UiO-66-NH2 initiated cascade reaction: Constructing a ratiometric fluorescence sensor for ultrasensitive detection of nerve agent simulant.

BACKGROUND: Highly toxic organophosphorus nerve agents often exist in the form of gas in the environment and can damage human neuroregulatory system by inhibiting the activity of acetylcholinesterase (AChE). However, fluorescent probes based on small organic molecules bring a secondary burden to environment, and their sensitivity and specificity for sarin simulant diethyl chlorophosphate (DCP) detection are unsatisfactory. Nanozyme cascade systems with signal amplification can be used for highly sensitive identification of analytes, but are rarely used in ratiometric analysis of DCP. Combination of enzyme cascades and ratiometric fluorescence ensures the accuracy and sensitivity of the output signal. RESULTS: We prepared a self-assembled nanohybrid (Ag-AuNCs@UiO-66-NH2) by metal-organic framework material and gold nanoclusters. On the one hand, UiO-66-NH2 with enzyme-like activity was used to hydrolyze DCP into diethyl phosphate (DEP) and chloridion (Cl-). Cl- hindered aggregation-induced enhanced emission (AIEE) of AuNCs by binding with Ag+ and decreased the fluorescence of AuNCs. On the other hand, ligand metal charge transfer effect (LMCT) of UiO-66-NH2 was blocked by DCP to enhance the fluorescence of UiO-66-NH2. Combining ratiometric analysis and nanozyme cascade reaction, an ultra-sensitive fluorescence sensor for detecting DCP was constructed, and ensured the accuracy of experimental results. In addition, Ag-AuNCs@UiO-66-NH2 was embedded into the agarose hydrogel substrate, the resulting agarose hydrogel film allowed quantitative assessment of DCP vapor and high sensitivity was demonstrated (detection limit as low as 1.02 ppb). SIGNIFICANCE: A strategy combining enzyme cascade with ratiometric fluorescence was proposed, which improved the accuracy and sensitivity of the analysis results. The soft-solid platform based on agarose hydrogel film was constructed to realize the quantitative monitoring of sarin simulant gas. The LOD value obtained in this work is much lower than the immediately life-threatening or health threatening concentration of sarin.

Pancreatic ductal adenocarcinoma chemoresistance: From metabolism reprogramming to novel treatment / 中华医学杂志(英文版)

As pancreatic cancer (PC) is highly malignant, its patients tend to develop metastasis at an early stage and show a poor response to conventional chemotherapies. First-line chemotherapies for PC, according to current guidelines, include fluoropyrimidine- and gemcitabine-based regimens. Accumulating research on drug resistance has shown that biochemical metabolic aberrations in PC, especially those involving glycolysis and glutamine metabolism, are highly associated with chemoresistance. Additionally, lipid metabolism is a major factor in chemoresistance. However, emerging compounds that target these key metabolic pathways have the potential to overcome chemoresistance. This review summarizes how PC develops chemoresistance through aberrations in biochemical metabolism and discusses novel critical targets and pathways within cancer metabolism for new drug research.

Zirconium-based metal-organic framework loaded agarose hydrogels for fluorescence turn-on detection of nerve agent simulant vapor.

Developing reliable sensors that accurately detect deadly chemical gases is critical to global security. Nerve agents are one of the most dangerous chemicals in the world and are often found in gaseous forms in the environment, which remain a challenge to detect because of their low levels. In this paper, a fluorescent probe based on a Zr-based metal-organic framework UiO-66-NH2 was proposed. The specific binding between the Zr-O site of UiO-66-NH2 and diethyl chlorophosphate (DCP) blocked the ligand-to-metal charge transfer (LMCT) process in UiO-66-NH2, thereby enabling the fluorescence turn-on detection of DCP. More importantly, a simple and portable hydrogel soft-solid platform (UiO-66-NH2@Aga) was constructed by incorporating UiO-66-NH2 into the formation process of agarose (Aga) hydrogel for fast and sensitive detection of gaseous DCP. When the hydrogel was exposed to a low concentration of DCP vapor, its fluorescence changed from colorless to bright blue, allowing visualization of the DCP gas for analysis. The UiO-66-NH2@Aga integrated solid-state platform showed an excellent response to DCP vapor in the detection range of 1.98 to 9.90 ppm and with a detection limit of 1.16 ppm. This work opened up a unique way to design a convenient, low cost and practical gas physical examination platform.

