Crategolic acid

Chem Pharm Bull (Tokyo). 1992 Feb;40(2):401-5.

Studies on differentiation-inducing activities of triterpenes.[Pubmed: 1606636]

Differentiation-inducing activity of over 180 extracts of crude drugs and plants was tested using mouse myeloid leukemia cell line (M1).
METHODS AND RESULTS:
The methanol extracts of clove (Syzygium aromaticum Merrill et Perry, Myrtaceae) showed remarkable induction of differentiation of M1 cells into macrophage-like cells. From the extract, oleanolic acid (1) and Crategolic acid (2) were isolated as the active components. We also tested other triterpenes, such as oleananes, ursanes and dammaranes, to investigate the structure-activity relationship. Some triterpene aglycones showed differentiation-inducing activity, but triterpene glycosides showed little activity. Furthermore, the differentiation-inducing activity of these triterpene compounds was tested against human acute promyelocytic leukemia cell line (HL-60).

Bioorg Med Chem. 2009 Feb 1;17(3):1139-45.

Solution- and solid-phase synthesis and anti-HIV activity of maslinic acid derivatives containing amino acids and peptides.[Pubmed: 19135380 ]

METHODS AND RESULTS:
Maslinic acid (1,Crategolic acid,) has been coupled at C-28 with several alpha- and omega-amino acids by using solution- and solid-phase synthetic procedures. Twelve derivatives (2-13) with a single amino acid residue were prepared in solution phase, whereas a dipeptide (14), a tripeptide (15), and a series of conjugate dipeptides (16-24) were synthesized in solid phase. The anti-HIV activity of these compounds was assessed on MT-2 cells infected with viral clones carrying the luciferase gene as a reporter.
CONCLUSIONS:
While in maslinic acid (1) were present both cytotoxic and antiviral activities, only the derivatives 13 and 24 showed anti-HIV-1 activity and therefore represent a novel class of anti-HIV-1 compounds.

J Bone Miner Res. 2011 Mar;26(3):644-56.

Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-κB and MAPK signaling pathways.[Pubmed: 20814972 ]

Activation of NF-κB and MAPK/activator protein 1 (AP-1) signaling pathways by receptor activator NF-κB ligand (RANKL) is essential for osteoclast activity. Targeting NF-κB and MAPK/AP-1 signaling to modulate osteoclast activity has been a promising strategy for osteoclast-related diseases.
METHODS AND RESULTS:
In this study we examined the effects of maslinic acid (Crategolic acid,MA), a pentacyclic triterpene acid that is widely present in dietary plants, on RANKL-induced osteoclastogenesis, osteoclast function, and signaling pathways by in vitro and in vivo assay systems. In mouse bone marrow monocytes (BMMs) and RAW264.7 cells, MA inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner within nongrowth inhibitory concentration, and MA decreased osteoclastogenesis-related marker gene expression, including TRACP, MMP9, c-Src, CTR, and cathepsin K. Specifically, MA suppressed osteoclastogenesis and actin ring formation at early stage. In ovariectomized mice, administration of MA prevented ovariectomy-induced bone loss by inhibiting osteoclast activity. At molecular levels, MA abrogated the phosphorylation of MAPKs and AP-1 activity, inhibited the IκBα phosphorylation and degradation, blocked NF-κB/p65 phosphorylation, nuclear translocation, and DNA-binding activity by downregulating RANK expression and blocking RANK interaction with TRAF6.
CONCLUSIONS:
Together our data demonstrate that MA suppresses RANKL-induced osteoclastogenesis through NF-κB and MAPK/AP-1 signaling pathways and that MA is a promising agent in the treatment of osteoclast-related diseases such as osteoporosis.

Mol Nutr Food Res . 2016 Feb;60(2):399-409.

