Inhibition of interleukin-12 production in lipopolysaccharide-activated mouse macrophages by parthenolide, a predominant sesquiterpene lactone in Tanacetum parthenium : involvement of nuclear factor-kB

Kang, B.Y.,Chung, S.W.,Kim, T.S. 전남대학교 약품개발연구소 2001 약품개발연구지 Vol.10 No.-

Pharmacological control of interleukin-12 (IL-12) production may be a key therapeutic strategy for modulating immunological diseases dominated by type-1 cytokine responses. In this study, we investigated the effects of parthenolide, an anti-inflammatory sesquiterpene, on the production of IL-12 from mouse macrophages stimulated with lipopolysaccharide (LPS). Parthenolide potently inhibited the LPS-induced IL-12 production in a dose-dependent manner. The effect of parthenolide on IL-12 p40 promoter activation was analyzed by transfecting RAW264.7 monocytic cells with p40 promoter/luciferase constructs. The repressive effect mapped to a region in the p40 promoter containing a binding site for nuclear factor-kB (p40-kB). Furthermore, activation of macrophages by LPS resulted in markedly enhanced binding activity to the kB site, which significantly decreased upon addition of parthenolide. These results suggest that parthenolide-induced inhibition of IL-12 production in macrophages may explain some of the biological effects of parthenolide including its anti-inflammatory activity.

Parthenolide-Induced Apoptosis, Autophagy and Suppression of Proliferation in HepG2 Cells

Sun, Jing,Zhang, Chan,Bao, Yong-Li,Wu, Yin,Chen, Zhong-Liang,Yu, Chun-Lei,Huang, Yan-Xin,Sun, Ying,Zheng, Li-Hua,Wang, Xue,Li, Yu-Xin Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.12

Purpose: To investigate the anticancer effects and underlying mechanisms of parthenolide on HepG2 human hepatocellular carcinoma cells. Materials and Methods: Cell viability was assessed by MTT assay and cell apoptosis through DAPI, TUNEL staining and Western blotting. Monodansylcadaverin(MDC) and AO staining were used to detect cell autophagy. Cell proliferation was assessed by Ki67 immunofluorescence staining. Results: Parthenolide induced growth inhibition in HepG2 cells. DAPI and TUNEL staining showed that parthenolide could increase the number of apoptotic nuclei, while reducing the expression of the anti-apoptotic protein Bcl-2 and elevating the expression of related proteins, like p53, Bax, cleaved caspase9 and cleaved caspase3. Parthenolide could induce autophagy in HepG2 cells and inhibited the expression of proliferation-related gene, Ki-67. Conclusions: Parthenolide can exert anti-cancer effects by inducing cell apoptosis, activating autophagy and inhibiting cell proliferation.

Balsalazide Potentiates Parthenolide-Mediated Inhibition of Nuclear Factor-κB Signaling in HCT116 Human Colorectal Cancer Cells

( Hyun Young Kim ),( Se Lim Kim ),( Young Ran Park ),( Yu Chuan Liu ),( Seung Young Seo ),( Seong Hun Kim ),( In Hee Kim ),( Seung Ok Lee ),( Soo Teik Lee ),( Sang Wook Kim ) 대한장연구학회 2015 Intestinal Research Vol.13 No.3

Background/Aims: Balsalazide is an anti-inflammatory drug used in the treatment of inflammatory bowel disease. Balsalazide can reduce inflammatory responses via several mechanisms, including inhibition of nuclear factor-κB (NF-κB) activity. Parthenolide (PT) inhibits NF-κB and exerts promising anticancer effects by promoting apoptosis. The present investigated the antitumor effects of balsalazide, combined with PT, on NF-κB in a representative human colorectal carcinoma cell line, HCT116. Methods: We counted cells and conducted annexin-V assays and cell cycle analysis to measure apoptotic cell death. Western blotting was used investigate the levels of proteins involved in apoptosis. Results: PT and balsalazide produced synergistic anti-proliferative effects and induced apoptotic cell death. The combination of balsalazide and PT markedly suppressed nuclear translocation of the NF-κB p65 subunit and the phosphorylation of inhibitor of NF-κB. Moreover, PT and balsalazidedramatically enhanced NF-κB p65 phosphorylation. Apoptosis, through the mitochondrial pathway, was confirmed by detecting effects on Bcl-2 family members, cytochrome c release, and activation of caspase-3 and -8. Conclusions: Combination treatment with PT and balsalazide may offer an effective strategy for the induction of apoptosis in HCT116 cells. (Intest Res 2015;13:233-241)

Parthenolide-induced apoptosis of hepatic stellate cells and anti-fibrotic effects in an in vivo rat model

김인희,김상욱,Seong Hun Kim,이승옥,이수택,이미진,박우현,김대곤 생화학분자생물학회 2012 Experimental and molecular medicine Vol.44 No.7

