Rational Fabrication of Nickel Vanadium Sulfide Encapsulated on Graphene as an Advanced Electrode for High-Performance Supercapacitors.

Supercapacitors (SCs) are widely recognized as competitive power sources for energy storage. The hierarchical structure of nickel vanadium sulfide nanoparticles encapsulated on graphene nanosheets (NVS/G) was fabricated using a cost-effective and scalable solvothermal process. The reaction contents of the composites were explored and optimized. TEM images displayed the nickel vanadium sulfide nanoparticles (NVS NPs) with 20-30 nm average size anchored to graphene nanosheets. The interconnection of graphene nanosheets encapsulating NVS nanoparticles effectively reduces the ion diffusion path between the electrode and electrolyte, thereby enhancing electrochemical performance. The NVS/G composite demonstrated improved electrochemical performance, achieving a maximum of 1437 F g-1 specific capacitance at 1 A g-1, remarkable rate capability retaining of 1050 F g-1 at 20 A g-1, and exceptional cycle stability with 91.2% capacitance retention following 10,000 cycles. The NVS/G composite was employed as a cathode, and reduced graphene oxide (rGO) was used as an anode material to assemble a device. Importantly, asymmetric SCs using NVS/G//rGO achieved 74.7 W h kg-1 energy density at 0.8 kW kg-1 power density, along with outstanding stability with 88.2% capacitance retention following 10,000 cycles. These superior properties of the NVS/G electrode highlight its significant potential in energy storage applications.

Cancer prediction from few amounts of histology samples through self-attention based multi-routines cross-domains network.

OBJECTIVE: Rapid and efficient analysis of cancer has become a focus of research. Artificial intelligence can use histopathological data to quickly determine the cancer situation, but still faces challenges. For example, the convolutional network is limited by the local receptive field, human histopathological information is precious and difficult to be collected in large quantities, and cross-domain data is hard to be used to learn histopathological features. In order to alleviate the above questions, we design a novel network, Self-attention based multi-routines cross-domains network (SMC-Net). APPROACH: Feature analysis module and decoupling analysis module designed are the core of the SMC-Net. The feature analysis module base on multi-subspace self-attention mechanism with pathological feature channel embedding. It in charge of learning the interdependence between pathological features to alleviate the problem that the classical convolution model is difficult to learn the impact of joint features on pathological examination results. The decoupling analysis module base on the designed multi-channel and multi-discriminator architecture. Its function is to decouple the features related to the target task in cross-domain samples so that the model has cross-domain learning ability. MAIN RESULTS: To evaluate the performance of the model more objectively, three datasets are used. Compared with other popular methods, our model achieves better performance without performance imbalance. In this work, a novel network is design. It can use domain-independent data to assist in the learning of target tasks, and can achieve acceptable histopathological diagnosis results even in the absence of data. SIGNIFICANCE: The proposed method has higher clinical embedding potential and provides a viewpoint for the combination of deep learning and histopathological examination.

Recombinant Irisin Protects Against Alveolar Bone Destruction During Orthodontic Tooth Movement.

Patients with periodontitis have higher risk of alveolar bone loss when seek for orthodontic therapy. Inflammation and osteogenesis are key factors in alveolar bone destruction in periodontitis and orthodontic tooth movement (OTM). Here we evaluated the effects of irisin on alveolar bone destruction in rats with periodontitis and OTM. We isolated and cultured human periodontal ligament stem cells (PDLSCs). Irisin was administrated to PDLSCs. Cell proliferations, osteogenic differentiation, expression of RUNX2 and ALP, and the expression of OPG and RANKL were measured. We induced periodontitis and OTM in rats and treated rats with irisin. The alveolar bone loss, inflammatory cytokine levels, and expression of OPG and RANKL in gingival tissues were measured. Irisin promoted the cell proliferation and osteogenic differentiation of PDLSCs. Irisin elevated the expression of RUNX2, ALP, and OPG while decreased the expression of RANKL in PDLSCs. Irisin ameliorated the alveolar bone loss, suppressed cytokine levels, and increased OPG/RANKL expression ratio in rat with periodontitis and orthodontic tooth movement. Irisin prevented alveolar bone destruction during OTM in rats with periodontitis.

