesentliche Unterschiede zwischen den Alters- (Beispiele: unter 65-Jährige in Deutschland (SMR: 1,00, 95%-KI: 0,98-1,01) vs. über 65-Jährige (SMR: 1,06, 95%-KI: 1,04-1,09)) und Geschlechterkategorien (Beispiele: über 65-jährige Männer in Deutschland (SMR: 1,08, 95-KI: 1,05-1,11) vs. über 65-jährige Frauen (SMR: 1,04, 95%-KI: 1,02-1,07)) sowie eine große Heterogenität in dem Verlauf und Ausmaß der SMRs zwischen den 16 BL (Beispiele: SMR in Sachsen 1,13, 95%-KI: 1,11-1,16 vs. SMR in Schleswig-Holstein 1,01, 95%-KI: 0,98-1,04). Die Heterogenität zwischen Bundesländern wird exemplarisch für Nordrhein-Westfalen versus Thüringen exploriert: Während sich NRW und Thüringen in ihren quantitativen Ergebnissen für das gesamte Jahr gleichen (SMR= 1,04, 95%-KI: 1,02-1,06 für NRW und 1,04, 95%-KI: 1,01-1,06 für Thüringen), gibt es deutliche Unterschiede in den Risiko-Verläufen während des Beobachtungsjahres. Für die gesamte deutsche Bevölkerung lag der SMR-Jahresdurchschnitt 2020 bei +5% im Vergleich zu den Vorjahren (SMR=1,05 (95%-KI: 1,03-1,07)), wobei ältere Menschen (SMR: 1,06, 95%-KI: 1,04-1,09) gegenüber den Jüngeren (SMR: 1,00, 95%-KI: 0,98-1,01) und Männer (SMR: 1,07, 95%-KI: 1,05-1,09) gegenüber Frauen (SMR: 1,04, 95%-KI: 1,02-1,06) stärker betroffen waren. Die Betrachtung von Wochen- und Monatsdaten bzw. -graphen zeigte zwei der Pandemie zuzurechnende Wellen-Peaks der Übersterblichkeit im Frühjahr und ab Herbst des Jahres 2020. Eine anteilige Erklärung für höhere SMRs während der Herbstmonate, in denen sich die zweite Welle in Deutschland 2020 abzuzeichnen begann, könnte die Saisonalität von Corona-Viren mit Virus-Lows zur Mitte des Jahres sein. Damit ist nicht auszuschließen, dass beim SMR-Verlauf in den Sommermonaten 2020 die Effekte einer Saisonalität von SARS-CoV-2 unter- und Effekte der vorherigen Gegen-/Präventionsmaßnahmen überschätzt wurden. In der Gesamtschau bietet diese Arbeit durch hohe zeitliche und räumliche Auflösungen einen Zugewinn an Informationen – z.B. in Ergänzung der Auswertungen durch das Robert-Koch-Institut (RKI) –, da sie die Übersterblichkeit während der Pandemie für Wochen und Monate, wie auch für das gesamte Land und die einzelnen Bundesländer getrennt, betrachtet und somit wichtige Unterschiede und Merkmale der Pandemie bezüglich der Mortalität aufdecken kann. Auch zukünftig sollten regelmäßig hochaufgelöste Übersterblichkeitsanalysen durchgeführt werden, um epidemiologisch angemessen in Geschehen mit pandemischen Potential eingreifen zu können

Turmeric inhibits parathyroid hormone-related protein (PTHrP) secretion from human rheumatoid synoviocytes

Excessive production of parathyroid hormone-related protein (PTHrP) by tumor-like synoviocytes contributes to joint destruction in rheumatoid arthritis (RA). Having previously demonstrated that curcuminoid-only and essential oil-only fractions of turmeric prevent joint destruction in an animal model of RA, we hypothesized that synoviocyte PTHrP production could be one signaling pathway targeted by turmeric (Curcuma longa L.) in RA

Isolation of modulators of Organic Anion Transporting Polypeptides (OATPs) from Rollinia emarginata Schlecht (Annonaceae)

Comparative Medicine - OneHealth and Comparative Medicine Poster SessionOrganic Anion Transporting Polypeptides (OATPs) comprise a superfamily of sodium-independent membrane transporters which are involved in transporting numerous endogenous and exogenous substances. OATPs are expressed in different tissues such as intestine, liver, kidney and brain, and are responsible for the uptake of important drugs including cholesterol-lowering agents (statins), endothelin receptor antagonists (sartans), the anticancer drugs methotrexate, SN-38, paclitaxel and docetaxel, as well as the antibiotic rifampicin. Through a strategic collaboration, we search for novel small molecules from the organic extract of Rollinia emarginata Schlecht. (Annonaceae) that interact with the liver specific OATP1B1 and OATP1B3 applying a bioassay guided isolation approach. The organic extract was fractionated using different chromatographic techniques, and each fraction was tested for its effect on OATP1B1- and OATP1B3-mediated transport of 1µM estrone-3-sulfate and 0.1µM estradiol-17||-glucuronide. Several inhibitors, including both substrate-specific and non-specific, were isolated and chemically identified. For instance, the compound Quercetin 3-O-||-L-arabinopyranosyl (1 ->2)||-L-rhamnopyranoside was shown to inhibit both OATP1B1- and OATP1B3-mediated transport of estradiol-17||-glucuronide by more than 90%, relative to control (DMSO). However, with respect to transport of 1µM estrone-3-sulfate it inhibits OATP1B1 by only 45% while, interestingly, stimulating transport mediated by OATP1B3 (2 fold over control). Thanks to our collaborative efforts, we were able to show that plants can be suitable source of small molecules that modulate OATPs using bioassay guided isolation approach

