ABSTRACT
BACKGROUND: Acute suppurative terminal cholangitis (ASTC) is rarer than acute obstructive cholangitis and is not well studied. To explore this subtype of acute cholangitis, we described our clinical experience with ASTC. METHODS: We performed a retrospective review of patients with ASTC admitted to our center from September 2014 to August 2020. We analyzed their clinical characteristics, including etiology, clinical manifestations, imaging features, treatment and prognosis. RESULTS: A total of 32 ASTC patients were included in the analysis. The majority of the patients had a history of biliary operations, and clinical manifestations were occult and atypical. The positive rate of bacterial culture was 46.9%. All the patients had typical imaging features on computed tomography and magnetic resonance imaging. Treatment with effective antibiotics was provided as soon as diagnosis was established. After treatment, most patients had a good outcome. Elevated levels of total bilirubin, aspartate aminotransferase, procalcitonin and gamma-glutamyltransferase were the characteristics of critically ill patients and were associated with relatively poor prognosis. CONCLUSIONS: Our results demonstrated that ASTC should be recognized as a new subtype of acute cholangitis, and that earlier diagnosis and more personalized treatments are needed.
Subject(s)
Cholangitis , Humans , Suppuration/complications , Prognosis , Cholangitis/diagnosis , Cholangitis/therapy , Hospitalization , Tomography, X-Ray Computed , Acute Disease , Retrospective StudiesABSTRACT
Nanohydrogelation of covalent organic frameworks (COFs) will undoubtedly open up new applications for them in water, such as aqueous catalysis and biomedicine. It is currently a great challenge to achieve water dispersion of COFs through either bottom-up construction strategies or top-down exfoliating technologies. Herein, poly(N-isopropylacrylamide) (PNIPAM)-postmodified COF nanohydrogels (COF-NHGs) are successfully designed and synthesized via in situ atom-transfer radical polymerization (ATRP) on a scaffold of COFs. During the polymer growth process, the bulk COFs are exfoliated into nanosheets with a lateral size of â¼500 nm and a thickness of â¼6.5 nm. Moreover, their size can be precisely controlled by the degree of polymerization of PNIPAMs. In aqueous solution, the obtained COF-NHGs are assembled into nanohydrogels retaining intra-plane crystallinity and exhibit a temperature-sensitive sol-gel phase transition. With excellent solubility in organic solvents, the COF-NHGs' intrinsic physical properties in the solution state can be characterized through their solution nuclear magnetic resonance and ultraviolet absorption spectra. These results put forward new opportunities for regulating the solution processability of COFs and building an intelligent, stimuli-response platform of COF-polymer composite nanohydrogels for device applications.
ABSTRACT
Metabolic cardiomyopathy (MC) is characterized by intracellular lipid accumulation and utilizing fatty acids as a foremost energy source, thereby leading to excess oxidative stress and mitochondrial dysfunction. There is no effective therapy available yet. In this study we investigated whether defective mitophagy contributed to MC and whether urolithin A (UA), a naturally occurring microflora-derived metabolite, could protect against MC in experimental obese mice. Mice were fed high fat diet for 20 weeks to establish a diet-induced obese model. We showed that mitochondrial autophagy or mitophagy was significantly downregulated in the heart of experimental obese mice. UA (50 mg·kg-1·d-1, for 4 weeks) markedly activated mitophagy and ameliorated MC in obese mice by gavage. In PA-challenged H9C2 cardiomyocytes, UA (5 µM) significantly increased autophagosomes and decreased autolysosomes. Furthermore, UA administration rescued PINK1/Parkin-dependent mitophagy and relieved mitochondrial defects in the heart of obese mice, which led to improving cardiac diastolic function and ameliorating cardiac remodelling. In PA-challenged primarily isolated cardiomyocytes, both application of mitophagy inhibitor Mdivi-1 (15 µM) and silencing of mitophagy gene Parkin blunted the myocardial protective effect of UA. In summary, our data suggest that restoration of mitophagy with UA ameliorates symptoms of MC, which highlights a therapeutic potential of UA in the treatment of MC.
