chronic-acute-reactivated-hiv-infection-humanized-immunodeficient

Chronic, Acute, and Reactivated HIV Infection in Humanized Immunodeficient Mouse Models

Humanized NOD/SCID/IL-2 receptor &#947;-chainnull mice recapitulate some features of human immunity, which can be exploited in basic and pre-clinical ...

University of Maryland

Acute arenavirus disease in primates, like Lassa hemorrhagic fever in humans, begins with flu-like symptoms and leads to death approximately 2 weeks after infection. Our goal was to identify molecular changes in blood that are related to disease progression. Rhesus macaques (Macaca mulatta) infected intravenously with a lethal dose of lymphocytic choriomeningitis virus (LCMV) provide a model for Lassa virus infection of humans. Blood samples taken before and during the course of infection were used to monitor gene expression changes that paralleled disease onset. Changes in blood showed major disruptions in eicosanoid, immune response, and hormone response pathways. Approximately 12% of host genes alter their expression after LCMV infection, and a subset of these genes can discriminate between virulent and non-virulent LCMV infection. Major transcription changes have been given preliminary confirmation by quantitative PCR and protein studies and will be valuable candidates for future validation as biomarkers for arenavirus disease.

Early blood profiles of virus infection in a monkey model for Lassa fever.

A single injection of ML29 reassortant vaccine for Lassa fever induces low, transient viremia, and low or moderate levels of ML29 replication in tissues of common marmosets depending on the dose of the vaccination. The vaccination elicits specific immune responses and completely protects marmosets against fatal disease by induction of sterilizing cell-mediated immunity. DNA array analysis of human peripheral blood mononuclear cells from healthy donors exposed to ML29 revealed that gene expression patterns in ML29-exposed PBMC and control, media-exposed PBMC, clustered together confirming safety profile of the ML29 in non-human primates. The ML29 reassortant is a promising vaccine candidate for Lassa fever.

Safety, immunogenicity, and efficacy of the ML29 reassortant vaccine for Lassa fever in small non-human primates.

Rhesus macaques infected with lymphocytic choriomeningitis virus (LCMV) provide a model for human Lassa fever. Disease begins with flu-like symptoms and progresses rapidly with fatal consequences. Previously, we profiled the blood transcriptome of LCMV-infected monkeys (M. Djavani et al J. Virol. 2007) showing distinct pre-viremic and viremic stages that discriminated virulent from benign infections. In the present study, changes in liver gene expression from macaques infected with virulent LCMV-WE were compared to gene expression in uninfected monkeys as well as to monkeys that were infected but not diseased.

Gene expression in primate liver during viral hemorrhagic fever.

Lassa fever (LF) is one of the most prevalent viral hemorrhagic fevers in West Africa responsible for thousands of deaths annually. The BSL-4 containment requirement and lack of small animal model to evaluate Lassa virus (LASV)-specific cell-mediated immunity (CMI) complicate development of effective LF vaccines. Here we have described a CBA/J-ML29 model allowing evaluation of LASV-specific CMI responses in mice. This model is based on Mopeia virus reassortant clone ML29, an attractive immunogenic surrogate for LASV. A single intraperitoneal (i.p.) immunization of CBA/J mice with ML29 protected animals against a lethal homologous intracerebral (i.c.) challenge with 588 LD(50). The ML29-immunized mice displayed negligible levels of LASV-specific antibody titers, but LASV-specific CMI responses were detectable early and peaked on day 8-10 after immunization. A T cell cytotoxicity assay in vivo showed a correlation between LASV-specific cytotoxicity and the timing of protection induced by the ML29 immunization. Notably, CBA/J mice that received CD8+ T cell-depleted splenocytes from ML29-immunized donors all succumbed to a lethal i.c. challenge, demonstrating that CD8+ T cells are critical in protection. The CBA/J-ML29 model can be useful immunological tool for the preliminary evaluation of immunogenicity and efficacy of vaccine candidates against LASV outside of BSL-4 containment facilities.

Evaluation of Lassa virus vaccine immunogenicity in a CBA/J-ML29 mouse model.

The HIV-1 transgenic (TG) rat has been shown to be a useful model of nervous system disease that occurs in human HIV-1 infection. Studies were, therefore, performed to examine characteristics of the immune response in the periphery and brain of the animals and expression of factors in the nervous system that might be associated with neurotoxicity. Activated splenocytes from wild-type (WT) and TG rats were stimulated with either CD3/CD28 or with lipopolysaccharide (LPS) and examined for proliferative responses and for proinflammatory cytokine (IFN-γ, TNF-α and IL-1β) secretion. Brain tissue lysates from the rats were also examined for proinflammatory cytokine levels and tissue sections were stained by immunofluorescence for class II MHC+, ED1+ or Iba1+ (for macrophages and microglial cells), and for GFAP+ (for astrocytes) cells and for co-labeling of these cells for TNF-α. Co-labeling was also performed to identify cells expressing HIV-1 gp160, tat, nef and vif. Finally, on Western blots brain tissue lysates were examined for phosphorylation of Erk1/2, p38, JNK-SAPK and Erk5. TG rat splenocyte proliferative responses were higher than for WT with CD3/CD28-stimulation but lower than WT with LPS stimulation. CD3/CD28-stimulated TG rat splenocytes also secreted higher levels of IFN-γ, TNF-α and IL-1β whereas LPS-stimulated TG rat splenocytes secreted higher levels of only TNF-α than cultures from WT rats. Levels of all three cytokines were higher in brain lysates from TG rats than for WT rats. On immunofluorescence staining of corresponding sections of brain, TG rats contained increased numbers of class II MHC+ and ED1+ cells, and there was also increased co-labeling or these cells as well as astrocytes for TNF-α. Iba1+ cells showed positive staining for all of the HIV proteins whereas astrocytes showed significant positive staining for only nef and vif. Phosphorylation of Erk1/2, p38 and JNK/SAPK was detected for both TG and WT rat tissues with higher levels of phosphorylation forms of these proteins detected in the TG rat brain. Phosphorylation of Erk5, a marker that is associated with specifically neuronal repair, was detected only in TG rat brain. These studies suggest that activated nervous system mononuclear phagocytes and astrocytes expressing HIV-1 gene products in specific patterns are associated with neurodegeneration in the HIV-1 TG rat.

Immune activation, viral gene product expression and neurotoxicity in the HIV-1 transgenic rat.

