A mechanism for the anti-fibrogenic effects of the pregnane X receptor (PXR) in the liver: inhibition of NF-kappaB?

The liver is susceptible to chronic damage through exposure to a variety of toxins (e.g. alcohol) and viruses (e.g. hepatitis C). Obesity, autoimmune diseases (e.g. autoimmune hepatitis) and a variety of genetic diseases (e.g. Wilson's disease) also lead to chronic liver damage. This damage results in scarring fibrogenesis, structural disruption and functional impairment of the organ. Recent work suggests that there is cross-talk between the PXR and NF-kappaB pathways. This cross-talk may explain the observation that PXR activators inhibit liver fibrosis in in vitro and in vivo animal models of the disease. This reveiw will focus on the two transcription factors and their potential interaction.

Cytokine imbalance in acute coronary syndrome.

The excessive mortality of coronary heart disease is attributed primarily to rupture and thrombotic transformation of the atherosclerotic plaque. Inflammation plays a critical role in plaque destabilization and vulnerability. Inflammation is not confined to the culprit segment but is convincingly widespread in the coronary and remote vascular beds. Systemic inflammatory, thrombotic and hemodynamic factors are relevant to the pathological and clinical outcome. In addition to their fundamental role in thrombosis, there is ample evidence that platelets contribute significantly to promoting plaque inflammation. A new paradigm of unbalanced cytokine-mediated inflammation is emerging, providing diagnostic and therapeutic opportunity for intervention. Amplifying intrinsic anti-inflammatory mechanisms constitutes attractive avenues for future investigation.

Treatment with ß-elemene combined with paclitaxel inhibits growth, migration, and invasion and induces apoptosis of ovarian cancer cells by activation of STAT-NF-κB pathway

In this study, we aimed to analyze the anti-cancer effects of β-elemene combined with paclitaxel for ovarian cancer. RT-qPCR, MTT assay, western blot, flow cytometry, and immunohistochemistry were used to analyze in vitro and in vivo anti-cancer effects of combined treatment of β-elemene and paclitaxel. The in vitro results showed that β-elemene+paclitaxel treatment markedly inhibited ovarian cancer cell growth, migration, and invasion compared to either paclitaxel or β-elemene treatment alone. Results demonstrated that β-elemene+paclitaxel induced apoptosis of SKOV3 cells, down-regulated anti-apoptotic Bcl-2 and Bcl-xl gene expression and up-regulated pro-apoptotic P53 and Apaf1 gene expression in SKOV3 cells. Administration of β-elemene+paclitaxel arrested SKOV3 cell cycle at S phase and down-regulated CDK1, cyclin-B1, and P27 gene expression and apoptotic-related resistant gene expression of MDR1, LRP, and TS in SKOV3 cells. In vivo experiments showed that treatment with β-elemene+paclitaxel significantly inhibited ovarian tumor growth and prolonged the overall survival of SKOV3-bearing mice. In addition, the treatment inhibited phosphorylated STAT3 and NF-κB expression in vitro and in vivo. Furthermore, it inhibited migration and invasion through down-regulation of the STAT-NF-κB signaling pathway in SKOV3 cells. In conclusion, the data suggested that β-elemene+paclitaxel can inhibit ovarian cancer growth via down-regulation of the STAT3-NF-κB signaling pathway, which may be a potential therapeutic strategy for ovarian cancer therapy.

Captopril alleviates hypertension-induced renal damage, inflammation, and NF-κB activation

Hypertensive renal damage generally occurs during the middle and late stages of hypertension, which is typically characterized by proteinuria and renal inflammation. Captopril, an angiotensin-converting enzyme (ACE) inhibitor, has been widely used for therapy of arterial hypertension and cardiovascular diseases. However, the protective effects of captopril on hypertension-induced organ damage remain elusive. The present study was designed to explore the renoprotective action of captopril in spontaneously hypertensive rats (SHR). The 6-week-old male SHR and age-matched Wistar-Kyoto rats were randomized into long-term captopril-treated (34 mg/kg) and vehicle-treated groups. The results showed that in SHR there was obvious renal injury characterized by the increased levels of urine albumin, total protein, serum creatinine, blood urea nitrogen, renal inflammation manifested by the increased mRNA and protein expression of inflammatory factors including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and inducible nitric oxide synthase, and enhanced nuclear factor-κB (NF-κB) activation. Captopril treatment could lower blood pressure, improve renal injury, and suppress renal inflammation and NF-κB activation in SHR rats. In conclusion, captopril ameliorates renal injury and inflammation in SHR possibly via inactivation of NF-κB signaling.

Short-term insulin intensive therapy decreases MCP-1 and NF-κB expression of peripheral blood monocyte and the serum MCP-1 concentration in newlydiagnosed type 2 diabetics

ABSTRACT Objective To observe the effect of short-term insulin intensive treatment on the monocyte chemoattractant protein-1 (MCP-1) as well as on the nuclear factor-kappa B (NF-κB) expression of peripheral blood monocyte. This is also in addition to observing the serum MCP-1 level in newlydiagnosed type 2 diabetic patients and probing its anti-inflammation effects. Subjects and methods Twenty newly-diagnosed type 2 diabetic patients were treated with an insulin intensive treatment for 2 weeks. MCP-1 and NF-κB expression on the monocyte surface were measured with flow cytometry, the serum MCP-1 level was measured by enzyme linked immunosorbent assay (ELISA) during pretreatment and post-treatment. Results After 2 weeks of the treatment, MCP-1 and NF-κB protein expression of peripheral blood monocyte and serum MCP-1 levels decreased significantly compared with those of pre-treatment, which were (0.50 ± 0.18)% vs (0.89 ± 0.26)% (12.22 ± 2.80)% vs (15.53 ± 2.49)% and (44.53 ± 3.97) pg/mL vs (49.53 ± 3.47) pg/mL, respectively (P < 0.01). The MCP-1 expression on monocyte surface had a significant positive relationship with serum MCP-1 levels (r = 0.47, P < 0.01). Conclusions Short-term insulin intensive therapy plays a role in alleviating the increased inflammation reaction in type 2 diabetics.

