Glycyrrhizin Improves the Resistance of MAIDS Mice to Opportunistic Infection of Candida albicans through the Modulation of MAIDS-Associated Type 2 T Cell Responses

Utsunomiya, T.; Kobayashi, Makiko; Ito, Masahiko; Pollard, Richard B.; Suzuki, Fujio

doi:10.1006/clim.2000.4854

Cited by 24 publications

(32 citation statements)

References 46 publications

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“…Recently, GRA has been shown to induce Th1 immunological adjuvant activity in Candida albicans infection (45,46). GRA treatment showed enhanced expression of iNOS, NF-B, and IL-12 (47,48) and shifted the kinase/phosphatase balance toward kinases, where p38 plays a pivotal role (8).…”

Section: Discussionmentioning

confidence: 99%

Antileishmanial Effect of 18β-Glycyrrhetinic Acid Is Mediated by Toll-Like Receptor-Dependent Canonical and Noncanonical p38 Activation

Gupta

Das

Ukil

2015

Antimicrob Agents Chemother

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b 18␤-Glycyrrhetinic acid (GRA), a natural immunomodulator, greatly reduced the parasite load in experimental visceral leishmaniasis through nitric oxide (NO) upregulation, proinflammatory cytokine expression, and NF-B activation. For the GRAmediated effect, the primary kinase responsible was found to be p38, and analysis of phosphorylation kinetics as well as studies with dominant-negative (DN) constructs revealed mitogen-activated protein kinase kinase 3 (MKK3) and MKK6 as the immediate upstream regulators of p38. However, detection of remnant p38 kinase activity in the presence of both DN MKK3 and MKK6 suggested alternative pathways of p38 activation. That residual p38 activity was attributed to an autophosphorylation event ensured by the transforming growth factor ␤-activated kinase 1 (TAK1)-binding protein 1 (TAB1)-p38 interaction and was completely abolished upon pretreatment with SB203580 in DN MKK3/6 double-transfected macrophage cells. Further upstream signaling evaluation by way of phosphorylation kinetics and transfection studies with DN constructs identified TAK1, myeloid differentiation factor 88 (MyD88), interleukin 1 receptor (IL-1R)-activated kinase 1 (IRAK1), and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) as important contributors to GRA-mediated macrophage activation. Finally, gene knockdown studies revealed Toll-like receptor 2 (TLR2) and TLR4 as the membrane receptors associated with GRA-mediated antileishmanial activity. Together, the results of this study brought mechanistic insight into the antileishmanial activity of GRA, which is dependent on the TLR2/4-MyD88 signaling axis, leading to MKK3/6-mediated canonical and TAB1-mediated noncanonical p38 activation. The term leishmaniasis encompasses a spectrum of vectorborne protozoan parasitic diseases affecting 12 million people worldwide with 0.5 million new cases per annum. With no available vaccines for treatment of leishmaniasis, chemotherapy remains the major tool to combat infection (1). The primary treatment for leishmaniasis includes pentavalent antimonials, amphotericin B, pentamidine, miltefosine, and aminosidine, which often pose problems of high toxicity and several adverse effects. In addition, the combination of lengthy treatment schedules and the high cost of the compounds makes the treatment unsuitable in many cases (2). Evidence for a drug that specifically eliminates the infection and is safe enough to be used in the clinical field is still lacking. We have previously shown that 18␤-glycyrrhetinic acid (GRA), a pentacyclic triterpene derivative of the ␤-amyrin type, extracted from the root of the medicinal plant licorice (Glycyrrhizza glabra L.), might completely cure experimental visceral leishmaniasis (3). The pharmacological properties of GRA include antitumorigenic (4), hepatoprotective (5), antiulcerative (6), and immunomodulatory effects (7). Apart from immunomodulation, GRA plays a role in shifting the cellular kinase/phosphatase balance toward kinases during infection (8). This host-favorable act...