Subject(s)
Cardiomyopathies , Mitophagy , Mice , Animals , Mice, Obese , Protein Kinases/metabolism , Cardiomyopathies/metabolism , Myocytes, Cardiac/metabolism , Obesity/complications , Obesity/drug therapy , Obesity/metabolism , Ubiquitin-Protein Ligases/metabolismABSTRACT
Ubiquitin-specific protease 3 (USP3), a kind of cysteine protease, is a crucial family member of deubiquitinating enzymes. USP3 is aberrantly expressed in several tumors, which may contribute to cancer progression. However, the role of USP3 in gallbladder cancer (GBC) is still unknown. In the current study, we detected the expression of USP3 in GBC tissues, measured its contribution to the cell proliferation in GBC progression, and further studied the underlying mechanism of USP3 in GBC through pyruvate kinase L/R (PKLR; a kind of glycolytic enzyme). We found that the expression of USP3 in GBC tissues were higher than that of adjacent tissues, and the protein levels of USP3 and PKLR were positively correlated. Additionally, overexpressed USP3 significantly promoted cell proliferation in vitro and tumor growth in vivo, while the silencing of USP3 inhibited proliferation and tumor growth. Glycolysis in GBC cells ws promoted by the USP3 overexpression and inhibited bye USP3 downregulation. Moreover, the loss of USP3 promoted the ubiquitination and weakened the stability of PKLR. Results of the rescue assay confirmed that PKLR knockdown suppressed USP3-induced oncogenic activity in USP3 overexpressed GBC cells. These findings imply that USP3 is an essential positive regulator in GBC progression, and USP3-PKLR plays a vital role in the progression and metabolism of GBC.
Subject(s)
Gallbladder Neoplasms , Humans , Gallbladder Neoplasms/genetics , Gallbladder Neoplasms/metabolism , Gallbladder Neoplasms/pathology , Pyruvate Kinase/metabolism , Ubiquitin-Specific Proteases/genetics , Ubiquitin-Specific Proteases/metabolism , Cell Proliferation , Ubiquitination , Cell Line, TumorABSTRACT
Hepatic stellate cell (HSC) activation plays an important role in the pathogenesis of liver fibrosis, and epithelial-mesenchymal transition (EMT) is suggested to potentially promote HSC activation. Superoxide dismutase 3 (SOD3) is an extracellular antioxidant defense against oxidative damage. Here, we found downregulation of SOD3 in a mouse model of liver fibrosis induced by carbon tetrachloride (CCl4 ). SOD3 deficiency induced spontaneous liver injury and fibrosis with increased collagen deposition, and further aggravated CCl4 -induced liver injury in mice. Depletion of SOD3 enhanced HSC activation marked by increased α-smooth muscle actin and subsequent collagen synthesis primarily collagen type I in vivo, and promoted transforming growth factor-ß1 (TGF-ß1)-induced HSC activation in vitro. SOD3 deficiency accelerated EMT process in the liver and TGF-ß1-induced EMT of AML12 hepatocytes, as evidenced by loss of E-cadherin and gain of N-cadherin and vimentin. Notably, SOD3 expression and its pro-fibrogenic effect were positively associated with sirtuin 1 (SIRT1) expression. SOD3 deficiency inhibited adenosine monophosphate-activated protein kinase (AMPK) signaling to downregulate SIRT1 expression and thus involving in liver fibrosis. Enforced expression of SIRT1 inhibited SOD3 deficiency-induced HSC activation and EMT, whereas depletion of SIRT1 counteracted the inhibitory effect of SOD3 in vitro. These findings demonstrate that SOD3 deficiency contributes to liver fibrogenesis by promoting HSC activation and EMT process, and suggest a possibility that SOD3 may function through modulating SIRT1 via the AMPK pathway in liver fibrosis.
