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1.
Front Pharmacol ; 11: 576887, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33041822

RESUMO

In this review, we will focus on the activity of ginsenosides on membranes and their related effects, from physicochemical, biophysical, and pharmacological viewpoints. Ginsenosides are a class of saponins with a large structural diversity and a wide range of pharmacological effects. These effects can at least partly be related to their activity on membranes which results from their amphiphilic character. Some ginsenosides are able to interact with membrane lipids and associate into nanostructures, making them possible adjuvants for vaccines. They are able to modulate membrane biophysical properties such as membrane fluidity, permeability or the formation of lateral domains with some degree of specificity towards certain cell types such as bacteria, fungi, or cancer cells. In addition, they have shown antioxidant properties which protect membranes from lipid oxidation. They further displayed some activity on membrane proteins either through direct or indirect interaction. We investigate the structure activity relationship of ginsenosides on membranes and discuss the implications and potential use as anticancer, antibacterial, and antifungal agents.

2.
Sci Rep ; 9(1): 7285, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086211

RESUMO

The membrane activity of some saponins, such as digitonin or alpha-hederin, is usually attributed to their interaction with membrane cholesterol (Chol). This contrasts with our recent publication showing that Chol, contrary to sphingomyelin (SM), can delay the cytotoxicity of the saponin ginsenoside Rh2, challenging the usual view that most saponins mediate their membrane effects through interaction with Chol. The aim of the present study was to elucidate the respective importance of Chol and SM as compared to phosphatidylcholine (PC) species in the membrane-related effects of Rh2. On simple lipid monolayers, Rh2 interacted more favorably with eggSM and DOPC than with Chol and eggPC. Using Large Unilamellar Vesicles (LUVs) of binary or ternary lipid compositions, we showed that Rh2 increased vesicle size, decreased membrane fluidity and induced membrane permeability with the following preference: eggSM:eggPC > eggSM:eggPC:Chol > eggPC:Chol. On Giant Unilamellar Vesicles (GUVs), we evidenced that Rh2 generated positive curvatures in eggSM-containing GUVs and small buds followed by intra-luminal vesicles in eggSM-free GUVs. Altogether, our data indicate that eggSM promotes and accelerates membrane-related effects induced by Rh2 whereas Chol slows down and depresses these effects. This study reconsiders the theory that Chol is the only responsible for the activity of saponins.


Assuntos
Colesterol/metabolismo , Proteínas do Ovo/metabolismo , Ginsenosídeos/farmacologia , Esfingomielinas/metabolismo , Lipossomas Unilamelares/metabolismo , Animais , Permeabilidade da Membrana Celular/efeitos dos fármacos , Galinhas , Fluidez de Membrana/efeitos dos fármacos , Panax/química , Fosfatidilcolinas/metabolismo
3.
Front Immunol ; 10: 154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30787931

RESUMO

NKG2D is an activating receptor expressed on the surface of immune cells including subsets of T lymphocytes. NKG2D binds multiple ligands (NKG2DL) whose expression are differentially triggered in a cell type and stress specific manner. The NKG2D-NKG2DL interaction has been involved in autoimmune disorders but its role in animal models of multiple sclerosis (MS) remains incompletely resolved. Here we show that NKG2D and its ligand MULT1 contribute to the pathobiology of experimental autoimmune encephalomyelitis (EAE). MULT1 protein levels are increased in the central nervous system (CNS) at EAE disease peak; soluble MULT1 is elevated in the cerebrospinal fluid of both active and passive EAE. We establish that such soluble MULT1 enhances effector functions (e.g., IFNγ production) of activated CD8 T lymphocytes from wild type but not from NKG2D-deficient (Klrk1-/-) mice in vitro. The adoptive transfer of activated T lymphocytes from wild type donors induced a significantly reduced EAE disease in Klrk1-/- compared to wild type (Klrk1+/+) recipients. Characterization of T lymphocytes infiltrating the CNS of recipient mice shows that donor (CD45.1) rather than endogenous (CD45.2) CD4 T cells are the main producers of key cytokines (IFNγ, GM-CSF). In contrast, infiltrating CD8 T lymphocytes include mainly endogenous (CD45.2) cells exhibiting effector properties (NKG2D, granzyme B and IFNγ). Our data support the notion that endogenous CD8 T cells contribute to passive EAE pathobiology in a NKG2D-dependent manner. Collectively, our results point to the deleterious role of NKG2D and its MULT1 in the pathobiology of a MS mouse model.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Proteínas de Membrana/imunologia , Esclerose Múltipla/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Animais , Encéfalo/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Progressão da Doença , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Medula Espinal/imunologia
4.
Toxicol Appl Pharmacol ; 352: 59-67, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29782965

