Research on the mechanism of sea buckthorn leaf Fu tea in the treatment of hyperlipidemia.

Background: Hyperlipidemia (HLP) presents a significant challenge to global public health. Mounting evidence suggests that statins, the recommended first-line lipid-lowering agents, have significant adverse effects. Consequently, the quest for natural and efficacious alternative therapies is steadily emerging as a research priority for HLP prevention and treatment. Consumption of tea, which is rich in diverse biologically active compounds with the capacity to regulate lipid metabolism and combat obesity, has emerged as a promising alternative therapy. Sea buckthorn leaves are rich in a multitude of biologically active substances, have a hypolipidemic effect, and can be used as a raw material for tea because of their unique flavor. There is a suggestion that combining Aspergillus cristatus with tea could modify or boost the lipid-lowering active compounds present in tea, thereby increasing its efficacy in regulating lipid metabolism. Results: Sea Buckthorn Leaf Fu Tea (SBLFT) was obtained by fermentation when sea buckthorn leaves contained 42 % moisture, inoculated with Aspergillus cristatus 0.2 mL/g, and incubated for 8 d at constant temperature. Animal experiments demonstrated that SBLFT significantly inhibited body weight gain in HLP rats and reduced lipid content and serum oxidative stress. In addition, liver tissue sections and functional indices showed that SBLFT can improve liver morphology and function abnormalities. Reverse transcription-polymerase chain reaction results indicated that the expression of Liver kinase B1 (LKB1), adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), acetyl CoA carboxylase 1 (ACC1), and sterol-regulatory element binding protein-1 (SREBP1c) gene related to lipid metabolism was altered. Conclusion: SBLFT improved HLP, specifically via promoting the expression of LKB1 in the liver of HLP rats, activating AMPK, and inhibiting ACC1 and SREBP1c expression, resulting in the inhibition of fatty acid and triglyceride synthesis-related enzymes at the transcriptional level.

Novel imidazo[1,2,4] triazole derivatives: Synthesis, fluorescence, bioactivity for SHP1.

The Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) is a convergent node for oncogenic cell-signaling cascades. Consequently, SHP1 represents a potential target for drug development in cancer treatment. The development of efficient methods for rapidly tracing and modulating the SHP1 activity in complex biological systems is of considerable significance for advancing the integration of diagnosis and treatment of the related disease. Thus, we designed and synthesized a series of imidazo[1,2,4] triazole derivatives containing salicylic acid to explore novel scaffolds with inhibitory activities and good fluorescence properties for SHP1. The photophysical properties and inhibitory activities of these imidazo[1,2,4] triazole derivatives (5a-5y) against SHP1PTP were thoroughly studied from the theoretical simulation and experimental application aspects. The representative compound 5p exhibited remarkable fluorescence response (P: 0.002) with fluorescence quantum yield (QY) of 0.37 and inhibitory rate of 85.21 ± 5.17% against SHP1PTP at the concentration of 100 µM. Furthermore, compound 5p showed obvious aggregation caused quenching (ACQ) effect and had high selectivity for Fe3+ ions, good anti-interference and relatively low detection limit (5.55 µM). Finally, the cellular imaging test of compound 5p also exhibited good biocompatibility and certain potential biological imaging application. This study provides a potential way to develop molecules with fluorescent properties and bioactivities for SHP1.

AgAuS Quantum Dots as a Highly Efficient Near-Infrared Electrochemiluminescence Emitter for the Ultrasensitive Detection of MicroRNA.

Herein, the novel alloyed silver gold sulfur quantum dots (AgAuS QDs) with highly efficient near-infrared (NIR) electrochemiluminescence (ECL) emission at 707 nm were successfully prepared to construct a biosensing platform for ultrasensitive detection of microRNA-222 (miRNA-222). Interestingly, AgAuS QDs revealed excellent ECL efficiency (34.91%) compared to that of Ag2S QDs (10.30%), versus the standard [Ru(bpy)3]2+/S2O82- system, which benefited from the advantages of abundant surface defects and narrow bandgaps by Au incorporation. Additionally, an improved localized catalytic hairpin self-assembly (L-CHA) system was developed to display an increased reaction speed by improving the local concentration of DNA strands, which addressed the obstacles of time-consuming traditional CHA systems. As a proof of concept, based on AgAuS QDs as an ECL emitter and improved localized CHA systems as a signal amplification strategy, a "signal on-off" ECL biosensor was developed to exhibit a superior reaction rate and excellent sensitivity with a detection limit of 10.5 aM for the target miRNA-222, which was further employed for the analysis of miRNA-222 from cancer cell (MHCC-97L) lysate. This work advances the exploration of highly efficient NIR ECL emitters to construct an ultrasensitive biosensor for the detection of biomolecules in disease diagnosis and NIR biological imaging.