ETHNOPHARMACOLOGICAL &#x76F8;&#x5173;&#x6027;&#xFF1A; &#x6591;&#x9E20;&#x83CA; guineensisBenth&#x3002;(&#x83CA;&#x79D1;) &#x7B79;&#x5907;&#x5DE5;&#x4F5C;&#x5728;&#x5580;&#x9EA6;&#x9686;&#x6C11;&#x65CF;&#x836F;&#x7528;&#x4E8E;&#x6CBB;&#x7597;&#x591A;&#x79CD;&#x75BE;&#x75C5;&#xFF0C;&#x5305;&#x62EC;&#x524D;&#x5217;&#x817A;&#x764C;&#xFF0C;&#x759F;&#x75BE;&#xFF0C;&#x5E76;&#x4E14;&#x88AB;&#x7528;&#x4F5C;&#x9A71;&#x866B;&#x3001; &#x5E2E;&#x52A9;&#x548C;&#x89E3;&#x6BD2;&#x5242;&#x3002;&#x8FD9;&#x9879;&#x7814;&#x7A76;&#x7684;&#x76EE;&#x7684;&#x662F;&#x7EE7;&#x7EED;&#x6D3B;&#x52A8;&#x7684;&#x6591;&#x9E20;&#x83CA; guineensisBenth &#x9A8C;&#x8BC1;&#x3002;&#x63D0;&#x53D6;&#x548C;&#x5B64;&#x7ACB;&#x7684;&#x5206;&#x5B50;&#x9488;&#x5BF9;&#x4EE5;&#x524D;&#x5206;&#x79BB;&#x53CA;&#x524D;&#x5217;&#x817A;&#x764C;&#x7684;&#x764C;&#x7EC6;&#x80DE;&#x7CD6;&#x916F;&#x6839;&#x63D0;&#x53D6;&#x7269;&#x3002;&#x6750;&#x6599;&#x548C;&#x65B9;&#x6CD5;&#xFF1A; &#x4E19;&#x916E;&#x63D0;&#x53D6;&#x7269;&#x6591;&#x9E20;&#x83CA; guineensisBenth&#x3002;&#x53F6; 10 &#x764C;&#x7EC6;&#x80DE;&#x5BF9;&#x6D3B;&#x52A8;&#x8FDB;&#x884C;&#x4E86;&#x6D4B;&#x8BD5; &#xFF08;&#x4E73;&#x817A;&#x764C;-MDA-MB-231&#xFF0C;&#x4E73;&#x817A;&#x764C; MCF-7&#x3001; &#x5192;&#x53F7;-HCT-116&#xFF0C;&#x767D;&#x8840;&#x75C5;-HL-60&#x3001; &#x80BA;&#x764C; A549&#x3001; &#x9ED1;&#x8272;&#x7D20;&#x7624; A375 &#x5375;&#x5DE2;-OVCAR3&#xFF0C;&#x80F0;&#x817A;-Mia-paca&#x3001; &#x524D;&#x5217;&#x817A;-PC-3 &#x548C;&#x524D;&#x5217;&#x817A;-&#x675C;-145&#xFF09;&#x3002;&#x4E19;&#x916E;&#x63D0;&#x53D6;&#x906D;&#x5230;&#x751F;&#x7269;&#x6D3B;&#x6027;&#x6307;&#x5BFC;&#x5206;&#x998F;&#x3002;&#x589E;&#x6B96;&#x6291;&#x5236;&#x548C;&#x514B;&#x9686;&#x6D3B;&#x52A8;&#x7684;&#x5B64;&#x7ACB;&#x7684;&#x5316;&#x5408;&#x7269;&#x8FDB;&#x884C;&#x4E86;&#x6D4B;&#x8BD5;&#x3002;Wst-1 &#x7528;&#x4E8E;&#x589E;&#x6B96;&#x6D3B;&#x52A8;&#x540C;&#x65F6;&#x6807;&#x51C6;&#x514B;&#x9686;&#x6D4B;&#x8BD5;&#x7528;&#x4E8E;&#x786E;&#x5B9A;&#x514B;&#x9686;&#x6D3B;&#x52A8;&#x3002;&#x7ED3;&#x679C;&#xFF1A; &#x6591;&#x9E20;&#x83CA; guineensisBenth &#x4E19;&#x916E;&#x63D0;&#x53D6;&#x3002;&#x8868;&#x660E;&#x4ECE; IC(50) 4&micro;g/mL-26&micro;g/mL &#x5BF9;&#x5341;&#x4E2A;&#x7EC6;&#x80DE;&#x7684;&#x4F53;&#x5916;&#x6D3B;&#x6027;&#x3002;&#x6D3B;&#x52A8;&#x6307;&#x5BFC;&#x5206;&#x998F;&#x6B64;&#x63D0;&#x53D6;&#x7269;&#x4EA7;&#x751F;&#x4E24;&#x500D;&#x534A;&#x841C;&#x5185;&#x916F;&#xFF0C;&#x5B64;&#x7ACB;&#x7684;&#x4ECE;&#x6591;&#x9E20;&#x83CA;&#x5C5E;&#x9996;&#x6B21;&#x3002;&#x5316;&#x5408;&#x7269;&#x7684;&#x7279;&#x70B9;&#x662F;&#x4F7F;&#x7528;&#x5149;&#x8C31;&#x5B9E;&#x9A8C;&#x5305;&#x62EC; 1d &#x548C; 2D NMR &#x6570;&#x636E;&#x7684;&#x7EC4;&#x5408;&#x3002;Vernopicrin (1) &#x548C; Vernomelitensin (2) &#x8868;&#x660E;&#x5BF9;&#x80BF;&#x7624;&#x7EC6;&#x80DE;&#x7684;&#x4F53;&#x5916;&#x6D3B;&#x6027;&#x4E0E;&#x4ECE; 0.35&micro;M IC(50)-2.04&micro;M (P &lt; 0.05) &#x548C; 0.13&micro;M-1.5&micro;M (P &lt; 0.05&#xFF09;&#x3001; &#x6700;&#x5927;&#x4E0E;&#x6700;&#x4E0D;&#x654F;&#x611F;&#x7684;&#x7EC6;&#x80DE;&#x7CFB;&#xFF0C;&#x6BCF;&#x4E2A;&#x5316;&#x5408;&#x7269;&#x3002;Vernopicrin &#x662F;&#x5BF9;&#x4EBA;&#x9ED1;&#x8272;&#x7D20;&#x7624; &#xFF08;A375&#xFF09; &#x7684;&#x5355;&#x5143;&#x683C;&#x884C;&#x6700;&#x6D3B;&#x8DC3;&#x548C;&#x6700;&#x4E0D;&#x79EF;&#x6781;&#x53CD;&#x5BF9; (A549) &#x7EC6;&#x80DE;&#x80BA;&#x764C;&#x7EC6;&#x80DE;&#x682A; vernomelitensin &#x867D;&#x7136;&#x4E5F;&#x5BF9;&#x4EBA;&#x9ED1;&#x8272;&#x7D20;&#x7624; &#xFF08;A375&#xFF09; &#x7684;&#x5355;&#x5143;&#x683C;&#x884C;&#x6700;&#x6D3B;&#x8DC3;&#x548C;&#x6700;&#x4E0D;&#x6D3B;&#x8DC3;&#x5BF9;&#x4E73;&#x817A;&#x764C; &#xFF08;mcf-7&#xFF09; &#x7EC6;&#x80DE;&#x682A;&#x3002;&#x8FD9;&#x4E24;&#x79CD;&#x5316;&#x5408;&#x7269;&#x4E5F;&#x8868;&#x660E; anticlonogenic &#x6D3B;&#x52A8;&#x3002;&#x7ED3;&#x8BBA;&#xFF1A; &#x7EC6;&#x80DE;&#x6BD2;&#x6027;&#x8868;&#x73B0;&#x51FA;&#x7C97;&#x63D0;&#x53D6;&#x7269;&#xFF0C;&#x5E76;&#x9488;&#x5BF9;&#x764C;&#x7EC6;&#x80DE;&#x7684;&#x5B64;&#x7ACB;&#x7684;&#x841C;&#x7A81;&#x51FA;&#x8BC9;&#x68D5;&#x836F;&#x7528;&#x7684;&#x6F5C;&#x529B;&#x3002;&#x9009;&#x62E9;&#x6027;&#x589E;&#x6B96;&#x6291;&#x5236;&#x548C;&#x5242;&#x91CF;&#x4F9D;&#x8D56; anticlonogenic &#x6D3B;&#x52A8;&#x5EFA;&#x8BAE;&#x5DF2;&#x67E5;&#x660E;&#x7684;&#x841C;&#x53EF;&#x80FD;&#x662F;&#x6F5C;&#x5728;&#x7684;&#x6297;&#x80BF;&#x7624;&#x836F;&#x7269;&#x3002;

&#x4ECE;&#x68D5;&#x6591;&#x9E20;&#x83CA;&#x8C46;&#x53F6;&#x7EC6;&#x80DE;&#x6BD2;&#x7684;&#x500D;&#x534A;&#x841C;&#x5185;&#x916F;&#x3002;(&#x83CA;&#x79D1;)&#x3002;