Parthenolide (PT), a sesquiterpene lactone derived from the plant feverfew, has pro-apoptotic activity in a number of cancer cell types. We assessed whether PT induces the apoptosis of hepatic stellate cells (HCSs)and examined its effects on hepatic fibrosis in an in vivo model. The effects of PT on rat HSCs were investigated in relation to cell growth inhibition, apoptosis, NF-κB binding activity, intracellular reactive oxygen species (ROS) generation, and glutathione (GSH) levels. In addition,the anti-fibrotic effects of PT were investigated in a thioacetamide-treated rat model. PT induced growth inhibition and apoptosis in HSCs, as evidenced by cell growth inhibition and apoptosis assays. PT increased the expression of Bax proteins during apoptosis,but decreased the expression of Bcl-2 and Bcl-XL proteins. PT also induced a reduction in mitochondrial membrane potential, poly(ADP-ribose) polymerase cleavage, and caspase-3 activation. PT inhibited TNF-α-stimulated NF-κB binding activity in HSCs. The pro-apoptotic activity of PT in HSCs was associated with increased intracellular oxidative stress as evidenced by increased intracellular ROS levels and depleted intracellular GSH levels. Furthermore, PT ameliorated hepatic fibrosis significantly in a thioacetamide-treated rat model. In conclusion, PT exhibited pro-apoptotic effects in rat HSCs and ameliorated hepatic fibrosis in a thioacetamide-induced rat model.

구연 : 아이리스 ; Parthenolide에 의한 백서 간성상세포의 세포사멸 유도와 동물모델에서 간섬유화 개선효과 (초)

김인희,김윤아,김상욱,이승옥,이수택,김대곤,박우현 대한간학회 2010 Clinical and Molecular Hepatology(대한간학회지) Vol.16 No.3(S)

Enhancement of parthenolide-induced apoptosis by a PKC-alpha inhibition through heme oxygenase-1 blockage in cholangiocarcinoma cells

Yun, Bo-Ra,Lee, Mi-Jin,Kim, Jong-Hyun,Kim, In-Hee,Yu, Goung-Ran,Kim, Dae-Ghon Korean Society for Biochemistry and Molecular Bion 2010 Experimental and molecular medicine Vol.42 No.11

Cholangiocarcinoma (CC) is a chemoresistant intrahepatic bile duct carcinoma with a poor prognosis. The aims of this study were to identify molecular pathways that enhance sesquiterpene lactone parthenolide (PTL)-induced anticancer effects on CC cells. The effects of PTL on apoptosis and hemoxygenase-1 (HO-1) induction were examined in CC cell lines. The enhancement of PTL-mediated apoptosis by modulation of HO-1 expression and the mechanisms involved were also examined in an in vitro cell system. Low PTL concentrations (5 to 10 ${\mu}M$) led to Nrf2-dependent HO-1 induction, which attenuated the apoptogenic effect of PTL in Choi-CK and SCK cells. PTL-mediated apoptosis was enhanced by the protein kinase C-alpha inhibitor Ro317549 (Ro) through inhibition of expression and nuclear translocation of Nrf2, resulting in blockage of HO-1 expression. Finally, HO-1 silencing resulted in enhancement of apoptotic cell death in CC cells. The combination of PTL and Ro efficiently improved tumor growth inhibition compared to treatment with either agent alone in an in vivo subcutaneous tumor model. In conclusion, the modulation of HO-1 expression substantially improved the anticancer effect of PTL. The combination of PTL and Ro could prove to be a valuable chemotherapeutic strategy for CC.

Enhancement of parthenolide-induced apoptosis by a PKC-alpha inhibition through heme oxygenase-1 blockage in cholangiocarcinoma cells

Bo-Ra Yun,이미진,Jong-Hyun Kim,김인희,Goung-Ran Yu,김대곤 생화학분자생물학회 2010 Experimental and molecular medicine Vol.42 No.11

Cholangiocarcinoma (CC) is a chemoresistant intrahepatic bile duct carcinoma with a poor prognosis. The aims of this study were to identify molecular pathways that enhance sesquiterpene lactone parthenolide (PTL)-induced anticancer effects on CC cells. The effects of PTL on apoptosis and hemoxygenase-1 (HO-1)induction were examined in CC cell lines. The enhancement of PTL-mediated apoptosis by modulation of HO-1 expression and the mechanisms involved were also examined in an in vitro cell system. Low PTL concentrations (5 to 10 μM) led to Nrf2-dependent HO-1 induction,which attenuated the apoptogenic effect of PTL in Choi-CK and SCK cells. PTL-mediated apoptosis was enhanced by the protein kinase C-alpha inhibitor Ro317549 (Ro) through inhibition of expression and nuclear translocation of Nrf2, resulting in blockage of HO-1 expression. Finally, HO-1 silencing resulted in enhancement of apoptotic cell death in CC cells. The combination of PTL and Ro efficiently improved tumor growth inhibition compared to treatment with either agent alone in an in vivo subcutaneous tumor model. In conclusion, the modulation of HO-1 expression substantially improved the anticancer effect of PTL. The combination of PTL and Ro could prove to be a valuable chemotherapeutic strategy for CC.

