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The present study was designed to identify and understand the potential effectiveness of therapeutic target in intervertebral disc degeneration (IVDD) and its regulation mechanism. The role and mechanism of interleukin-18 (IL-18) in the disease were investigated. The IVDD degenerative nucleus pulposus (NP) tissues from the human and mouse models were used. A total of three groups of Male BALB/c mice were randomly made i.e control, IVDD, and IVDD+Ad-shIL-18 groups. After Ad-shIL-18 transfection, the expression of ECM synthesis related protein Aggrecan (ACAN) and Collagen II, apoptotic effector Caspases (Caspase-3, 8, 9, 12 and Cleaved-Caspase 3, 8, 9, 12), pro-apoptotic gene Bax and anti-apoptotic factors Bcl-2 in NP cells of the human were evaluated. The results of our study revealed that the mRNA and protein expression levels of IL-18 were notably increased in the NP tissues of IVDD patients and mice models. In the IVDD mice model, Ad-sh-IL-18 treatment reversed the IVDD progression. The levels of Aggrecan and Collagen II, contributing to ECM degradation in NP cells, were also significantly increased. Additionally, Ad-sh-IL-18 could inhibit the NP cell's apoptosis via regulating the caspase-3/9 pathway. The IL-18 knockdown via the caspase-3/9 pathway, might reduce the NP cell's death as well as the imbalance between catabolism and anabolism of ECM in IVDD. [ABSTRACT FROM AUTHOR]

In this study, we investigated the impact of endogenous hydrogen sulfide (H2S) on toll-like receptors (TLRs)-mediated inflammatory response and apoptosis in renal ischemia-reperfusion injury (IRI). Twenty-four male Wistar rats were randomly divided into four groups: sham, IR, IR + propargylglycine (PAG) and IR + hydroxylamine (HA). After right nephrectomy, rats were given saline for the sham and IR group, PAG for the IR + PAG group and HA for the IR + HA group, through the left renal artery for 20 min. Five minutes after drug administration, all rats except sham underwent 45 min of left renal ischemia followed by 24 h of reperfusion. Kidneys were harvested for histological and biochemical evaluation. Levels of TLRs, downstream signaling molecules and pro-inflammatory cytokines were determined by Western blot or immunohistochemistry. Hematoxylin and eosin (H&E) stained renal sections were used for histological grading of renal injury. Apoptotic cells were detected by TUNEL assay. Compared to the sham group, rats in the IR group showed higher renal levels of TLR-2, TLR-4, nuclear NF-κB p65, phosphorylated ASK1, phosphorylated TRAF2, IL-1β, IL-6, IL-18 and TNF-α ( p < 0.05), and exhibited acute kidney injury ( p < 0.05) and apoptosis ( p < 0.05). Compared to the IR group, rats receiving PAG or HA showed significantly higher levels of TLR-2, TLR-4, nuclear NF-κB p65, phosphorylated ASK1, phosphorylated TRAF2, IL-1β, IL-6, IL-18 and TNF-α ( p < 0.01), more severe acute kidney injury ( p < 0.05) and increased apoptosis ( p < 0.01). Thus, inflammatory response and apoptosis mediated by TLRs are involved in renal IRI. Inhibition of endogenous H2S significantly activated inflammatory response and apoptosis, and thus promoted renal IRI. [ABSTRACT FROM AUTHOR]

The effects of coptisine against advanced stage of human pancreatic carcinoma PANC-1 cells was investigated in vitro. Coptisine (25–150 μM) treatment for 48 h caused dose-dependent cell growth inhibition by using CCK-8 assay. Additionally, coptisine was found to inhibit PANC-1 cells metastasis by the wound healing assay. Flow cytometry data indicated that coptisine (25–100 μM) exhibited dose-dependent G1 phase arrest and moderate reduction of S phase. Coptisine was also found to inhibit ERK phosphorylation and total ERK levels. Our research suggested that coptisine would be a potential therapeutic drug for the treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Curcumin, the biologically active compound from the rhizome of Curcuma longa, could inhibit cell growth and induce apoptosis in gastric carcinoma. However, the underlying mechanism of curcumin on gastric carcinoma cells still needs further investigation. In this study, morphological observation indicated that curcumin inhibited the proliferation of AGS cells in a dose-dependent manner. According to the flow cytometric analysis, curcumin treatment resulted in G2/M arrest in AGS cells, accompanied with an increased expression of cyclin B1 and a decreased expression of cyclin D1. In addition, DNA ladders were observed by gel electrophoresis. Meanwhile, the activities of caspase-3, -8, and -9 were also enhanced in curcumin-treated AGS cells. Nevertheless, the increased activities could be inhibited by benzyloxycarbonyl-Val-Ala-Asp (OME)-fluoromethylketone (z-VAD-fmk), which suggested that the apoptosis was caspase-dependent. Furthermore, downregulation of rat sarcoma (Ras) and upregulation of extracellular-signal-regulated kinase (ERK) were also observed in AGS cells treated with curcumin by Western blot. U0126, an ERK inhibitor, blocked curcumin-induced apoptosis. The results suggested that curcumin inhibited the growth of the AGS cells and induced apoptosis through the activation of Ras/ERK signaling pathway and downstream caspase cascade, and curcumin might be a potential target for the treatment of gastric carcinoma. [ABSTRACT FROM AUTHOR]

CCAAT/enhancer binding protein homologous protein (CHOP) expression increases when Na+-H+ exchanger 1 (NHE1) is inhibited. Endoplasmic reticulum (ER) stress has been shown to trigger tumor cell death through CHOP. We therefore hypothesized that NHE1 activity correlates with ER stress and confers pharmaceutical potential to NHE1 inhibitor as an anti-tumor agent. The present study showed that treatment with the NHE1 inhibitor cariporide led to ER stress-induced up-regulation of the death receptor 5 (DR5) which is mediated by CHOP at the transcriptional level. We also determined that ER stress-induced Janus kinase (JNK) activation was responsible for the modulation of CHOP. Combining cariporide with tumor necrosis factor related apoptosis-inducing ligand (TRAIL) led to a significantly enhanced level of apoptosis that was abrogated by siRNA silencing of CHOP. This study provides a potential mechanistic rationale for the use of NHE1 inhibitor in combination with DR5 agonists to induce apoptosis in leukemia. [ABSTRACT FROM AUTHOR]