RESUMO

Saponins exhibit several biological and pharmacological activities, such as antibacterial, anti-inflammatory and anticancer effects. Many studies attribute their activities to their interactions with cholesterol. In this study, we focus on the steroid saponin ginsenoside Rh2, one of the active principles of Panax ginseng root. Some evidence suggests that lipid rafts, defined as nanodomains enriched in cholesterol and sphingolipids, could be involved in the Rh2-induced apoptosis. However, the role of membrane lipids, especially cholesterol, in this process is still poorly understood. Here, we demonstrate that (i) A549, THP-1 and U937 cells are all susceptible to the Rh2-induced apoptosis but to a differential extent and (ii) the cytotoxic effect inversely correlates with the cell membrane cholesterol content. Upon cholesterol depletion via methyl-ß-cyclodextrin, those three cells lines become more sensitive to Rh2-induced apoptosis. Then, focusing on the cholesterol-auxotroph U937 cell line, we showed that Rh2 alters plasma membrane fluidity by compacting the hydrophobic core of lipid bilayer (DPH anisotropy) and relaxing the interfacial packaging of the polar head of phospholipids (TMA-DPH anisotropy). The treatment with Rh2 conducts to the dephosphorylation of Akt and the activation of the intrinsic pathway of apoptosis (loss of mitochondrial membrane potential, caspase-9 and -3 activation). All these features are induced faster in cholesterol-depleted cells, which could be explained by faster cell accumulation of Rh2 in these conditions. This work is the first reporting that membrane cholesterol could delay the activity of ginsenoside Rh2, renewing the idea that saponin cytotoxicity is ascribed to an interaction with membrane cholesterol.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Colesterol/metabolismo , Ginsenosídeos/farmacologia , Microdomínios da Membrana/efeitos dos fármacos , Células A549 , Caspase 3/metabolismo , Caspase 9/metabolismo , Colesterol/deficiência , Humanos , Fluidez de Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Microdomínios da Membrana/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Células U937
5.
Toxicol Appl Pharmacol ; 309: 24-36, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27568863

RESUMO

Gentamicin, an aminoglycoside used to treat severe bacterial infections, may cause acute renal failure. In the renal cell line LLC-PK1, gentamicin accumulates in lysosomes, induces alterations of their permeability, and triggers the mitochondrial pathway of apoptosis via activation of caspase-9 and -3 and changes in Bcl-2 family proteins. Early ROS production in lysosomes has been associated with gentamicin induced lysosomal membrane permeabilization. In order to better understand the multiple interconnected pathways of gentamicin-induced apoptosis and ensuing renal cell toxicity, we investigated the effect of gentamicin on p53 and p21 levels. We also studied the potential effect of gentamicin on proteasome by measuring the chymotrypsin-, trypsin- and caspase-like activities, and on endoplasmic reticulum by determining phopho-eIF2α, caspase-12 activation and GRP78 and 94. We observed an increase in p53 levels, which was dependent on ROS production. Accumulation of p53 resulted in accumulation of p21 and of phospho-eIF2α. These effects could be related to an impairment of proteasome as we demonstrated an inhibition of trypsin-and caspase-like activities. Moderate endoplasmic reticulum stress could also participate to cellular toxicity induced by gentamicin, with activation of caspase-12 without change in GRP74 and GRP98. All together, these data provide new mechanistic insights into the apoptosis induced by aminoglycoside antibiotics on renal cell lines.


Assuntos
Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Gentamicinas/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Frações Subcelulares/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/fisiologia , Gentamicinas/efeitos adversos , Células LLC-PK1 , Chaperonas Moleculares/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Frações Subcelulares/metabolismo , Suínos , Proteína Supressora de Tumor p53/genética
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