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Tris DBA Ameliorates Accelerated and Severe Lupus Nephritis in Mice by Activating Regulatory T Cells and Autophagy and Inhibiting the NLRP3 Inflammasome.
J Immunol. 2020 Mar 15; 204(6):1448-1461.JI

Abstract

Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, has been shown to inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukemia, and multiple myeloma. In the current study, we examined the therapeutic effects of Tris DBA on glomerular cell proliferation, renal inflammation, and immune cells. Treatment of accelerated and severe lupus nephritis (ASLN) mice with Tris DBA resulted in improved renal function, albuminuria, and pathology, including measurements of glomerular cell proliferation, cellular crescents, neutrophils, fibrinoid necrosis, and tubulointerstitial inflammation in the kidneys as well as scoring for glomerulonephritis activity. The treated ASLN mice also showed significantly decreased glomerular IgG, IgM, and C3 deposits. Furthermore, the compound was able to 1) inhibit bone marrow-derived dendritic cell-mediated T cell functions and reduce serum anti-dsDNA autoantibody levels; 2) differentially regulate autophagy and both the priming and activation signals of the NLRP3 inflammasome; and 3) suppress the phosphorylation of JNK, ERK, and p38 MAPK signaling pathways. Tris DBA improved ASLN in mice through immunoregulation by blunting the MAPK (ERK, JNK)-mediated priming signal of the NLRP3 inflammasome and by regulating the autophagy/NLRP3 inflammasome axis. These results suggest that the pure compound may be a drug candidate for treating the accelerated and deteriorated type of lupus nephritis.

Authors+Show Affiliations

Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 114.Department of Biotechnology and Animal Science, National Ilan University, Yilan, Taiwan 260.Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan 106; shukmanka@gmail.com annchen31717@gmail.com.Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 114.Department of Dermatology, Emory School of Medicine, Atlanta, GA 30322. Winship Cancer Institute, Emory School of Medicine, Atlanta, GA 30322. Atlanta Veterans Administration Medical Center, Decatur, GA 30033.Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 114; shukmanka@gmail.com annchen31717@gmail.com.Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 114.Division of Rheumatology/Immunology and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 114.Institute of Physics, Academia Sinica, Taipei, Taiwan 114.Graduate Institute of Aerospace and Undersea Medicine, Academy of Medicine, National Defense Medical Center, Taipei, Taiwan 114; and.Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 114; shukmanka@gmail.com annchen31717@gmail.com. Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 114.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32060137

Citation

Wu, Chung-Yao, et al. "Tris DBA Ameliorates Accelerated and Severe Lupus Nephritis in Mice By Activating Regulatory T Cells and Autophagy and Inhibiting the NLRP3 Inflammasome." Journal of Immunology (Baltimore, Md. : 1950), vol. 204, no. 6, 2020, pp. 1448-1461.
Wu CY, Hua KF, Chu CL, et al. Tris DBA Ameliorates Accelerated and Severe Lupus Nephritis in Mice by Activating Regulatory T Cells and Autophagy and Inhibiting the NLRP3 Inflammasome. J Immunol. 2020;204(6):1448-1461.
Wu, C. Y., Hua, K. F., Chu, C. L., Yang, S. R., Arbiser, J. L., Yang, S. S., Lin, Y. C., Liu, F. C., Yang, S. M., Ka, S. M., & Chen, A. (2020). Tris DBA Ameliorates Accelerated and Severe Lupus Nephritis in Mice by Activating Regulatory T Cells and Autophagy and Inhibiting the NLRP3 Inflammasome. Journal of Immunology (Baltimore, Md. : 1950), 204(6), 1448-1461. https://doi.org/10.4049/jimmunol.1801610
Wu CY, et al. Tris DBA Ameliorates Accelerated and Severe Lupus Nephritis in Mice By Activating Regulatory T Cells and Autophagy and Inhibiting the NLRP3 Inflammasome. J Immunol. 2020 Mar 15;204(6):1448-1461. PubMed PMID: 32060137.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tris DBA Ameliorates Accelerated and Severe Lupus Nephritis in Mice by Activating Regulatory T Cells and Autophagy and Inhibiting the NLRP3 Inflammasome. AU - Wu,Chung-Yao, AU - Hua,Kuo-Feng, AU - Chu,Ching-Liang, AU - Yang,Shin-Ruen, AU - Arbiser,Jack L, AU - Yang,Sung-Sen, AU - Lin,Yu-Chuan, AU - Liu,Feng-Cheng, AU - Yang,Shun-Min, AU - Ka,Shuk-Man, AU - Chen,Ann, Y1 - 2020/02/14/ PY - 2018/12/10/received PY - 2020/01/10/accepted PY - 2020/2/16/pubmed PY - 2020/2/16/medline PY - 2020/2/16/entrez SP - 1448 EP - 1461 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 204 IS - 6 N2 - Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, has been shown to inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukemia, and multiple myeloma. In the current study, we examined the therapeutic effects of Tris DBA on glomerular cell proliferation, renal inflammation, and immune cells. Treatment of accelerated and severe lupus nephritis (ASLN) mice with Tris DBA resulted in improved renal function, albuminuria, and pathology, including measurements of glomerular cell proliferation, cellular crescents, neutrophils, fibrinoid necrosis, and tubulointerstitial inflammation in the kidneys as well as scoring for glomerulonephritis activity. The treated ASLN mice also showed significantly decreased glomerular IgG, IgM, and C3 deposits. Furthermore, the compound was able to 1) inhibit bone marrow-derived dendritic cell-mediated T cell functions and reduce serum anti-dsDNA autoantibody levels; 2) differentially regulate autophagy and both the priming and activation signals of the NLRP3 inflammasome; and 3) suppress the phosphorylation of JNK, ERK, and p38 MAPK signaling pathways. Tris DBA improved ASLN in mice through immunoregulation by blunting the MAPK (ERK, JNK)-mediated priming signal of the NLRP3 inflammasome and by regulating the autophagy/NLRP3 inflammasome axis. These results suggest that the pure compound may be a drug candidate for treating the accelerated and deteriorated type of lupus nephritis. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/32060137/Tris_DBA_Ameliorates_Accelerated_and_Severe_Lupus_Nephritis_in_Mice_by_Activating_Regulatory_T_Cells_and_Autophagy_and_Inhibiting_the_NLRP3_Inflammasome L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=32060137 DB - PRIME DP - Unbound Medicine ER -
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