Cholesterol crystals activate NLRP3 inflammasomes and promote gallstone formation by increasing mucin secretion.

Cholesterol crystals participate in cholesterol nucleation; however, the role of cholesterol crystals in gallstone development is unknown. Mucin secretion contributes to increased size of gallstones. Cholesterol crystals activate inflammasomes and participate in many sterile inflammation related human diseases. We investigated the role of cholesterol crystals and mucins in sterile inflammation and gallstone enlargement. We found that expression of mucin 5AC (MUC5AC), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and interleukin-1b (IL-1b) was increased significantly in tissues adjacent to gallstones. Experiments in vitro showed that cholesterol crystals promote MUC5AC secretion; they also increase expression of NLRP3, NLR family CARD domain-containing 4 (NLRC4), apoptosis-associated speck-like protein containing caspase recruitment domain (ASC), and cleaved caspase-1 in biliary epithelial cells. Inhibition of Inflammasomes by NLRP3, ASC or caspase-1 small interfering RNAs reduced MUC5AC secretion. Also, the IL-1 receptor antagonist, IL1RA, and caspase-1 inhibitor, Ac-YVAD, both inhibited MUC5AC secretion induced by cholesterol crystals. We found that inflammasome activation participates in cholesterol crystal induced mucin secretion and gallstone development.

Autophagy, not apoptosis, plays a role in lumen formation of eccrine gland organoids / 中华医学杂志(英文版)

BACKGROUND@#Sweat secreted by eccrine sweat glands is transported to the skin surface through the lumen. The eccrine sweat gland develops from the initial solid bud to the final gland structure with a lumen, but how the lumen is formed and the mechanism of lumen formation have not yet been fully elucidated. This study aimed to investigate the mechanism of lumen formation of eccrine gland organoids (EGOs).@*METHODS@#Human eccrine sweat glands were isolated from the skin for tissue culture, and the primary cultured cells were collected and cultured in Matrigel for 14 days in vitro. EGOs at different development days were collected for hematoxylin and eosin (H&E) staining to observe morphological changes and for immunofluorescence staining of proliferation marker Ki67, cellular motility marker filamentous actin (F-actin), and autophagy marker LC3B. Western blotting was used to detect the expression of Ki67, F-actin, and LC3B. Moreover, apoptosis was detected using a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay kit, and the expression of poly (ADP-ribose) polymerase and Caspase-3 was detected by Western blot. In addition, 3-methyladenine (3MA) was used as an autophagy inhibitor to detect whether the formation of sweat glands can be effectively inhibited.@*RESULTS@#The results showed that a single gland cell proliferated rapidly and formed EGOs on day 4. The earliest lumen formation was observed on day 6. From day 8 to day 14, the rate of lumen formation in EGOs increased significantly. The immunofluorescence and Western blot analyses showed that the expression of Ki67 gradually decreased with the increase in days, while the F-actin expression level did not change. Notably, the expression of autophagy marker LC3B was detected in the interior cells of EGOs as the apoptosis signal of EGOs was negative. Compared with the control group, the autophagy inhibitor 3MA can effectively limit the formation rate of the lumen and reduce the inner diameter of EGOs.@*CONCLUSION@#Using our model of eccrine gland 3D-reconstruction in Matrigel, we determined that autophagy rather than apoptosis plays a role in the lumen formation of EGOs.

Stable dual-emissive fluorescin@UiO-67 metal-organic frameworks for visual and ratiometric sensing of Al3+ and ascorbic acid.

Encapsulation of fluorophore in metal organic framework (MOF) is an effective method to construct multi-emissive composites. Unfortunately, the small molecules loaded in MOF pores are easy to leak. To overcome this difficulty, fluorescin (FL) is proposed to be encapsulated tightly in the cage of the small tetrahedron of UiO-67, as one of the organic ligands coordinated with the central ion Zr. Finally, stable multi-emission fluorescence was successfully achieved, and Förster resonance energy transfer (FRET) occurred between FL and UiO-67. Ascorbic acid (AA) can dynamically quench the fluorescence of FL@UiO-67 nanoclusters (NCs) through internal filtering effect, photoinduced electron transfer (PET). The detection limit of the probe for AA was as low as 0.20 µM, and the detection range was 0.67 µM-0.36 mM. The probe was further employed to detect Al3+ due to the coordination between Al3+ and the carboxyl group in the FL@UiO-67 NCs. The detection limit for Al3+ was 3.3 nM, and the linear range was 11 nM-5 µM agarose film and test paper were both prepared successfully for visual detection of AA and Al3+. This work provides new ideas for low-cost and convenient real-time detection method.