ETHNOPHARMACOLOGICAL RELEVANCE: Vernonia guineensisBenth. (Asteraceae) preparations are used in folk medicine in Cameroon to treat a number of ailments including prostate cancer, malaria, and is used as anthelmintic, adaptogen and antidote. The aim of this study was to continue the validation of the activity of Vernonia guineensisBenth. extracts and isolated molecules against cancer cell lines following the previous isolation of an anti-prostate cancer sugar ester from the root extract. MATERIALS AND METHODS: Acetone extracts of Vernonia guineensisBenth. leaves were tested for activity against 10 cancer cell lines (Breast -MDA-MB-231, Breast-MCF-7, Colon-HCT-116, Leukaemia-HL-60, Lung-A549, Melanoma-A375, Ovarian-OVCAR3, Pancreas-Mia-paca, Prostate-PC-3 and Prostate- DU-145). The acetone extract was subjected to bioactivity guided fractionation. Anti-proliferation and clonogenic activity of the isolated compounds were tested. The WST-1 assay was used for the anti-proliferation activity meanwhile the standard clonogenic test was used to determine the clonogenic activity. RESULTS: The acetone extract of Vernonia guineensisBenth. demonstrated in vitro activity ranging from IC(50) 4Âµg/mL - 26Âµg/mL against the ten cell lines. Activity guided fractionation of this extract yielded two sesquiterpene lactones, isolated for the first time from the genus Vernonia. The compounds were characterized using spectroscopic experiments including a combination of 1D and 2D NMR data. Vernopicrin (1) and Vernomelitensin (2) demonstrated in-vitro activity against the human cancer cell lines with IC(50) ranging from 0.35ÂµM-2.04ÂµM (P<0.05) and 0.13ÂµM-1.5ÂµM (P<0.05), respectively between the most and least sensitive cell lines for each compound. Vernopicrin was most active against the human melanoma (A375) cell line and least active against the lung cancer (A549) cell line while vernomelitensin was also most active against the human melanoma (A375) cell line and least active against the breast cancer (MCF-7) cell line. Both compounds also demonstrated anticlonogenic activity. CONCLUSION: The cytotoxicity demonstrated by the crude extract and isolated sesquiterpenes against cancer cell lines highlights the medicinal potential of V. guineensis. The selective anti-proliferation and dose dependent anticlonogenic activities suggest that the identified sesquiterpenes could be potential antitumor agents.

Cytotoxic sesquiterpene lactones from the leaves of Vernonia guineensis Benth. (Asteraceae).

ETHNOPHARMACOLOGICAL pertinence : Vernonia guineensisBenth. Pr&eacute;parations (Asteraceae) sont utilis&eacute;s dans la m&eacute;decine populaire au Cameroun pour traiter un certain nombre d&#39;affections, y compris le cancer de la prostate, le paludisme et est utilis&eacute; comme anthelminthique, adaptog&egrave;ne et antidote. Le but de cette &eacute;tude &eacute;tait de poursuivre la validation de l&#39;activit&eacute; de Vernonia guineensisBenth. extraits et des mol&eacute;cules isol&eacute;es contre des lign&eacute;es de cellules canc&eacute;reuses apr&egrave;s l&#39;isolement pr&eacute;c&eacute;dent d&#39;un cancer anti-prostate ester de l&#39;extrait de racine de sucre. MAT&Eacute;RIEL et m&eacute;thodes : L&#39;ac&eacute;tone extraits de Vernonia guineensisBenth. les feuilles ont &eacute;t&eacute; test&eacute;s pour l&#39;activit&eacute; contre 10 lign&eacute;es de cellules canc&eacute;reuses (Breast - MDA-MB-231, Breast-MCF-7, Colon-HCT-116, leuc&eacute;mie-HL-60, m&eacute;lanome A375-Office, A549-poumon, ovaire-OVCAR3, pancr&eacute;as-Mia-paca, Prostate-PC-3 et de la Prostate-DU-145). L&#39;extrait &agrave; l&#39;ac&eacute;tone a &eacute;t&eacute; soumis &agrave; fractionnement guid&eacute; de bioactivit&eacute;. Anti-prolif&eacute;ration et activit&eacute; clonog&eacute;niques des compos&eacute;s isol&eacute;s ont &eacute;t&eacute; test&eacute;s. Le test de WST-1 a &eacute;t&eacute; utilis&eacute; pour l&#39;activit&eacute; contre la prolif&eacute;ration en attendant que le test clonog&eacute;niques standard a &eacute;t&eacute; utilis&eacute; pour d&eacute;terminer l&#39;activit&eacute; clonog&eacute;niques. R&Eacute;SULTATS : L&#39;ac&eacute;tone extrait de Vernonia guineensisBenth. a d&eacute;montr&eacute; une activit&eacute; in vitro allant de l&#39;IC (50) 4&micro;g/mL-26&micro;g/mL contre les lign&eacute;es cellulaires de dix. Fractionnement guid&eacute; l&#39;activit&eacute; de cet extrait a donn&eacute; deux lactones sesquiterp&eacute;niques, isol&eacute;s pour la premi&egrave;re fois du genre Vernonia. Les compos&eacute;s ont &eacute;t&eacute; caract&eacute;ris&eacute;s &agrave; l&#39;aide d&#39;exp&eacute;riences spectroscopiques, y compris une combinaison de donn&eacute;es de la RMN 1D et 2D. Vernopicrin (1) et Vernomelitensin (2) d&eacute;montr&eacute; une activit&eacute; in vitro contre les lign&eacute;es de cellules canc&eacute;reuses humaines avec IC (50) allant de 0.35&micro;M-2.04&micro;M (P &lt; 0,05) et 0.13&micro;M-1.5&micro;M (P &lt; 0,05), respectivement entre les plus et les moins sensibles lign&eacute;es cellulaires pour chacun des compos&eacute;s. Vernopicrin a &eacute;t&eacute; plus active contre la lign&eacute;e de cellules de m&eacute;lanome humain (A375 Office) et moins actif contre la lign&eacute;e de cellules de cancer (A549) poumon tandis que vernomelitensin &eacute;tait aussi plus actifs contre la lign&eacute;e de cellules de m&eacute;lanome humain (A375 Office) et moins actif contre la lign&eacute;e cellulaire de cancer du sein cancer (MCF-7). Les deux compos&eacute;s a &eacute;galement d&eacute;montr&eacute; une activit&eacute; anticlonogenic. CONCLUSION : La cytotoxicit&eacute; t&eacute;moigne de l&#39;extrait brut et sesquiterp&egrave;nes isol&eacute;s contre les lign&eacute;es cellulaires canc&eacute;reuses met en &eacute;vidence le potentiel m&eacute;dicinal de V. guineensis. Activit&eacute;s anti-prolif&eacute;ration et dose d&eacute;pendant anticlonogenic s&eacute;lectives sugg&egrave;rent que les sesquiterp&egrave;nes identifi&eacute;s pourraient &ecirc;tre agents antitumoraux potentiels.

Lactones sesquiterp&eacute;niques cytotoxique des feuilles de Vernonia guineensis Benth. (Asteraceae).

ETHNOPHARMACOLOGICAL Relevanz: Vernonia GuineensisBenth. (Asteraceae) Zubereitungen werden in der Volksmedizin in Kamerun verwendet, um eine Anzahl von Krankheiten einschlie&szlig;lich Prostata-Krebs, Malaria, zu behandeln und dient als Anthelminthikum, Adaptogen und Gegenmittel. Ziel dieser Studie war die &Uuml;berpr&uuml;fung der Aktivit&auml;t von Vernonia GuineensisBenth weiter. Extrakte und isolierten Molek&uuml;len gegen Krebs-Zelllinien, die nach die fr&uuml;here Isolation ein anti-prostate Krebs Zucker Ester aus dem Wurzel-Extrakt. Material und Methoden: Aceton extrahiert von Vernonia GuineensisBenth. Bl&auml;tter wurden f&uuml;r Aktivit&auml;t gegen 10 Krebszelllinien getestet (Breast - MDA-MB-231, Brust-MCF-7, Colon-HCT-116, Leuk&auml;mie-HL-60, Lungenkrebs-A549, Melanom-A375 Ovarian-OVCAR3, Pankreas-Mia-Paca, Prostata-PC-3 und Prostata-DU-145). Der Aceton-Extrakt wurde Bioaktivit&auml;t gef&uuml;hrte Fraktionierung unterzogen. Anti-Proliferation und Clonogenic Aktivit&auml;t der isolierten Verbindungen wurden getestet. Der WST-1-Assay wurde inzwischen die anti-proliferation Aktivit&auml;t verwendet, die der Norm Clonogenic-Test verwendet wurde, um zu bestimmen, die Clonogenic-Aktivit&auml;t. Ergebnisse: Das Aceton Extrahieren von Vernonia GuineensisBenth. in-vitro-Aktivit&auml;t von IC (50) 4&micro;g/mL-26&micro;g/mL gegen die zehn Zelllinien gezeigt. Gef&uuml;hrte Aktivit&auml;t Fraktionierung dieses Extrakts ergab zwei Sesquiterpenlactone, zum ersten Mal aus der Gattung Vernonia isoliert. Die Verbindungen waren gekennzeichnet mit spektroskopische Experimenten das Kombinieren von 1D und 2D NMR-Daten. Vernopicrin (1) und Vernomelitensin (2) zeigten in-vitro-Aktivit&auml;t gegen die menschliche Krebszelllinien mit IC (50) von 0.35-2.04&micro;M (P &lt; 0,05) und 0.13&micro;M-1.5&micro;M (P &lt; 0,05), bzw. zwischen am meisten und am wenigsten empfindlich Zelllinien f&uuml;r jede Substanz. Vernopicrin war gegen die menschliche Melanom (A375)-Zelllinie aktivsten und am wenigsten aktiv gegen die Lunge Krebs (A549)-Zelllinie w&auml;hrend Vernomelitensin auch gegen die menschliche Melanom (A375)-Zelllinie aktivsten und am wenigsten aktiv gegen die Brust-Krebs (MCF-7)-Zelllinie. Beide Verbindungen zeigten auch Anticlonogenic Aktivit&auml;t. Fazit: Die Zytotoxizit&auml;t von grober Auszug demonstriert und isolierte Sesquiterpene gegen Krebszelllinien highlights das medizinische Potenzial der V. Guineensis. Die selektiven Anti-proliferation und Dosis-abh&auml;ngige Anticlonogenic-Aktivit&auml;ten vorschlagen, dass die ermittelten Sesquiterpene potenzielle antitumor-Agenten sein k&ouml;nnte.