Survival benefits of para-aortic lymphadenectomy in colorectal cancer with clinically suspected para-aortic lymph node metastasis: a meta-analysis and systematic review.

BACKGROUND AND OBJECTIVES: In patients with colorectal cancer and clinically suspected para-aortic lymph node metastasis, the survival benefit of para-aortic lymphadenectomy is unknown. We conducted a meta-analysis and systematic review to investigate it. METHODS: PubMed, Web of Science, and EMBASE were searched until January 2000 to April 2022 to identify studies reporting overall survivals, complication rates, and hazard ratios of prognostic factors in patients with colorectal cancer undergoing para-aortic lymphadenectomy, and those data were pooled. RESULTS: Twenty retrospective studies (1021 patients undergoing para-aortic lymphadenectomy) met the inclusion criteria. Meta-analysis indicates that participants undergoing para-aortic lymphadenectomy were associated with 5-year survival benefit, compared to those not receiving para-aortic lymphadenectomy (odds ratio = 3.73, 95% confidence interval: 2.05-6.78), but there was no significant difference in complication rate (odds ratio = 0.97, 95% confidence interval: 0.46-2.08). Further analysis of para-aortic lymphadenectomy group showed that 5-year survival of the positive group with pathologically para-aortic lymph node metastasis was lower than that of the negative group (odds ratio = 0.19, 95% confidence interval: 0.11-0.31). Moreover, complete resection (odds ratio = 5.26, 95% confidence interval: 2.02-13.69), para-aortic lymph node metastasis (≤4) (hazard ratio = 1.88, 95% confidence interval: 0.97-3.62), and medium-high differentiation (hazard ratio = 2.98, 95% confidence interval: 1.48-5.99) were protective factors for survival. Preoperative extra-retroperitoneal metastasis was associated with poorer relapse-free survival (hazard ratio = 1.85, 95% confidence interval: 1.10-3.10). CONCLUSION: Para-aortic lymphadenectomy had promising clinical efficacy in prolonging survival rather than complication rate in patients with colorectal cancer and clinically diagnostic para-aortic lymph node metastasis. Further prospective studies should be performed. TRIAL REGISTRATION: PROSPERO: CRD42022379276.

Application of immune checkpoint inhibitors in immunotherapy for gastric cancer.

Gastric cancer is the fifth most common cancer worldwide. With the development of immunotherapy, especially the application of immune checkpoint inhibitors (ICIs), the prognosis of advanced gastric cancer has improved. At present, ICIs combined with other therapies or dual ICI strategies in the treatment of advanced gastric cancer have shown clinical effectiveness and controllable safety. In addition, predictive biomarkers facilitate the precise selection of patients. Therefore, it is crucial to explore rational combinations and reliable predictive biomarkers for ICI therapy. This article reviews the recent advances in ICIs and relevant predictive biomarkers in the treatment of gastric cancer.

In recent years, with the application of immunotherapy, clinical efficacy in gastric cancer has been effectively improved. At present, it is encouraging that immunotherapy combined with chemotherapy has become the first choice for the treatment of patients with advanced gastric cancer. However, researchers remain committed to exploring the efficacy of immunotherapy in combination with various therapies. Equally important, the identification of biomarkers can facilitate the selection of patients suitable for immunotherapy. This article summarizes important immunotherapy clinical trials and discusses therapeutic combinations and biomarkers being explored.

HDAC5-Mediated Acetylation of p100 Suppresses Its Processing.