Effect of Hematopoietic Pre-B-cell Leukemia Transcription Factor Interacting Protein Knockdown on Proliferation,Cell Cycle and Apoptosis in Pancreatic Cancer Cells / 中国医学科学院学报

To unravel the role of hematopoietic pre-B-cell leukemia transcription factor interacting protein(HPIP)in the proliferation,cell cycle,and apoptosis of pancreatic ductal adenocarcinoma(PDAC)cells. The HPIP expression in PDAC tissue was determined by immunohistochemical staining.Knockdown of HPIP was accomplished in MIA PaCa-2 and BxPC-3 cell lines by transient transfection of HPIP siRNA and validated by Western blotting.Cell proliferation was assessed using the cell counting kit-8 assay and colony formation assay.Cell cycle and apoptosis were detected by flow cytometry.Western blotting was performed to detect the expression levels of cyclin D1,caspase 7,and cleaved caspase 7. HPIP was overexpressed in PDAC tissue compared with matched adjacent pancreatic tissue(=-2.060,=0.039).Knockdown of HPIP inhibited the proliferation of MIA PaCa-2 and BxPC-3 cells(all <0.05).Knockdown of HPIP significantly reduced the positive colonies formed by MIA PaCa-2 and BxPC-3 cells(=4.706,=0.009;=9.514,=0.000).Knockdown of HPIP decreased the proportion of S phase cells(=7.642,=0.001;=2.714,=0.051)and increased the proportion of G/G phase cells(=3.244,=0.031;=6.095,=0.003)in MIA PaCa-2 and BxPC-3 cells.Meanwhile,knockdown of HPIP increased the proportions of late-phase MIA PaCa-2 and BxPC-3 cells(=24.58,=0.000;=36.45,=0.000)and the overall apoptosis rate(=29.43,=0.000;=43.52,=0.000).In MIA PaCa-2 and BxPC-3 cells,knockdown of HPIP decreased the expression level of cyclin D1(=6.705,=0.002;=6.238,=0.003)and increased the expression level of cleaved caspase 7(=3.991,=0.016;=6.536,=0.002). HPIP is overexpressed in PDAC tissue.Knockdown of HPIP inhibits the proliferation and G/G to S transition of PDAC cells.Meanwhile,knockdown of HPIP promotes the apoptosis of PDAC cells.Thus,HPIP may act as an oncogene in PDAC.

Arginine metabolism: a potential target in pancreatic cancer therapy / 中华医学杂志(英文版)

Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant disease, which has an extremely low survival rate of <9% in the United States. As a new hallmark of cancer, metabolism reprogramming exerts crucial impacts on PDAC development and progression. Notably, arginine metabolism is altered in PDAC cells and participates in vital signaling pathways. In addition, arginine and its metabolites including polyamine, creatine, agmatine, and nitric oxide regulate the proliferation, growth, autophagy, apoptosis, and metastasis of cancer cells. Due to the loss of argininosuccinate synthetase 1 (ASS1) expression, the key enzyme in arginine biosynthesis, arginine deprivation is regarded as a potential strategy for PDAC therapy. However, drug resistance develops during arginine depletion treatment, along with the re-expression of ASS1, metabolic dysfunction, and the appearance of anti-drug antibody. Additionally, arginase 1 exerts crucial roles in myeloid-derived suppressor cells, indicating its potential targeting by cancer immunotherapy. In this review, we introduce arginine metabolism and its impacts on PDAC cells. Also, we discuss the role of arginine metabolism in arginine deprivation therapy and immunotherapy for cancer.

Primary hepatoid adenocarcinoma of the lung in Yungui Plateau, China: A case report.

BACKGROUND: Hepatoid adenocarcinoma (HAC) occurs in extrahepatic organs such as the gastrointestinal tract, testes, ovaries, lungs, mediastinum and pancreas, and frequently produces α-fetoprotein (AFP). HAC of the lung (HAL) is rare, characterized by difficult treatment and poor prognosis. There are no reports of HAL in Yunnan-Guizhou Plateau, China. CASE SUMMARY: A 60-year-old male patient was clinically diagnosed with HAL pT3N0M0, stage IIB. Chest computed tomography revealed a 7.5 cm × 7.2 cm soft tissue mass located in the right lung upper lobe and the adjacent superior mediastinum. Right upper lobectomy was performed. The diagnosis of HAL was confirmed by pathological examination, and the patient received paclitaxel and carboplatin as adjuvant chemotherapy after surgery. CONCLUSION: Clinical manifestations, pathological features, imaging findings, auxiliary examination, and treatment planning of HAL are presented to help clinicians improve their diagnosis and treatment.

