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Demethylzeylasteral (T-96) Treatment Ameliorates Mice Lupus Nephritis Accompanied by Inhibiting Activation of NF-κB Pathway.

Hu Q, Yang C, Wang Q, Zeng H, Qin W - PLoS ONE (2015)

Bottom Line: Over the past 30 years, research has demonstrated that Tripterygium wilfordii Hook F (TWHF) possesses potent anti-inflammatory and immunosuppressive activities, and that demethylzeylasteral (T-96), an extract of TWHF, may be one of the responsible compounds.Moreover, T-96 significantly suppressed phosphorylations of cytoplasmic IKK and nuclear p65.Because of these potent properties, T-96 should be considered as a promising therapeutic drug for LN.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, P.R. China.

ABSTRACT

Background: Inflammation plays a vital role in the pathogenesis in lupus nephritis (LN), which is largely attributable to the activation of nuclear factor kappa B (NF-κB) signal pathway. NF-κB up-regulates pro-inflammatory mediators, such as TNF-α, cyclo-oxygenase-2 (COX-2) and ICAM-1, and promotes macrophage infiltration into renal tissue, further inducing the progression of LN. Over the past 30 years, research has demonstrated that Tripterygium wilfordii Hook F (TWHF) possesses potent anti-inflammatory and immunosuppressive activities, and that demethylzeylasteral (T-96), an extract of TWHF, may be one of the responsible compounds. Here, we investigate the pharmacodynamic role and therapeutic mechanism by which T-96 suppresses inflammation and reduces renal pathology in the lupus-prone MRL/lpr mice.

Methods: Forty-eight MRL/lpr mice were equally randomly divided into 6 groups (1.2, 0.6 or 0.3 mg/10 g T-96, 0.022 pills/10 g kang lang chuang san (one of Traditional Chinese herb as positive control), 0.125 mg/10 g prednisone and 0.1 ml/10 g normal saline as the LN disease control group). Also, eight WT C57BL/6 mice were used as normal control. After treatment by gavage with 0.10 ml/10 g/day volumes for 8 weeks, all mice were sacrificed and renal tissues were collected. The amount of 24 h proteinuria and the levels of anti-dsDNA antibody in serum were assessed respectively at weeks 0, 4 and 8. Inflammation, cytokines and NF-κB levels were assessed by histological examinations, immunohistochemical analyses and Western blot analyses.

Results: In comparison with untreated MRL/lpr mice, mice treated with 1.2 and 0.6 mg/10 g of T-96 showed a significant improvement in 24 h proteinuria and the levels of anti-dsDNA antibody in serum. In addition, T-96 reduced the secretion of pro-inflammatory mediators such as TNF-α, COX-2 and ICAM-1, and the infiltration of macrophages in renal tissue. Moreover, T-96 significantly suppressed phosphorylations of cytoplasmic IKK and nuclear p65.

Conclusion: This study suggests that T-96 exhibits reno-protective effects in LN accompanied by inhibiting the activation of NF-κB, reducing the downstream pro-inflammatory mediators and thus restricting macrophage infiltration. Because of these potent properties, T-96 should be considered as a promising therapeutic drug for LN.

No MeSH data available.


Related in: MedlinePlus

The chemical structure of demethylzeylasteral.
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pone.0133724.g001: The chemical structure of demethylzeylasteral.

Mentions: Demethylzeylasteral (T-96) (yellow amorphous powder, Molecular formula: C29H36O6, MW: 480) was isolated and provided by Professor C.X. Yang (Department of Pharmaceutical Chemistry, Zhongshan Hospital, Fudan University, Shanghai, China). T-96 was isolated from the crushed root bark of TWHF by means of ethyl acetate extraction and silica gel column chromatography utilizing a chloroform-methanol gradient elution technique. Subsequent concentration and recrystallization yielded yellow T-96 crystals. The chemical structure of demethylzeylasteral is shown in Fig 1. Kang lang chuang san (one of Traditional Chinese herb) was purchased from Huaying Pharmaceutical Co., Ltd (Hebei, China, No. Z1990006). Prednisone was purchased from SINE Pharmaceutical Co., Ltd (Shanghai, China, No. 101101), 0.9% normal saline was purchased from Shanghai Changzheng Fumin Jinshan Pharmaceutical Co., Ltd (Shanghai, China, No. 11080907).


