Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-κB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis.

AIMS/HYPOTHESIS: Chronic inflammatory processes have been increasingly shown to be involved in the pathogenesis of diabetes and diabetic nephropathy. Recently, we demonstrated that a lectin-like domain of thrombomodulin (THBD), which is known as THBD domain 1 (THBDD1) and which acts independently of protein C activation, neutralised an inflammatory response in a mouse model of sepsis. Here, therapeutic effects of gene therapy with adeno-associated virus (AAV)-carried THBDD1 (AAV-THBDD1) were tested in a mouse model of type 2 diabetic nephropathy. METHODS: To assess the therapeutic potential of THBDD1 and the mechanisms involved, we delivered AAV-THBDD1 (10(11) genome copies) into db/db mice and tested the effects of recombinant THBDD1 on conditionally immortalised podocytes. RESULTS: A single dose of AAV-THBDD1 improved albuminuria, renal interstitial inflammation and glomerular sclerosis, as well as renal function in db/db mice. These effects were closely associated with: (1) inhibited activation of the nuclear factor κB (NF-κB) pathway and the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome; (2) promotion of nuclear factor (erythroid-derived 2)-like 2 (NRF2) nuclear translocation; and (3) suppression of mitochondria-derived apoptosis in the kidney of treated mice. CONCLUSIONS/INTERPRETATION: AAV-THBDD1 gene therapy resulted in improvements in a model of diabetic nephropathy by suppressing the NF-κB-NLRP3 inflammasome-mediated inflammatory process, enhancing the NRF2 antioxidant pathway and inhibiting apoptosis in the kidney.

Curcumin-induced heme oxygenase-1 expression plays a negative role for its anti-cancer effect in bladder cancers.

Some phytochemicals with the characteristics of cytotoxicity and anti-metastasis has generated intense interest among the invasive cancer study. Curcumin, one of these anti-cancer phytochemicals, has been reported to induce the cytoprotective enzyme heme oxygenase-1 expression. Since heme oxygenase-1 has been suggested to enhance cancer cell invasion, we investigated the anti-invasive effect of curcumin when heme oxygenase-1 was knocked down in vitro, and the heme oxygenase-1 expression after curcumin treatment in vivo. Curcumin inhibited cell viability and the MMP-2/9 activities of human bladder cancer cells. At 10 µM, curcumin inhibited cell viability and cell invasive activity by 15% and 40%, respectively. Ten micrometer curcumin increased the intracellular reactive oxygen species concentration and heme oxygenase-1 protein and mRNA expression in bladder cancer cells. The anti-invasive activity of curcumin was elevated when heme oxygenase-1 was knocked down by siRNA or inhibited by pharmacological inhibitor. In vivo, curcumin induced heme oxygenase-1 protein expression in the lung tissue of murine lung metastasis tumor model and in the bladder tissue of murine orthotopic bladder tumor model. Taken together, our data suggest that curcumin-induced heme oxygenase-1 attenuates the anti-invasive effect of curcumin in cancer therapy, and co-treatment by heme oxygenase-1 inhibitor enhances the anti-invasive activity of curcumin.