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Phytother Res. 2017 Apr;31(4):663-670. doi: 10.1002/ptr.5780. Epub 2017 Feb 10.

Alkaloids from Piper nigrum Exhibit Antiinflammatory Activity via Activating the Nrf2/HO-1 Pathway.

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College of Pharmacy, Drug Research, and Development Center, Catholic University of Daegu, Gyeongbuk, 38430, Korea.
Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, 24341, Korea.
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Korea.
Korean Medicine of College, DaeguHaany University, Daegu, 42158, Korea.
Department of Bio Environmental Chemistry, Chungnam National University, Deajeon, 34134, Korea.
College of Agriculture and Life Sciences, Chonnam National University, Gwangju, 61186, Korea.
Department of Food and Life Science, Pukyong National University, Busan, 48513, Korea.


In the present study, ten alkaloids, namely chabamide (1), pellitorine (2), retrofractamide A (3), pyrroperine (4), isopiperolein B (5), piperamide C9:1 (8E) (6), 6,7-dehydrobrachyamide B (7), 4,5-dihydropiperine (8), dehydropipernonaline (9), and piperine (10), were isolated from the fruits of Piper nigrum. Among these, chabamide (1), pellitorine (2), retrofractamide A (3), isopiperolein B (5), and 6,7-dehydrobrachyamide B (7) exhibited significant inhibitory activity on lipopolysaccharide-induced nitric oxide (NO) production in RAW264.7 cells, with IC50 values of 6.8, 14.5, 30.2, 23.7, and 38.5 μM, respectively. Furthermore, compound 1 inhibited lipopolysaccharide-induced NO production in bone marrow-derived macrophages with IC50 value of 9.5 μM. Consistent with NO inhibition, treatment of RAW264.7 cells with chabamide (1), pellitorine (2), and 6,7-dehydrobrachyamide B (7) suppressed expression of inducible NO synthase and cyclooxygenase-2. Chabamide (1), pellitorine (2), and 6,7-dehydrobrachyamide B (7) induced heme-oxygenase-1 expression at the transcriptional level. In addition, compound 1 induced the nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) and upregulated the expression of Nrf2 target genes, NAD(P)H:quinone oxidoreductase 1 and γ-glutamyl cysteine synthetase catalytic subunit, in a concentration-dependent manner in RAW264.7 cells. These findings suggest that chabamide (1) from P. nigrum exert antiinflammatory effects via the activation of the Nrf2/heme-oxygenase-1 pathway; hence, it might be a promising candidate for the treatment of inflammatory diseases.


Nrf2; Piper nigrum; alkaloid; antiinflammation; chabamide; heme oxygenase-1

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