Macrophage Activation by Ursolic and Oleanolic Acids during Mycobacterial Infection

López-García, Sonia; Castañeda‐Sánchez, Jorge Ismael; Jiménez-Arellanes, María Adelina; Domínguez-López, Lilia; Castro-Mussot, María Eugenia; Hernández‐Sánchez, Javier; Luna-Herrera, Julieta

doi:10.3390/molecules200814348

Cited by 38 publications

(36 citation statements)

References 52 publications

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“…In addition, leaves of the plants have been used as a means to weight loss due to its ability to inhibit lipid absorption activities in the digestive system (25). Major bioactive components of the plant include polyphenolics, such as carnosic acid (CA), carnosol, rosmarinic acid and ursolic acid (26)(27)(28)(29). CA ( Fig.…”

Section: Carnosic Acid Induces Apoptosis Through Inactivation Of Src/mentioning

confidence: 99%

Carnosic acid induces apoptosis through inactivation of Src/STAT3 signaling pathway in human renal carcinoma Caki cells

Park

Chae

et al. 2016

Oncology Reports

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Carnosic acid (CA), the major bioactive compound of Rosmarinus officinalis L., has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of CA remain poorly understood. In the present study, we investigated that CA significantly reduced the viability of human renal carcinoma Caki cells. CA-induced apoptosis was connected with the cleavage of caspase-9,-7 and-3, and that of PARP. Moreover, CA increased the expression of pro-apoptotic protein Bax and diminished the expression of anti-apoptotic protein Bcl-2 and Bcl-xL, thereby releasing cytochrome c into the cytosol. Treatment with CA in Caki cells also induced the expression of p53 and its target gene product, p27, through down-regulation of Murine double minute-2 (Mdm2). Furthermore, CA generated reactive oxygen species (ROS), and pretreatment with ROS scavenger N-acetyl cysteine (NAC) abrogated CA-induced cleavage of PARP and expression of p53. One of the key oncogenic signals is mediated through signal transducer and activator of transcription-3 (STAT3), which promotes abnormal cell proliferation. Incubation of cells with CA markedly diminished the phosphorylation of STAT3 and its upstream, Src, and reduced the expression of STAT3 responsive gene products, such as D-series of cyclins and survivin. Taken together, the present study revealed that CA induced apoptosis in Caki cells by induction of p53 and suppression of STAT3 signaling.

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Section: Carnosic Acid Induces Apoptosis Through Inactivation Of Src/mentioning

confidence: 99%

Carnosic acid induces apoptosis through inactivation of Src/STAT3 signaling pathway in human renal carcinoma Caki cells

Park

Chae

et al. 2016

Oncology Reports

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“…This antiinflammatory effect is crucial against several infections, such as those caused by intracellular pathogens. In Mycobacterium tuberculosis, UA has shown the ability to inhibit the expression of certain inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and TGF-β [32,33]. UA also has exhibited activity against other intracellular pathogens, such as Toxoplasma gondii, leading to an increased production of NO, ROS, IL-10, IL-12, granulocyte macrophage colony stimulating factor (GM-CSF) and interferon-β, while reducing the expression of IL-1β, IL-6, TNF-α and TGF-β in infected immune cells [34].…”

Section: Introductionmentioning

confidence: 99%

Evaluating the Potential of Ursolic Acid as Bioproduct for Cutaneous and Visceral Leishmaniasis

et al. 2020

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Leishmaniasis affects around 12 million people worldwide and is estimated to cause the ninth-largest disease burden. There are three main forms of the disease, visceral (VL), cutaneous (CL), and mucocutaneous (MCL), leading to more than one million new cases every year and several thousand deaths. Current treatments based on chemically synthesized molecules are far from ideal. In this study, we have tested the in vitro and in vivo efficacy of ursolic acid (UA), a multifunctional triterpenoid with well-known antitumoral, antioxidant, and antimicrobial effects on different Leishmania strains. The in vitro antileishmanial activity against the intracellular forms was six and three-fold higher compared to extracellular forms of L. amazonensis and L. infantum, respectively. UA also showed to be a potent antileishmanial drug against both VL and CL manifestations of the disease in experimental models. UA parenterally administered at 5 mg/kg for seven days significantly reduced the parasite burden in liver and spleen not only in murine acute infection but also in a chronic-infection model against L. infantum. In addition, UA ointment (0.2%) topically administered for four weeks diminished (50%) lesion size progression in a chronic infection model of CL caused by L. amazonensis, which was much greater than the effect of UA formulated as an O/W emulsion. UA played a key role in the immunological response modulating the Th1 response. The exposure of Leishmania-infected macrophages to UA led to a significant different production in the cytokine levels depending on the Leishmania strain causing the infection. In conclusion, UA can be a promising therapy against both CL and VL.

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“…These data suggest that exposure of cystic cholangiocytes to TGR5 agonists might account for overexpression of both TGR5 and Gα s in PLD, leading to cAMP elevation. An increased expression of TGR5 upon exposure to its ligands has also been observed in esophageal epithelium, gastric myenteric plexus, and macrophages …”

Section: Discussionmentioning

confidence: 93%

“…An increased expression of TGR5 upon exposure to its ligands has also been observed in esophageal epithelium, gastric myenteric plexus, and macrophages. (35)(36)(37) To our knowledge, no reports describe the identification, synthesis, or pharmacologic activity of TGR5 antagonists. SBI-115 (further details of which will be published elsewhere), a novel small molecule, was identified from a high-throughput screen in CHO-K1 cells expressing TGR5.…”

Section: Discussionmentioning

confidence: 99%

TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling

Masyuk¹,

Masyuk²,

Pisarello³

et al. 2017

Hepatology

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Hepatic cystogenesis in Polycystic Liver Disease (PLD) is associated with increased levels of cAMP in cholangiocytes lining liver cysts. TGR5, a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with PLD. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to: (i) TGR5 agonists [taurolithocholic acid (TLCA), oleanolic acid (OA) and two synthetic compounds]; (ii) a novel TGR5 antagonist (SBI-115); and (iii) a combination of SBI-115 and pasireotide, a somatostatin receptor (SSTR) analog. In vivo, we examined hepatic cystogenesis in OA-treated PCK rats and after genetic elimination of TGR5 in double mutant TGR5−/−;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq) proteins was increased 2–3-fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation and cyst growth by ~40%; these effects were abolished after TGR5 reduction by shRNA. OA increased cystogenesis in PCK rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5-deficient TGR5−/−;Pkhd1del2/del2 mice. TGR5 expression and its co-localization with Gαs were increased ~2-fold upon OA treatment. Levels of cAMP, cell proliferation and cyst growth in vitro were decreased by ~30% in cystic cholangiocytes after treatment with SBI-115 alone and by ~50% when SBI-115 was combined with pasireotide. Conclusion: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation. Our data suggest that a TGR5 antagonist alone or concurrently with SSTR agonists represents novel therapeutic approaches in PLD.

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Macrophage Activation by Ursolic and Oleanolic Acids during Mycobacterial Infection

Cited by 38 publications

References 52 publications

Carnosic acid induces apoptosis through inactivation of Src/STAT3 signaling pathway in human renal carcinoma Caki cells

Carnosic acid induces apoptosis through inactivation of Src/STAT3 signaling pathway in human renal carcinoma Caki cells

Evaluating the Potential of Ursolic Acid as Bioproduct for Cutaneous and Visceral Leishmaniasis

TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling

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