INTRODUCTION: Periodontitis is a condition involving chronic inflammation in the gums, periodontal ligaments, cementum, and alveolar bone. Nuclear factor-κB (NF-κB) activation is the prominent mediator of inflammation and osteoclast differentiation. The role of histone deacetylase 5 (HDAC5) in periodontitis development and NF-κB regulation is not fully understood. METHODS: We used primary mouse bone marrow-derived osteoclast cultures in vitro and a mouse model of chronic periodontists (CPD) treated with the HDAC4/5 inhibitor LMK-235. Real-time polymerase chain reaction, micro computed tomography, flow cytometry, western blot, and immunoprecipitation were used to study proinflammatory cytokines, NF-κB activation, HDAC5 activity, and the interaction of HDAC5 with NF-κB p100. RESULTS: LMK-235, a selective inhibitor of HDAC4 and HDAC5, reduced osteoclast marker gene expression (Cstk, Acp5, and Calcr) and tartrate-resistant acid phosphatase activity in primary osteoclast cultures. LMK-235 reduced the increase in cementoenamel junction-alveolar bone crest distance, inflammatory cell infiltration of gingival tissues, and expression levels of interleukin (IL)-1ß, tumor necrosis factor alpha, IL-6, and IL-23a, indicating an ameliorative effect on CPD. Immunoprecipitation experiments have further confirmed p100-HDAC5 interaction, acetylation levels of p100, and NF-κB activation. CONCLUSIONS: These results indicate that HDAC5 binds and deacetylates p100, leading to its activation, increased proinflammatory cytokine production, gingival infiltration, and osteoclast differentiation, thus promoting alveolar bone resorption. HDAC5 inhibition is therefore a potentially promising therapeutic strategy for the treatment of periodontitis.

Correlation Analysis of miR-1246 Expression in Saliva of Patients with Chronic Periodontitis and Periodontal Indexes, Inflammatory Cytokines, and Protease Molecules.

Objective: The study aimed to investigate the correlation of miR-1246 in saliva with periodontal indicators, inflammatory cytokines, and protease molecules in patients with chronic periodontitis. Methods: Thirty-five patients with chronic periodontitis were included as the chronic periodontitis group, and 35 healthy individuals were selected as the healthy control group during the same period. The miR-1246 levels, inflammatory cytokine interleukin (IL)-1ß, IL-6, IL-17, tumor necrosis factor-α (TNF-α), matrix metalloproteinase (MMP-1), MMP-8, and MMP tissue inhibitor (TIMP-1) in saliva were determined, and periodontal indexes, including the plaque index (PLI), bleeding index (BI), periodontal probing depth (PD), and attachment loss (AL) were examined. Results: The salivary levels of miR-1246, IL-1ß, IL-6, IL-17, TNF-α, MMP-1, MMP-8, and TIMP-1 and the periodontal indexes PLI, GI, PD, and AL in the chronic periodontitis group were significantly higher than those in the healthy control (P < 0.05). Salivary levels of miR-1246 in patients with chronic periodontitis were positively correlated with the levels of IL-1ß, IL-6, IL-17, TNF-α, MMP-1, MMP-8, TIMP-1, PLI, GI, PD, and AL (P < 0.05). Conclusion: Abnormally elevated levels of miR-1246 in saliva of patients with chronic periodontitis correlate with levels of periodontal indices, inflammatory cytokines, and protease molecules.

The Expression of PPAR Pathway-Related Genes Can Better Predict the Prognosis of Patients with Colon Adenocarcinoma.

The postoperative survival time and quality of life of patients with colon adenocarcinoma (COAD) varies widely. In order to make accurate decisions after surgery, clinicians need to distinguish patients with different prognostic trends. However, we still lack effective methods to predict the prognosis of COAD patients. Accumulated evidences indicated that the inhibition of peroxisome proliferator-activated receptors (PPARs) and a portion of their target genes were associated with the development of COAD. Our study found that the expression of several PPAR pathway-related genes were linked to the prognosis of COAD patients. Therefore, we developed a scoring system (named PPAR-Riskscore) that can predict patients' outcomes. PPAR-Riskscore was constructed by univariate Cox regression based on the expression of 4 genes (NR1D1, ILK, TNFRSF1A, and REN) in tumor tissues. Compared to typical TNM grading systems, PPAR-Riskscore has better predictive accuracy and sensitivity. The reliability of the system was tested on six external validation datasets. Furthermore, PPAR-Riskscore was able to evaluate the immune cell infiltration and chemotherapy sensitivity of each tumor sample. We also combined PPAR-Riskscore and clinical features to create a nomogram with greater clinical utility. The nomogram can help clinicians make precise treatment decisions regarding the possible long-term survival of patients after surgery.

