title: NF-κB dependent anti-inflammatory activity of chlorojanerin isolated from Saussurea heteromalla.
abstract: Medicinal plants have shown great promise as a source of novel drug compounds for the treatment of inflammatory disorders. In our search for new entities with anti-inflammatory potential, the extracts of the whole plant of Saussurea heteromalla (family-Asteraceae), collected from Himalayas, were evaluated in the high throughput screen for TNF-α and IL-6 inhibitors. The extract blocked TNF-α and IL-6 production in LPS stimulated THP-1 cells (human acute monocyte leukemia cell line) completely at 10 and 30 μg/ml. The plant has been found as a new source of chlorojanerin, a guaianolide type of sesquiterpene lactone. Chlorojanerin was shown to be significantly effective in inhibiting TNF-α and IL-6 production in LPS-stimulated THP-1 cells (IC(50)=2.3±0.2 μM and 1.8±0.7 μM respectively). The compound also blocked TNF-α and IL-6 production from LPS-stimulated human monocytes (IC(50)=1.5±0.4 and 0.7±0.2 μM respectively) and synovial cells from a patient with rheumatoid arthritis (IC(50)<0.03 and 0.5 μM respectively). Transcriptional profiling of the LPS stimulated THP-1 cells revealed that chlorojanerin exerted its anti-inflammatory effect by inhibiting the expression of 8 genes involved in activating the transcription factor - NF-κB. Real time analysis of these genes validated the effect of chlorojanerin on the classical downstream targets of NF-κB. Thus, this study clearly delineated 8 genes which were specifically mitigated due to the effect of chlorojanerin on NF-κB induced signaling at the mRNA level. Further, chlorojanerin at 5 μM also inhibited the binding of NF-κB in a GFP reporter assay system by 55.5% thus validating the microarray gene expression data. This work is a step towards the isolation and characterization of lead anti-inflammatory agents from the extract of Saussurea heteromalla, which can be developed into better therapeutic molecules targeted towards some specific inflammatory diseases.
authors: Department of Natural Products-Botany, Piramal Healthcare Limited, 1 Nirlon Complex, Goregaon (East), Mumbai 400063, India.
authors: Arvind
authors: A
authors: Saklani
authors: Bindu
authors: B
authors: Hegde
authors: Prabha
authors: P
authors: Mishra
authors: Ruchi
authors: R
authors: Singh
authors: Monica
authors: M
authors: Mendon
authors: Debarshi
authors: D
authors: Chakrabarty
authors: Divya V
authors: DV
authors: Kamath
authors: Aurelio
authors: A
authors: Lobo
authors: Prabhu Dutt
authors: PD
authors: Mishra
authors: Nilesh M
authors: NM
authors: Dagia
authors: Muralidhara
authors: M
authors: Padigaru
authors: Asha A
authors: AA
authors: Kulkarni-Almeida
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal; D012313:RNA / Q000235:genetics; D030441:Saussurea / Q000737:chemistry*; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult; D000093242:Interleukin-6 Inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D015850:Interleukin-6; D007783:Lactones; D016328:NF-kappa B; D010936:Plant Extracts; D012313:RNA; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C521621:chlorojanerin