Nitrogen-, Sulfur-, and Fluorine-Codoped Carbon Dots with Low Excitation Potential and High Electrochemiluminescence Efficiency for Sensitive Detection of Matrix Metalloproteinase-2.

In this study, nitrogen-, sulfur-, and fluorine-codoped carbon dots (NSF-CDs) with high electrochemiluminescence (ECL) efficiency were developed as novel emitters to fabricate an ECL biosensor for sensitive detection of matrix metalloproteinase 2 (MMP-2). Impressively, compared to previously reported CDs, NSF-CDs with narrow band gap not only decreased the excitation voltage to reduce the side reaction and the damage on biomolecules but also had hydrogen bonds to vastly enhance the ECL efficiency. Furthermore, an improved exonuclease III (Exo III)-assisted nucleic acid amplification method was established to convert trace MMP-2 into a mass of output DNA, which greatly improved the target conversion efficiency and ECL signal. Hence, the ECL biosensor has realized the sensitive detection of MMP-2 proteins from 10 fg/mL to 10 ng/mL with a limit of detection of 6.83 fg/mL and has been successfully applied in the detection of MMP-2 from Hela and MCF-7 cancer cells. This strategy offered neoteric CDs as ECL emitters for sensitive testing of biomarkers in medical research.

Highly Efficient Electrochemiluminescence of MnS:CdS@ZnS Core-Shell Quantum Dots for Ultrasensitive Detection of MicroRNA.

In this work, a novel electrochemiluminescence (ECL) biosensor was developed for ultrasensitive detection of microRNA let-7a (miRNA let-7a) based on MnS:CdS@ZnS core-shell quantum dots (QDs) as ECL luminophores with high ECL efficiency. Impressively, compared to the CdS:Mn@ZnS QDs prepared by ionic doping with ECL efficiency of 0.87%, MnS:CdS@ZnS QDs synthesized by bimetallic clusters (Cd2Mn2O4) doping exhibited high ECL efficiency of up to 15.84% with S2O82- as cathodic coreactant due to the elimination of the dopants size mismatch and "self-purification" effect, which could achieve the surface defect passivation of MnS:CdS@ZnS QDs for effectively improving the ECL emission. Furthermore, with the help of strand displacement amplification (SDA), the trace target miRNA let-7a was able to be converted to a number of output DNA labeled with ferrocene (Fc) to construct an ultrasensitive ECL biosensor. The well-designed ECL biosensor for miRNA let-7a exhibited high stability and excellent sensitivity of a concentration variation from 10 aM to 1 nM and a low detection limit of 4.1 aM, which was further applied to the analysis of miRNA let-7a from cancer cell (MCF-7) lysate. Thus, this strategy provides a novel method to prepare high-efficient ECL emitters for the construction of ECL biosensing platforms in biological fields and clinical diagnosis.

Impact of Transmission Control Measures on the Epidemiology of Maxillofacial Injuries in Wuhan City During the COVID-19 Epidemic.

ABSTRACT: In December 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2) emerged in Wuhan City. The present study aimed to assess the demographic variables, causes, and patterns of maxillofacial injuries managed at a teaching hospital in Wuhan City during the transmission control measures in the coronavirus disease 2019 (COVID-19) epidemic. In this retrospective study, all patients treated for maxillofacial injuries in the hospital between January 23 and April 7 (2019 and 2020) were involved. Epidemiologic information, including the number of patients, gender, age, etiology, time since injury to the clinic visit, and type of maxillofacial injuries, was recorded. Data of the 2 periods (2019 and 2020) were compared and analyzed. A total of 337 patients had maxillofacial injuries at the 2-time intervals: 74 in 2020 and 263 in 2019. The characteristics of maxillofacial injuries had changes during the transmission control measures in the COVID-19 epidemic, which included the number of patients, gender, age, etiology, time since injury to the clinic visit, and type of maxillofacial injuries. The transmission control measures during the COVID-19 epidemic had a significant impact on the epidemiology of maxillofacial injuries in Wuhan City.

