A Standardized Chemically Modified Curcuma longa Extract Modulates IRAK-MAPK Signaling in Inflammation and Potentiates Cytotoxicity
The TLR/IL-1R pathway is a critical signaling module that is misregulated in pathologies like inflammation and cancer. Extracts from turmeric (Curcuma longa L.) enriched in curcumin and carbonyls like turmerones have been shown to exert potent anti-inflammatory effects. The present study evaluated t...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphar.2016.00223/full |
| _version_ | 1818218564791828480 |
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| author | Minakshi Rana Preeti Maurya Sukka Santosh Reddy Vishal Singh Hafsa Ahmad Anil Kumar Dwivedi Madhu Dikshit Manoj Kumar Barthwal |
| author_facet | Minakshi Rana Preeti Maurya Sukka Santosh Reddy Vishal Singh Hafsa Ahmad Anil Kumar Dwivedi Madhu Dikshit Manoj Kumar Barthwal |
| author_sort | Minakshi Rana |
| collection | DOAJ |
| description | The TLR/IL-1R pathway is a critical signaling module that is misregulated in pathologies like inflammation and cancer. Extracts from turmeric (Curcuma longa L.) enriched in curcumin and carbonyls like turmerones have been shown to exert potent anti-inflammatory effects. The present study evaluated the anti-inflammatory activity, cytotoxic effect and the underlying mechanism of a novel chemically modified, non-carbonyl compound enriched Curcuma longa L. (C. longa) extract (CMCE). CMCE (1 or 10 µg/mL; 14 h) significantly decreased LPS (50-100 ng/mL) induced TNF-α and IL-1β production in THP-1 cells, human, and mouse whole blood as measured by ELISA. LPS-induced IRAK1, MAPK activation, TLR4 expression, TLR4-MyD88 interaction and IκBα degradation were significantly reduced in CMCE pre-treated THP-1 cells as assessed by Western blotting. CMCE (30, 100 and 300 mg/kg; 10 days p.o.) pre-treated and LPS (10 mg/kg) challenged Swiss mice exhibited attenuated plasma TNF-α, IL-1β, nitrite, aortic iNOS expression and vascular dysfunction. In a PI permeability assay, cell lines derived from acute myeloid leukemia were most sensitive to the cytotoxic effects of CMCE. Analysis of Sub-G1 phase, Annexin V-PI positivity, loss of mitochondrial membrane potential, increased caspase-3 and PARP-1 activation confirmed CMCE induced apoptosis in HL-60 cells. IRAK inhibition also sensitized HL-60 cells to CMCE induced cytotoxicity. The present study defines the mechanism underlying the action of CMCE and suggests a therapeutic potential for its use in sepsis and leukemia. |
| first_indexed | 2024-12-12T07:25:46Z |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-12T07:25:46Z |
| publishDate | 2016-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-2988d93c46aa4707bc572243d849c99f2022-12-22T00:33:09ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122016-07-01710.3389/fphar.2016.00223191522A Standardized Chemically Modified Curcuma longa Extract Modulates IRAK-MAPK Signaling in Inflammation and Potentiates CytotoxicityMinakshi Rana0Preeti Maurya1Sukka Santosh Reddy2Vishal Singh3Hafsa Ahmad4Anil Kumar Dwivedi5Madhu Dikshit6Manoj Kumar Barthwal7CSIR-Central Drug Research InstituteCSIR-Central Drug Research InstituteCSIR-Central Drug Research InstituteCSIR-Central Drug Research InstituteCSIR-Central Drug Research InstituteCSIR-Central Drug Research InstituteCSIR-Central Drug Research InstituteCSIR-Central Drug Research InstituteThe TLR/IL-1R pathway is a critical signaling module that is misregulated in pathologies like inflammation and cancer. Extracts from turmeric (Curcuma longa L.) enriched in curcumin and carbonyls like turmerones have been shown to exert potent anti-inflammatory effects. The present study evaluated the anti-inflammatory activity, cytotoxic effect and the underlying mechanism of a novel chemically modified, non-carbonyl compound enriched Curcuma longa L. (C. longa) extract (CMCE). CMCE (1 or 10 µg/mL; 14 h) significantly decreased LPS (50-100 ng/mL) induced TNF-α and IL-1β production in THP-1 cells, human, and mouse whole blood as measured by ELISA. LPS-induced IRAK1, MAPK activation, TLR4 expression, TLR4-MyD88 interaction and IκBα degradation were significantly reduced in CMCE pre-treated THP-1 cells as assessed by Western blotting. CMCE (30, 100 and 300 mg/kg; 10 days p.o.) pre-treated and LPS (10 mg/kg) challenged Swiss mice exhibited attenuated plasma TNF-α, IL-1β, nitrite, aortic iNOS expression and vascular dysfunction. In a PI permeability assay, cell lines derived from acute myeloid leukemia were most sensitive to the cytotoxic effects of CMCE. Analysis of Sub-G1 phase, Annexin V-PI positivity, loss of mitochondrial membrane potential, increased caspase-3 and PARP-1 activation confirmed CMCE induced apoptosis in HL-60 cells. IRAK inhibition also sensitized HL-60 cells to CMCE induced cytotoxicity. The present study defines the mechanism underlying the action of CMCE and suggests a therapeutic potential for its use in sepsis and leukemia.http://journal.frontiersin.org/Journal/10.3389/fphar.2016.00223/fullEndotoxemiacaspase-3mitochondrial membrane potentialChemically Modified Curcuma longa ExtractInterleukin-1 receptor-associated kinase 1 |
| spellingShingle | Minakshi Rana Preeti Maurya Sukka Santosh Reddy Vishal Singh Hafsa Ahmad Anil Kumar Dwivedi Madhu Dikshit Manoj Kumar Barthwal A Standardized Chemically Modified Curcuma longa Extract Modulates IRAK-MAPK Signaling in Inflammation and Potentiates Cytotoxicity Frontiers in Pharmacology Endotoxemia caspase-3 mitochondrial membrane potential Chemically Modified Curcuma longa Extract Interleukin-1 receptor-associated kinase 1 |
| title | A Standardized Chemically Modified Curcuma longa Extract Modulates IRAK-MAPK Signaling in Inflammation and Potentiates Cytotoxicity |
| title_full | A Standardized Chemically Modified Curcuma longa Extract Modulates IRAK-MAPK Signaling in Inflammation and Potentiates Cytotoxicity |
| title_fullStr | A Standardized Chemically Modified Curcuma longa Extract Modulates IRAK-MAPK Signaling in Inflammation and Potentiates Cytotoxicity |
| title_full_unstemmed | A Standardized Chemically Modified Curcuma longa Extract Modulates IRAK-MAPK Signaling in Inflammation and Potentiates Cytotoxicity |
| title_short | A Standardized Chemically Modified Curcuma longa Extract Modulates IRAK-MAPK Signaling in Inflammation and Potentiates Cytotoxicity |
| title_sort | standardized chemically modified curcuma longa extract modulates irak mapk signaling in inflammation and potentiates cytotoxicity |
| topic | Endotoxemia caspase-3 mitochondrial membrane potential Chemically Modified Curcuma longa Extract Interleukin-1 receptor-associated kinase 1 |
| url | http://journal.frontiersin.org/Journal/10.3389/fphar.2016.00223/full |
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