Collectively, we suggest that HO-1 induced by TMP might, at least in part, protect against gentamicin-induced nephrotoxicity through antiapoptotic and anti-inflammatory mechanisms, and that it may have therapeutic potential for patients with renal disease. This is also the first demonstration that HO-1 increases Hax-1 mitochondrial localization.

Protective effects of adiponectin (APN; an adipocytokine) were shown against various oxidative challenges; however, its therapeutic implications and the mechanisms underlying hepatic iron overload remain unclear. Herein, we show that the deleterious effects of iron dextran on liver function and iron deposition were significantly reversed by adiponectin gene therapy, which was accompanied by AMP-activated protein kinase (AMPK) phosphorylation and heme oxygenase (HO)-1 induction. Furthermore, AMPK-mediated peroxisome proliferator-activated receptor-␣ (PPAR␣) activation by APN was ascribable to HO-1 induction. Additionally, we revealed direct transcriptional regulation of HO-1 by the binding of PPAR␣ to a PPAR-responsive element (PPRE) by various experimental assessments. Interestingly, overexpression of HO-1 in hepatocytes mimicked the protective effect of APN in attenuating iron-mediated injury, whereas it was abolished by SnPP and small interfering HO-1. Furthermore, bilirubin, the end-product of the HO-1 reaction, but not CO, protected hepatocytes from iron dextran-mediated caspase activation. Herein, we demonstrate a novel functional PPRE in the promoter regions of HO-1, and APN-mediated HO-1 induction elicited an antiapoptotic effect and a decrease in iron deposition in hepatocytes subjected to iron challenge.

Endotoxin lipopolysaccharide (LPS) plays an important role in the acceleration of hepatic inflammation. Natural medicinal plants that can prevent inflammation by targeting LPS have potential therapeutic clinical application. The aim of the study is to examine the anti-inflammatory effects of lotus seedpod extract (LSE), used as a traditional Chinese herbal medicine with hemostasis function and for eliminating bruise, on the LPS-induced hepatic inflammation and its underlying molecular mechanisms in vitro and in vivo. In vitro, LSE and its purified compound (-)-epigallocatechin (EGC) dose-dependently inhibited the expressions of pro-inflammatory cytokines and mediators, including tumor necrosis factor (TNF)-[Formula: see text], interleukin (IL)-6, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), without affecting cell viability in LPS-stimulated human hepatoma cell line HepG2. Molecular studies showed the anti-LPS effect of HLP or EGC might be mediated via downregulation of Toll-like receptor 4. (TLR4)-mediated both NF-[Formula: see text]B and p38 signaling, as demonstrated by the usage of pyrrolidine dithiocarbamate (PDTC), a specific NF-[Formula: see text]B inhibitor. In vivo, LPS-induced hepatic inflammation was significantly ameliorated in LSE-fed mice as gauged by dose-dependent inhibition of serum levels of biochemical markers of liver damage, the changes of hepatic lobular architecture and the secretion of pro-inflammatory mediators, as well as induction of anti-oxidant enzymes. As a result, our data presented the first evidence of EGC-enriched LSE as an anti-inflammatory agent in LPS-stimulated HepG2 cells and mice, and these findings may open interesting perspectives to the strategy in treatment for hepatic inflammation.

BackgroundPterostilbene (PTER) is a dimethylated analog of the phenolic phytoalexin, resveratrol, with higher anticancer activity in various tumors. Herein, the molecular mechanisms by which PTER exerts its anticancer effects against acute myeloid leukemia (AML) cells were investigated.Methodology and Principal FindingsResults showed that PTER suppressed cell proliferation in various AML cell lines. PTER-induced G0/G1-phase arrest occurred when expressions of cyclin D3 and cyclin-dependent kinase (CDK)2/6 were inhibited. PTER-induced cell apoptosis occurred through activation of caspases-8-9/-3, and a mitochondrial membrane permeabilization (MMP)-dependent pathway. Moreover, treatment of HL-60 cells with PTER induced sustained activation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK)1/2, and inhibition of both MAPKs by their specific inhibitors significantly abolished the PTER-induced activation of caspases-8/-9/-3. Of note, PTER-induced cell growth inhibition was only partially reversed by the caspase-3-specific inhibitor, Z-DEVE-FMK, suggesting that this compound may also act through a caspase-independent pathway. Interestingly, we also found that PTER promoted disruption of lysosomal membrane permeabilization (LMP) and release of activated cathepsin B.ConclusionTaken together, our results suggest that PTER induced HL-60 cell death via MAPKs-mediated mitochondria apoptosis pathway and loss of LMP might be another cause for cell apoptosis induced by PTER.