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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

T-96 improves 24 h proteinuria and anti-dsDNA antibody in serum of MRL/lpr mice.(A) 24 hour urinary protein was detected by Coomassie Brilliant Blue test at weeks 0, 4 and 8. (B) Anti-dsDNA antibody levels in serum were measured by ELISA at weeks 0, 4 and 8. Data were expressed as mean ± SD. * indicates P < 0.05, ** indicates P < 0.01, *** indicates P < 0.001.
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pone.0133724.g002: T-96 improves 24 h proteinuria and anti-dsDNA antibody in serum of MRL/lpr mice.(A) 24 hour urinary protein was detected by Coomassie Brilliant Blue test at weeks 0, 4 and 8. (B) Anti-dsDNA antibody levels in serum were measured by ELISA at weeks 0, 4 and 8. Data were expressed as mean ± SD. * indicates P < 0.05, ** indicates P < 0.01, *** indicates P < 0.001.

Mentions: To investigate whether T-96 had an effect on the development of renal disease over time, proteinuria was determined every 4 weeks during treatment with T-96 from week 0 to week 8. Group F, the normal saline-treated MRL/lpr mice, showed a progressive rise of 24 h proteinuria over time compared with group N, C57BL/6 normal control (Fig 2A). However, at week 4, the amount of 24 h proteinuria was significantly decreased in mice receiving 1.2 and 0.6 mg/10g T-96 relative to the normal saline-treated MRL/lpr mice (Fig 2A; both p < 0.01). At week 8, mice treated with 1.2 to 0.3 mg/10g T-96 had markedly less 24 h proteinuria than the normal saline-treated MRL/lpr mice (Fig 2A; all p < 0.001). Additionally, the amount of 24 h proteinuria in mice treated with 1.2 mg/10g T-96 fell from 0.96 ± 0.31 g/24h at week 0 to 0.34 ± 0.11 g/24h at week 8 (Fig 2A; p < 0.01); at week 0, the amount of 24 h proteinuria was 0.92 ± 0.14 g/24h in mice with 0.6 mg/10g T-96, the number declined dramatically to 0.50 ± 0.13 g/24h by week 4 and continued to declined to 0.35 ± 0.16 g/24h by week 8 (Fig 2A; p < 0.001). Mice treated with kang lang chuang san had lower proteinuria than the normal saline-treated MRL/lpr mice at week 8; and the amount descended significantly from week 0 to week 8 (Fig 2A). Furthermore, there was a significant difference in the 24 h proteinuria between T-96 and prednisone treatment at week 4, as well as week 8 (Fig 2A). Taken together, T-96 demonstrated a significant proteinuria reduction both in a time and concentration-dependent manner.


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)

T-96 improves 24 h proteinuria and anti-dsDNA antibody in serum of MRL/lpr mice.(A) 24 hour urinary protein was detected by Coomassie Brilliant Blue test at weeks 0, 4 and 8. (B) Anti-dsDNA antibody levels in serum were measured by ELISA at weeks 0, 4 and 8. Data were expressed as mean ± SD. * indicates P < 0.05, ** indicates P < 0.01, *** indicates P < 0.001.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133724.g002: T-96 improves 24 h proteinuria and anti-dsDNA antibody in serum of MRL/lpr mice.(A) 24 hour urinary protein was detected by Coomassie Brilliant Blue test at weeks 0, 4 and 8. (B) Anti-dsDNA antibody levels in serum were measured by ELISA at weeks 0, 4 and 8. Data were expressed as mean ± SD. * indicates P < 0.05, ** indicates P < 0.01, *** indicates P < 0.001.
Mentions: To investigate whether T-96 had an effect on the development of renal disease over time, proteinuria was determined every 4 weeks during treatment with T-96 from week 0 to week 8. Group F, the normal saline-treated MRL/lpr mice, showed a progressive rise of 24 h proteinuria over time compared with group N, C57BL/6 normal control (Fig 2A). However, at week 4, the amount of 24 h proteinuria was significantly decreased in mice receiving 1.2 and 0.6 mg/10g T-96 relative to the normal saline-treated MRL/lpr mice (Fig 2A; both p < 0.01). At week 8, mice treated with 1.2 to 0.3 mg/10g T-96 had markedly less 24 h proteinuria than the normal saline-treated MRL/lpr mice (Fig 2A; all p < 0.001). Additionally, the amount of 24 h proteinuria in mice treated with 1.2 mg/10g T-96 fell from 0.96 ± 0.31 g/24h at week 0 to 0.34 ± 0.11 g/24h at week 8 (Fig 2A; p < 0.01); at week 0, the amount of 24 h proteinuria was 0.92 ± 0.14 g/24h in mice with 0.6 mg/10g T-96, the number declined dramatically to 0.50 ± 0.13 g/24h by week 4 and continued to declined to 0.35 ± 0.16 g/24h by week 8 (Fig 2A; p < 0.001). Mice treated with kang lang chuang san had lower proteinuria than the normal saline-treated MRL/lpr mice at week 8; and the amount descended significantly from week 0 to week 8 (Fig 2A). Furthermore, there was a significant difference in the 24 h proteinuria between T-96 and prednisone treatment at week 4, as well as week 8 (Fig 2A). Taken together, T-96 demonstrated a significant proteinuria reduction both in a time and concentration-dependent manner.

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