The Sp1/FOXC1/HOTTIP/LATS2/YAP/ß-catenin cascade promotes malignant and metastatic progression of osteosarcoma.

The prognosis for osteosarcoma (OS) is dismal due to the aggressive tumor growth and high incidence of metastasis. The long noncoding RNA human homeobox A transcript at the distal tip (HOTTIP) and the transcription factor forkhead box C1 (FOXC1) present oncogenic activities in OS. Here, we aimed at gaining insights into the underlying mechanisms and their crosstalk. The expression of FOXC1 and HOTTIP in OS tissues or cell lines was examined by real-time PCR (RT-PCR) and western blot. The in vitro effects of FOXC1 or HOTTIP on cell viability, proliferation, migration, invasion, and expression of target genes were examined using MTT, colony-forming assay, wound-healing, Transwell invasion, and western blot, respectively; the in vivo effects were examined using xenograft and experimental metastasis models. Molecular control of HOTTIP on large tumor suppressor 2 (LATS2) or transactivation of FOXC1 or Sp1 on HOTTIP was assessed by combining RNA immunoprecipitation, qRT-PCR, western blot, ChIP, and luciferase assay. Both FOXC1 and HOTTIP were potently up-regulated in OS tissues and cell lines. FOXC1 and HOTTIP essentially maintained viability, proliferation, migration, and invasion of OS cells in vitro and contributed to xenograft growth or lung metastasis in vivo. Mechanistically, HOTTIP recruited enhancer of zeste homolog 2 (EZH2) and lysine-specific demethylase 1 (LSD1) to silence LATS2 and thus activated YAP/ß-catenin signaling. Upstream, Sp1 activated FOXC1 and they both directly transactivated HOTTIP. In summary, we showed that the Sp1/FOXC1/HOTTIP/LATS2/YAP/ß-catenin cascade presented oncogenic activities in OS cells. Targeting FOXC1 or HOTTIP may therefore prove beneficial for OS treatment.

Salidroside Decreases Atherosclerosis Plaque Formation via Inhibiting Endothelial Cell Pyroptosis.

Pyroptosis, a new pro-inflammatory programmed cell death, is linked to atherosclerosis (AS). Our previous studies suggested that salidroside (SAL) can alleviate AS and exert anti-oxidative and anti-inflammatory properties. However, the effect of SAL on atherosclerosis-related pyroptosis has not been studied. Here, we investigated the effect of SAL on pyroptosis to explain the underlying mechanisms of SAL on atherosclerosis-related inflammation. We established an atherosclerosis mouse model via western diet (HFD) to explore the protective effect of SAL. According to our results, administration of SAL for 12 weeks markedly reduced the atherosclerotic plaque in aorta. Meanwhile, SAL also alleviated the pyroptosis, as evidenced by inhibiting caspase-1 activation, interleukin-1ß (IL-1ß) release, and TUNEL-positive staining, and decreasing the expression of Gasdermin D (GSDMD). Furthermore, SAL also decreased the activation of caspase-1 and inhibited the release of IL-1ß induced by lipopolysaccharide (LPS) and adenosine triphosphate (ATP) in human umbilical vein endothelial cell (HUVECs). Our data indicate that SAL inhibit NLRP3-related pyroptosis, which might be the underlying mechanism of SAL anti-inflammatory in atherosclerosis.

Reactive oxygen species are responsible for the cell aggregation and production of pro-inflammatory mediators in phorbol ester (PMA)-treated U937 cells on gelatin-coated dishes through upregulation of autophagy.