Zytotoxische Sesquiterpenlactone aus den Bl&auml;ttern von Vernonia Guineensis Benth. (Asteraceae).

ETNOFARMACOLOGICA pertinenza: Woodland guineensisBenth. Preparazioni (Asteraceae) sono usati nella medicina popolare in Camerun per trattare un certo numero di malattie tra cui il cancro alla prostata, la malaria e viene utilizzato come antielmintico, adattogeno e antidoto. Lo scopo di questo studio era quello di continuare la convalida dell&#39;attivit&agrave; di Woodland guineensisBenth. estratti e molecole isolate contro linee cellulari di cancro dopo la precedente isolamento di un cancro ricerca estere dall&#39;Estratto di radice di zucchero. MATERIALI e metodi: Acetone estratti di Woodland guineensisBenth. foglie sono stati testati per attivit&agrave; contro 10 linee di cellule di cancro (mammella - MDA-MB-231, seno-MCF-7, Colon-HCT-116, leucemia-HL-60, polmonari A549, Melanoma A375, Ovarian-OVCAR3, Pancreas-Mia-paca, prostata-PC-3 e prostata-DU-145). L&#39;Estratto di acetone &egrave; stato sottoposto a frazionamento bioattivit&agrave; guidate. Anti-proliferation e attivit&agrave; clonogenica dei composti isolati sono stati testati. Il dosaggio di WST-1 era utilizzato per l&#39;attivit&agrave; di antiproliferazione nel frattempo che il test secondo standard &egrave; stato utilizzato per determinare l&#39;attivit&agrave; clonogenica. RISULTATI: L&#39;acetone Estratto di Woodland guineensisBenth. attivit&agrave; in vitro ha dimostrato che vanno da IC(50) 4&micro;g/mL-26&micro;g/mL contro i dieci di cellula. Frazionamento di attivit&agrave; guidate di questo estratto ha reso due lattoni sesquiterpene, isolati per la prima volta dal genere Woodland. I composti sono stati caratterizzati utilizzando esperimenti spettroscopici compreso una combinazione di dati NMR 1D e 2D. Vernopicrin (1) e Vernomelitensin (2) dimostrato attivit&agrave; in vitro contro le linee di cellule tumorali umane con IC(50) che vanno da 0.35&micro;M-2.04&micro;M (P &lt; 0,05) e 0.13&micro;M-1.5&micro;M (P &lt; 0.05), rispettivamente tra pi&ugrave; e meno sensibili linee cellulari per ciascun composto. Vernopicrin era pi&ugrave; attivi contro la linea di cellule di melanoma umano (A375) e meno attivo contro la linea cellulare del polmone cancro (A549) mentre vernomelitensin era anche pi&ugrave; attivi contro la linea di cellule di melanoma umano (A375) e meno attivo contro la linea cellulare al seno cancro (MCF-7). Entrambi i composti dimostrato anche attivit&agrave; anticlonogenic. CONCLUSIONE: La citotossicit&agrave; dimostrato dall&#39;Estratto del grezzo e sesquiterpeni isolato contro linee cellulari di cancro mette in evidenza il potenziale medicinale di V. guineensis. Le attivit&agrave; di anticlonogenic dipendente dalla dose e anti-proliferation selettive suggeriscono che i sesquiterpeni identificati potrebbero essere potenziali agenti antitumorali.

Citotossici sesquiterpene lattoni da foglie di Woodland guineensis Benth. (Asteraceae).