Plasminogen Activator Inhibitor 1 as a Poor Prognostic Indicator in Resectable Pancreatic Ductal Adenocarcinoma / 中华医学杂志(英文版)

Background@#Plasminogen activator inhibitor 1 (PAI-1) was previously established to impact several phenotypes in many kinds of cancer, including pancreatic cancer. However, its prognostic significance in pancreatic ductal adenocarcinoma (PDAC) needs support of further evidence. This study was designed to address the issue.@*Methods@#PAI-1 expression was detected by tissue microarray-based immunohistochemical staining in formalin-fixed paraffin-embedded specimens from 93 PDAC patients with surgical resection from September 2004 to December 2008. Its relationships with clinicopathologic variables and tumor-specific survival (TSS) were further evaluated using Chi-square, Kaplan-Meier, log-rank, as well as Cox regression analyses.@*Results@#Expression of PAI-1 was much higher in tumor than that in nontumor tissues, based on comparison of all samples and 74 matched ones (95 [47.5, 180] vs. 80 [45, 95], Z = -2.439, P = 0.015 and 100 [46.9, 182.5] vs. 80 [45, 95], Z = -2.594, P = 0.009, respectively). In addition, tumoral PAI-1 expression was positively associated with N stage (22/35 for N1 vs. 21/51 for N0, χ = 3.903, P = 0.048). Univariate analyses showed that TSS of patients with high PAI-1 tumors was significantly poorer than that of those with low PAI-1 tumors (log rank value = 19.00, P < 0.0001). In multivariate Cox regression test, PAI-1 expression was identified as an independent predictor for long-term prognosis of resectable PDAC (hazard ratio = 2.559, 95% confidence interval = 1.499-4.367, P = 0.001).@*Conclusion@#These results suggest that expression of PAI-1 is upregulated in PDAC and might serve as a poor prognostic indicator.

[Development of Tianma HPLC fingerprint and discriminant analysis].

Tianma(the tuber of Gastrodia eleta) is a widely used and pricy Chinese herb. Its counterfeits are often found in herbal markets, which are the plant materials with similar macroscopic characteristics of Tianma. Moreover, the prices of Winter Tianma(cultivated Tianma) and Spring Tianma(mostly wild Tianma) have significant difference. However, it is difficult to identify the true or false, good or bad quality of Tianma samples. Thus, a total of 48 Tianma samples with different characteristics(including Winter Tianma, Spring Tianma, slice, powder, etc.) and 9 plant species 10 samples of Tianma counterfeits were collected and analyzed by HPLC-DAD-MS techniques. After optimizing the procedure of sample preparation, chromatographic and mass-spectral conditions, the HPLC chromatograms of all those samples were collected and compared. The similarities and Fisher discriminant analysis were further conducted between the HPLC chromatograms of Tianma and counterfeit, Winter Tianma and Spring Tianma. The results showed the HPLC chromatograms of 48 Tianma samples were similar at the correlation coefficient more than 0.848(n=48). Their mean chromatogram was simulated and used as Tianma HPLC fingerprint. There were 11 common peaks on the HPLC chromatograms of Tianma, in which 6 main peaks were chosen as characteristic peaks and identified as gastrodin, p-hydroxybenzyl alcohol, parishin A, parishin B, parishin C, parishin E, respectively by comparison of the retention time, UV and MS data with those of standard chemical compounds. All the six chemical compounds are bioactive in Tianma. However, the HPLC chromatograms of the 10 counterfeit samples were significantly different from Tianma fingerprint. The correlation coefficients between HPLC fingerprints of Tianma with the HPLC chromatograms of counterfeits were less than 0.042 and the characteristic peaks were not observed on the HPLC chromatograms of these counterfeit samples. It indicated the true or false Tianma can be identified by either the similarity or characteristic peaks on HPLC fingerprint. Comparing the Winter Tianma with Spring Tianma showed that the HPLC chromatograms of 15 winter Tianma samples and 11 spring Tianma samples were similar at the mean correlation coefficient of 0.908. But the intensity of the characteristic peaks were different between the two groups of Tianma samples, i.e. the intensity of gastrodin, paishin A and C in winter Tianma was lower than those in spring Tianma. The Winter Tianma and Spring Tianma could be discriminated by either the Fisher unstandardized discrimination function or Linear discriminant function, based on the peak areas of 11 common peaks on HPLC chromatograms as variate.