Subject(s)
Chemical and Drug Induced Liver Injury/enzymology , Collagen Type I/metabolism , Epithelial-Mesenchymal Transition , Hepatic Stellate Cells/enzymology , Liver Cirrhosis, Experimental/enzymology , Liver/enzymology , Superoxide Dismutase/deficiency , AMP-Activated Protein Kinases/metabolism , Animals , Carbon Tetrachloride , Cells, Cultured , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/genetics , Chemical and Drug Induced Liver Injury/pathology , Hepatic Stellate Cells/pathology , Liver/pathology , Liver Cirrhosis, Experimental/chemically induced , Liver Cirrhosis, Experimental/genetics , Liver Cirrhosis, Experimental/pathology , Male , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction , Sirtuin 1/metabolism , Superoxide Dismutase/geneticsABSTRACT
BACKGROUND: Delayed gastric emptying (DGE) is the main complication after pancreaticoduodenectomy (PD), but the mechanism is still unclear. The aim of this study was to elucidate the role of complete resection of the gastric antrum in decreasing incidence and severity of DGE after PD. METHODS: Sprague-Dawley rats were divided into three groups: expanded resection (ER group), complete resection (CR group), and incomplete resection (IR group) of the gastric antrum. The tension (g) of remnant stomach contraction was observed. We analyzed the histological morphology of the gastric wall by different excisional methods after distal gastrectomy. Moreover, patients underwent PD at our department between January 2012 and May 2016 were included in the study. These cases were divided into IR group and CR group of the gastric antrum, and the clinical data were retrospectively analyzed. RESULTS: The ex vivo remnant stomachs of CR group exhibited much greater contraction tension than others (P < 0.05). The contraction tension of the remnant stomach increased with increasing acetylcholine concentration, while remained stable at the concentration of 10 × 10-5 mol/L. Furthermore, 174 consecutive patients were included and retrospectively analyzed in the study. The incidence of DGE was significantly lower (3.5% vs. 21.3%, P < 0.01) in CR group than in IR group. In addition, hematoxylin-eosin staining analyses of the gastric wall confirmed that the number of transected circular smooth muscle bundles were higher in IR group than in CR group (8.24 ± 0.65 vs. 3.76 ± 0.70, P < 0.05). CONCLUSIONS: The complete resection of the gastric antrum is associated with decreased incidence and severity of DGE after PD. Gastric electrophysiological and physiopathological disorders caused by damage to gastric smooth muscles might be the mechanism underlying DGE.
Subject(s)
Gastroparesis , Pancreaticoduodenectomy , Animals , Gastric Emptying , Gastroparesis/epidemiology , Gastroparesis/etiology , Gastroparesis/prevention & control , Humans , Incidence , Pancreaticoduodenectomy/adverse effects , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/prevention & control , Pyloric Antrum/diagnostic imaging , Pyloric Antrum/surgery , Rats , Rats, Sprague-Dawley , Retrospective StudiesABSTRACT
A series of organic-inorganic hybrid perovskites ABX3 (A=diprotonated 1,4-diazabicyclo[2.2.2]octane or piperazine; B=Na+ or K+ ; X=ClO4- or BF4- ) has been synthesized. They feature a cubic cage-like host-guest structures of which A is the cationic guest residing in the anionic cage B8 X12 , B is the vertex of the cage with variable coordination numbers between six and twelve, and X is the bridging ligand with mono- and/or bidentate coordination modes. The extended Goldschmidt tolerance factor t is used to describe the phase stability of the compounds. Differential scanning calorimetry, variable-temperature structural analyses, and dielectric measurements reveal that order-disorder transitions of the A guest and/or X bridging ligand are supposed to be responsible for structural phase transitions and dielectric switching in the compounds.