ETHNOPHARMACOLOGICAL &#x306E;&#x95A2;&#x9023;&#x6027;: &#x30F4;&#x30A1;&#x30FC;&#x30CE;&#x30CB;&#x30A2;&#x306E; guineensisBenth&#x3002;(&#x30AD;&#x30AF;&#x79D1;) &#x306E;&#x6E96;&#x5099;&#x306F;&#x3001;&#x30AB;&#x30E1;&#x30EB;&#x30FC;&#x30F3;&#x306E;&#x6C11;&#x9593;&#x85AC;&#x3067;&#x30DE;&#x30E9;&#x30EA;&#x30A2;&#x3001;&#x524D;&#x7ACB;&#x817A;&#x304C;&#x3093;&#x306A;&#x3069;&#x306E;&#x75C5;&#x6C17;&#x306E;&#x6570;&#x306E;&#x6CBB;&#x7642;&#x306B;&#x4F7F;&#x7528;&#x3055;&#x308C;&#x307E;&#x3059;&#x3001;&#x99C6;&#x866B;&#x85AC;&#x3001;&#x30A2;&#x30C0;&#x30D7;&#x30C8;&#x30B2;&#x30F3;&#x89E3;&#x6BD2;&#x5264;&#x3068;&#x3057;&#x3066;&#x4F7F;&#x7528;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x30F4;&#x30A1;&#x30FC;&#x30CE;&#x30CB;&#x30A2; guineensisBenth &#x306E;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D3;&#x30C6;&#x30A3;&#x306E;&#x691C;&#x8A3C;&#x3092;&#x7D99;&#x7D9A;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x62BD;&#x51FA;&#x7269;&#x3001;&#x5B64;&#x7ACB;&#x5206;&#x5B50;&#x6B21;&#x306E;&#x524D;&#x306E;&#x5206;&#x96E2;&#x3001;anti-prostate &#x304C;&#x3093;&#x306E;&#x304C;&#x3093;&#x7D30;&#x80DE;&#x682A;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x6839;&#x306E;&#x62BD;&#x51FA;&#x7269;&#x304B;&#x3089;&#x3092;&#x7802;&#x7CD6;&#x3057;&#x307E;&#x3059;&#x3002;&#x6750;&#x6599;&#x3068;&#x65B9;&#x6CD5;: &#x30F4;&#x30A1;&#x30FC;&#x30CE;&#x30CB;&#x30A2; guineensisBenth &#x306E;&#x30A2;&#x30BB;&#x30C8;&#x30F3;&#x3092;&#x62BD;&#x51FA;&#x3057;&#x307E;&#x3059;&#x3002;&#x8449; 10 &#x304C;&#x3093;&#x7D30;&#x80DE;&#x682A;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x6D3B;&#x52D5;&#x3092;&#x884C;&#x3063;&#x305F; (&#x80F8;&#x80F8;-MCF-7&#x3001;&#x30B3;&#x30ED;&#x30F3;-HCT-116-MDA-MB-231 &#x767D;&#x8840;&#x75C5; HL 60&#x3001;&#x80BA; A549&#x3001;&#x60AA;&#x6027;&#x9ED2;&#x8272;&#x816B;, A375&#x3001;&#x5375;&#x5DE3; OVCAR3 &#x81B5;&#x81D3; Mia &#x30D1;&#x30AB;&#x3001;&#x524D;&#x7ACB;&#x817A; PC 3 &#x304A;&#x3088;&#x3073;&#x524D;&#x7ACB;&#x817A;-&#x30C7;&#x30E5;-145)&#x3002;&#x30A2;&#x30BB;&#x30C8;&#x30F3;&#x62BD;&#x51FA;&#x8A98;&#x5C0E;&#x6D3B;&#x6027;&#x306E;&#x5206;&#x5225;&#x306B;&#x670D;&#x5F93;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;Anti-proliferation &#x3068;&#x5206;&#x96E2;&#x5316;&#x5408;&#x7269;&#x306E;&#x30AF;&#x30ED;&#x30FC;&#x30F3;&#x6D3B;&#x52D5;&#x304C;&#x30C6;&#x30B9;&#x30C8;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;1 &#x6CD5;&#x6A19;&#x6E96;&#x30AF;&#x30ED;&#x30FC;&#x30F3; &#x30C6;&#x30B9;&#x30C8; &#x30AF;&#x30ED;&#x30FC;&#x30F3;&#x6D3B;&#x52D5;&#x3092;&#x6C7A;&#x5B9A;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x4F7F;&#x7528;&#x3055;&#x308C;&#x305F;&#x3001;anti-proliferation &#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D3;&#x30C6;&#x30A3;&#x306E;&#x4E00;&#x65B9;&#x306F;&#x4F7F;&#x7528;&#x3002;&#x7D50;&#x679C;: &#x30F4;&#x30A1;&#x30FC;&#x30CE;&#x30CB;&#x30A2; guineensisBenth &#x306E;&#x30A2;&#x30BB;&#x30C8;&#x30F3;&#x62BD;&#x51FA;&#x3057;&#x307E;&#x3059;&#x3002;&#x81F3;&#x308B;&#x307E;&#x3067; ic50 &#x5024; &#xFF08;50 4&micro;g/mL &#x306E;-26&micro;g/mL 10 &#x7D30;&#x80DE;&#x682A;&#x306B;&#x5BFE;&#x3059;&#x308B; in vitro &#x6D3B;&#x6027;&#x3092;&#x793A;&#x3057;&#x305F;&#x3002;&#x3053;&#x306E;&#x62BD;&#x51FA;&#x7269;&#x306E;&#x30AC;&#x30A4;&#x30C9;&#x4ED8;&#x304D;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D3;&#x30C6;&#x30A3;&#x5206;&#x5225;&#x5C5E;&#x30F4;&#x30A1;&#x30FC;&#x30CE;&#x30CB;&#x30A2;&#x304B;&#x3089;&#x521D;&#x3081;&#x3066;&#x5206;&#x96E2;&#x3055;&#x308C;&#x305F; 2 &#x3064;&#x306E;&#x30BB;&#x30B9;&#x30AD;&#x30C6;&#x30EB;&#x30DA;&#x30F3;&#x30E9;&#x30AF;&#x30C8;&#x30F3;&#x304C;&#x5F97;&#x3089;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x5316;&#x5408;&#x7269;&#x3092;&#x4F7F;&#x7528;&#x3057;&#x3066; 1 D &#x304A;&#x3088;&#x3073; 2 D &#x306E; NMR &#x30C7;&#x30FC;&#x30BF;&#x306E;&#x7D44;&#x307F;&#x5408;&#x308F;&#x305B;&#x3092;&#x542B;&#x3080;&#x5206;&#x5149;&#x5B9F;&#x9A13;&#x7279;&#x5FB4;&#x3065;&#x3051;&#x3089;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;Vernopicrin (1) &#x3068; Vernomelitensin (2) &#x793A;&#x3057;&#x305F;&#x3072;&#x3068;&#x764C;&#x7D30;&#x80DE;&#x682A;&#x306B;&#x5BFE;&#x3059;&#x308B; in vitro &#x6D3B;&#x6027; ic50 &#x5024; &#xFF08;50 &#x304B;&#x3089; 0.35&micro;M &#x306B;&#x81F3;&#x308B;&#x307E;&#x3067;-2.04&micro;M (P &lt; 0.05&#xFF09; &#x3068; 0.13&micro;M-1.5 &micro; m &#xFF08;P &lt; 0.05)&#x3001;&#x5404;&#x5316;&#x5408;&#x7269;&#x306E;&#x6700;&#x3082;&#x3001;&#x6700;&#x3082;&#x654F;&#x611F;&#x306E;&#x30BB;&#x30EB;&#x306E;&#x9593;&#x3067;&#x305D;&#x308C;&#x305E;&#x308C;&#x3002;Vernomelitensin &#x3082;&#x3072;&#x3068;&#x9ED2;&#x8272;&#x816B; (A375) &#x7D30;&#x80DE;&#x682A;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x6700;&#x3082;&#x6D3B;&#x767A;&#x306A;&#x5C11;&#x306A;&#x304F;&#x3068;&#x3082;&#x4E73;&#x623F;&#x304C;&#x3093; &#xFF08;MCF-7) &#x306E;&#x7D30;&#x80DE;&#x682A;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D6;&#x4E2D; Vernopicrin &#x306F;&#x3072;&#x3068;&#x9ED2;&#x8272;&#x816B; (A375) &#x7D30;&#x80DE;&#x682A;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x6700;&#x3082;&#x6D3B;&#x767A;&#x306A;&#x5C11;&#x306A;&#x304F;&#x3068;&#x3082;&#x80BA;&#x304C;&#x3093; (A549) &#x306E;&#x7D30;&#x80DE;&#x682A;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D6;&#x3060;&#x3063;&#x305F;&#x3002;&#x4E21;&#x65B9;&#x306E;&#x5316;&#x5408;&#x7269;&#x306F;&#x3001;&#x307E;&#x305F; anticlonogenic &#x306E;&#x6D3B;&#x52D5;&#x3092;&#x793A;&#x3057;&#x305F;&#x3002;&#x7D50;&#x8AD6;: &#x7C97;&#x62BD;&#x51FA;&#x7269;&#x306E;&#x7D30;&#x80DE;&#x6BD2;&#x6027;&#x306E;&#x5B9F;&#x8A3C;&#x3068;&#x764C;&#x7D30;&#x80DE;&#x682A;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x5206;&#x96E2;&#x30BB;&#x30B9;&#x30AD;&#x30C6;&#x30EB;&#x30DA;&#x30F3;&#x306E;&#x85AC;&#x52B9;&#x306E;&#x53EF;&#x80FD;&#x6027; guineensis &#x5BFE;&#x3002;&#x9078;&#x629E;&#x7684; anti-proliferation &#x3068;&#x7528;&#x91CF;&#x4F9D;&#x5B58; anticlonogenic &#x6D3B;&#x52D5;&#x306F;&#x7279;&#x5B9A;&#x306E;&#x30BB;&#x30B9;&#x30AD;&#x30C6;&#x30EB;&#x30DA;&#x30F3;&#x304C;&#x6F5C;&#x5728;&#x7684;&#x306A;&#x6297;&#x816B;&#x760D;&#x5264;&#x3053;&#x3068;&#x3092;&#x304A;&#x52E7;&#x3081;&#x3057;&#x307E;&#x3059;&#x3002;

&#x30F4;&#x30A1;&#x30FC;&#x30CE;&#x30CB;&#x30A2; guineensis Benth &#x306E;&#x8449;&#x304B;&#x3089;&#x306E;&#x7D30;&#x80DE;&#x6BD2;&#x6027;&#x306E;&#x30BB;&#x30B9;&#x30AD;&#x30C6;&#x30EB;&#x30DA;&#x30F3;&#x30E9;&#x30AF;&#x30C8;&#x30F3;&#x3002;(&#x30AD;&#x30AF;&#x79D1;)&#x3002;

