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Exenatide could reduce blood glucose and alleviate cognitive dysfunction induced by diabetes mellitus (DM). In the present study, a diabetic model was established in Sprague-Dawley rats to further explore the mechanism of exenatide on diabetes-induced cognitive impairment. Notably, the model rats performed poorly in the Morris water maze test and had more apoptotic neurons compared with the control rats. By contrast, exenatide attenuated cognitive impairment and inhibited neuronal apoptosis in the DM rat model. To explore the neuroprotective mechanisms of exenatide, western blotting was performed to detect the expression levels of markers of endoplasmic reticulum stress, including cytochrome c (Cyt-c), Caspase-3, JNK and c-JUN, in hippocampal tissue. Reverse transcription-quantitative PCR was also performed to measure the mRNA expression levels of Cyt-c and Caspase-3. After 16 weeks of treatment, exenatide treatment downregulated Cyt-c, Caspase-3, phosphorylated (p)-JNK and p-c-JUN expression in the hippocampal tissue of diabetic rats. Moreover, Cyt-c, Caspase-3, JNK and JUN expression levels were detected following treatment with a specific inhibitor of JNK (SP600125). The results revealed that SP600125 had similar inhibitory effects on the JNK pathway and ERS-related protein expression (Cyt-t, Caspase-3, p-JNK and p-c-JUN). These results suggested that exenatide improved cognitive dysfunction in DM rats and that the underlying mechanism may be associated with inhibiting apoptosis by suppressing the activation of JNK/c-JUN.

Human papillomavirus (HPV)-16 infection may be related to non-smoking associated lung cancer. Our previous studies have found that HPV-16 oncoproteins promoted angiogenesis via enhancing hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) expression in non-small cell lung cancer (NSCLC) cells. In this study, we further investigated the roles of PI3K/Akt and c-Jun signaling pathways in it. Human NSCLC cell lines, A549 and NCI-H460, were stably transfected with pEGFP-16 E6 or E7 plasmids. Western blotting was performed to analyze the expression of HIF-1α, p-Akt, p-P70S6K, p-P85S6K, p-mTOR, p-JNK, and p-c-Jun proteins. VEGF and IL-8 protein secretion and mRNA levels were determined by ELISA and Real-time PCR, respectively. The in vitro angiogenesis was observed by human umbilical vein endothelial cells (HUVECs) tube formation assay. Co-immunoprecipitation was performed to analyze the interaction between c-Jun and HIF-1α. HPV-16 E6 and E7 oncoproteins promoted the activation of Akt, P70S6K, P85S6K, mTOR, JNK, and c-Jun. LY294002, a PI3K inhibitor, inhibited HPV-16 oncoprotein-induced activation of Akt, P70S6K, and P85S6K, expression of HIF-1α, VEGF, and IL-8, and in vitro angiogenesis. c-Jun knockdown by specific siRNA abolished HPV-16 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression and in vitro angiogenesis. Additionally, HPV-16 oncoproteins promoted HIF-1α protein stability via blocking proteasome degradation pathway, but c-Jun knockdown abrogated this effect. Furthermore, HPV-16 oncoproteins increased the quantity of c-Jun binding to HIF-1α. PI3K/Akt signaling pathway and c-Jun are involved in HPV-16 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression and in vitro angiogenesis. Moreover, HPV-16 oncoproteins promoted HIF-1α protein stability possibly through enhancing the interaction between c-Jun and HIF-1α, thus making a contribution to angiogenesis in NSCLC cells.

Curcumae radix is the dry root of Curcuma longa L. (turmeric) that can be used either as a spice or traditional medicine. The aim of this study was to investigate the survival benefits and the anti-metastatic activity of curcumae radix extract (CRE) in MCF7 cells and in MMTV-PyMT transgenic mice—a mouse model of breast cancer metastasis. In vitro wound scratch assay revealed that CRE treatment inhibited cell motility and cell migration in a dose-dependent manner. To investigate the effect of CRE in breast cancer metastasis, MMTV-PyMT transgenic female virgin mice were used and randomly divided into two groups. For survival curve analysis, CRE was administered in a dose of 50 mg/kg to 8–20-week-old mice. Interestingly, CRE treatment significantly increased the median and prolonged survival of MMTV-PyMT mice. Furthermore, CRE treatment decreased tumor burden and inhibited cell proliferation in primary breast tumor, and also suppressed mammary tumor-derived lung metastasis. The size of the lung metastases substantially decreased in the CRE-treated group compared with the ones in the control group. Curcumae radix extract showed anti-metastatic activity through regulating the expression of metastasis markers including C-C Chemokine Receptor Type 7, Matrix Metalloproteinase 9 and the proto-oncogenes c-fos and c-jun. We demonstrated that these metastatic regulators were decreased when CCR7 expression was suppressed in MCF7 cells transfected with CCR7 siRNA. The results of this study show that curcumae radix exerts antitumor and anti-metastatic activities, and we suggest that curcumae radix might be a potential supplement for the treatment and prevention of breast cancer metastasis.

