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Tris DBA ameliorates IgA nephropathy by blunting the activating signal of NLRP3 inflammasome through SIRT1- and SIRT3-mediated autophagy induction.

ABSTRACT: Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, can inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukaemia and multiple myeloma. Given that this compound is particularly active against B-cell malignancies, we have been suggested that it can alleviate immune complexes (ICs)-mediated conditions, especially IgA nephropathy (IgAN). The therapeutic effects of Tris DBA on glomerular cell proliferation and renal inflammation and mechanism of action were examined in a mouse model of IgAN. Treatment of IgAN mice with Tris DBA resulted in markedly improved renal function, albuminuria and renal pathology, including glomerular cell proliferation, neutrophil infiltration, sclerosis and periglomerular inflammation in the renal interstitium, together with (Clin J Am Soc Nephrol. 2011, 6, 1301-1307) reduced mitochondrial ROS generation; (Am J Physiol-Renal Physiol. 2011. 301, F1218-F1230) differentially regulated autophagy and NLRP3 inflammasome; (Clin J Am Soc Nephrol. 2012, 7, 427-436) inhibited phosphorylation of JNK, ERK and p38 MAPK signalling pathways, and priming signal of the NLRP3 inflammasome; and (Free Radic Biol Med. 2013, 61, 285-297) blunted NLRP3 inflammasome activation through SIRT1- and SIRT3-mediated autophagy induction, in renal tissues or cultured macrophages. In conclusion, Tris DBA effectively ameliorated the mouse IgAN model and targeted signalling pathways downstream of ICs-mediated interaction, which is a novel immunomodulatory strategy. Further development of Tris DBA as a therapeutic candidate for IgAN is warranted.

SUBMITTER: Wu CY

PROVIDER: S-EPMC7753881 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Tris DBA ameliorates IgA nephropathy by blunting the activating signal of NLRP3 inflammasome through SIRT1- and SIRT3-mediated autophagy induction.

Wu Chung-Yao CY Hua Kuo-Feng KF Yang Shin-Ruen SR Tsai Yi-Shan YS Yang Shun-Min SM Hsieh Chih-Yu CY Wu Chia-Chao CC Chang Jia-Feng JF Arbiser Jack L JL Chang Chiz-Tzung CT Chen Ann A Ka Shuk-Man SM

Journal of cellular and molecular medicine 20201101 23

Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, can inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukaemia and multiple myeloma. Given that this compound is particularly active against B-cell malignancies, we have been suggested that it can alleviate immune complexes (ICs)-mediated conditions, especially IgA nephropathy (IgAN). The therapeutic effects of Tris DBA on glomerular cell proliferation and renal inflammation and mechani ...[more]

PMID: 33135320

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Project description:Diabetic nephropathy (DN) as the primary cause of end-stage kidney disease is a common complication of diabetes. Recent researches have shown the activation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome are associated with inflammation in the progression of DN, but the exact mechanism is unclear. Long noncoding RNAs (lncRNAs) have roles in the development of many diseases including DN. However, the relationship between lncRNAs and inflammation in DN remains largely unknown. Our previous study has revealed that 14 lncRNAs are abnormally expressed in DN by RNA sequencing and real-time quantitative PCR (qRT-PCR) in the renal tissues of db/db DN mice. In this study, these lncRNAs were verified their expressions by qRT-PCR in mesangial cells (MCs) cultured under high- and low-glucose conditions. Twelve lncRNAs displayed the same expressional tendencies in both renal tissues and MCs. In particular, long intergenic noncoding RNA (lincRNA)-Gm4419 was the only one associating with NF-κB among these 12 lncRNAs by bioinformatics methods. Moreover, Gm4419 knockdown could obviously inhibit the expressions of pro-inflammatory cytokines and renal fibrosis biomarkers, and reduce cell proliferation in MCs under high-glucose condition, whereas overexpression of Gm4419 could increase the inflammation, fibrosis and cell proliferation in MCs under low-glucose condition. Interestingly, our results showed that Gm4419 could activate the NF-κB pathway by directly interacting with p50, the subunit of NF-κB. In addition, we found that p50 could interact with NLRP3 inflammasome in MCs. In conclusion, our findings suggest lincRNA-Gm4419 may participate in the inflammation, fibrosis and proliferation in MCs under high-glucose condition through NF-κB/NLRP3 inflammasome signaling pathway, and may provide new insights into the regulation of Gm4419 during the progression of DN.

Project description:Background and purposeIL-1β produced by macrophages via the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, mediates the inflammatory crosstalk between macrophages and adipocytes. In our previous study, (16S,20S,24R)-12β-acetoxy-16,23-epoxy-24,25-dihydroxy-3β-(β-D-xylopyranosyloxy)-9,19-cyclolanost-22(23)-ene (AEDC), a cycloartane triterpenoid isolated from Actaea vaginata (Ranunculaceae), was found to possess anti-inflammatory effect on LPS-treated RAW264.7 macrophages. This study was designed to investigate whether AEDC modulates macrophage-adipocyte crosstalk to alleviate adipose tissue inflammation.Experimental approachThe anti-inflammatory effect of AEDC was evaluated on LPS plus ATP-induced THP-1 macrophages and C57BL/6J mice. The expression of autophagy-related and NLRP3 inflammasome complex proteins was analysed by western blots, immunofluorescence staining and co-immunoprecipitation. The pro-inflammatory cytokines levels were determined by ELISA kits. The adipose tissue inflammation was evaluated by histological analysis and immunohistochemical staining.Key resultsAEDC (5 and 10 μM) activated autophagy, which in turn suppressed the NLRP3 inflammasome activation and IL-1β secretion in THP-1 macrophages. AEDC increased the expression of SIRT3 deacetylase and enhanced its deacetylating activity to reverse mitochondrial dysfunction and activate AMP-activated protein kinase, which together induced autophagy. Moreover, AEDC (10 μM) attenuated macrophage conditioned medium-induced inflammatory responses in adipocytes and blocked THP-1 macrophages migration towards 3T3-L1 adipocytes. In inflammation mice, AEDC (5 and 20 mg·kg-1 ) treatment reduced the levels of pro-inflammatory cytokines in serum and epididymal adipose tissue and reduced macrophage infiltration to alleviate adipose tissue inflammation.Conclusion and implicationsAEDC attenuated the inflammatory crosstalk between macrophages and adipocytes through SIRT3-autophagy-mediated NLRP3 inflammasome inhibition, which might used for the treatment of adipose tissue inflammation-related metabolic disorders.

Dataset Information

Tris DBA ameliorates IgA nephropathy by blunting the activating signal of NLRP3 inflammasome through SIRT1- and SIRT3-mediated autophagy induction.

Publications

Tris DBA ameliorates IgA nephropathy by blunting the activating signal of NLRP3 inflammasome through SIRT1- and SIRT3-mediated autophagy induction.

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