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简介：AbstractImportance:Cadherin-11 (CDH11), a cell-to-cell adhesion molecule, is implicated in the fibrotic process of several organs. Biliary atresia (BA) is a common cholestatic liver disease featuring cholestasis and progressive liver fibrosis in children. Cholestatic liver fibrosis may progress to liver cirrhosis and lacks effective therapeutic strategies. Currently, the role of CDH11 in cholestatic liver fibrosis remains unclear.Objective:This study aimed to explore the functions of CDH11 in cholestatic liver fibrosis.Methods:The expression of CDH11 in BA livers was evaluated by database analysis and immunostaining. Seven BA liver samples were used for immunostaining. The wild type (Wt) and CDH11 knockout (CDH11-/-) mice were subjected to bile duct ligation (BDL) to induce cholestatic liver fibrosis. The serum biochemical analysis, liver histology, and western blotting were used to assess the extent of liver injury and fibrosis as well as activation of transforming growth factor-β (TGF-β)/Smad pathway. The effect of CDH11 on the activation of hepatic stellate cell line LX-2 cells was investigated.Results:Analysis of public RNA-seq datasets showed that CDH11 expression levels were significantly increased in livers of BA, and CDH11 was correlated with liver fibrosis in BA. BDL-induced liver injury and liver fibrosis were attenuated in CDH11-/- mice compared to Wt mice. The protein expression levels of phosphorylated Smad2/3 were decreased in livers of CDH11-/- BDL mice compared to Wt BDL mice. CDH11 knockdown inhibited the activation of LX-2 cells.Interpretation:CDH11 plays an important role in cholestatic liver fibrosis and may represent a potential therapeutic target for cholestatic liver disease, such as BA.

简介：Overthepast50addyears,outstandingachievementshavebeenmadeinthedevelopmentofruralsmallhydropower(SLIP)andelectrificationinChina.Bytheendof2003,42,221SHPplantswithatotalinstalledcapacityof28,489MWhavebeenconstructedandunderoperation.Halfofthecountry'sterritory,andonequarterofpopulationofthewholenationarenowaccessibletoSHP.

简介：Objective:Stromalinteractionmolecule1(STIM1)overexpressionhasbeenreportedtoplayanimportantroleinprogressionofseveralcancers.However,themechanismofSTIM1overexpressionanditsrelationshipwithhypoxiainpancreaticductaladenocarcinoma(PDAC)remainsunclear.Methods:STIM1andHIF-1αexpressionwastestedusingimmunohistochemistryintissuemicroarray(TMA)includingpancreaticcancerandmatchednormalpancreatictissues,andtheirrelationshipswithclinicopathologicalparameterswerestatisticallyanalyzed.q-PCR,Westernblot,ChIP,andluciferaseassaywereemployedto030analyzetranscriptionalregulationbetweenHIF-1αandSTIM1inpancreaticcancerPANC-1cells.Results:BothSTIM1andHIF-1αshowedhigherpositiveratesandup-regulatedexpressionincancertissuescomparedtothatofnormaltissues(P<0.05).TheKaplan–MeiermethodrevealedthathigherHIF-1αandSTIM1expressionlevelsweresignificantlycorrelatedwithdecreaseddisease-freesurvival(P=0.025andP=0.029,respectively).TheexpressionofHIF-1αshowedasignificantpositivecorrelationwiththatofSTIM1incancertissues(rs=0.3343,P=0.0011)andpancreaticcancercelllines.Furthermore,ChIPandluciferaseassaysconfirmedthatHIF-1αboundtotheSTIM1promoterandregulateditsexpressioninPANC-1cells.Conclusions:Inhypoxiamicroenvironment,up-regulatedexpressionofSTIM1mediatedbyHIF-1αpromotesPDACprogression.HIF-1αandSTIM1arepotentialprognosticmarkersand/ortherapeutictargetsforPDACtreatment.

简介：Theemergingperfect-absorbermetamaterials(PAMs)provideanalternativematerialapproachforthenextgenerationofelectromagneticdetectionatanyfrequencybandofinterest.Onetypeofdualcross-shapedPAMsisdevelopedtoobtainmultiplex-bandspectrumabsorptionatmid-infraredregion.Threedistinctabsorptionpeaksareattributedtothepolarizationsensitivityexcitationoftheplasmonicresonance.Thechargedensitydistributions,whichareexcitedbyresonantelectromagneticwavespassingthroughthePAMsmedium,provideinsightsintotheobservedabsorptionbehavior.WefindthattheretrievedopticalpropertiesofthePAMsincludingpermittivityandpermeabilityarestillconsistentwiththesumoftheDrudeandLorentztypemodelsatwavelengthsrangingfrom2.0to10.0mm.Suchmultiplex-bandabsorptionpropertiesenabletheproposedPAMsapowerfultoolforthedirectdetectionofmultiplemolecularvibrationalstructures,andformultiplespectrainfrareddetection.