Purpose: Our previous studies indicate that phorbol 12-myristate 13-acetate (PMA)-treated U937 cells cultured on collagen I-coated dishes express lowered production of pro-inflammatory mediators in parallel through reduced reactive oxygen species (ROS) levels. By contrast, PMA-treated U937 cells on gelatin, the denatured collagen, show enhanced production of pro-inflammatory mediators, mediated by up-regulating autophagy levels. The present study is aimed to investigate the effect of ROS levels in PMA-treated U937 cells cultured on gelatin-coated surface. Material and methods: MTT assay, flow cytometric analysis of ROS and autophagy, biochemical detection of antioxidant levels, enzyme-linked immunosorbent assay, and western blot were used. Results: Gelatin-coating increased ROS levels in PMA-treated U937 cells. Increased ROS levels are involved in the regulation of cell aggregation and the release of pro-inflammatory mediators in gelatin-coated culture. These results lead to the query about the crosstalk between the two positive regulators, the autophagy and ROS. Autophagy induction is attenuated by N-acetyl-L-cysteine treatment, but the treatment with autophagy inhibitor, 3-methyladenine, does not affect ROS levels, suggesting ROS are upstream of autophagy in the regulation axis of differentiated U937 cells on gelatin-coated surface. Further study confirmed that upregulation of autophagy was responsible for ROS-induced cell aggregation and production of pro-inflammatory mediators. Conclusion: The results suggest that gelatin-coating promotes the aggregation of PMA-treated U937 cells and the production of pro-inflammatory mediators by ROS-autophagy signaling pathway.

The lymphocyte-to-monocyte ratio is a superior predictor of overall survival compared to established biomarkers in HCC patients undergoing liver resection.

The aim of this study was to investigate the prognostic value of the lymphocyte-to-monocyte ratio (LMR) in patients undergoing hepatectomy and to compare it to established biomarkers including the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Medical records were retrospectively analyzed for 652 HCC patients undergoing hepatectomy at the Affiliated Tumor Hospital of Guangxi Medical University and the First People's Hospital of Changde between April 2004 to April 2012. The correlation between the LMR and clinical variables were analyzed in Kaplan-Meier log-rank survival analysis and then multivariate Cox regression models trying to find relation with disease-free survival (DFS) and overall survival (OS). The area under the ROC curve (AUC) of the LMR(AUC:0.627) for predicting long-term survival was greater than that of the NLR(AUC:0.600) and the PLR(AUC:0.520).Multivariate analysis showed LMR to be an independent risk factor for OS (P = 0.002), and the NLR and PLR were not independently significant. Subgroup analysis also showed that LMR was significantly associated with poor DFS and OS in patients positive for HBsAg or with cirrhosis (both P < 0.001).Elevated preoperative LMR is an independently associated with poor OS and DFS in HCC patients following curative resection and appears to be superior to NLR and PLR.

Dual role for DOCK7 in tangential migration of interneuron precursors in the postnatal forebrain.

Throughout life, stem cells in the ventricular-subventricular zone generate neuroblasts that migrate via the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into local interneurons. Although progress has been made toward identifying extracellular factors that guide the migration of these cells, little is known about the intracellular mechanisms that govern the dynamic reshaping of the neuroblasts' morphology required for their migration along the RMS. In this study, we identify DOCK7, a member of the DOCK180-family, as a molecule essential for tangential neuroblast migration in the postnatal mouse forebrain. DOCK7 regulates the migration of these cells by controlling both leading process (LP) extension and somal translocation via distinct pathways. It controls LP stability/growth via a Rac-dependent pathway, likely by modulating microtubule networks while also regulating F-actin remodeling at the cell rear to promote somal translocation via a previously unrecognized myosin phosphatase-RhoA-interacting protein-dependent pathway. The coordinated action of both pathways is required to ensure efficient neuroblast migration along the RMS.

Stratified aspartate aminotransferase-to-platelet ratio index accurately predicts survival in hepatocellular carcinoma patients undergoing curative liver resection.