ETHNOPHARMACOLOGICAL &#xAD00;&#xB828;&#xC131;: Vernonia Guineensisbenth&#xC785;&#xB2C8;&#xB2E4;. (&#xAD6D;&#xD654;&#xACFC;) &#xC900;&#xBE44; &#xB2E4;&#xC591; &#xD55C; &#xC804;&#xB9BD;&#xC120; &#xC554;, &#xB9D0;&#xB77C;&#xB9AC;&#xC544; &#xB4F1; &#xC9C8;&#xBCD1; &#xCE58;&#xB8CC;&#xC5D0; &#xCE74;&#xBA54;&#xB8EC;&#xC5D0;&#xC11C;&#xC758; &#xBBFC;&#xC18D; &#xC758;&#xD559;&#xC5D0; &#xC0AC;&#xC6A9; &#xB418; &#xACE0; anthelmintic, adaptogen, &#xD574;&#xB3C5; &#xC81C;&#xB85C; &#xC0AC;&#xC6A9; &#xB429;&#xB2C8;&#xB2E4;. &#xC774; &#xC5F0;&#xAD6C;&#xC758; &#xBAA9;&#xD45C;&#xB294; Vernonia Guineensisbenth&#xC758; &#xD65C;&#xB3D9;&#xC758; &#xC720;&#xD6A8;&#xC131; &#xAC80;&#xC0AC;&#xB97C; &#xACC4;&#xC18D; &#xD588;&#xB2E4;. &#xCD94;&#xCD9C; &#xBB3C;&#xACFC; anti-prostate &#xC554; &#xC774;&#xC804; &#xC808;&#xC5F0;&#xC5D0; &#xB530;&#xB77C; &#xC554; &#xC138;&#xD3EC; &#xB77C;&#xC778;&#xC5D0; &#xB300; &#xD55C; &#xACA9;&#xB9AC; &#xB41C; &#xBD84;&#xC790; &#xC124;&#xD0D5; &#xB8E8;&#xD2B8; &#xCD94;&#xCD9C; &#xBB3C;&#xC5D0;&#xC11C; &#xC5D0;&#xC2A4;&#xD14C; &#xB974;. &#xC7AC;&#xB8CC; &#xBC0F; &#xBC29;&#xBC95;: Vernonia Guineensisbenth&#xC758; &#xC544;&#xC138;&#xD1A4; &#xCD94;&#xCD9C;&#xD569;&#xB2C8;&#xB2E4;. &#xB098;&#xBB47;&#xC78E; 10 &#xAC1C; &#xC554; &#xC138;&#xD3EC; &#xB77C;&#xC778;&#xC5D0; &#xB300; &#xD55C; &#xC791;&#xC5C5;&#xC5D0; &#xB300; &#xD55C; &#xD14C;&#xC2A4;&#xD2B8;&#xB97C; &#xD588;&#xB2E4; (&#xC720; &#xBC29;-MDA-MB-231, &#xC720; &#xBC29;-MCF-7, &#xCF5C;&#xB860;-HCT-116, &#xBC31;&#xD608;&#xBCD1;-HL-60, &#xD3D0;&#xC554; A549, &#xD751;&#xC0C9; &#xC885; A375, &#xB09C;&#xC18C; OVCAR3 &#xCDCC; &#xBBF8;&#xC544; paca, &#xC804;&#xB9BD;&#xC120;-PC-3, &#xC804;&#xB9BD;&#xC120;-&#xB4A4;-145). &#xC544;&#xC138;&#xD1A4; &#xCD94;&#xCD9C;&#xC740; &#xAC00;&#xC774;&#xB4DC; bioactivity &#xBD84;&#xB958;&#xC758; &#xB300;&#xC0C1;. Anti-proliferation &#xBC0F; &#xACA9;&#xB9AC; &#xD654;&#xD569;&#xBB3C;&#xC758; clonogenic &#xC791;&#xC5C5;&#xC5D0;&#xC11C; &#xD14C;&#xC2A4;&#xD2B8; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC11C; &#xBD80; &#xD45C;&#xC900;&#xC2DC; 1 &#xBD84;&#xC11D; &#xACB0;&#xACFC; &#xBC18;&#xD655;&#xC0B0; &#xD65C;&#xB3D9; &#xD55C;&#xD3B8; &#xD45C;&#xC900; clonogenic &#xD14C;&#xC2A4;&#xD2B8;&#xB294; clonogenic &#xD65C;&#xB3D9;&#xC744; &#xACB0;&#xC815; &#xD558;&#xB294; &#xB370; &#xC0AC;&#xC6A9; &#xB429;&#xB2C8;&#xB2E4; &#xC0AC;&#xC6A9; &#xB418;&#xC5C8;&#xB2E4;. &#xACB0;&#xACFC;: Vernonia Guineensisbenth&#xC758; &#xC544;&#xC138;&#xD1A4; &#xCD94;&#xCD9C;&#xC785;&#xB2C8;&#xB2E4;. IC(50) 4&micro;g/mL-10 &#xC140; &#xB77C;&#xC778;&#xC5D0; &#xB300; &#xD55C; 26&micro;g/Ml&#xC5D0;&#xC11C;&#xC5D0;&#xC11C; &#xBC30;&#xC5F4; &#xD558;&#xB294; &#xCCB4; &#xC678; &#xD65C;&#xB3D9;&#xC744; &#xC2DC;&#xC5F0; &#xD588;&#xB2E4;. &#xC774; &#xCD94;&#xCD9C;&#xC758; &#xBD84;&#xB958; &#xD65C;&#xB3D9; &#xC548;&#xB0B4; Vernonia &#xC18D;&#xC5D0;&#xC11C; &#xCC98;&#xC74C;&#xC73C;&#xB85C; &#xBD84;&#xB9AC; &#xB41C; &#xB450; &#xAC1C;&#xC758; sesquiterpene lactones &#xB098;&#xC654;&#xACE0;. &#xD654;&#xD569;&#xBB3C;&#xC740; 1d &#xBC0F; 2D NMR &#xB370;&#xC774;&#xD130;&#xC758; &#xC870;&#xD569;&#xC744; &#xD3EC;&#xD568; &#xD558; &#xC5EC; &#xBD84; &#xAD11; &#xC2E4;&#xD5D8;&#xC744; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xD2B9;&#xC9D5;&#xC785;&#xB2C8;&#xB2E4;. Vernopicrin (1) &#xBC0F; Vernomelitensin (2) &#xC778;&#xAC04;&#xC758; &#xC554; &#xC138;&#xD3EC; &#xB77C;&#xC778;&#xC5D0; &#xB300; &#xD55C; &#xC2DC;&#xD5D8;&#xAD00; &#xD65C;&#xB3D9; &#xD568;&#xAED8; &#xC2DC;&#xC5F0; IC(50)&#xC5D0;&#xC11C; 0.35&micro;m&#xAE4C;&#xC9C0;-2.04&micro;M (P &lt; 0.05)&#xC640; 0.13&micro;M-1.5&micro;M (P &lt; 0.05), &#xAC01;&#xAC01; &#xAC00;&#xC7A5; &#xC0AC;&#xC774; &#xAC01; &#xD654;&#xD569;&#xBB3C;&#xC5D0; &#xB300; &#xD55C; &#xAC00;&#xC7A5; &#xBBFC;&#xAC10;&#xD55C; &#xC140; &#xB77C;&#xC778;. Vernopicrin&#xB294; &#xC778;&#xAC04;&#xC758; &#xD751;&#xC0C9; (A375) &#xC140; &#xB77C;&#xC778;&#xC5D0;&#xC11C; &#xAC00;&#xC7A5; &#xD65C;&#xC131;&#xD654; &#xBC0F; &#xD3D0; &#xC554; (A549) &#xC138;&#xD3EC; &#xB77C;&#xC778;&#xC5D0; &#xB300; &#xD55C; &#xCD5C;&#xC18C; &#xD65C;&#xC131; vernomelitensin&#xB294; &#xB610;&#xD55C; &#xC778;&#xAC04;&#xC758; &#xD751;&#xC0C9; (A375) &#xC140; &#xB77C;&#xC778;&#xC5D0;&#xC11C; &#xAC00;&#xC7A5; &#xD65C;&#xC131;&#xD654; &#xBC0F; &#xC774;&#xC0C1; &#xC720; &#xBC29; &#xC554; (MCF-7) &#xC140; &#xB77C;&#xC778;&#xC5D0;&#xC11C; &#xD65C;&#xC131;&#xD654; &#xD558;&#xB294; &#xB3D9;&#xC548;. &#xB450; &#xD654;&#xD569;&#xBB3C;&#xC740; &#xB610;&#xD55C; anticlonogenic &#xD65C;&#xB3D9;&#xC744; &#xC124;&#xBA85; &#xD588;&#xB2E4;. &#xACB0;&#xB860;:&#xB294; &#xC138;&#xD3EC; &#xB3C5;&#xC131; &#xC6D0;&#xC720; &#xCD94;&#xCD9C;&#xC5D0; &#xC758;&#xD574; &#xC99D;&#xBA85; &#xBC0F; &#xC554; &#xC138;&#xD3EC; &#xB77C;&#xC778;&#xC5D0; &#xB300; &#xD55C; &#xACA9;&#xB9AC; &#xB41C; sesquiterpenes guineensis &#xB300;&#xC758; &#xC57D; &#xC7A0;&#xC7AC;&#xB825;&#xC744; &#xAC15;&#xC870;. &#xC120;&#xD0DD;&#xC801; anti-proliferation &#xBCF5;&#xC6A9;&#xB7C9; &#xC758;&#xC874; anticlonogenic &#xD65C;&#xB3D9; &#xD655;&#xC778; &#xB41C; sesquiterpenes &#xC7A0;&#xC7AC;&#xC801;&#xC778; antitumor &#xC5D0;&#xC774;&#xC804;&#xD2B8; &#xC218; &#xAC83;&#xC774; &#xC88B;&#xC2B5;&#xB2C8;&#xB2E4;.

