A standardized chemically modified Curcuma longa extract modulates IRAK-MAPK signaling in inflammation and potentiates cytotoxicity

Minakshi Rana, Preeti Maurya, Sukka S. Reddy, Vishal Singh, Hafsa Ahmad, Anil K. Dwivedi, Madhu Dikshit, Manoj K. Barthwal

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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 I?Ba 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 and 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.

Original languageEnglish (US)
Article number223
JournalFrontiers in Pharmacology
Volume7
Issue numberJUL
DOIs
StatePublished - Jul 25 2016

Fingerprint

Curcuma
HL-60 Cells
Interleukin-1
Anti-Inflammatory Agents
Inflammation
Curcumin
Mitochondrial Membrane Potential
Annexin A5
G1 Phase
Nitrites
Acute Myeloid Leukemia
Caspase 3
Blood Vessels
Permeability
Sepsis
Leukemia
Western Blotting
Enzyme-Linked Immunosorbent Assay
Apoptosis
Pathology

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Rana, Minakshi ; Maurya, Preeti ; Reddy, Sukka S. ; Singh, Vishal ; Ahmad, Hafsa ; Dwivedi, Anil K. ; Dikshit, Madhu ; Barthwal, Manoj K. / A standardized chemically modified Curcuma longa extract modulates IRAK-MAPK signaling in inflammation and potentiates cytotoxicity. In: Frontiers in Pharmacology. 2016 ; Vol. 7, No. JUL.
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abstract = "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 I?Ba 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 and 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.",
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A standardized chemically modified Curcuma longa extract modulates IRAK-MAPK signaling in inflammation and potentiates cytotoxicity. / Rana, Minakshi; Maurya, Preeti; Reddy, Sukka S.; Singh, Vishal; Ahmad, Hafsa; Dwivedi, Anil K.; Dikshit, Madhu; Barthwal, Manoj K.

In: Frontiers in Pharmacology, Vol. 7, No. JUL, 223, 25.07.2016.

Research output: Contribution to journalArticle

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AU - Rana, Minakshi

AU - Maurya, Preeti

AU - Reddy, Sukka S.

AU - Singh, Vishal

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AU - Barthwal, Manoj K.

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AB - 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 I?Ba 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 and 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.

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