Antileishmanial Potential of Crude Plant Extracts Derived from Medicinal Plants in Palestine

Herbal and traditional medicine is commonly and widely used in Palestine. There has been no ethno pharmacological study to document the usefulness of traditional or medicinal plants from Palestine against leishmaniasis, a spectrum of severe parasitic diseases that occur worldwide and is caused by protozoa of the genus Leishmania. The aim of the present study was to collect and analyze some of the traditionally used medicinal plants from Palestine against Leishmania major parasites that cause cutaneous leishmaniasis. Plant materials were collected during spring and summer of the year 2011, identified and the voucher numbers were kept at Al-Quds University Gardens (AQUG). The whole plant (except roots), flowers, fruits or seeds were collected, washed with distilled water, air dried in the shade for 20 days and then powdered in an electric grinder. For each plant species, alcoholic and dimethyl sulfoxide extracts were tested in vitro against L. major promastigotes and their antileishmanial activities were evaluated by Alamar Blue bioassay. Twenty plant species belonging to14 families were examined for their in vitro anti-parasitic effect against L. major. Among the total crude extracts tested; five were found to have various levels of activities (20%), some extracts having significant antileishmanial activity with IC50 values ranging from 8.83 to 100 μg/mL. The most active crude extracts were from the shoots of Artemisia inculta and Malva sylvestris with activity of 84.1%, IC50 = 8.8 μg/mL. And 90.1%, IC50 = 19.5 μg/mL respectively. The results demonstrate that the crude extracts of Artemisia inculta and Malva sylvestris showed promising antileishmanial activity, further and extensive studies should be carried out; particularly bio-guided fractionation to identify the active fraction and further chemical characterization of structureThe authors gratefully thank the Deutscher Akademischer Austauschdienst (DAAD) and Zamallah program for providing travel grant. IMIB - Institute for Molecular Infection Biology, for providing support to validate this work at Würzburg University, financial support by the Deutsche Forschungsgemeinschaft (SFB 630) given To HM is gratefully acknowledge

Pathogen- and Host-Directed Antileishmanial Effects Mediated by Polyhexanide (PHMB)

BACKGROUND:Cutaneous leishmaniasis (CL) is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. CL causes enormous suffering in many countries worldwide. There is no licensed vaccine against CL, and the chemotherapy options show limited efficacy and high toxicity. Localization of the parasites inside host cells is a barrier to most standard chemo- and immune-based interventions. Hence, novel drugs, which are safe, effective and readily accessible to third-world countries and/or drug delivery technologies for effective CL treatments are desperately needed. METHODOLOGY/PRINCIPAL FINDINGS:Here we evaluated the antileishmanial properties and delivery potential of polyhexamethylene biguanide (PHMB; polyhexanide), a widely used antimicrobial and wound antiseptic, in the Leishmania model. PHMB showed an inherent antileishmanial activity at submicromolar concentrations. Our data revealed that PHMB kills Leishmania major (L. major) via a dual mechanism involving disruption of membrane integrity and selective chromosome condensation and damage. PHMB's DNA binding and host cell entry properties were further exploited to improve the delivery and immunomodulatory activities of unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN). PHMB spontaneously bound CpG ODN, forming stable nanopolyplexes that enhanced uptake of CpG ODN, potentiated antimicrobial killing and reduced host cell toxicity of PHMB. CONCLUSIONS:Given its low cost and long history of safe topical use, PHMB holds promise as a drug for CL therapy and delivery vehicle for nucleic acid immunomodulators

Abundance analysis of APOGEE spectra for 58 metal-poor stars from the bulge spheroid