The aspartate aminotransferase-to-platelet ratio index has been reported to predict prognosis of patients with hepatocellular carcinoma. This study examined the prognostic potential of stratified aspartate aminotransferase-to-platelet ratio index for hepatocellular carcinoma patients undergoing curative liver resection. A total of 661 hepatocellular carcinoma patients were retrieved and the associations between aspartate aminotransferase-to-platelet ratio index and clinicopathological variables and survivals (overall survival and disease-free survival) were analyzed. Higher aspartate aminotransferase-to-platelet ratio index quartiles were significantly associated with poorer overall survival (p = 0.002) and disease-free survival (p = 0.001). Multivariate analysis showed aspartate aminotransferase-to-platelet ratio index to be an independent risk factor for overall survival (p = 0.018) and disease-free survival (p = 0.01). Patients in the highest aspartate aminotransferase-to-platelet ratio index quartile were at 44% greater risk of death than patients in the first quartile (hazard ratio = 1.445, 95% confidence interval = 1.081 - 1.931, p = 0.013), as well as 49% greater risk of recurrence (hazard ratio = 1.49, 95% confidence interval = 1.112-1.998, p = 0.008). Subgroup analysis also showed aspartate aminotransferase-to-platelet ratio index to be an independent predictor of poor overall survival and disease-free survival in patients positive for hepatitis B surface antigen or with cirrhosis (both p < 0.05). Similar results were obtained when aspartate aminotransferase-to-platelet ratio index was analyzed as a dichotomous variable with cutoff values of 0.25 and 0.62. Elevated preoperative aspartate aminotransferase-to-platelet ratio index may be independently associated with poor overall survival and disease-free survival in hepatocellular carcinoma patients following curative resection.

Pogostone induces autophagy and apoptosis involving PI3K/Akt/mTOR axis in human colorectal carcinoma HCT116 cells.

ETHNOPHAMACOLOGICAL RELEVANCE: Pogostemon cablin is a medicinal herb widely used to treat gastrointestinal diseases in many Asian countries. Pogostone is an important constituent of Pogostemon cablin, and possesses various bioactivitys. In this study, we performed to investigate the anti-colorectal tumor property of Pogostone by inducing aurophagy and apoptosis in human colorectal cancer cells, and to define the potential molecular mechanisms. MATERIALS AND METHODS: In vitro, The anti-tumor activity of pogostone was assessed using MTT assay. Autophagy was monitored by transmission electron microscopy observation and mRFP-GFP-LC3 fluorescence analysis in colorectal tumor cell line. Apoptosis was measured by flow cytometry and annexinV-FITC/PI staining. The protein expressions or activition of LC3-Ⅱ, AKT, mTOR, caspase-3 and caspase-7 were detected through western blotting. In vivo, the anti-tumor effect of pogostone was tested with HCT116 colorectal tumor cells transplantation tumor model. The expression of Ki-67 was determined by Immunohistochemistry staining and the apoptosis was evaluated using TUNEL assay. RESULTS: In vitro, pogostone exhibits significant anti-tumor activity against human cancer cell lines, especially for HCT116 (18.7±1.93µg/ml). Transmission electron microscopy observation, mRFP-GFP-LC3 fluorescence analysis, flow cytometry and assay and western blotting detection revealed that the anti-colorectal tumor activity of pogostone was dependent on inducing autophagy and apoptosis through up-regulating the expression of LC3-Ⅱ, cleaved caspase-7 and caspase-3, and decreasing the phosphorylation of AKT/mTOR. In vivo, 150mg/kg pogostone inhibited the HCT116 tumor growth in immunodeficient mice with an inhibitory rate of 43.3%, decreased the expression of Ki67, and induced apoptosis in three days. CONCLUSION: Pogostone showed anti-colorectal tumor effects by inducing autophagy and apoptosis involving PI3K/Akt/mTOR axis. Thus, pogostone may be a promising lead compound to be further developed for cancer therapy.

Cyclooxygenase-2 expression is associated with initiation of hepatocellular carcinoma, while prostaglandin receptor-1 expression predicts survival.

AIM: To determine whether cyclooxygenase-2 (COX-2) and prostaglandin E1 receptor (EP1) contribute to disease and whether they help predict prognosis. METHODS: We retrospectively reviewed the records of 116 patients with hepatocellular carcinoma (HCC) who underwent surgery between 2008 and 2011 at our hospital. Expression of COX-2 and EP1 receptor was examined by immunohistochemistry of formalin-fixed, paraffin-embedded tissues using polyclonal antibodies. Possible associations between immunohistochemical scores and survival were determined. RESULTS: Factors associated with poor overall survival (OS) were alpha-fetoprotein > 400 ng/mL, tumor size ≥ 5 cm, and high EP1 receptor expression, but not high COX-2 expression. Disease-free survival was not significantly different between patients with low or high levels of COX-2 or EP1. COX-2 immunoreactivity was significantly higher in well-differentiated HCC tissues (Edmondson grade I-II) than in poorly differentiated tissues (Edmondson grade III-IV) (P = 0.003). EP1 receptor immunoreactivity was significantly higher in poorly differentiated tissue than in well-differentiated tissue (P = 0.001). CONCLUSION: COX-2 expression appears to be linked to early HCC events (initiation), while EP1 receptor expression may participate in tumor progression and predict survival.