ABSTRACT
BACKGROUND: The role of physical activity in preventing gallstone disease independent of its effect on the body weight has not been well established. We performed a systematic review and meta-analysis of cohort and case-control studies to analyze this potential association. METHODS: We searched PubMed and EMBASE to identify all published studies in English through April 2016. We pooled the relative risks (RRs) or odds ratios (ORs) and corresponding 95% confidence intervals (CIs) from individual studies using a random-effects model to investigate associations between physical activity and the risk of gallstone disease. RESULTS: A total of 16 studies comprising 19 independent reports of approximately 260,000 participants met the inclusion criteria, including 6 case-control studies and 13 cohort studies. In a pooled analysis of cohort studies, physical activity (in a comparison of the highest-level and the lowest-level groups) was associated with a reduced risk of gallstone disease (RR=0.85; 95% CI, 0.78-0.92; I=79.5%). For men, the RR was 0.76 (95% CI, 0.60-0.97), and for women, the RR was similar (RR=0.77; 95% CI, 0.66-0.91). In a dose-response analysis, the RR of gallstone disease was 0.87 (95% CI, 0.83-0.92; I=1.0%) per 20 metabolic equivalent-hours of recreational physical per week. In comparison, case-control studies yielded a stronger significant risk reduction for gallstone disease (OR=0.64; 95% CI, 0.46-0.90; I=76.6%). CONCLUSIONS: This study suggests an inverse association between physical activity and gallstone disease in both men and women; however, these findings should be interpreted cautiously because of study heterogeneity.
Subject(s)
Exercise , Gallstones/prevention & control , Risk Reduction Behavior , Case-Control Studies , Female , Gallstones/diagnosis , Gallstones/epidemiology , Humans , Male , Odds Ratio , Prognosis , Protective Factors , Risk Factors , Sedentary BehaviorABSTRACT
BACKGROUND: Postoperative pancreatic fistula (POPF) is a serious complication and results in prolonged hospitalization and high mortality. The present study aimed to evaluate the safety and effectiveness of total closure of pancreatic section for end-to-side pancreaticojejunostomy in pancreaticoduodenectomy (PD). METHODS: This was a prospective randomized clinical trial comparing the outcomes of PD between patients who underwent total closure of pancreatic section for end-to-side pancreaticojejunostomy (Group A) vs those who underwent conventional pancreaticojejunostomy (Group B). The primary endpoint was the incidence of pancreatic fistula. Secondary endpoints were morbidity and mortality rates. RESULTS: One hundred twenty-three patients were included in this study. The POPF rate was significantly lower in Group A than that in Group B (4.8% vs 16.7%, P<0.05). About 38.3% patients in Group B developed one or more complications; this rate was 14.3% in Group A (P<0.01). The wound/abdominal infection rate was also much higher in Group B than that in Group A (20.0% vs 6.3%, P<0.05). Furthermore, the average hospital stays of the two groups were 18 days in Group A, and 24 days in Group B, respectively (P<0.001). However, there was no difference in the probability of mortality, biliary leakage, delayed gastric emptying, and pulmonary infection between the two groups. CONCLUSION: Total closure of pancreatic section for end-to-side pancreaticojejunostomy is a safe and effective method for pancreaticojejunostomy in PD.
Subject(s)
Pancreatic Fistula/prevention & control , Pancreatic Neoplasms/surgery , Pancreaticoduodenectomy/methods , Pancreaticojejunostomy/methods , Aged , China/epidemiology , Female , Humans , Incidence , Length of Stay , Male , Middle Aged , Pancreatic Fistula/diagnosis , Pancreatic Fistula/mortality , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Pancreaticoduodenectomy/adverse effects , Pancreaticoduodenectomy/mortality , Pancreaticojejunostomy/adverse effects , Pancreaticojejunostomy/mortality , Prospective Studies , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Immunosuppression reagents have side effects and cause considerable long-term morbidity and mortality in patients after liver transplantation. Sufficient evidences showed that minimization or withdrawal of immunosuppression reagents does not deteriorate the recipient's immune response and physiological function and therefore, is feasible in some recipients of liver transplantation. However, the mechanisms are not clear. The present review was to update the current status of immunosuppression in liver transplantation and the mechanism of minimization or withdrawal of immunosuppression in liver recipients. DATA SOURCES: We searched articles in English on minimization or withdrawal of immunosuppression in liver transplantation in PubMed. We focused on the basic mechanisms of immune tolerance in liver transplantation. Studies on immunosuppression minimization or withdrawal protocols and biomarker in tolerant recipients were also analyzed. RESULTS: Minimization or withdrawal of immunosuppression can be achieved by the induction of immune tolerance, which may not be permanent and can be affected by various factors. However, accurately evaluating immune status post-transplant is a prerequisite to achieve individualized immunosuppression. Numerous mechanisms for immune tolerance have been found, including immunophenotypic shift of memory CD8+ T cells and CD4+ T cell subsets. Activation of the inflammasome through apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) in dendritic cells is associated with rejection after liver transplantation. CONCLUSIONS: Minimization or withdrawal of immunosuppression can be achieved by the induction of immune tolerance via different mechanisms. This process could be affected by immunophenotypic shift of memory CD8+ T cells and CD4+ T cell subsets, which may be correlated with activation of the inflammasome through ASC in dendritic cells.