5-Fluorouracil suppresses human hepatocellular carcinoma cell growth via promoting miR-22 expression / 基础医学与临床

Objective To investigate the impact of 5-fluorouracil (5-FU) on miR-22 expression in human hepato-cellular carcinoma (HCC) cell lines and to elucidate the molecular mechanism of 5-fluorouracil for HCC chemo-therapy. Methods Real-time PCR analysis was conducted to determine the expression levels of miR-22 in HCC tissue specimens and HCC cell lines. The expression of miR-22 and pri-miR-22 (primary miR-22) was evaluated in HepG2 and Huh7 cells with 5-FU treatment by using real-time PCR and we also performed Western blot analysis to detect the protein level of HDAC4 in HCC cells with the same treatment. A rescue assay was employed by using 5-FU treatment in combination with miR-22 inhibitor(Anti-22) to further investigate the correlation among 5-FU, miR-22,and HCC cell growth. Results miR-22 expression depicted a significant downregulation in HCC tissues and cell lines (P<0.01). 5-FU treatment led to an augment of miR-22 expression in HepG2 and Huh7 cells(P<0.001) and resulted in a decrease of HDAC4 protein levels, which was verified as a direct target of miR-22 in HCC cells (P<0.01). Conclusions 5-FU has suppressive effect on HCC growth which could be potentially ex-plained by miR-22-mediated HDAC4 axis.

5-Fluorouracil suppresses human hepatocellular carcinoma cell growth via promoting miR-22 expression / 基础医学与临床

Objective To investigate the impact of 5-fluorouracil (5-FU) on miR-22 expression in human hepato-cellular carcinoma (HCC) cell lines and to elucidate the molecular mechanism of 5-fluorouracil for HCC chemo-therapy. Methods Real-time PCR analysis was conducted to determine the expression levels of miR-22 in HCC tissue specimens and HCC cell lines. The expression of miR-22 and pri-miR-22 (primary miR-22) was evaluated in HepG2 and Huh7 cells with 5-FU treatment by using real-time PCR and we also performed Western blot analysis to detect the protein level of HDAC4 in HCC cells with the same treatment. A rescue assay was employed by using 5-FU treatment in combination with miR-22 inhibitor(Anti-22) to further investigate the correlation among 5-FU, miR-22,and HCC cell growth. Results miR-22 expression depicted a significant downregulation in HCC tissues and cell lines (P<0.01). 5-FU treatment led to an augment of miR-22 expression in HepG2 and Huh7 cells(P<0.001) and resulted in a decrease of HDAC4 protein levels, which was verified as a direct target of miR-22 in HCC cells (P<0.01). Conclusions 5-FU has suppressive effect on HCC growth which could be potentially ex-plained by miR-22-mediated HDAC4 axis.

Interleukin-1ß-mediated suppression of microRNA-101 and upregulation of enhancer of zeste homolog 2 is involved in particle-induced lung cancer.

Lung cancer may be a result of complex factors. Small mineral particle is the well-known inducer of lung cancer. Previous study revealed the high morbidity of lung cancer in Xuan Wei in China, and the main cause of lung cancer is the use of smoky coal there. And it is generally accepted that chronic inflammation induced by small mineral particle may be a cause of lung cancer. But the relationship between chronic lung inflammation and lung cancer is largely unknown. In the present study, we found that silica particle was able to induce the secretion of interleukin-1ß from a Xuan Wei lung cancer cell line, XWLC-05. At the same time, microRNA-101 (mir-101) was found to be downregulated by the treatment of silica particle. Interestingly, the interleukin 1 receptor antagonist and interleukin-1ß antibody can reduce silica particle-induced downregulation of mir-101. Twenty-four Xuan Wei lung tumor tissues were collected to detect the expression level of mir-101 and enhancer of zeste homolog 2 (EZH2), which is the potential target of mir-101. The results showed that mir-101 was down-regulated and EZH2 were upregulated. Subsequently, the roles of mir-101 and EZH2 in tumor growth and progression in vitro were tested. Overexpression of mir-101 mimics was able to suppress the expression of EZH2 in XWLC-05 cells. And this resulted in the inhibited tumor cell growth and attenuated cell migration. The results in the present study showed that particle can induce the secretion of interleukin-1ß. Interleukin-1ß subsequently induces the downregulation of mir-101, which may result in the upregulated level of EZH2, and occurrence of lung cancer. We for the first time proposed the role interleukin-1ß-mir-101-EZH2 axes in the particle-induced lung cancer. Further study may be needed to decipher the detailed mechanism involved.