简介：Recentstudiesindicatethatcell-cyclecheckpointsaretightlycorrelatedwiththeregulationofapoptosis,inwhichp53playsanimportantrole.OurpresentworksshowthattheexpressionofE6/E7oncogenesofhumanpapillomavirusinHeLacellsisinhibitedinthepresenceofanti-tumorreagenttripchlorolide(TC),whichresultsintheup-regulationofp53inHeLacells.Interestingly,underthesameTC-treatment,thecellsattheearlyS-phasearemoresusceptibletoapoptosisthanthoseatthemiddleS-phasealthoughp53proteinisstabilizedtothesamelevelinbothsituations.Significantdifferenceisexhibitedbetweenthetwospecifiedexpressionprofiles.Furtheranalysisdemonstratesthatanti-apoptoticgenesurvivinisup-regulatedbyp53intheTC-treatedmiddle-Scells,whereasitisdown-regulatedbyp53intheTC-treatedearly-Scells.Takentogether,thepresentstudyindicatesthatthedifferentialp53-regulatedexpressionofsurvivinatdifferentstagesofthecellcycleresultsindifferentcellularoutputsunderthesameapoptosis-inducer.

简介：AbstractBackground:Fibrosis in the peripheral airways contributes to airflow limitation in patients with chronic obstructive pulmonary disease (COPD). However, the key proteins involved in its development are still poorly understood. Thus, we aimed to identify the differentially expressed proteins (DEPs) between smoker patients with and without COPD and elucidate the molecular mechanisms involved by investigating the effects of the identified biomarker candidate on lung fibroblasts.Methods:The potential DEPs were identified by isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis. The messenger RNA and protein levels of clusterin (CLU) in COPD patients and 12% cigarette smoke extract (CSE)-treated human bronchial epithelial cells were determined at the indicated time points. Furthermore, an in vitro COPD model was established via the administration of 8% CSE to normal human lung fibroblasts (NHLFs) at indicated time points. The effects of CSE treatment and CLU silencing on proliferation and activation of lung fibroblasts were analyzed.Results:A total of 144 DEPs were identified between COPD patients and normal smokers. The iTRAQ-based proteomics and bioinformatics analyses identified CLU as a serum biomarker candidate. We also discovered that CLU levels were significantly increased (P < 0.0001) in Global Initiative for Obstructive Lung Disease II, III, and IV patients and correlated (P < 0.0001) with forced expiratory volume in 1 s (R=-0.7705), residual volume (RV) (R = 0.6281), RV/total lung capacity (R = 0.5454), and computerized tomography emphysema (R = 0.7878). Similarly, CLU levels were significantly increased in CSE-treated cells at indicated time points (P < 0.0001). The CSE treatment significantly inhibited the proliferation, promoted the inflammatory response, differentiation of NHLFs, and collagen matrix deposition, and induced the apoptosis of NHLFs; however, these effects were partially reversed by CLU silencing.Conclusion:Our findings suggest that CLU may play significant roles during airway fibrosis in COPD by regulating lung fibroblast activation.

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简介：AbstractBackground:Systemic lupus erythematosus (SLE) is a complex autoimmune disease, and the mechanism of SLE is yet to be fully elucidated. The aim of this study was to explore the role of two-pore segment channel 2 (TPCN2) in SLE pathogenesis.Methods:Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of TPCN2 in SLE. We performed a loss-of-function assay by lentiviral construct in Jurkat and THP-1 cell. Knockdown of TPCN2 were confirmed at the RNA level by qRT-PCR and protein level by Western blotting. Cell Count Kit-8 and flow cytometry were used to analyze the cell proliferation, apoptosis, and cell cycle of TPCN2-deficient cells. In addition, gene expression profile of TPCN2-deficient cells was analyzed by RNA sequencing (RNA-seq).Results:TPCN2 knockdown with short hairpin RNA (shRNA)-mediated lentiviruses inhibited cell proliferation, and induced apoptosis and cell-cycle arrest of G2/M phase in both Jurkat and THP-1 cells. We analyzed the transcriptome of knockdown- TPCN2-Jurkat cells, and screened the differential genes, which were enriched for the G2/M checkpoint, complement, and interleukin-6-Janus kinase-signal transducer and activator of transcription pathways, as well as changes in levels of forkhead box O, phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin, and T cell receptor pathways; moreover, TPCN2 significantly influenced cellular processes and biological regulation.Conclusion:TPCN2 might be a potential protective factor against SLE.