Predictors for Submucosal Fibrosis in Patients With Superficial Squamous Esophageal Neoplasia Undergoing Endoscopic Submucosal Dissection.

INTRODUCTION: Submucosal fibrosis greatly hinders the success of endoscopic submucosal dissection (ESD). This study determined ESD outcomes in patients with esophageal submucosal fibrosis and further explored the predictors. METHODS: We retrospectively analyzed 163 patients with superficial squamous esophageal neoplasia. The degree of submucosal fibrosis was classified as follows: F0, none; F1, mild; and F2, severe. ESD outcomes as a function of the degree of submucosal fibrosis and biopsy were determined. The potential predictors of submucosal fibrosis were analyzed. RESULTS: En bloc resection, R0 resection, and procedure time were significantly different between the F0-F2 groups (P = 0.009, P = 0.002, and P < 0.001, respectively). Perforation and immediate bleeding rates of F2 were significantly higher than the F0/F1 groups (P < 0.001 and P < 0.001, respectively). However, the nonbiopsy group vs the biopsy group and the delayed ESD group (postbiopsy >21 days) vs the early ESD group (postbiopsy ≤21 days) showed no statistical differences regarding the en bloc resection, R0 resection, and ESD complications (all P > 0.05). Further analysis indicated that it was not the biopsy history and delayed ESD (both P > 0.05), rather submucosal invasion vs intramucosal tumor (odds ratio = 4.534, P = 0.003) and current smoker vs nonsmoker (odds ratio = 2.145, P = 0.043) were independent risk factors for endoscopic submucosal fibrosis. DISCUSSION: Esophageal submucosal fibrosis was shown to be closely related to unsatisfactory ESD outcomes. Biopsy history and delayed ESD had no adverse effect on submucosal fibrosis and ESD outcomes. Submucosal invasion and current cigarette smoking were predictors of submucosal fibrosis.

The circular RNA circMAST1 promotes hepatocellular carcinoma cell proliferation and migration by sponging miR-1299 and regulating CTNND1 expression.

Circular RNAs (circRNAs) are a class of non-coding RNAs with a loop structure; however, their functions remain largely unknown. Growing evidence suggests that circRNAs play a pivotal role in the progression of malignant diseases. However, the expression profiles and function of circRNAs in hepatocellular carcinoma (HCC) remain unclear. We investigated the expression of microtubule-associated serine/threonine kinase 1 (MAST1) circRNA (circMAST1) in HCC and healthy tissues using bioinformatics, quantitative real-time PCR (qRT-PCR), and fluorescence in situ hybridization. Luciferase reporter assays were performed to assess the interaction between circMAST1 and miR-1299. Proliferation assays, colony formation assays, flow cytometry, transwell assays, and western blotting were also performed. A mouse xenograft model was also used to determine the effect of circMAST1 on HCC growth in vivo. CircMAST1 was upregulated in HCC tissues and cell lines; silencing via small interfering RNA inhibited migration, invasion, and proliferation of HCC cell lines in vitro as well as tumor growth in vivo. Furthermore, the expression of circMAST1 was positively correlated with catenin delta-1 (CTNND1) and negatively correlated with microRNA (miR)-1299 in HCC clinical samples. Importantly, circMAST1 sponged miR-1299 to stabilize the expression of CTNND1 and promoted tumorigenic features in HCC cell lines. We found that circMAST1 may serve as a novel biomarker for HCC. Moreover, circMAST1 elicits HCC progression by sponging miRNA-1299 and stabilizing CTNND1. Our data provide potential options for therapeutic targets in patients with HCC.

MicroRNA-200a Promotes Phagocytosis of Macrophages and Suppresses Cell Proliferation, Migration, and Invasion in Nasopharyngeal Carcinoma by Targeting CD47.