Cytotoxic sesquiterpene lactones Vernonia guineensis Benth&#xC758; &#xC78E;&#xC5D0;&#xC11C;. (&#xAD6D;&#xD654;&#xACFC;)&#xC785;&#xB2C8;&#xB2E4;.

RELEVANCIA de la ETNOFARMACOLOG&Iacute;A: Vernonia guineensisBenth. Preparaciones (Asteraceae) se utilizan en medicina popular en Camer&uacute;n para tratar una serie de dolencias incluyendo el c&aacute;ncer de pr&oacute;stata, la malaria y se utiliza como antihelm&iacute;ntico, adapt&oacute;geno y ant&iacute;doto. El objetivo de este estudio deb&iacute;a continuar la validaci&oacute;n de la actividad de Vernonia guineensisBenth. extractos y mol&eacute;culas aisladas contra l&iacute;neas celulares de c&aacute;ncer tras el aislamiento anterior de un c&aacute;ncer de anti-prostate az&uacute;car &eacute;ster del extracto de la ra&iacute;z. MATERIALES y m&eacute;todos: Los extractos de acetona de Vernonia guineensisBenth. hojas fueron probados para la actividad contra 10 l&iacute;neas celulares de c&aacute;ncer (mama - MDA-MB-231, mama-MCF-7, Colon-HCT-116, leucemia-HL-60, pulm&oacute;n-A549, Melanoma-A375, ovario-OVCAR3, p&aacute;ncreas-Mia-paca, pr&oacute;stata-PC-3 y pr&oacute;stata-DU-145). El extracto de la acetona se someti&oacute; a fraccionamiento bioactividad guiado. Se probaron antiproliferaci&oacute;n y clonogenic actividad de los compuestos aislados. El an&aacute;lisis de WST-1 fue utilizado para la actividad proliferaci&oacute;n mientras tanto que se emple&oacute; el test de clonogenic est&aacute;ndar para determinar la actividad de clonogenic. Resultados: La acetona Extracto de Vernonia guineensisBenth. demostrado actividad in vitro que van desde IC(50) 4&micro;g/mL-26&micro;g/mL contra las l&iacute;neas celulares de diez. Fraccionamiento de la actividad guiada de este extracto rindi&oacute; dos lactonas sesquiterp&eacute;nicas, aislados por primera vez del g&eacute;nero Vernonia. Los compuestos se caracterizaron mediante experimentos espectrosc&oacute;picos, incluyendo una combinaci&oacute;n de datos de NMR de 1D y 2D. Vernopicrin (1) y Vernomelitensin (2) demostraron actividad in vitro contra las l&iacute;neas celulares de c&aacute;ncer humano con IC(50) desde 0.35&micro;M-2.04&micro;M (P &lt; 0.05) y 0.13&micro;M-1.5&micro;M (P &lt; 0.05), respectivamente, entre los m&aacute;s y menos sensibles l&iacute;neas celulares para cada compuesto. Vernopicrin era m&aacute;s activo contra la l&iacute;nea de c&eacute;lulas de melanoma humano (A375) y menos activo contra la l&iacute;nea de c&eacute;lulas de pulm&oacute;n C&aacute;ncer (549), mientras que vernomelitensin era tambi&eacute;n m&aacute;s activo contra la l&iacute;nea de c&eacute;lulas de melanoma humano (A375) y menos activo contra la l&iacute;nea de c&eacute;lulas de mama c&aacute;ncer (MCF-7). Ambos compuestos tambi&eacute;n demostraron actividad anticlonogenic. CONCLUSI&Oacute;N: La citotoxicidad demostrada por el extracto crudo y sesquiterpenos aislados contra las l&iacute;neas celulares de c&aacute;ncer destacan el potencial medicinal de V. guineensis. Las actividades de anticlonogenic dependiente de antiproliferaci&oacute;n y dosis selectivas sugieren que los sesquiterpenos identificada podr&iacute;an ser potenciales agentes antitumorales.

Lactonas sesquiterp&eacute;nicas citot&oacute;xica de las hojas de Vernonia guineensis Benth. (Asteraceae).

Lassa hemorrhagic fever (LHF) is a rodent-borne viral disease that can be fatal for human beings. In this study, an attenuated Lassa vaccine candidate, ML29, was tested in SIV-infected rhesus macaques for its ability to elicit immune responses without instigating signs pathognomonic for arenavirus disease. ML29 is a reassortant between Lassa and Mopeia viruses that causes a transient infection in non-human primates and confers sterilizing protection from lethal Lassa viral challenge. However, since the LHF endemic area of West Africa also has high HIV seroprevalence, it is important to determine whether vaccination could be safe in the context of HIV infection.

An attenuated Lassa vaccine in SIV-infected rhesus macaques does not persist or cause arenavirus disease but does elicit Lassa virus-specific immunity.

Vernonia guineensis Benth. (Asteraceae) root decoction is used in folk medicine in Cameroon to treat some ailments including prostate cancer. The aim of this study was to validate the claimed antiprostate cancer activity of Vernonia guineensis Benth. in vivo and to investigate the cytotoxicity of a pentaisovaleryl sucrose isolated from Vernonia guineensis on some cancer cell lines.

In vivo antiprostate tumor potential of Vernonia guineensis Benth. (Asteraceae) tuber extract (VGDE) and the cytotoxicity of its major compound pentaisovaleryl sucrose.

Massive liquid crystal droplets have been found during embryonic development in more than twenty different tissues and organs, including the liver, brain and kidney. Liquid crystal deposits have also been identified in multiple human pathologies, including vascular disease, liver dysfunction, age-related macular degeneration, and other chronic illnesses. Despite the involvement of liquid crystals in such a large number of human processes, this phenomenon is poorly understood and there are no in vitro systems to further examine the function of liquid crystals in biology.

Characterization of tubular liquid crystal structure in embryonic stem cell derived embryoid bodies.

HIV-associated nephropathy (HIVAN) is an AIDs-related disease of the kidney. HIVAN is characterized by severe proteinuria, podocyte hyperplasia, collapse, glomerular, and tubulointerstitial damage. HIV-1 transgenic (Tg26) mouse is the most popular model to study the HIV manifestations that develop similar renal presentations as HIVAN. Viral proteins, including Tat, Nef, and Vpr play a significant role in renal cell damage. It has been shown that mitochondrial changes are involved in several kidney diseases, and therefore, mitochondrial dysfunction may be implicated in the pathology of HIVAN. In the present study, we investigated the changes of mitochondrial homeostasis, biogenesis, dynamics, mitophagy, and examined the role of reactive oxygen species (ROS) generation and apoptosis in the Tg26 mouse model. The Tg26 mice showed significant impairment of kidney function, which was accompanied by increased blood urea nitrogen (BUN), creatinine and protein urea level. In addition, histological, western blot and PCR analysis of the Tg26 mice kidneys showed a downregulation of NAMPT, SIRT1, and SIRT3 expressions levels. Furthermore, the kidney of the Tg26 mice showed a downregulation of PGC1α, MFN2, and PARKIN, which are coupled with decrease of mitochondrial biogenesis, imbalance of mitochondrial dynamics, and downregulation of mitophagy, respectively. Furthermore, our results indicate that mitochondrial dysfunction were associated with ER stress, ROS generation and apoptosis. These results strongly suggest that the impaired mitochondrial morphology, homeostasis, and function associated with HIVAN. These findings indicated that a new insight on pathological mechanism associated with mitochondrial changes in HIVAN and a potential therapeutic target.

Glomerular mitochondrial changes in HIV associated renal injury.