Subject(s)
Immune Tolerance/immunology , Immunosuppressive Agents/administration & dosage , Liver Transplantation , Withholding Treatment , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Humans , Inflammasomes/immunologyABSTRACT
Glutathione (GSH) is a major antioxidant in organisms. An alteration in GSH concentration has been implicated in a number of pathological conditions. Therefore, GSH sensing has become a critical issue. In this study, a disposable strip used for tyrosinase-modified electrochemical testing was fabricated for the detection of GSH levels in vivo. The system is based on tyrosinase as a biorecognition element and a screen-printed carbon electrode (SPCE) as an amperometric transducer. On the tyrosinase-SPCE strips, the oxidation reaction from catechol to o-quinone was catalyzed by tyrosinase. The tyrosinase-SPCE strips were modified with gold nanoparticles (AuNPs). In the presence of AuNPs of 25 nm diameter, the cathodic peak current of cyclic voltammetry (CV) was significantly enhanced by 5.2 fold. Under optimized conditions (250 µM catechol, 50 mM phosphate buffer, and pH 6.5), the linear response of the tyrosinase-SPCE strips ranged from 31.25 to 500 µM GSH, with a detection limit of approximately 35 µM (S/N > 3). The tyrosinase-SPCE strips have been used to detect real samples of plasma and tissue homogenates in a mouse experiment. The mice were orally administrated with N-acetylcysteine (NAC) 100 mg kg-1 once a day for 7 days; the plasma GSH significantly enhanced 2.8 fold as compared with saline-treated mice (1123 vs. 480 µM µg-1 protein). NAC administration also could alleviate the adverse effect of GSH reduction in the mice treated with doxorubicin.
ABSTRACT
BACKGROUND: Collateralized intra- and extra-hepatic routes in patients with Budd-Chiari syndrome (BCS) were important. This study aimed to investigate the feasibility and clinical outcomes of the staged management of BCS based on the degree of compensation provided by intra- or extra-hepatic collateral circulations. METHODS: A total of 103 adult patients with BCS caused by co-obstruction of the inferior vena cava (IVC) and main hepatic veins (MHVs) between March 2001 and October 2009 were enrolled in this study. Based on the pathological classification and degree of hemodynamic compensation by collateral circulations, treatment priority for IVC hypertension was determined in the first-stage treatment. Patients were deemed eligible for second-stage treatment when the first-stage treatment failed to relieve. RESULTS: Imaging results revealed that most patients had collateral circulations to different extents. Based on the degree of compensation provided by these collateral circulations, 74 patients underwent single-stage treatment for IVC hypertension, i.e., radiologic intervention (RI) for 61 patients and surgical procedures (SPs) for 13. One patient was treated for portal hypertension. Twenty-nine patients underwent second-stage treatment (25 underwent RI and SP, and 4 only SP). The general morbidity and mortality after all procedures were 8.3% and 1.5%, respectively. After a median follow-up of 35 months, 4 patients underwent second-stage treatment and 7 underwent recanalization of the IVC/MHVs. Two patients died of hepatocellular carcinoma and 1 died of graft obstruction. CONCLUSION: Staged management produces excellent outcomes for patients with BCS caused by co-obstruction of the IVC and MHVs.