The central part of the Galaxy hosts a multitude of stellar populations, including the spheroidal bulge stars, stars moved to the bulge through secular evolution of the bar, inner halo, inner thick disc, inner thin disc, as well as debris from past accretion events. We identified a sample of 58 candidate stars belonging to the stellar population of the spheroidal bulge, and analyse their abundances. The present calculations of Mg, Ca, and Si lines are in agreement with the ASPCAP abundances, whereas abundances of C, N, O, and Ce are re-examined. We find normal α-element enhancements in oxygen, similar to magnesium, Si, and Ca abundances, which are typical of other bulge stars surveyed in the optical in Baade’s Window. The enhancement of [O/Fe] in these stars suggests that they do not belong to accreted debris. No spread in N abundances is found, and none of the sample stars is N-rich, indicating that these stars are not second generation stars originated in globular clusters. Ce instead is enhanced in the sample stars, which points to an s-process origin such as due to enrichment from early generations of massive fast rotating stars, the so-called spinstars.RR acknowledges a CNPq master fellowship. TM acknowledges FAPESP postdoctoral fellowship no. 2018/03480-7. HE acknowledges a CAPES PhD fellowship. A.P.-V. and S.O.S. acknowledge the DGAPA-PAPIIT grant IA103122. SOS acknowledges a FAPESP PhD fellowship no. 2018/22044-3. SOS and MV acknowledge the support of the Deutsche Forschungsgemeinschaft (DFG, project number: 428473034). BB acknowledges grants from FAPESP, CNPq, and CAPES – Financial code 001. J.G.F-T gratefully acknowledges the grant support provided by Proyecto Fondecyt Iniciación No. 11220340, and also from ANID Concurso de Fomento a la Vinculación Internacional para Instituciones de Investigación Regionales (Modalidad corta duración) Proyecto No. FOVI210020, and from the ESO – Government of Chile Joint Committee 2021 (ORP 023/2021). D.G. gratefully acknowledges support from the ANID BASAL project ACE210002. D.G. also acknowledges financial support from the Dirección de Investigación y Desarrollo de la Universidad de La Serena through the Programa de Incentivo a la Investigación de Académicos (PIA-DIDULS). The work of V.M.P. is supported by NOIRLab, which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation. MZ was funded by ANID FONDECYT Regular 1191505, ANID Millennium Institute of Astrophysics (MAS) under grant ICN12_009, the ANID BASAL Center for Astrophysics and Associated Technologies (CATA) through grants AFB170002, ACE210002 and FB210003. DM gratefully acknowledges support by the ANID BASAL projects ACE210002 and FB210003 and by Fondecyt Project No. 1220724. RR, BB, TM, HE, SOS, are part of the Brazilian Participation Group (BPG) in the Sloan Digital Sky Survey (SDSS), from the Laboratório Interinstitucional de e-Astronomia – LIneA, Brazil. Funding for the Sloan Digital Sky Survey IV has been provided by the Alfred P. Sloan Foundation, the U.S. Department of Energy Office of Science, and the Participating Institutions. SDSS acknowledges support and resources from the Center for High-Performance Computing at the University of Utah. The SDSS web site is www.sdss.org. SDSS is managed by the Astrophysical Research Consortium for the Participating Institutions of the SDSS Collaboration including the Brazilian Participation Group, the Carnegie Institution for Science, Carnegie Mellon University, Center for Astrophysics | Harvard & Smithsonian (CfA), the Chilean Participation Group, the French Participation Group, Instituto de Astrofísica de Canarias, The Johns Hopkins University, Kavli Institute for the Physics and Mathematics of the Universe (IPMU) / University of Tokyo, the Korean Participation Group, Lawrence Berkeley National Laboratory, Leibniz Institut für Astrophysik Potsdam (AIP), Max-Planck-Institut für Astronomie (MPIA Heidelberg), Max-Planck-Institut für Astrophysik (MPA Garching), Max-Planck-Institut für Extraterrestrische Physik (MPE), National Astronomical Observatories of China, New Mexico State University, New York University, University of Notre Dame, Observatório Nacional / MCTI, The Ohio State University, Pennsylvania State University, Shanghai Astronomical Observatory, United Kingdom Participation Group, Universidad Nacional Autónoma de México, University of Arizona, University of Colorado Boulder, University of Oxford, University of Portsmouth, University of Utah, University of Virginia, University of Washington, University of Wisconsin, Vanderbilt University, and Yale University. This work makes use of data from the European Space Agency (ESA) space mission Gaia. The Gaia mission website is https://www.cosmos.esa.int/gaia. The Gaia archive website is https://archives.esac.esa.int/gaia.Peer reviewe

Light elements Na and Al in 58 bulge spheroid stars from APOGEE

We identified a sample of 58 candidate stars with metallicity [Fe/H] ≲ −0.8 that likely belong to the old bulge spheroid stellar population, and analyse their Na and Al abundances from Apache Point Observatory Galactic Evolution Experiment (APOGEE) spectra. In a previous work, we inspected APOGEE-Stellar Parameter and Chemical Abundance Pipeline abundances of C, N, O, Mg, Al, Ca, Si, and Ce in this sample. Regarding Na lines, one of them appears very strong in about 20 per cent of the sample stars, but it is not confirmed by other Na lines, and can be explained by sky lines, which affect the reduced spectra of stars in a certain radial velocity range. The Na abundances for 15 more reliable cases were taken into account. Al lines in the H band instead appear to be very reliable. Na and Al exhibit a spread in abundances, whereas no spread in N abundances is found, and we found no correlation between them, indicating that these stars could not be identified as second-generation stars that originated in globular clusters. We carry out the study of the behaviour of Na and Al in our sample of bulge stars and literature data by comparing them with chemodynamical evolution model suitable for the Galactic bulge. The Na abundances show a large spread, and the chemodynamical models follow the main data, whereas for aluminum instead, the models reproduce very satisfactorily the nearly secondary-element behaviour of aluminum in the metallicity range below [Fe/H] ≲ −1.0. For the lower-metallicity end ([Fe/H < −2.5), hypernovae are assumed to be the main contributor to yields.BB acknowledges grants from FAPESP, CNPq, and CAPES – Financial code 001. SOS acknowledges the FAPESP PhD fellowship no. 2018/22044-3. JGF-T gratefully acknowledges the grant support provided by Proyecto Fondecyt Iniciación no. 11220340, and from the Joint Committee ESO-Government of Chile 2021 (ORP 023/2021), and from Becas Santander Movilidad Internacional Profesores 2022, Banco Santander Chile. DG gratefully acknowledges the support provided by FONDECYT regular no. 1220264. The work of VMP is supported by NOIRLab, which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation. MZ was funded by ANID FONDECYT Regular 1191505, ANID Millennium Institute of Astrophysics (MAS) under grant ICN12_009, the ANID BASAL Center for Astrophysics and Associated Technologies (CATA) through grants AFB170002, ACE210002, and FB210003. TCB acknowledges partial support from grant PHY 14-30152; Physics Frontier Center/JINA Center for the Evolution of the Elements (JINA-CEE), and from OISE-1927130: The International Research Network for Nuclear Astrophysics (IReNA), awarded by the US National Science Foundation.Peer reviewe