Cognitive impairment in HIV-1 infection is associated with the induction of chronic proinflammatory responses in the brains of infected individuals. The risk of HIV-related cognitive impairment is increased by cigarette smoking, which induces brain inflammation in rodent models. To better understand the role of smoking and the associated immune response on behavioral and motor function in HIV infection, wild-type F344 and HIV-1 transgenic (HIV1Tg) rats were exposed to either smoke from nicotine-containing (regular) cigarettes, smoke from nicotine-free cigarettes, or to nicotine alone. The animals were then tested using the rotarod test (RRT), the novel object recognition test (NORT), and the open field test (OFT). Subsequently, brain frontal cortex from the rats was analyzed for levels of TNF-α, IL-1, and IL-6. On the RRT, impairment was noted for F344 rats exposed to either nicotine-free cigarette smoke or nicotine alone and for F344 and HIV1Tg rats exposed to regular cigarette smoke. Effects from the exposures on the OFT were seen only for HIV1Tg rats, for which function was worse following exposure to regular cigarette smoke as compared to exposure to nicotine alone. Expression levels for all three cytokines were overall higher for HIV1Tg than for F344 rats. For HIV1Tg rats, TNF-α, IL-1, and IL-6 gene expression levels for all exposure groups were higher than for control rats. All F344 rat exposure groups also showed significantly increased TNF-α expression levels. However, for F344 rats, IL-1 expression levels were higher only for rats exposed to nicotine-free and nicotine-containing CS, and no increase in IL-6 gene expression was noted with any of the exposures as compared to controls. These studies, therefore, demonstrate that F344 and HIV1Tg rats show differential behavioral and immune effects from these exposures. These effects may potentially reflect differences in the responsiveness of the various brain regions in the two animal species as well as the result of direct toxicity mediated by the proinflammatory cytokines that are produced by HIV proteins and by other factors that are present in regular cigarette smoke.

Cigarette smoke and nicotine effects on brain proinflammatory responses and behavioral and motor function in HIV-1 transgenic rats.

Inflammatory signals have been shown to play a critical role in controlling the maintenance and functions of hematopoietic stem cells (HSCs). While the significance of inflammation in hematopoiesis has begun to unfold, molecular mechanisms and players that govern this mode of HSC regulation remain largely unknown. The E3 ubiquitin ligase A20 has been considered as a central gatekeeper of inflammation. Here, we have specifically depleted A20 in multi-potent progenitors (MPPs) and studied its impact on hematopoiesis. Our data suggest that lack of A20 in Flt3 progenitors causes modest alterations in hematopoietic differentiation. Analysis of hematopoietic stem and progenitor cell (HSPC) pool revealed alterations in HSPC subsets including, HSCs, MPP1, MPP2, MPP3 and MPP4. Interestingly, A20 deficiency in MPPs caused loss of HSC quiescence and compromised long-term hematopoietic reconstitution. Mechanistic studies identified that A20 deficiency caused elevated levels of Interferon-γ signaling and downregulation of p57 in HSCs. In essence, these studies identified A20 as a key regulator of HSC quiescence and cell fate decisions.

A20 deficiency in multipotent progenitors perturbs quiescence of hematopoietic stem cells.

Human immunodeficiency virus associated nephropathy (HIVAN) is a unique form of a renal parenchymal disorder. This disease and its characteristics can be accredited to incorporation of DNA and mRNA of human immunodeficiency virus type 1 into the renal parenchymal cells. A proper understanding of the intricacies of HIVAN and the underlying mechanisms associated with renal function and disorders is vital for the potential development of a reliable treatment for HIVAN. Specifically, the renal tubule segment of the kidney is characterized by its transport capabilities and its ability to reabsorb water and salts into the blood. However, the segment is also known for certain disorders, such as renal tubular epithelial cell infection and microcyst formation, which are also closely linked to HIVAN. Furthermore, certain organelles, like the endoplasmic reticulum (ER), mitochondria, and lysosome, are vital for certain underlying mechanisms in kidney cells. A paradigm of the importance of said organelles can be seen in documented cases of HIVAN where the renal disorder results increased ER stress due to HIV viral propagation. This balance can be restored through the synthesis of secretory proteins, but, in return, the secretion requires more energy; therefore, there is a noticeable increase in mitochondrial stress. The increased ER changes and mitochondrial stress will greatly upregulate the process of autophagy, which involves the cell's lysosomes. In conjunction, we found that ER stress and mitochondrial changes are associated in the Tg26 animal model of HIVAN. The aim of our review is to consolidate current knowledge of important mechanisms in HIVAN, specifically related to the renal tubules' association with ER stress, mitochondrial changes and autophagy. Although the specific regulatory mechanism detailing the cross-talk between the various organelles is unknown in HIVAN, the continued research in this field may potentially shed light on a possible improved treatment for HIVAN.

HIVAN associated tubular pathology with reference to ER stress, mitochondrial changes, and autophagy.

The development of mouse models that mimic the kinetics of Human Immunodeficiency Virus (HIV) infection is critical for the understanding of the pathogenesis of disease and for the design of novel therapeutic strategies. Here, we describe the dynamics of HIV infection in humanized NOD/Shi-scid-IL2rγ (NOG) mice bearing the human genes for interleukin (IL)-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (NOG-EXL mice). The kinetics of viral load, as well as the frequencies of T-cells, B-cells, Natural killer cells (NK), monocytes, and dendritic cells in blood and secondary lymphoid organs were evaluated throughout the time of infection. In comparison with a non-transgenic humanized mouse (NSG) strain, lymphoid and myeloid populations were more efficiently engrafted in humanized NOG-EXL mice, both in peripheral blood and lymphoid tissues. In addition, HIV actively replicated in humanized NOG-EXL mice, and infection induced a decrease in the percentage of CD4⁺ T-cells, inversion of the CD4:CD8 ratio, and changes in some cell populations, such as monocytes and dendritic cells, that recapitulated those found in human natural infection. Thus, the humanized IL-3/GM-CSF-transgenic NOG mouse model is suitable for the study of the dynamics of HIV infection and provides a tool for basic and preclinical studies.

Article	Year
Early blood profiles of virus infection in a monkey model for Lassa fever. Journal of virology\| PubMed ID: 17522210	2007
Safety, immunogenicity, and efficacy of the ML29 reassortant vaccine for Lassa fever in small non-human primates. Vaccine\| PubMed ID: 18692539	2008
Gene expression in primate liver during viral hemorrhagic fever. Virology journal\| PubMed ID: 19216742	2009
Evaluation of Lassa virus vaccine immunogenicity in a CBA/J-ML29 mouse model. Vaccine\| PubMed ID: 22234266	2012
Immune activation, viral gene product expression and neurotoxicity in the HIV-1 transgenic rat. Journal of neuroimmunology\| PubMed ID: 22503372	2012
Cytotoxic sesquiterpene lactones from the leaves of Vernonia guineensis Benth. (Asteraceae). Journal of ethnopharmacology\| PubMed ID: 23376285	2013
An attenuated Lassa vaccine in SIV-infected rhesus macaques does not persist or cause arenavirus disease but does elicit Lassa virus-specific immunity. Virology journal\| PubMed ID: 23402317	2013
In vivo antiprostate tumor potential of Vernonia guineensis Benth. (Asteraceae) tuber extract (VGDE) and the cytotoxicity of its major compound pentaisovaleryl sucrose. Journal of ethnopharmacology\| PubMed ID: 24095832	2013
Characterization of tubular liquid crystal structure in embryonic stem cell derived embryoid bodies. Cell & bioscience\| PubMed ID: 28066542	2017
Glomerular mitochondrial changes in HIV associated renal injury. Experimental and molecular pathology\| PubMed ID: 29608912	2018
Cigarette smoke and nicotine effects on brain proinflammatory responses and behavioral and motor function in HIV-1 transgenic rats. Journal of neurovirology\| PubMed ID: 29644536	2018
A20 deficiency in multipotent progenitors perturbs quiescence of hematopoietic stem cells. Stem cell research\| PubMed ID: 30445411	2018
HIVAN associated tubular pathology with reference to ER stress, mitochondrial changes, and autophagy. Experimental and molecular pathology\| PubMed ID: 30605635	2019
HIV Replication in Humanized IL-3/GM-CSF-Transgenic NOG Mice. Pathogens (Basel, Switzerland)\| PubMed ID: 30871027	2019

Harry Davis

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