简介：AbstractBackground:Pancreatic stellate cells (PSCs) activation plays a critical role in the development of chronic pancreatitis. Previous studies confirmed that thromboxane A2 receptor (TxA2r) was overexpressed in activated PSCs in rats. The purpose of this study was to investigate the role of TxA2r in the activation of PSCs induced by 8-epi-prostaglandin F2α (8-epi-PGF2α).Methods:TxA2r expression in both quiescent and activated PSCs was detected by immunocytochemistry and immunoblot assay. Isolated PSCs were treated with 8-epi-PGF2α (10-6, 10-7, 10-8 mol/L) for 48 h, and SQ29548 (10-4, 10-6, and 10-7 mol/L), a TxA2r-specific antagonist, for 48 h, respectively, to identify the drug concentration with the best biological effect and the least cytotoxicity. Then isolated PSCs were treated with SQ29548 (10-4 mol/L) for 2 h, followed by 10-7 mol/L 8-epi-PGF2α for 48 h. Real-time polymerase chain reaction was performed to detect the messenger RNA (mRNA) levels of α-smooth muscle actin (α-SMA) and collagen I. Comparisons between the groups were performed using Student’s t test.Results:TxA2r was up-regulated in activated PSCs in vitro compared with quiescent PSCs (all P < 0.001). Compared with the control group, different concentrations of 8-epi-PGF2a significantly increased mRNA levels of α-SMA (10-6 mol/L: 2.23 ± 0.18 vs. 1.00 ± 0.07, t= 10.70, P < 0.001; 10-7 mol/L: 2.91 ± 0.29 vs. 1.01 ± 0.08, t= 10.83, P <0.001; 10-8 mol/L, 1.67 ± 0.07 vs. 1.00 ± 0.08, t= 11.40, P < 0.001) and collagen I (10-6 mol/L: 2.68 ± 0.09 vs. 1.00 ± 0.07, t = 24.94, P < 0.001; 10-7 mol/L: 2.12 ± 0.29 vs. 1.01 ± 0.12, t = 6.08, P < 0.001; 10-8 mol/L: 1.46 ± 0.15 vs. 1.00 ± 0.05, t = 4.93, P = 0.008). However, different concentrations of SQ29548 all significantly reduced the expression of collagen I (10-4 mol/L: 0.55 ± 0.07 vs. 1.00 ± 0.07, t = 10.47, P < 0.001; 10-6 mol/L: 0.56 ± 0.10 vs. 1.00 ± 0.07, t = 6.185, P < 0.001; 10-7 mol/L: 0.27 ± 0.04 vs. 1.00 ± 0.07, t= 15.41, P < 0.001) and α-SMA (10-4 mol/L: 0.06 ± 0.01 vs. 1.00 ± 0.11, t= 15.17, P < 0.001; 10-6 mol/L: 0.28 ± 0.03 vs. 1.00 ± 0.11, t= 11.29, P < 0.001; 10-7 mol/L: 0.14 ± 0.04 vs. 1.00 ± 0.11, t= 12.86, P < 0.001). After being treated with SQ29548 (10-4 mol/L) and then 8-epi-PGF2α (10-7 mol/L), the mRNA levels of a-SMA (0.20 ± 0.08 vs. 1.00 ± 0.00, t= 17.46, P < 0.001) and collagen I (0.69 ± 0.13 vs. 1.00 ± 0.00, t = 4.20, P = 0.014) in PSCs were significantly lower than those of the control group.Conclusions:The results show that 8-epi-PGF2α promoted PSCs activation, while SQ29548 inhibited PSCs activation induced by 8-epi-PGF2α. The result indicated that TxA2r plays an important role during PSC activation and collagen synthesis induced by 8-epi-PGF2αin vitro. This receptor may provide a potential target for more effective antioxidant therapy for pancreatic fibrosis.