Subject(s)
Angioplasty, Balloon , Budd-Chiari Syndrome/therapy , Hepatic Veins/surgery , Vascular Surgical Procedures , Vena Cava, Inferior/surgery , Adult , Angioplasty, Balloon/adverse effects , Angioplasty, Balloon/instrumentation , Angioplasty, Balloon/mortality , Budd-Chiari Syndrome/diagnosis , Budd-Chiari Syndrome/etiology , Budd-Chiari Syndrome/mortality , Budd-Chiari Syndrome/physiopathology , Budd-Chiari Syndrome/surgery , Collateral Circulation , Feasibility Studies , Female , Hepatic Veins/physiopathology , Humans , Hypertension, Portal/etiology , Hypertension, Portal/physiopathology , Hypertension, Portal/therapy , Liver Circulation , Male , Middle Aged , Stents , Time Factors , Treatment Outcome , Vascular Surgical Procedures/adverse effects , Vascular Surgical Procedures/mortality , Vena Cava, Inferior/physiopathology , Venous Pressure , Young AdultABSTRACT
A pair of chiral, emissive and porous tubular multi-functional organic molecular cages were synthesized easily by imine chemistry of 4,4',4'',4'''-(ethene-1,1,2,2-tetrayl)-tetrabenzaldehyde (ETTBA) with (R,R)- or (S,S)-diaminocyclohexane (CHDA). It was found that the chirality of CHDA was transferred and amplified to tetraphenylethylene (TPE) in the process of formation of cages, which further endowed the cages with circularly polarized luminescence (CPL) characteristics. As a result of the synergy of the chirality and porous structure in the solid state, both cages exhibited a good chiral adsorption enantioselectivity to a series of aromatic racemates.
ABSTRACT
It remains a great challenge to design and synthesize organic luminescent molecules with strong emission in both dilute solution and aggregate state. Herein, an organic cage with dodecadansyl groups (D-RCC1) from an easy sulfonation reaction displays strong emissive behavior in dilute organic solution with a quantum yield of 42%. Moreover, D-RCC1 exhibits an ultrahigh quantum yield of 92% in the solid state, which is more than 3 times that of 27% for the model compound D-DEA. The results of the experiment and theoretical calculation show that the three-dimensional symmetrical skeleton of the organic cage anchored evenly by multiple dye molecules effectively satisfies both high local density and a symmetrical distribution of chromophores, which prevents the interaction of dye molecules and ensures that dye molecules have strong emission in both single-molecule and aggregate states.
ABSTRACT
As the most aggressive tumor, the outcome of pancreatic cancer (PACA) has not improved observably over the last decade. Anatomy-based TNM staging does not exactly identify treatment-sensitive patients, and an ideal biomarker is urgently needed for precision medicine. Based on expression files of 1280 patients from 10 multicenter cohorts, we screened 32 consensus prognostic genes. Ten machine-learning algorithms were transformed into 76 combinations, of which we selected the optimal algorithm to construct an artificial intelligence-derived prognostic signature (AIDPS) according to the average C-index in the nine testing cohorts. The results of the training cohort, nine testing cohorts, Meta-Cohort, and three external validation cohorts (290 patients) consistently indicated that AIDPS could accurately predict the prognosis of PACA. After incorporating several vital clinicopathological features and 86 published signatures, AIDPS exhibited robust and dramatically superior predictive capability. Moreover, in other prevalent digestive system tumors, the nine-gene AIDPS could still accurately stratify the prognosis. Of note, our AIDPS had important clinical implications for PACA, and patients with low AIDPS owned a dismal prognosis, higher genomic alterations, and denser immune cell infiltrates as well as were more sensitive to immunotherapy. Meanwhile, the high AIDPS group possessed observably prolonged survival, and panobinostat may be a potential agent for patients with high AIDPS. Overall, our study provides an attractive tool to further guide the clinical management and individualized treatment of PACA.
Subject(s)
Gene Expression Profiling , Pancreatic Neoplasms , Humans , Gene Expression Profiling/methods , Consensus , Artificial Intelligence , Panobinostat , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Machine Learning , Biomarkers , Pancreatic NeoplasmsABSTRACT
It remains a great challenge to effectively control the pore size in porous organic polymers (POPs) because of the disordered linking modes. Herein, we used organic molecular cages (OMCs), possessing the properties of fixed intrinsic cavities, high numbers of reactive sites and dissolvable processability, as building blocks to construct a molecular cage-based POP (TPP-pOMC) with high valency through covalent cross coupling reaction. In the formed TPP-pOMC, the originating blocking pore channels of TPP-OMC were "turned on" and formed fixed pore channels (5.3 Å) corresponding to the connective intrinsic cavities of cages, and intermolecular pore channels (1.34 and 2.72 nm) between cages. Therefore, TPP-pOMC showed significant enhancement in Brunauer-Emmett-Teller (BET) surface area and CO2 adsorption capacity.
ABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) exhibits high invasiveness and mortality rates, and the molecular mechanisms of HCC have gained increasing research interest. The abnormal DNA damage response has long been recognized as one of the important factors for tumor occurrence and development. Recent studies have shown the potential of the protein RING finger and WD repeat domain 3 (RFWD3) that positively regulates p53 stability in response to DNA damage as a therapeutic target in cancers. AIM: To investigate the relationship between HCC and RFWD3 in vitro and in vivo and explored the underlying molecular signalling transduction pathways. METHODS: RFWD3 gene expression was analyzed in HCC tissues and adjacent normal tissues. Lentivirus was used to stably knockdown RFWD3 expression in HCC cell lines. After verifying the silencing efficiency, Celigo/cell cycle/apoptosis and MTT assays were used to evaluate cell proliferation and apoptosis. Subsequently, cell migration and invasion were assessed by wound healing and transwell assays. In addition, transduced cells were implanted subcutaneously and injected into the tail vein of nude mice to observe tumor growth and metastasis. Next, we used lentiviral-mediated rescue of RFWD3 shRNA to verify the phenotype. Finally, the microarray, ingenuity pathway analysis, and western blot analysis were used to analyze the regulatory network underlying HCC. RESULTS: Compared with adjacent tissues, RFWD3 expression levels were significantly higher in clinical HCC tissues and correlated with tumor size and TNM stage (P < 0.05), which indicated a poor prognosis state. RFWD3 silencing in BEL-7404 and HCC-LM3 cells increased apoptosis, decreased growth, and inhibited the migration in shRNAi cells compared with those in shCtrl cells (P < 0.05). Furthermore, the in vitro results were supported by the findings of the in vivo experiments with the reduction of tumor cell invasion and migration. Moreover, the rescue of RFWD3 shRNAi resulted in the resumption of invasion and metastasis in HCC cell lines. Finally, gene expression profiling and subsequent experimental verification revealed that RFWD3 might influence the proliferation and metastasis of HCC via the Wnt/ß-catenin signalling pathway. CONCLUSION: We provide evidence for the expression and function of RFWD3 in HCC. RFWD3 affects the prognosis, proliferation, invasion, and metastasis of HCC by regulating the Wnt/ß-catenin signalling pathway.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Animals , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Liver Neoplasms/pathology , Mice , Mice, Nude , RNA, Small Interfering , Tumor Suppressor Protein p53/metabolism , Ubiquitin-Protein Ligases , WD40 Repeats , Wnt Signaling Pathway/genetics , beta Catenin/metabolismABSTRACT
BACKGROUND: Mesenchymal stem cells (MSCs) and fibroblasts have intimate relationships, and the phenotypic homology between fibroblasts and MSCs has been recently described. The aim of this study was to investigate the hepatic differentiating potential of human fibroblasts in cirrhotic liver. METHODS: The phenotypes of fibroblasts in cirrhotic liver were labeled by biological methods. After that, the differentiation potential of these fibroblasts in vitro was characterized in terms of liver-specific gene and protein expression. Finally, an animal model of hepatocyte regeneration in severe combined immunodeficient (SCID) mice was created by retrorsine injection and partial hepatectomy, and the expression of human hepatocyte proteins in SCID mouse livers was checked by immunohistochemical analysis after fibroblast administration. RESULTS: Surface immunophenotyping revealed that a minority of fibroblasts expressed markers of MSCs and hepatic epithelial cytokeratins as well as alpha-smooth muscle actin, but homogeneously expressed vimentin, desmin, prolyl 4-hydroxylase and fibronectin. These fibroblasts presented the characteristics of hepatocytes in vitro and differentiated directly into functional hepatocytes in the liver of hepatectomized SCID mice. CONCLUSIONS: This study demonstrated that fibroblasts in cirrhotic liver have the potential to differentiate into hepatocyte-like cells in vitro and in vivo. Our findings infer that hepatic differentiation of fibroblasts may serve as a new target for reversion of liver fibrosis and a cell source for tissue engineering.