Anti-inflammatory and anti-arthritic effects of pentacyclic triterpenoids maslinic acid through NF-κB inactivation[Pubmed: 26499467]

Abstract Scope: Consumption of olives (Olea europaea L.), including table olives and oil, is associated with low incidence of inflammation-related diseases. In this study, the effects of maslinic acid (MA), the main constituent of olive pomace, on the expression of genes and proteins involved in inflammatory activity in RAW 264.7 cells were investigated. Furthermore, the effect of MA on carrageenan-induced paw edema and collagen antibody induced arthritis in mice was determined. Methods and results: We confirmed the suppressive effects of MA on LPS-induced tumor necrosis factor α production and on the expression of inflammatory response associated genes in RAW 264.7 cells. We also clarified the suppressive effect of MA on LPS-induced nuclear factor-kappa B activation as well as the phosphorylation of IκB-α. Furthermore, MA (200 mg/kg in the edema model or 100 mg/kg in the arthritis model) exerted anti-inflammatory and antiarthritis effects as shown by the suppression of paw edema, arthritis score, inflammatory cells, and destruction of synovium in knee joints. Conclusion: Olive products containing MA are useful as a new preventive and therapeutic food ingredient for inflammatory and arthritic diseases. Keywords: Arthritis; Inflammation; Locomotive syndrome; Maslinic acid; Olive fruit.

Mol. Cancer, 2010, 9(1):1-13.

Maslinic acid potentiates the anti-tumor activity of tumor necrosis factor α by inhibiting NF-κB signaling pathway[Pubmed: 20367887]

Tumor necrosis factor alpha (TNFalpha) has been used to treat certain tumors in clinic trials. However, the curative effect of TNFalpha has been undermined by the induced-NF-kappaB activation in many types of tumor. Maslinic acid (Crategolic acid,MA),a pharmacological safe natural product, has been known for its important effects as anti-oxidant, anti-inflammatory, and anti-viral activities. The aim of this study was to determine whether MA potentiates the anti-tumor activity of TNFalpha though the regulation of NF-kappaB activation.
METHODS AND RESULTS:
In this study, we demonstrate that MA significantly enhanced TNFalpha-induced inhibition of pancreatic cancer cell proliferation, invasion, and potentiated TNFalpha-induced cell apoptosis by suppressing TNFalpha-induced NF-kappaB activation in a dose- and time-dependent manner. Addition of MA inhibited TNFalpha-induced IkappaBalpha degradation, p65 phosphorylation, and nuclear translocation. Furthermore, MA decreased the expression levels of NF-kappaB-regulated genes, including genes involved in tumor cell proliferation (Cyclin D1, COX-2 and c-Myc), apoptosis (Survivin, Bcl-2, Bcl-xl, XIAP, IAP-1), invasion (MMP-9 and ICAM-1), and angiogenesis (VEGF). In athymic nu/nu mouse model, we further demonstrated that MA significantly suppressed pancreatic tumor growth, induced tumor apoptosis, and inhibited NF-kappaB-regulated anti-apoptotic gene expression, such as Survivin and Bcl-xl.
CONCLUSIONS:
Our data demonstrate that MA can potentiate the anti-tumor activities of TNFalpha and inhibit pancreatic tumor growth and invasion by activating caspase-dependent apoptotic pathway and by suppressing NF-kappaB activation and its downstream gene expression. Therefore, MA together with TNFalpha could be new promising agents in the treatment of pancreatic cancer.

Eur J Pharmacol. 2011 Nov 16;670(1):148-53.

Maslinic acid, a natural triterpenoid compound from Olea europaea, protects cortical neurons against oxygen-glucose deprivation-induced injury.[Pubmed: 21839077]