Blood neutrophil-lymphocyte ratio predicts survival after hepatectomy for hepatocellular carcinoma: A propensity score-based analysis.

AIM: To investigate whether an elevated preoperative neutrophil-to-lymphocyte ratio (NLR) can predict poor survival in patients with hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed 526 patients with HCC who underwent surgery between 2004 and 2011. RESULTS: Preoperative NLR ≥ 2.81 was an independent predictor of poor disease-free survival (DFS, P < 0.001) and overall survival (OS, P = 0.044). Compared with patients who showed a preoperative NLR < 2.81 and postoperative increase, patients who showed preoperative NLR ≥ 2.81 and postoperative decrease had worse survival (DFS, P < 0.001; OS, P < 0.001). Among patients with preoperative NLR ≥ 2.81, survival was significantly higher among those showing a postoperative decrease in NLR than among those showing an increase (DFS, P < 0.001; OS, P < 0.001). When elevated, alpha-fetoprotein (AFP) provided no prognostic information, and so preoperative NLR ≥ 2.81 may be a good complementary indicator of poor OS whenever AFP levels are low or high. CONCLUSION: Preoperative NLR ≥ 2.81 may be an indicator of poor DFS and OS in patients with HCC undergoing surgery. Preoperative NLR ≥ 2.81 may be a good complementary indicator of poor OS when elevated AFP levels provide no prognostic information.

Cytotoxic monoterpenoid indole alkaloids isolated from the barks of Voacanga africana Staph.

A new monoterpenoid indole alkaloid compound (1) and six known monoterpenoid indole alkaloids compounds (2-7) were isolated from the barks of Voacanga africana Staph. The structures were established by spectral analysis as ibogamine-16-carboxylic acid,17,20-didehydro-5,6-dioxo-10-methoxy-methyl ester (1), voacamine (2), vobasine (3), voacangine (4), voacristine (5), 19-epi-voacristine (6) and 19-epi-heyneanine (7). Compound 1 was confirmed by X-ray crystallographic analysis. All of the isolated compounds were evaluated for cytotoxicity against five cell lines (HEPG-2, A375, MDA-MB-231, SH-SY5Y, CT26). Among them, compounds 2 and 6 displayed significant inhibitory activities, compounds 3, 4 and 5 showed moderate inhibitory activities, while compounds 1 and 7 showed no inhibitory activities against the five cell lines.

Overexpression Of Hepatocyte Nuclear Factor-1beta Predicting Poor Prognosis Is Associated With Biliary Phenotype In Patients With Hepatocellular Carcinoma.

Hepatocyte nuclear factor-1beta (HNF-1B) is involved in the hepatobiliary specification of hepatoblasts to cholangiocytes during liver development, and is strongly expressed throughout adult biliary epithelium. The aim of this study was to examine the expression of HNF-1B in different pathologic subtypes of primary liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (ICC), and the relationship between HNF-1B expression, clinicopathological features and prognosis. We retrospectively investigated 2 cohorts of patients, including 183 HCCs and 69 ICCs. The expression of HNF-1B was examined by immunohistochemistry. We found that HNF-1B expression was associated with pathological subtype of primary tumor, and HNF-1B expression in HCC tissue may be associated with the change of phenotype on recurrence. The HNF-1B expression was positively correlated with biliary/HPC (hepatic progenitor cell) markers expression. Further, multivariable analysis showed that HNF-1B expression was an independent prognostic factor for both overall survival and disease-free survival of HCC patients. However, no correlation between HNF-1B expression and survival was found in ICC patients. In summary, HCC with high HNF-1B expression displayed biliary phenotype and tended to show poorer prognosis. HNF-1B-positive malignant cells could be bipotential cells and give rise to both hepatocytic and cholangiocytic lineages during tumorigenesis.