Subject(s)
Cell Differentiation , Fibroblasts/pathology , Hepatocytes/pathology , Liver Cirrhosis/pathology , Actins/metabolism , Albumins/metabolism , Animals , Antigens, CD/metabolism , Cell Proliferation , Cells, Cultured , Desmin/metabolism , Fibroblasts/metabolism , Fibroblasts/transplantation , Fibronectins/metabolism , Gene Expression , Hepatocytes/metabolism , Humans , Immunophenotyping , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/pathology , Mice , Mice, SCID , Vimentin/metabolism , alpha-Fetoproteins/metabolismABSTRACT
BACKGROUND: The development of collaterals in Budd-Chiari syndrome has been described and these collaterals play an important role in the presentation of this disease. These collaterals are diagnostic and their use in management strategy has never been evaluated. This study aimed to investigate the indications, feasibility and necessity of invasive treatment for patients with Budd-Chiari syndrome and to determine whether such a strategy is necessary for optimal management. METHODS: Twenty-nine patients who had been treated at our unit were enrolled in this study. Based on physical and biochemical examination, and hemodynamic compensation by collaterals, 18 patients underwent radiological intervention (group A), while the other 11 had no invasive treatment (group B). The related hemodynamic parameters were acquired when percutaneous angiography was performed. RESULTS: In group A, all patients underwent successfully inferior vena cava (IVC) balloon angioplasty with or without stenting. Four patients also underwent hepatic vein angioplasty. In these patients, the mean IVC pressure before and after treatment was statistically different (29.3+/-9.2 vs 15.1+/-4.6 mmHg, P<0.01). The mean IVC pressure was much lower in group B than in group A (12.9+/-2.4 vs 29.3+/-9.2 mmHg, P<0.01), but there was no difference from that of the patients after radiological treatment (12.9+/-2.4 vs 15.1+/-4.6 mmHg, P>0.05). Median follow-up was 32.3 months (mean 21.3 months; range 3-61 months). In the course of follow-up, the patients in group A survived with good systemic status except for re-stenosis in one patient who underwent re-canalization of the IVC. In group B, 10 patients had good systemic status except one patient who had a meso-caval shunt because of deterioration. CONCLUSIONS: The rationale of "early diagnosis and early treatment" is not suitable for all patients with Budd-Chiari syndrome. Satisfactory survival can be achieved in some patients without invasive treatment, who are completely compensated by rich collaterals. Nonetheless, a positive treatment procedure should be performed if the patient's situation worsens in the course of regular follow-up.
Subject(s)
Angioplasty, Balloon , Budd-Chiari Syndrome/therapy , Collateral Circulation , Hepatic Veins/physiopathology , Liver Circulation , Vena Cava, Inferior/physiopathology , Venous Pressure , Adult , Angioplasty, Balloon/adverse effects , Angioplasty, Balloon/instrumentation , Anticoagulants/therapeutic use , Budd-Chiari Syndrome/diagnosis , Budd-Chiari Syndrome/physiopathology , China , Female , Hepatic Veins/diagnostic imaging , Humans , Male , Middle Aged , Recurrence , Stents , Time Factors , Tomography, X-Ray Computed , Treatment Outcome , Ultrasonography, Doppler , Vena Cava, Inferior/diagnostic imaging , Young AdultABSTRACT
In this study, we introduced four "claw-like" units of dipicolylamine (DPA) to a tetraphenylethylene (TPE)-based organic molecular cage (DPA-TPE-Cage). Coordinated with Zn2+ ions, the obtained ZnDPA-TPE-Cage exhibited aggregation induced emission (AIE) effects and oxidase-like properties, which endowed it with the ability to selectively image and kill Gram-positive bacteria S. aureus efficiently.