Antiproliferative withanolides from several Solanaceous species

This is an Accepted Manuscript of an article published by Taylor & Francis in Natural Product Research in November 2014, available online: http://www.tandfonline.com/10.1080/14786419.2014.919286.To date, our work on Solanaceous species (Datura wrightii, Jaborosa caulescens, Physalis hispida, P. longifolia, Vassobia breviflora, and Withania somnifera) has resulted in the isolation of 65 withanolides, 31 of which were new, as well as the semi-synthesis of a further 30 withanolides. Structure identification and MTS assay-based antiproliferative evaluation of these 95 compounds revealed that a Δ2-1-oxo functionality in ring A; in conjunction with either a 5β,6β-epoxy or 5α-chloro-6β-hydroxy moiety in ring B; are the minimum structural requirements for withanolides to produce potent cytotoxic activity. Such structural-activity relationship analysis (SARA) also revealed that oxygenation (the –OH or –OR groups) at C-4, 7, 11, and 12; as well as C-14 to C-28; did not contribute toward the observed antiproliferative activity. Herein we present a complete overview of our work as it relates to the withanolides reported from 1965 to 2013

Bioactivity Profiling of Plant Biodiversity of Panama by High Throughput Screening

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.We report relative bioactivities of extracts prepared from a large collection of plants from three national parks in Panama. Over 181 plants were collected, taxonomically identified and their detannified dichloromethane (DCM)-methanolic extracts were used for profiling selected bioactivities. Assays were performed to evaluate the antioxidant activity of the extracts for Antioxidant Response Element (ARE) induction, total non-enzymatic antioxidant potential, anti-inflammatory and anticancer properties. The high throughput analysis of 280 extracts resulted in identification of 57.5% of the extracts that could induce ARE at one or more concentrations tested, 93.5% that harbored total antioxidant capacity, and 2.1% of the extracts that showed lung cancer cell line-specific cytotoxicity. Data from our profiling experiments indicate that a large number of extracts could be a source for further isolation and chemical identification of compounds that could serve as leads for discovery of antioxidant, anticancer and anti-inflammatory agents to prevent or treat complex diseases like cancer and neurodegenerative disorders

(ÿ)-Fern-7-en-3a-ol from Sebastiania brasiliensis

The structure of a fernane isolated from S. brasiliensis was established as fern-7en-3[alpha]-ol, C30H50O. Rings A and D assume a chair conformation, while rings B and C adopt a twist-boat conformation. Rings A/B, C/D, and D/E are trans fused. The relative orientation of the hydroxy group and that of the iso­propyl group is [alpha].This structure was determined in the Molecular Structure Laboratory of the Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA. The SMART1000 diffractometer was gratefully obtained with funds provided by NSF grant CHE9610374. This study was supported by NIH grant 5U01TW00316-10 awarded to BNT. This study was undertaken as part of the required course work for the class CHEM 517 offered by Dr J. H. Enemark at the University of Arizona. The authors thank Liliya Yatsunyk for her help in this study

(4R,4aR,6S,7S,7aS)-6-Hydroxy-7-hy- droxymethyl-4-methylperhydrocyclo- penta[c]pyran-1-one chloroform solvate from Valeriana laxiflora

The structure of an iridolactone isolated from Valeriana laxiflora was established as (4R,4aR,6S,7S,7aS)-6-hydroxy-7-hydroxy­methyl-4-methyl­per­hydro­cyclo­penta­[c]­pyran-1-one chloro­form solvate, C10H16O4·CHCl3. The two rings are cis-fused. The [delta]-lactone ring adopts a slightly twisted half-chair conformation with approximate planarity of the lactone group and the cyclo­pentane ring adopts an envelope conformation. The hydroxy group, the hydroxymethyl group and the methyl group all have [beta] orientations. The absolute configuration was determined using anomalous dispersion data enhanced by the adventitious inclusion of a chloro­form solvent mol­ecule. Hydro­gen bonding, crystal packing and ring conformations are discussed in detail.The structure of the title compound was determined in the Molecular Structure Laboratory of the Department of Chemistry, University of Arizona. The diffractometer was obtained with funds provided by the NSF (grant No. CHE9610374). This study was supported by NIH grant No. 5U01TW00316-10 awarded to BNT

Withaferin A Induces Proteasome-Dependent Degradation of Breast Cancer Susceptibility Gene 1 and Heat Shock Factor 1 Proteins in Breast Cancer Cells

This is the publisher's version, also available electronically from "http://www.hindawi.com".The purpose of this study was to examine the regulation of prosurvival factors heat shock factor 1 (HSF1) and breast cancer susceptibility gene 1 (BRCA1) by a natural withanolide withaferin A (WA) in triple negative breast cancer cell lines MDA-MB-231 and BT20. Western analysis was used to examine alternations in HSF1 and BRCA1 protein levels following WA treatment. A protein synthesis inhibitor cycloheximide and a proteasome inhibitor MG132 were used to investigate the mechanisms of HSF1 and BRCA1 regulation by WA. It was found that WA induced a dose-dependent decrease in HSF1 and BRCA1 protein levels. Further analysis showed that levels of HSF1 and BRCA1 proteins decreased rapidly after WA treatment, and this was attributed to WA-induced denaturation of HSF1 and BRCA1 proteins and subsequent degradation via proteasome-dependent, and protein-synthesis dependent mechanism. In summary, WA induces denaturation and proteasomal degradation of HSF1 and BRCA1 proteins. Further studies are warranted to examine the contribution of HSF1 and BRCA1 depletion to the anticancer effects of WA in breast cancer