Maslinic acid(Crategolic acid) is a triterpenoid compound present in plants of Olea europaea. This compound has been reported to have potent antioxidant, anti-cancer, anti-HIV and anti-inflammatory activities.
METHODS AND RESULTS:
In this study, we investigated the neuroprotective effect of maslinic acid (Crategolic acid)and its mechanism of action. With presence or absence of maslinic acid, cortical neurons were subjected to 1h of oxygen-glucose deprivation and 24h of reoxygenation. Cell injury was determined by lactate dehydrogenase (LDH) measurement and 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay. Neuronal apoptosis was evaluated by flow cytometry assay, caspase-3 expression/activity, caspase-9 activity and Bcl-2/Bax ratio. Nitric Oxide (NO) production and inducible nitric oxide synthase (iNOS) expression were also detected. Results showed that maslinic acid(Crategolic acid) dose-dependently ameliorated neuron injury and apoptosis. Maslinic acid (Crategolic acid)treatment normalized the caspase expression/activation and increased the Bcl-2/Bax ratio. In addition, maslinic acid (Crategolic acid)inhibited oxygen-glucose deprivation-induced NO production and iNOS expression.
CONCLUSIONS:
These results indicated that maslinic acid(Crategolic acid) has beneficial effects on hypoxic neurons by suppressing iNOS activation, which may, in turn, provide neuroprotection.

Eur J Pharmacol. 2011 Dec 15;672(1-3):169-74.

Anti-inflammatory effects of maslinic acid, a natural triterpene, in cultured cortical astrocytes via suppression of nuclear factor-kappa B.[Pubmed: 21970807 ]

Maslinic acid (Crategolic acid,2-α, 3-β-dihydroxyolean-12-en-28-oic acid) is a natural triterpenoid compound from Olea europaea. This compound prevents oxidative stress and pro-inflammatory cytokine generation in vitro.
METHODS AND RESULTS:
This study was planned to investigate the anti-inflammatory effects of maslinic acid (Crategolic acid)in central nervous system by using rat astrocyte cultures stimulated with lipopolysaccharide (LPS). We evaluated different proteins implicated in the nuclear factor kappa B (NF-κB) signal transducer pathway employing Western blot and quantitative real time PCR techniques. Results demonstrated that maslinic acid(Crategolic acid) treatment exerted potent anti-inflammatory action by inhibiting the production of Nitric Oxide and tumor necrosis factor alpha (TNF-α). Western blot analysis showed that maslinic acid(Crategolic acid) treatment attenuated LPS-induced translocation of NF-κB p65 subunit to the nucleus and prevented LPS-induced IκBα phosphorylation in a concentration-dependent manner, Moreover, maslinic acid(Crategolic acid) significantly suppressed the expression of cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) at protein and mRNA levels.
CONCLUSIONS:
These results suggest that maslinic acid(Crategolic acid) can potentially reduce neuroinflammation by inhibiting NF-κB signal transducer pathway in cultured cortical astrocytes.

Comp Biochem Physiol C Toxicol Pharmacol. 2006 Oct;144(2):130-40.

Maslinic acid as a feed additive to stimulate growth and hepatic protein-turnover rates in rainbow trout (Onchorhynchus mykiss).[Pubmed: 16934535 ]

Maslinic acid (Crategolic acid) is a triterpene present in a considerable proportion in solid residues from olive-oil production.
METHODS AND RESULTS:
In the present work the effects of maslinic acid on growth, protein-turnover rates and nucleic-acid concentration on liver were investigated in the rainbow trout. Five groups of 120 fish of a mean body mass of 20 g were fed for 225 days with diets containing 0, 1, 5, 25 and 250 mg of maslinic acid per kg diet. At the end of the experiment, whole-body and liver weight and growth rate of trout fed with maslinic acid were higher than controls. The highest weight increase was registered for the group fed 250 mg kg(-1), representing a 29% increase over controls. The total hepatic DNA or liver cell hyperplasia levels in trout fed with 25 and 250 mg of maslinic acid kg(-1) were 37% and 68% higher than controls. Also in these same groups of trout, fractional and absolute hepatic protein-synthesis rates were significantly higher than in control, and significant increments in hepatic protein-synthesis efficiency and protein-synthesis capacity were reported. In close agreement with these results, microscopy studies showed that trout fed on 25 and 250 mg kg(-1) hepatocytes appeared to be more compact, with a larger rough-endoplasmic reticulum and larger glycogen stores than controls.
CONCLUSIONS:
These results suggest that maslinic acid can act as a growth factor when added to trout diet.