Antileishmanial and Cytotoxic Compounds from Valeriana wallichii and Identification of a Novel Nepetolactone Derivative

The chloroform extract of Valeriana wallichii (V. wallichii) rhizomes was investigated to elucidate the structures responsible for reported antileishmanial activity. Besides bornyl caffeate (1, already been reported by us previously), bioassay-guided fractionation resulted in two additional cinnamic acid derivatives 2–3 with moderate leishmanicidal activity. The structure of a novel nepetolactone derivative 4 having a cinnamic acid moiety was elucidated by means of spectral analysis. To the best of our knowledge villoside aglycone (5) was isolated from this plant for the first time. The bioassay-guided fractionation yielded two new (compounds 6–7) and two known valtrates (compounds 8–9) with leishmanicidal potential against Leishmania major (L. major) promastigotes. In addition, β-bisabolol (10), α-kessyl alcohol (11), valeranone (12), bornyl isovalerate (13) and linarin-2-O-methylbutyrate (14) were identified. This is the first report on the isolation of 4'-demethylpodophyllotoxin (15), podophyllotoxin (16) and pinoresinol (17) in V. wallichii. In total thirteen known and four new compounds were identified from the extract and their cytotoxic and antileishmanial properties were evaluated

Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester

Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC50 = 48.8 µM). To investigate the structure-activity relationship (SAR), a library of compounds based on 1 was synthesized and tested in vitro against L. major and L. donovani promastigotes, and L. major amastigotes. Cytotoxicity was determined using a murine J774.1 cell line and bone marrow derived macrophages (BMDM). Some compounds showed antileishmanial activity in the concentration range of pentamidine and miltefosine which are the standard drugs in use. In the L. major amastigote assay compounds 15, 19 and 20 showed good activity with relatively low cytotoxicity against BMDM, resulting in acceptable selectivity indices. Molecules with adjacent phenolic hydroxyl groups exhibited elevated cytotoxicity against murine cell lines J774.1 and BMDM. The Michael system seems not to be essential for antileishmanial activity. Based on the results compound 27 can be regarded as new lead structure for further structure optimizatio

Aziridine-2,3-Dicarboxylates, Peptidomimetic Cysteine Protease Inhibitors with Antileishmanial Activity

Chemotherapy of leishmaniasis is mainly based on antimonials. However, they are extremely toxic and cause serious side effects, and there is a worldwide increasing frequency of chemoresistance to antimonials. These issues emphasize the urgent need for affordable alternative drugs against leishmaniasis. Leishmania cysteine proteases are essential for parasite growth, differentiation, pathogenicity, and virulence and are thus attractive targets for combating leishmaniasis. Herein we demonstrate that the cysteine protease inhibitors aziridine-2,3-dicarboxylates 13b and 13e impaired promastigote growth at mid-micromolar concentrations and decreased the infection rate of peritoneal macrophages at concentrations 8- to 13-fold lower than those needed to inhibit parasite replication. Simultaneous treatment of infected cells with compound 13b and gamma interferon resulted in an even further reduction of the concentration needed for a significant decrease in macrophage infection rate. Notably, treatment with the compounds alone modulated the cytokine secretion of infected macrophages, with increased levels of interleukin-12 and tumor necrosis factor alpha. Furthermore, the decreased infection rate in the presence of compound 13b correlated with increased nitric oxide production by macrophages. Importantly, at the concentrations used herein, compounds 13b and 13e were not toxic against fibroblasts, macrophages, or dendritic cells. Together, these results suggest that the aziridine-2,3-dicarboxylates 13b and 13e are potential antileishmanial lead compounds with low toxicity against host cells and selective antiparasitic effects