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简介：AbstractBackground:Circular RNAs (circRNAs) are considered to be important regulators in cancer biology. In this study, we focused on the effect of circRNA baculoviral inhibitor of apoptosis protein (IAP) repeat containing 6 (circBIRC6) on non-small cell lung cancer (NSCLC) progression.Methods:The NSCLC and adjacent non-tumor tissues were collected at Shanghai Ninth People's Hospital. Quantitative real-time polymerase chain reaction was conducted for assessing the levels of circBIRC6, amyloid beta precursor protein binding protein 2 (APPBP2) messenger RNA (mRNA), baculoviral IAP repeat containing 6 mRNA (BIRC6), and microRNA-217 (miR-217). Western blot assay was adopted for measuring the protein levels of APPBP2, E-cadherin, N-cadherin, and vimentin. Colony formation assay, transwell assay, and flow cytometry analysis were utilized for evaluating cell colony formation, metastasis, and apoptosis. Dualluciferase reporter assay and RNA immunoprecipitation assay were carried out to determine the interaction between miR-217 and circBIRC6 and APPBP2 in NSCLC tissues. The murine xenograft model assay was used to investigate the function of circBIRC6 in tumor formation in vivo. Differences were analyzed via Student's t test or one-way analysis of variance. Pearson's correlation coefficient analysis was used to analyze linear correlation.Results:CircBIRC6 was overexpressed in NSCLC tissues and cells. Knockdown of circBIRC6 repressed the colony formation and metastasis and facilitated apoptosis of NSCLC cells in vitro and restrained tumorigenesis in vivo. Mechanically, circBIRC6 functioned as miR-217 sponge to promote APPBP2 expression in NSCLC cells. MiR-217 inhibition rescued circBIRC6 knockdown-mediated effects on NSCLC cell colony formation, metastasis, and apoptosis. Overexpression of miR-217 inhibited the malignant phenotypes of NSCLC cells, while the effects were abrogated by elevating APPBP2.Conclusion:CircBIRC6 aggravated NSCLC cell progression by elevating APPBP2 via sponging miR-217, which might provide a fresh perspective on NSCLC therapy.

简介：AbstractBackground:Baicalein has been shown to have anti-inflammatory and anti-tumor activities. However, the mechanisms underlying its anti-inflammatory effect on colitis remain unclear.Methods:A dextran sodium sulfate (DSS)-induced model of acute colitis was established in BALB/c mice (6-8 weeks old, weighing 18-22 g). Six groups of mice received: (1) water for 10 days (control), n = 6; (2) DSS 4% solution in the drinking water for 7 days, followed by normal water for 3 days, n = 7; (3), (4), and (5) as for group 2 plus baicalein (10, 20, 40 mg/kg) administered once daily starting on day 1, n = 6; and (6) as for (2) plus 5-aminosalicylic acid (50 mg/kg) administered once daily starting on day 1, n = 6. Body weights, stool consistency, and hematochezia were recorded, and the severity of colitis was evaluated using a disease activity index. On day 11, the mice were euthanized, and organs and blood were collected for analysis. Serum inflammatory factors were detected by enzyme-linked immunosorbent assay; CD11b-positive cells were analyzed by immunofluorescence microscopy; expression of retinoic-acid-receptor-related orphan nuclear receptor gamma, sphingosine kinase 1 (SPHK1), and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) was detected by immunohistochemistry; and expression of nucleotide-binding oligomerization domain 2 (NOD2), SPHK1, sphingosine 1-phosphate receptor 1 (S1PR1), total STAT3, and p-STAT3 were detected by western blotting analysis. Inter-group differences were compared using Student’s t test.Results:Baicalein treatment dose-dependently reduced DSS-induced weight loss (P < 0.01 or P < 0.05), splenomegaly (P < 0.01), and colonic damage, as reflected by amelioration of diarrhea, rectal bleeding, and colonic ulceration, congestion, edema (shown as colon length, P < 0.05 or P < 0.01), and inflammatory cell infiltration. Baicalein also significantly decreased the levels of inflammatory mediators in the serum (P < 0.01) and colon, and significantly inhibited expression of NOD2 SPHK1, S1PR1, and p-STAT3 in the colon (P < 0.05).Conclusions:Baicalein treatment ameliorated colitis in mice by inhibiting S1P-STAT3 signaling, suggesting that this flavonoid might be beneficial in the treatment of colitis.