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Section: Discussionmentioning

confidence: 99%

Antileishmanial Effect of 18β-Glycyrrhetinic Acid Is Mediated by Toll-Like Receptor-Dependent Canonical and Noncanonical p38 Activation

Gupta

Das

Ukil

2015

Antimicrob Agents Chemother

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“…However, in previous studies, GR has been shown to have various immunomodulating activities including: the induction of IFN-Á production, the augmentation of NK cell activity, the inhibition of inflammation and the induction of antitype 2 T cells [10][11][12][13][14][15]. These facts suggest that GR may have the ability to stimulate lymphocytes to induce immunomodulatory soluble factors.…”

Section: Discussionmentioning

confidence: 99%

“…It has various biological activities including: induction of IFN-Á production [10], augmentation of NK cell activity [11], inhibition of inflammation [12] and suppression of herpesvirus replication [13]. In addition, GR is capable of inducing anti-type-2 T cells [14] and improving the resistance of hosts exposed to certain opportunistic pathogens [15]. Recently, GR was shown to be an inducer of ß-chemokines.…”

Section: Introductionmentioning

confidence: 99%

Effect of Glycyrrhizin, an Active Component of Licorice Roots, on HIV Replication in Cultures of Peripheral Blood Mononuclear Cells from HIV-Seropositive Patients

et al. 2002

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The effect of glycyrrhizin (GR) on HIV replication in cultures of peripheral blood mononuclear cells (PBMC) from HIV-infected patients was investigated. After the depletion of CD8+ T cells, PBMC from HIV+ patients (patient PBMC) and PBMC from healthy donors (healthy PBMC) were cocultured in the presence or absence of GR (100 µg/ml) for 21 days. In cultures of 13 of 42 samples of patient PBMC (13/42, 31%), GR inhibited more than 90% of HIV replication. Among 42 samples of patient PBMC, 20 were identified to be infected with a non-syncytium-inducing variant of HIV (NSI-HIV), 15 with a syncytium-inducing variant of HIV (SI-HIV), and the remaining 7 were classified as cells infected with SI-HIV and/or NSI-HIV. GR inhibited more than 90% of HIV replication in cultures of 12 patient PBMC samples infected with NSI-HIV (12/20, 60%). In patient PBMC infected with SI-HIV, GR inhibited HIV replication in only 1 patient (1/15, 7%). In cultures of patient PBMC, GR induced the production of CC chemokine ligand (CCL)4 and CCL5 in a dose-dependent manner. When the assay was performed in PBMC cultures supplemented with a mixture of monoclonal antibodies for CCL4 and CCL5, no evidence of anti-HIV activity of GR was found. These results indicate that GR has the potential to inhibit NSI-HIV replication in patient PBMC cultures by inducing the production of β-chemokines.

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“…Despite these consistent and striking parallels, future studies are needed to provide direct evidence for M-MDSC function in vivo. Of special importance, reaching beyond this experimental system are the observations that M-MDSCs alter positively, rather than always inhibit, certain B cell subset proportions and/or functions, including GC B cell and Ab-secreting cell percentages and Ab production ( Similar to patients with HIV-induced AIDS, mice with LP-BM5-induced MAIDS display increased susceptibility to opportunistic infections, ranging from bacterial (86)(87)(88) to viral (89)(90)(91)(92)(93)(94), fungal (95)(96)(97)(98), and protozoan parasitic infections (99)(100)(101)(102). Although data are limited regarding the role of B cell dysfunction in the increased susceptibility observed in LP-BM5-infected mice, humoral responses have been demonstrated to be important for clearance of many of these pathogens in other systems.…”

Section: Discussionmentioning

confidence: 99%

LP-BM5 Retrovirus–Expanded Monocytic Myeloid-Derived Suppressor Cells Alter B Cell Phenotype and Function

Rastad

Green

2018

ImmunoHorizons

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Glycyrrhizin Improves the Resistance of MAIDS Mice to Opportunistic Infection of Candida albicans through the Modulation of MAIDS-Associated Type 2 T Cell Responses

Cited by 24 publications

References 46 publications

Antileishmanial Effect of 18β-Glycyrrhetinic Acid Is Mediated by Toll-Like Receptor-Dependent Canonical and Noncanonical p38 Activation

Antileishmanial Effect of 18β-Glycyrrhetinic Acid Is Mediated by Toll-Like Receptor-Dependent Canonical and Noncanonical p38 Activation

Effect of Glycyrrhizin, an Active Component of Licorice Roots, on HIV Replication in Cultures of Peripheral Blood Mononuclear Cells from HIV-Seropositive Patients

LP-BM5 Retrovirus–Expanded Monocytic Myeloid-Derived Suppressor Cells Alter B Cell Phenotype and Function

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