Prenatal caffeine ingestion induces aberrant DNA methylation and histone acetylation of steroidogenic factor 1 and inhibits fetal adrenal steroidogenesis.

Prenatal caffeine ingestion is one of the risk factors for intrauterine growth retardation (IUGR). Adrenal plays a pivotal role, mainly through steroidogenesis, in the regulation of intrauterine homeostasis and in fetal development and maturation. We have shown that prenatal caffeine ingestion can inhibit fetal adrenal corticosterone production, but the underlying mechanism is unknown. This study investigated the effects of prenatal caffeine ingestion on corticosterone and its associated synthesized enzymes (steroidogenic acute regulatory protein, StAR; 3ß-hydroxysteroid dehydrogenase, 3ß-HSD; cytochrome P450 cholesterol side chain cleavage, P450scc; P450c21; and P450c11) in the fetal adrenal in rats and further explored the underlying mechanism by analyzing the epigenetic modification and expression of the key transcription factor steroidogenic factor-1 (SF-1). The pregnant rats were intragastrically treated with 120 mg/kg.d caffeine from gestational day 11-20. The results showed that the IUGR rate was 51.2% after caffeine treatment. The contents of corticosterone and the mRNA levels of StAR, P450scc, P450c21, and P450c11 were decreased significantly in the fetal adrenal. Furthermore, caffeine reduced both the protein and the mRNA expression of SF-1 in the fetal adrenal. The epigenetic analysis showed that caffeine treatment can significantly enhance the mRNA expression of DNA methyltransferase (Dnmt) 1, Dnmt3a, histone deacetylases (Hdac) 1, and Hdac2. The detection of DNA methylation by bisulfite-sequencing PCR uncovered a notably increased total methylation rate in the SF-1 promoter. The ChIP assay showed decreased acetylation levels of H3K9 and H3K14 in the SF-1 promoter. In conclusion, prenatal caffeine ingestion is able to induce aberrant DNA methylation and histone acetylation of the SF-1 promoter in the rat fetal adrenal. These effects may contribute to the inhibition of the expression of SF-1 and its associated steroidogenic enzymes and the production of corticosterone during fetal development.

Investigation of microRNA-373 function and mechanism in HepG2 cell growth suppression induced by 5-fluorouracil / 中华肝胆外科杂志

Objective To investigate the inhibitory effect of 5-fluorouracil (5-FU) on hepatocellular carcinoma (HCC) cell growth and to elucidate its potential molecular mechanism.Methods Real-time PCR analysis was conducted to determine the expression of miR-373 in HCC tissue specimens and HCC cell lines.The expression of miR-373 was also evaluated in HepG2 cells after 5-FU treatment.Western blot analysis was performed to detect the protein levels of PPP6C,a verified target of miR-373,with transfection of miR-373 mimics or 5-FU treatment.A rescue assay was conducted to investigate the cell growth in HepG2 cells by using CCK-8.Results miR-373 expression was up-regulated in both HCC tissues and cell lines.miR-373 expression depicted about 2.94-fold augment in HepG2 cells as compared to normal liver cells control (P ＜0.01).5-FU treatment led to a significant decrease of miR-373 levels (approximately 50％,P ＜0.01,48 h) and resulted in a marked increase of PPP6C protein (approximately 2.1-fold,48 h) in HepG2 cells.The overexpression of miR-373 could prevent the impact of 5-FU treatment on cell growth in HepG2 cells and CCK-8 assay showed that HepG2 cell growth was rescued approximately 81％ and 84％ at 24 h (P ＜ 0.05) and 48 h (P ＜ 0.01),respectively.Conclusion 5-FU can repress endogenous miR-373 level,which activates the expression of downstream targeted gene PPP6C,thereby exerting an inhibitory effect on HepG2 cells.