Demethylzeylasteral (T-96) Treatment Ameliorates Mice Lupus Nephritis Accompanied by Inhibiting Activation of NF-κB Pathway.

Hu Q, Yang C, Wang Q, Zeng H, Qin W - PLoS ONE (2015)

The chemical structure of demethylzeylasteral.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4514757&req=5

pone.0133724.g001: The chemical structure of demethylzeylasteral.
Mentions: Demethylzeylasteral (T-96) (yellow amorphous powder, Molecular formula: C29H36O6, MW: 480) was isolated and provided by Professor C.X. Yang (Department of Pharmaceutical Chemistry, Zhongshan Hospital, Fudan University, Shanghai, China). T-96 was isolated from the crushed root bark of TWHF by means of ethyl acetate extraction and silica gel column chromatography utilizing a chloroform-methanol gradient elution technique. Subsequent concentration and recrystallization yielded yellow T-96 crystals. The chemical structure of demethylzeylasteral is shown in Fig 1. Kang lang chuang san (one of Traditional Chinese herb) was purchased from Huaying Pharmaceutical Co., Ltd (Hebei, China, No. Z1990006). Prednisone was purchased from SINE Pharmaceutical Co., Ltd (Shanghai, China, No. 101101), 0.9% normal saline was purchased from Shanghai Changzheng Fumin Jinshan Pharmaceutical Co., Ltd (Shanghai, China, No. 11080907).

Bottom Line: Over the past 30 years, research has demonstrated that Tripterygium wilfordii Hook F (TWHF) possesses potent anti-inflammatory and immunosuppressive activities, and that demethylzeylasteral (T-96), an extract of TWHF, may be one of the responsible compounds.Moreover, T-96 significantly suppressed phosphorylations of cytoplasmic IKK and nuclear p65.Because of these potent properties, T-96 should be considered as a promising therapeutic drug for LN.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, P.R. China.

ABSTRACT

Background: Inflammation plays a vital role in the pathogenesis in lupus nephritis (LN), which is largely attributable to the activation of nuclear factor kappa B (NF-κB) signal pathway. NF-κB up-regulates pro-inflammatory mediators, such as TNF-α, cyclo-oxygenase-2 (COX-2) and ICAM-1, and promotes macrophage infiltration into renal tissue, further inducing the progression of LN. Over the past 30 years, research has demonstrated that Tripterygium wilfordii Hook F (TWHF) possesses potent anti-inflammatory and immunosuppressive activities, and that demethylzeylasteral (T-96), an extract of TWHF, may be one of the responsible compounds. Here, we investigate the pharmacodynamic role and therapeutic mechanism by which T-96 suppresses inflammation and reduces renal pathology in the lupus-prone MRL/lpr mice.

Methods: Forty-eight MRL/lpr mice were equally randomly divided into 6 groups (1.2, 0.6 or 0.3 mg/10 g T-96, 0.022 pills/10 g kang lang chuang san (one of Traditional Chinese herb as positive control), 0.125 mg/10 g prednisone and 0.1 ml/10 g normal saline as the LN disease control group). Also, eight WT C57BL/6 mice were used as normal control. After treatment by gavage with 0.10 ml/10 g/day volumes for 8 weeks, all mice were sacrificed and renal tissues were collected. The amount of 24 h proteinuria and the levels of anti-dsDNA antibody in serum were assessed respectively at weeks 0, 4 and 8. Inflammation, cytokines and NF-κB levels were assessed by histological examinations, immunohistochemical analyses and Western blot analyses.

Results: In comparison with untreated MRL/lpr mice, mice treated with 1.2 and 0.6 mg/10 g of T-96 showed a significant improvement in 24 h proteinuria and the levels of anti-dsDNA antibody in serum. In addition, T-96 reduced the secretion of pro-inflammatory mediators such as TNF-α, COX-2 and ICAM-1, and the infiltration of macrophages in renal tissue. Moreover, T-96 significantly suppressed phosphorylations of cytoplasmic IKK and nuclear p65.

Conclusion: This study suggests that T-96 exhibits reno-protective effects in LN accompanied by inhibiting the activation of NF-κB, reducing the downstream pro-inflammatory mediators and thus restricting macrophage infiltration. Because of these potent properties, T-96 should be considered as a promising therapeutic drug for LN.

No MeSH data available.


Related in: MedlinePlus