Exposure to rare earth elements (REEs) is known to impair intelligence in children and cause neurobehavioral abnormalities in animals. However, the mechanisms underlying these phenomena are not clear. Lanthanum is often used to study the effects of REEs. The aim of this study was to investigate the influence of lanthanum chloride (LaCl 3 ) on spatial learning and memory and a possible underlying mechanism involving nuclear factor-kappa B (NF-κB) signalling pathway expression in the hippocampus. The rats were exposed to 0, 0.25, 0.50 or 1.00 % LaCl 3 in drinking water during pregnancy and lactation (i.e. while feeding their offspring). After weaning, young rats continued to receive 0, 0.25, 0.50 and 1.00 % LaCl 3 in the drinking water for 1 month. LaCl 3 exposure impaired the spatial learning and memory of young rats and significantly decreased the expression of phosphorylated IκB kinase complex, phosphorylated IκBα, NF-κB, c-fos, c-jun and brain-derived neurotrophic factor in the hippocampus. These results indicate that LaCl 3 exposure impairs spatial learning and memory in rats by inhibiting NF-κB signalling pathway.

Proteasome inhibitor PS‐341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of NF‐κB in vitro and has afforded some objective responses in individuals with relapsed, refractory MM. However, the activity of PS‐341 against non‐hematological malignancies remains to be fully elucidated. In this study, we found that PS‐341 induced growth arrest and apoptosis of NCI‐H520 and ‐H460 non‐small cell lung cancer (NSCLC) cells in conjunction with markedly up‐regulated levels of p21waf1 and p53, and down‐regulation of bcl‐2 protein in these cells. Also, PS‐341 caused phosphorylation of c‐Jun NH2‐terminal kinase (JNK) and c‐Jun, and enhanced AP‐1/DNA binding activities in these cells as measured by western blotting and enzyme‐linked immunosorbent assay (ELISA), respectively. Interestingly, when the JNK/ c‐Jun/AP‐1 signal pathway was disrupted by the JNK inhibitor SP600125, the ability of PS‐341 to inhibit the growth of NSCLC cells and to up‐regulate the levels of p21waf1 in these cells was blunted, but the expression of p53 was sustained at a high level, suggesting that the JNK/c‐Jun/AP‐1 signal pathway might mediate the anti‐lung cancer effects of PS‐341, with p21waf1 playing the central role. Thus, PS‐341 might be useful for the treatment of individuals with NSCLC.

We have previously shown that angiotensin II (Ang II) stimulates astrocyte growth through activation of ERK1/2 mitogen activated protein (MAP) kinases. In the current study, we determined whether Ang II stimulates the expression of c-fos, c-jun and c-myc in brainstem astrocyte cultures. Reverse transcriptase-PCR analysis showed c-fos, c-jun, and c-myc mRNAs were induced by Ang II. The EC 50 values for Ang II stimulation of c-fos, c-jun and c-myc were 1.3, 1.68 and 1.4 nM, respectively. Ang II (100 nM) induced peak stimulation for all genes by 45 min followed by a gradual decline. Inhibition of ERK1/2 by PD98059 attenuated Ang II-induced c-fos and c-myc mRNA expression (by 75% and 100%, respectively) but was ineffective in preventing Ang II induction of c-jun. These studies show for the first time in brainstem astrocytes that Ang II induces the expression of c-fos, c-myc and c-jun, and showed that ERK1/2 mediate Ang II stimulation of c-fos and c-myc. These data implicate the ERK1/2 MAP kinase pathway as a divergent point in controlling Ang II stimulation of immediate early response genes in the central nervous system.

The in vitro exposure of Taenia crassiceps cysticerci to 17-β estradiol (E2) and progesterone (P4) stimulated their reproduction and infectivity. Testosterone (T4) and dihydrotestosterone (DHT) inhibited their reproduction and reduced their motility and infectivity. E2 and P4 increased, whereas T4 and DHT reduced, the expression of parasite c-fos and c-jun and DNA synthesis. In vitro exposure of cysticerci to sex steroids before their inoculation into recipient noninfected mice resulted in large parasite loads when pretreated with E2 and P4 and in smaller loads when pretreated with T4 and DHT. To determine the possible molecular mechanisms by which sex steroids affect T. crassiceps, sex steroid receptors were amplified. Taenia crassiceps expressed estrogen receptors (both α and β isoforms) and androgen receptors but no P4 receptors. These results demonstrate that sex steroids act directly on parasite reproduction by binding to a classic and specific sex steroid receptor on the parasite. The differential response of cysticerci to sex steroids may also be involved in their ability to grow faster in the murine female or feminized male host. This is the first report of direct sex steroid effects on the parasite possibly through sex steroid receptors in the cysticerci.

