Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway plays a crucial role in the formation and progression of many malignancies, and has been shown to be an important therapeutic target for cancer. In the present study, human gastric adenocarcinoma tissues of different grades (N=45) were collected. The protein expression of PI3Kp85α and phosphorylated AKT (p-AKT) was evaluated immunohistochemically in the biopsy samples. PI3K/AKT pathway was blocked by constructed recombinant small hairpin RNA adenovirus vector rAd5-PI3Kp85α (rAd5-P) used to transfect into human gastric cancer SGC-7901cell line. The transfection efficiency of rAd5-P in SGC-7901 cells was observed under fluorescent microscope. The expression of PI3Kp85α, p-AKT, Ki-67 and matrix metallopeptidase-2 (MMP-2) was detected by real-time PCR and Western blot assays. Cell proliferative activities and metastatic capabilities were determined by MTT and Transwell assays. As a consequence, the protein expression of PI3Kp85α and p-AKT was respectively observed in 80.0% and 82.2% gastric adenocarcinoma tissues, elevating with the ascending order of tumor malignancy. Targeted blockade of PI3K pathway decreased the expression of PI3Kp85α, p-AKT, Ki-67 and MMP-2, and inhibited the proliferative activities and metastatic capabilities of gastric cancer cells. In conclusion, PI3Kp85α and p-AKT were strongly expressed in gastric adenocarcinoma tissues, and targeted blockade of PI3K pathway may inhibit gastric cancer growth and metastasis through down-regulation of Ki-67 and MMP-2 expression. PI3K/AKT pathway may represent an important therapeutic target for gastric cancer.
Cellular plasticity has an important role in the progression of hepatocellular carcinoma (HCC). In this study, the involvement of a TGF-β1-CD147 self-sustaining network in the regulation of the dedifferentiation progress was fully explored in HCC cell lines, hepatocyte-specific basigin/CD147-knockout mice and human HCC tissues. We demonstrated that TGF-β1 stimulation upregulated CD147 expression and mediated the dedifferentiation of HCC cells, whereas all-trans-retinoic acid induced the downregulation of CD147 and promoted differentiation in HCC cells. Overexpression of CD147 induced the dedifferentiation and enhanced the malignancy of HCC cells, and increased the transcriptional expression of TGF-β1 by activating β-catenin. CD147-induced matrix metalloproteinase (MMP) production activated pro-TGF-β1. The activated TGF-β1 signaling subsequently repressed the HNF4α expression via Smad-Snail1 signaling and enhanced the dedifferentiation progress. Hepatocyte-specific basigin/CD147-knockout mice decreased the susceptibility to N-nitrosodiethylamine-induced tumorigenesis by suppressing TGF-β1-CD147 signaling and inhibiting dedifferentiation in hepatocytes during tumor progression. CD147 was positively correlated with TGF-β1 and negatively correlated with HNF4α in human HCC tissues. Positive CD147 staining and lower HNF4α levels in tumor tissues were significantly associated with poor survival of patients with HCC. The overexpression of HNF4α and Smad7 and the deletion of CD147 by lentiviral vectors jointly reprogrammed the expression profile of hepatocyte markers and attenuated malignant properties including proliferation, cell survival and tumor growth of HCC cells. Our results highlight the important role of the TGF-β1-CD147 self-sustaining network in driving HCC development by regulating differentiation plasticity, which provides a strong basis for further investigations of the differentiation therapy of HCC targeting TGF-β1 and CD147.
Oesophageal visceral hypersensitivity is thought to be important in generating symptoms in functional heartburn (FH). However, the neurophysiological mechanisms involved are poorly understood. The aim of this study was to compare the characteristics of oesophageal cortical evoked potentials (CEPs) induced by balloon distension and acid perfusion in FH and controls. We studied 21 FH patients and 12 healthy volunteers. Oesophageal mechanical stimulation was performed using the specially constructed mechanical pump. CEPs were recorded using the 10-20 international system of electroencephalogram recording. Oesophageal distention elicited recognizable, reproducible and muti-peak CEPs. CEP latencies for N1, P1 and N2 components were significantly shorter (P = 0.016, P = 0.003 and P = 0.031, respectively) in FH than in controls before perfusion. Acid perfusion significantly decreased the latencies of N1, P1 and N2 (P = 0.022, P = 0.007 and P = 0.041, respectively) and significantly increased the amplitude of P1-N2 components (P = 0.020) in FH patients, but not in controls. In conclusion, cortical evoked potential responses evoked by oesophageal distention and acid perfusion were greater in FH than in controls, suggesting that dysfunction of visceral neural pathways and/or alterations in cortical processing may produce and mediate oesophageal hypersensitivity in FH. These findings provide the evidence that central sensitization contributes to the development and maintenance of oesophageal hypersensitivity.
Prophylactic GTN is useful for prevention of post-ERCP pancreatitis, but the optimal dosage and the optimal route and timing of administration need further clarification before this treatment can come into routine clinical use.
We present the FERRUM Project, an international collaboration aiming at a production and evaluation of oscillator strengths (transition probabilities) of selected spectral lines of singly ionized iron group elements, that are of astrophysical relevance.The results obtained include measurements and calculations of permitted and forbidden lines of Fe II. The data have been applied to both emission and absorption lines in astrophysical spectra. We make comparisons between experimental, theoretical and astrophysical f-values. We give a general review of the various measurements, and discuss the UV8 multiplet of Fe II around 1610 Ð in detail.
Setting the frame rate of the capsule endoscope at 1 fps for the whole procedure increases the completion rate by prolonging the capsule's total operating time; the diagnostic yield does seem to be at least as high as with 2 fps.
Lidocaine, a typical local anesthetic, has been shown to directly induce neurotoxicity in clinical settings. Dexmedetomidine (DEX) is an alpha-2-adrenoreceptor agonist that has been used as anxiolytic, sedative, and analgesic agent which has recently found to protect against lidocaine-induced neurotoxicity. Nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1 (SIRT1)/forkhead box O3 (FOXO3a) signaling is critical for maintaining neuronal function and regulation of the apoptotic pathway. In the present study, we designed in vitro and in vivo models to investigate the potential effects of lidocaine and DEX on SIRT1 and FOXO3a and to verify whether SIRT1/FOXO3a-mediated regulation of apoptosis is involved in DEX-induced neuroprotective effects against lidocaine. We found that in both PC12 cells and brains of mice, lidocaine decreased SIRT1 level through promoting the degradation of SIRT1 protein. Lidocaine also increased FOXO3a protein level and increased the acetylation of SIRT1 through inhibiting SIRT1. Upregulation of SIRT1 or downregulation of FOXO3a significantly inhibited lidocaine-induced changes in both cell viability and apoptosis. DEX significantly inhibited the lidocaine-induced decrease of SIRT1 protein level and increase of FOXO3a protein level and acetylation of FOXO3a. Downregulation of SIRT1 or upregulation of FOXO3a suppressed DEX-induced neuroprotective effects against lidocaine. The data suggest that SIRT1/FOXO3a is a potential novel target for alleviating lidocaine-induced neurotoxicity and provide more theoretical support for the use of DEX as an effective adjunct to alleviate chronic neurotoxicity induced by lidocaine.
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