Medical ozone induces proliferation and migration inhibition through ROS accumulation and PI3K/AKT/NF-kB suppression in human liver cancer cells in vitro

Background Hepatocellular carcinoma is one of the most common malignancies and leading cancer-associated deaths worldwide. Ozone has been proposed as a promising therapeutic agent in the treatment of various disorders. Purpose The purpose of this paper is to assess the potential anticancer effects of the ozone on liver cancer cells. Method The liver cancer cell line of bel7402 and SMMC7721 was used in this study. Proliferation was evaluated using the CCK-8 and the colony formation assay. Wond healing assay and transwell assay without Matrigel were used to evaluate their migration ability. Flow cytometry was used for cell cycle analysis and reactive oxygen species (ROS) determination. Glutathione detection kit was used for measurement of glutathione level. Protein expression was estimated by western blot analysis. Results Ozone treatment inhibited liver cancer cell proliferation, colony formation. Ozone induced G2/M phase cell cycle arrest, which could be elucidated by the change of protein levels of p53, p21, Cyclin D1, cyclin B1, cdc2, and CDK4. We also found that ozone treatment inhibited migration ability by inhibiting EMT-relating protein. Ozone also induced ROS accumulation and decreased glutathione level decreased, which contributed to the inactivation of the PI3K/AKT/NF-κB pathway. Finally, we found that pre-treatment of liver cancer cells with N-acetylcysteine resisted ozone-induced effects. Conclusions Ozone restrains the proliferation and migration potential and EMT process of liver cancer cells via ROS accumulation and PI3K/AKT/NF-κB suppression (AU)

Mechanisms of synthetic serine protease inhibitor (FUT-175)-mediated cell death.

BACKGROUND: Constitutive activation of nuclear factor-kappaB (NF-kappaB) is a frequent molecular alteration in pancreatic cancer and a number of studies have suggested that constitutive NF-kappaB activity plays a key role in the aggressive behavior of this disease. In an attempt to identify an effective therapeutic agent for pancreatic cancer, the authors studied the role of FUT-175, a synthetic serine protease inhibitor, in the inhibition of NF-kappaB activation and the induction of apoptotic responses. METHODS: To examine the effect of FUT-175 on the inhibition of NF-kappaB and the induction of apoptosis in pancreatic cancer cell lines, Western and Northern blot analyses, electromobility shift (EMSA), luciferase reporter gene, DNA fragmentation, immunoprecipitation, in vitro kinase, small interfering RNA (siRNA), and chromatin immunoprecipitation (ChIP) assays were performed. RESULTS: In a time-dependent and dose-dependent manner, FUT-175 inhibited IkappaBalpha phosphorylation and NF-kappaB activation, thereby inhibiting the antiapoptotic activity of NF-kappaB. Simultaneously, FUT-175 up-regulated the expression of tumor necrosis factor receptor-1 (TNFR1), which in turn activated the proapoptotic caspase-8 and Bid pathways and induced apoptosis in pancreatic cancer cells. FUT-175-induced activation of Fas-associated death domain (FADD) and caspase-8 was suppressed by RNA interference-mediated inhibition of TNFR1 expression. Furthermore, expression of the transcription factor PEA3 was up-regulated by FUT-175 and was involved in FUT-175-mediated TNFR1 expression. CONCLUSIONS: These results suggested a possible mechanism by which FUT-175 may disrupt interconnected signaling pathways by both suppressing the NF-kappaB antiapoptotic activity and inducing TNFR-mediated apoptosis. Supported by this unique function as a NF-kappaB inhibitor and apoptosis inducer, this well-established synthetic serine protease inhibitor with as-of-yet poorly understood mechanisms of actions appears to be a potentially therapeutic agent for pancreatic cancer.

NF-kappaB in cancer--a friend turned foe.

The nuclear factor of kappaB (NF-kappaB) family of heterodimeric transcription factors plays an instrumental role in immune, inflammatory, and stress responses. NF-kappaB induces the expression of diverse target genes that promote cell cycle progression, regulate apoptosis, and facilitate cell adhesion, angiogenesis, and metastasis. Given the ability of NF-kappaB to influence these cardinal features of neoplastic transformation, it is no surprise that tumor cells of almost every tissue type acquire the ability to constitutively activate NF-kappaB via a host of diverse genetic alterations and viral proteins. The activation of NF-kappaB not only enables malignant transformation and tumor progression, but also provides a mechanism by which tumor cells escape immune surveillance and resist therapy. NF-kappaB may be inhibited by targeting either the apical signaling proteins responsible for its activation in specific types of cancer, the downstream kinases (IkappaB kinase and casein kinase 2) at which NF-kappaB-activating signaling pathways converge, the proteasome-mediated degradation of the inhibitor of kappaB (IkappaB) proteins, or the transcriptional activity of Rel proteins. Since NF-kappaB inhibitors can sensitize tumor cells to apoptosis signaling pathways activated by death receptors, interferons, and immune effector cells, they hold enormous promise for the development of effective combinatorial regimens against a wide spectrum of hematologic and epithelial malignancies.