The transcription factors NF-κ B and AP-1 have been implicated in the inducible expression of a variety of genes involved in responses to oxidative stress and cellular defense mechanisms. Here, we report that thioredoxin, an important cellular protein oxidoreductase with antioxidant activity, exerts different effects on the activation of NF-κ B and AP-1. Transient expression or exogenous application of thioredoxin resulted in a dose-dependent inhibition of NF-κ B activity, as demonstrated in gel shift and transactivation experiments. AP-1-dependent transactivation, in contrast, was strongly enhanced by thioredoxin. A similar increase of AP-1 activity was also observed with other, structurally unrelated antioxidants such as pyrrolidine dithiocarbamate and butylated hydroxyanisole, indicating that the thioredoxin-induced increase of AP-1 activation was indeed based on an antioxidant effect. Moreover, the stimulatory effect on AP-1 activity was found to involve de novo transcription of the c-jun and c-fos components but to be independent of protein kinase C activation. These results suggest that thioredoxin plays an important role in the regulation of transcriptional processes and oppositely affects NF-κ B and AP-1 activation.

The pathogenesis of necrotizing enterocolitis (NEC) is unknown. Ischemia and reperfusion (I/R) injury have been considered to be major contributing factors. More recent reports have noted that apoptosis is a significant and perhaps the principal contributor to cell death after I/R injury. Recent studies have revealed that activator protein 1 (AP-1) family proteins including c-Fos and c-Jun potentially induce either the proliferation or apoptosis of the cells in the brain, heart, kidney, and liver. c-Fos and c-Jun expression has also been reported to be upregulated in postischemic intestinal epithelial cells (IECs). Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a potent cytoprotective factor in various pathologic conditions and plays a pivotal role in mediating the earliest cellular responses to injury. This study aims to examine whether HB-EGF, a proven intestinal cytoprotective molecule, exerts its protective effects through modulation of AP-1 transcription factor after intestinal I/R injury. Thirty rats were randomly divided into the following 5 groups: (1) normal control group; (2) ischemia group; (3) I/R group; (4) ischemia group with HB-EGF (400 µg/kg), and (5) I/R group with HG-EGF (400 µg/kg). c-Fos and c-Jun messenger RNAs and protein levels were determined by real-time quantitative polymerase chain reaction (PCR) and Western analyses, respectively. Statistical analysis was performed using ANOVA with Dunn’s test. The messenger RNA levels of the c-Fos and c-Jun increased after intestinal ischemia or the intestinal reperfusion phase. HB-EGF pretreatment significantly decreased c-Fos and c-Jun messenger RNAs. The expression of protein levels of c-Fos and c-Jun were correlation with the expression of messenger RNA level. HB-EGF intestinal cytoprotection is mediated, in part, by downregulation of the expression of AP-1 transcription factor after intestinal I/R injury.

AP-1 transcriptional activity is stimulated by the transformation promoters phorbol 12-myristate 13-acetate (\"12-O-tetradecanoylphorbol 13-acetate,\" TPA) and epidermal growth factor (EGF) in promotion-sensitive (P+) but not in promotion-resistant (P-) JB6 mouse epidermal cell lines. Although TPA stimulates expression of the jun and fos family genes, only c-jun expression shows higher elevation in P+cells than in P-cells. The present study tests the hypothesis that induced AP-1 activity is required for tumor promoter-induced transformation in JB6 P+cells. Both retinoic acid and the glucocorticoid fluocinolone acetonide inhibited basal and TPA-induced AP-1 activities that were tested with a stromelysin promoter-chloramphenicol acetyltransferase reporter gene in P+cells. Since both retinoic acid and fluocinolone acetonide are active in inhibiting TPA-induced anchorage-independent transformation of P+cells in the dose range that blocks TPA-induced AP-1 activity, their antipromoting effects may occur through inhibition of AP-1 activity. To test the hypothesis with a more specific inhibitor, stable clonal transfectants of P+cells expressing dominant negative c-jun mutant encoding a transcriptionally inactive product were analyzed. All transfectants showed a block in TPA and EGF induction of AP-1 activity. All transfectants also showed inhibition of TPA-induced transformation, and most transfectants showed a block in EGF-induced transformation. These results indicate that AP-1 activity is required for TPA- or EGF-induced transformation. This work demonstrates that a specific block in induced AP-1 activity inhibits tumor promoter-induced transformation.