Preliminary study of non-invasive shock wave treatment of capsular contracture after breast implant: animal model.

The incidence rate of capsular contracture after breast implant is about 8% to 12%. Patients would feel extremely uncomfortable after scar formation. Administering oral medications (such as vitamin E and Zafirlukast tablets, etc.) or invasive breast capsulectomy surgery was commonly used for capsular contracture repair in clinical therapy. However, the therapeutic effect is still under investigation. Shock waves can be used to remove soft connective tissue in clinical applications. It has been widely used in orthopedics and rehabilitation. No related research paper about shock wave treatment of capsular contracture has been published yet. It might provide another choice for capsular contracture repair. In order to simulate breast implantation, two silica-gel bags filled with normal saline were implanted into New Zealand rabbit's thighs bilaterally as an animal model. Six weeks later, daily shock wave treatment on the right thigh was performed for six weeks after capsular contractures were formed, while the other thigh was used as a control. Then, magnetic resonance imaging (MRI) was used to compare the difference between treated and un-treated thighs. Afterwards, pathological sections were analyzed to confirm the findings. It has been demonstrated that shock wave treatments are capable of changing the structure and composition of capsular contractures. The structure of scar became myxoid changed or collagen deposition of scar decreased after shock wave treatment, hence, the formation of scars decreased. Increased myxoid and decreased collagen deposition has also been found.

The immediate early 2 protein of human cytomegalovirus (HCMV) mediates the apoptotic control in HCMV retinitis through up-regulation of the cellular FLICE-inhibitory protein expression.

Human CMV (HCMV) is a widespread human pathogen that causes blindness by inducing retinitis in AIDS patients. Previously, we showed that viral immediate early 2 (IE2) protein may allow HCMV to evade the immune control by killing the Fas receptor-positive T lymphocytes attracted to the infected retina with increased secretion of Fas ligand (FasL). In this study, we further demonstrate that the secreted FasL also kills uninfected Fas-rich bystander retinal cells and that IE2 simultaneously protects the infected cells from undergoing apoptotic death, in part, by activating the expression of cellular FLIP (c-FLIP), an antiapoptotic molecule that blocks the direct downstream executer caspase 8 of the FasL/Fas pathway. c-FLIP induction requires the N-terminal 98 residues of IE2 and the c-FLIP promoter region spanning nucleotides -978 to -696. In vivo association of IE2 to this region, IE2-specific c-FLIP activation, and decrease of FasL-up-regulated activities of caspases 8 and 3 were all demonstrated in HCMV-infected human retinal cells. Moreover, c-FLIP up-regulation by IE2 appeared to involve PI3K and might also render cells resistant to TRAIL-mediated death. Finally, enhanced c-FLIP signals were immunohistochemically detected in IE-positive cells in the HCMV-infected lesions of the human retina. Taken together, these data demonstrate specific activation of c-FLIP by HCMV IE2 and indicate a novel role for c-FLIP in the pathogenesis of HCMV retinitis.

HCMV IE2-mediated inhibition of HAT activity downregulates p53 function.

Targeting of cellular histone acetyltransferases (HATs) by viral proteins is important in the development of virus-associated diseases. The immediate-early 2 protein (IE2) of human cytomegalovirus (HCMV) binds to the tumor suppressor, p53, and inactivates its functions by unknown mechanisms. Here, we show that IE2 binds to the HAT domain of the p53 coactivators, p300 and CREB-binding protein (CBP), and blocks their acetyltransferase activity on both histones and p53. The minimal HAT inactivation region on IE2 involves the N-terminal 98 amino acids. The in vivo DNA binding of p53 and local histone acetylation on p53-dependent promoters are all reduced by IE2, but not by mutant IE2 proteins that lack the HAT inhibition region. Furthermore, the p53 acetylation site mutant, K320/373/382R, retains both DNA binding and promoter transactivation activity in vivo and these effects are repressed by IE2 as well. Together with the finding that only wild-type IE2 exerts an antiapoptotic effect, our results suggest that HCMV IE2 downregulates p53-dependent gene activation by inhibiting p300/CBP-mediated local histone acetylation and that IE2 may have oncogenic activity.