Parthenolide inhibits osteoclast differentiation and bone resorbing activity by down-regulation of NFATc1 induction and c-Fos stability, during RANKL-mediated osteoclastogenesis

( Ju Young Kim ),( Yoon Hee Cheon ),( Kwon Ha Yoon ),( Myeung Su Lee ),( Jaem Jn Oh ) 생화학분자생물학회(구 한국생화학분자생물학회) 2014 BMB Reports Vol.47 No.8

Parthenolide, a natural product derived from Feverfew, preventsseptic shock and inflammation. We aimed to identify the effectsof parthenolide on the RANKL (receptor activator of NF-κBligand)-induced differentiation and bone resorbing activity ofosteoclasts. In this study, parthenolide dose-dependentlyinhibited RANKL-mediated osteoclast differentiation in BMMs, without any evidence of cytotoxicity and the phosphorylation ofp38, ERK, and IκB, as well as IκB degradation by RANKLtreatment. Parthenolide suppressed the expression of NFATc1, OSCAR, TRAP, DC-STAMP, and cathepsin K in RANKL-treatedBMMs. Furthermore, parthenolide down-regulated the stabilityof c-Fos protein, but could not suppress the expression of c-Fos. Overexpression of NFATc1 and c-Fos in BMMs reversed theinhibitory effect of parthenolide on RANKL-mediated osteoclastdifferentiation. Parthenolide also inhibited the bone resorbingactivity of mature osteoclasts. Parthenolide inhibits thedifferentiation and bone-resolving activity of osteoclast byRANKL, suggesting its potential therapeutic value for bonedestructive disorders associated with osteoclast-mediated boneresorption.

Sequential anti-inflammatory and osteogenic effects of a dual drug delivery scaffold loaded with parthenolide and naringin in periodontitis

Rui Chen,Mengting Wang,Qiaoling Qi,Yanli Tang,Zhenzhao Guo,Shuai Wu,Qiyan Li 대한치주과학회 2023 Journal of Periodontal & Implant Science Vol.53 No.1

Purpose: Our pilot study showed that a 3-dimensional dual drug delivery scaffold (DDDS) loaded with Chinese herbs significantly increased the regenerated bone volume fraction. This study aimed to confirm the synergistic anti-inflammatory and osteogenic preclinical effects of this system. Methods: The targets and pathways of parthenolide and naringin were predicted. Three cell models were used to assess the anti-inflammatory effects of parthenolide and the osteogenic effects of naringin. First, the distance between the cementoenamel junction and alveolar bone crest (CEJ-ABC) and the bone mineral density (BMD) of surgical defects were measured in a rat model of periodontitis with periodontal fenestration defects. Additionally, the mRNA expression levels of matrix metallopeptidase 9 (MMP9) and alkaline phosphatase (ALP) were measured. Furthermore, the number of inflammatory cells and osteoclasts, as well as the protein expression levels of tumor necrosis factor-alpha (TNF-α) and levels of ALP were determined. Results: Target prediction suggested prostaglandin peroxidase synthase (PTGS2) as a potential target of parthenolide, while cytochrome P450 family 19 subfamily A1 (CYP19A1) and taste 2 receptor member 31 (TAS2R31) were potential targets of naringin. Parthenolide mainly targeted inflammation-related pathways, while naringin participated in steroid hormone synthesis and taste transduction. In vitro experiments revealed significant antiinflammatory effects of parthenolide on RAW264.7 cells, and significant osteogenic effects of naringin on bone marrow mesenchymal stem cells and MC3T3-E1 cells. DDDS loaded with parthenolide and naringin decreased the CEJ-ABC distance and increased BMD and ALP levels in a time-dependent manner. Inflammation was significantly alleviated after 14 days of DDDS treatment. Additionally, after 56 days, the DDDS group exhibited the highest BMD and ALP levels. Conclusions: DDDS loaded with parthenolide and naringin in a rat model achieved significant synergistic anti-inflammatory and osteogenic effects, providing powerful preclinical evidence.

Parthenolide Inhibits TRIF-Dependent Signaling Pathway of Toll-like Receptors in RAW264.7 Ma-crophages

Se-Jeong Park,Hwa-Jeong Shin,윤형선 한국분자세포생물학회 2011 Molecules and cells Vol.31 No.3

Toll-like receptors (TLRs) play an important role in induction of innate immune responses for host defense against invading microbial pathogens. Microbial component engagement of TLRs can trigger the activation of myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent downstream signaling pathways. Parthenolide,an active ingredient of feverfew (Tanacetum parthenium),has been used for centuries to treat many chronic diseases. Parthenolide inhibits the MyD88-dependent pathway by inhibiting the activity of inhibitor-κB kinase. However,it is not known whether parthenolide inhibits the TRIF-dependent pathway. To evaluate the therapeutic potential of parthenolide, its effect on signal transduction via the TRIF-dependent pathway of TLRs induced by lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly [I:C]) was examined. Parthenolide inhibited nuclear factor-κB and interferon regulatory factor 3 activation induced by LPS or poly[I:C], and the LPS-induced phosphorylation of interferon regulatory factor 3 as well as interferon-inducible genes such as interferon inducible protein-10. These results suggest that parthenolide can modulate TRIFdependent signaling pathways of TLRs, and may be the basis of effective therapeutics for chronic inflammatory diseases.