Krüpel-like factor 8 is a potential prognostic factor for pancreatic cancer / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Pancreatic cancer is a lethal disease that is often diagnosed at an advanced stage. There is a lack of information to predict the prognosis of pancreatic cancer. Krüppel-like factor (KLF) 8 has been found to be deregulated in multiple cancers, and its high expression was correlated with poor prognosis. However, so far, no information was reported about the expression of KLF8 in pancreatic cancer. In the present study, we investigated, possibly for the first time, the expression of KLF8 in pancreatic cancer samples and analyzed its correlation with clinical parameters and overall survival (OS) rate.</p><p><b>METHODS</b>We used immunohistochemical staining to detect KLF8 in 68 samples from patients who underwent surgery and its correlation with the clinicopathological characteristics. We used Kaplan-Meier curve to analyze the relationship between KLF8 expression and the OS time. Univariate analysis was performed in addition to multivariate hazard models with clinicopathological features to assess KLF8 as an independent prognostic factor.</p><p><b>RESULTS</b>KLF8 was present in the cytoplasm of pancreatic cancer cells and 52.9% of the 68 cases had positive expression. KLF8 expression was not associated with sex, age, tumor location, lymph node stage, and metastasis stage, but was associated with tumor stage (P = 0.04). Kaplan-Meier method demonstrated that patients with negative expression of KLF8 had a better prognosis. In univariate and multivariate models, KLF8 was a significant predictor of OS in pancreatic cancer.</p><p><b>CONCLUSION</b>Our results revealed that KLF8 may be a potential prognostic factor for pancreatic cancer.</p>

Roles of NF-κB signaling pathway in regulatory network of pancreatic cancer metastasis / 国际外科学杂志

Pancreatic cancer is one of the most malignant tumors with a high mortality rate attributed to its widespread metastasis.A number of cellular signal transduction pathways involved in multiple genes play an important role in regulating this complex metastatic cascade of pancreatic cancer.NF-kappa B is one of the crucial signaling pathways.Studies has indicated that NF-kappa B could modulate a series of biological events relevant to tumor progress by controlling multiple targeted genes expression,such as cell proliferation,anti-apoptosis,angiogenesis,epithelial-mesenchymal transition,inflammation,stress response,etc.Furthermore,it can also up-regulate Hedgehog and MMPs signaling pathways.To help us better understand the potential mechanism and identify more sensitive tumor markers and selective targets,this review will underline the significant roles of NF-kappa B signaling pathway in regulatory network of pancreatic cancer metastasis.

Prenatal nicotine exposure enhances the susceptibility to metabolic syndrome in adult offspring rats fed high-fat diet via alteration of HPA axis-associated neuroendocrine metabolic programming.

AIM: Prenatal nicotine exposure (PNE) alters the hypothalamic-pituitary-adrenocortical (HPA) axis-associated neuroendocrine metabolic programming in intrauterine growth retardation offspring rats. In this study we aimed to clarify the susceptibility to metabolic diseases of PNE offspring rats fed a high-fat diet. METHODS: Maternal Wistar rats were injected with nicotine (1.0 mg/kg, sc) twice per day from gestational day 11 until full-term delivery, and all pups were fed a high-fat diet after weaning and exposed to unpredictable chronic stress (UCS) during postnatal weeks 18-20. Blood samples were collected before and after chronic stress, and serum ACTH, corticosterone, glucose, insulin, total cholesterol, triglyceride and free fatty acids levels were measured. The hypothalamus, pituitary gland and liver were dissected for histological studies. RESULTS: UCS significantly increased the serum ACTH, corticosterone and insulin levels as well as the insulin resistant index without changing the serum glucose, total cholesterol, triglyceride and free fatty acids levels in adult offspring rats without PNE. The body weight of PNE offspring rats presented a typical "catch-up" growth pattern. PNE not only aggravated the UCS-induced changes in the HPA axis programmed alteration (caused further increases in the serum ACTH and corticosterone levels), but also significantly changed the glucose and lipid metabolism after UCS (caused further increases in the serum glucose level and insulin resistant index, and decrease in the serum free fatty acids). The effects of PNE on the above indexes after UCS showed gender differences. Pathological studies revealed that PNE led to plenty of lipid droplets in multiple organs. CONCLUSION: PNE enhances not only the HPA axis, but also the susceptibility to metabolic diseases in adult offspring rats fed a high-fat diet after UCS in a gender-specific manner and enhances the susceptibility to metabolic diseases in adult offspring rats fed a high-fat diet.