Nasopharyngeal carcinoma (NPC) causes severe oncogenic lesions in the nasopharynx. CD47, a transmembrane integrin-associated protein, plays a key role in the ability of tumor cells to escape phagocytosis, working as an immune checkpoint in the immune response. Besides this role, CD47 has been reported to regulate cell proliferation and migration. The present study addresses the relationship between CD47 and microRNA-200a and examines their regulatory mechanisms in NPC. Bioinformatics analyses and dual-luciferase reporter assays were used to confirm the putative relationship between miR-200a and CD47, and their interaction was further detected using western blotting and RT-PCR. Further, results showed that miR-200a affect NPC cell proliferation, migration, and invasion by regulating CD47. A cell phagocytosis assay showed that miR-200a and a CD47 monoclonal antibody increased the sensitivity of NPC cells to macrophage phagocytosis by inhibiting the functions of CD47. Additionally, miR-200a expression was suppressed and CD47 expression increased in both clinical NPC tissues and cell lines. Taken together, these results show the miR-200a/CD47 combination as a potential therapeutic for treatment of NPC.

Comparing endoscopic surgeries with open surgeries in terms of effectiveness and safety in salvaging residual or recurrent nasopharyngeal cancer: Systematic review and meta-analysis.

Consensus has yet to be reached on the optimal operation for patients with residual or recurrent nasopharyngeal carcinoma (NPC). To compare effectiveness and safety of open surgery and endoscopic surgery for patients with residual or recurrent NPC. Pubmed, Embase, and Cochrane were searched for relevant publications from January 1, 2000 to May 1, 2017. Included studies reported specific residual or local recurrent nasopharyngeal cancer survival data. Proportional meta-analysis was performed on both outcomes with a random-effects model, and the 95% confidential intervals were calculated by Stata 12.0 software. For patients with different tumor classification, a downward trend of 2-year overall survival (OS) was observed for both surgical populations. Endoscopic surgeries achieved bigger rates than open surgeries in patients with recurrent tumor (rT) 1, rT2, and rT3 (93% vs 87%, 77% vs 63%, 67% vs 53%). As for patients with rT4, 2-year OS was similar (35% vs 35%).In addition, the former is less severe complications, lower local recurrence rates (27% vs 32%). Our study found that, compared to open surgery, endoscopic surgery was a safer and more effective treatment modality in managing patients with recurrent or residual NPC.

Clinicopathological features and outcomes of esophageal lesions containing a basal layer type squamous cell carcinoma component.

PURPOSE: Basal layer type squamous cell carcinoma (BLSCC) is a unique type of squamous cell carcinoma (SCC), characterized by high-grade dysplastic cells occupying the lower half of the epithelium. So far, such special lesions do not seem to attract much attention. The aim of this study was to investigate the clinicopathological features and prognosis of esophageal squamous carcinoma lesions with a BLSCC component. MATERIALS AND METHODS: Between January 2011 and January 2018, 96 patients with esophageal squamous cell carcinoma underwent endoscopic submucosal resection in our hospital were retrospectively analyzed. Patients were divided into BLSCC or typical SCC groups according to the presence or absence of a BLSCC component. The endoscopic findings were compared between the two groups. Furthermore, patients were followed up until October 2018 to compare recurrence rates. RESULTS: BLSCC components were detected in 32 (33.3%, 32/96) lesions. Among them, 13 (40.62%, 13/32) were BLSCC predominant. The intraepithelial papillary capillary loops of 7 pure BLSCC showed type B1 under narrow-band imaging. Single-factor and multivariate analyses indicated that five or more independently scattered, deep-stained spots in iodine-unstained areas were significantly predictive of the presence of BLSCC components (OR=4.837, P=0.015). All patients of typical SCC group survived, but one of BLSCC group died for distant metastases during the follow-up period. The 1-year cumulative recurrence rate (CRR) of BLSCC group were 3.4%, lower than that of typical SCC group (7.1%). Although no significant difference of CRR was seen between the two groups (P>0.05), the 2-year CRR of BLSCC group increased to 11.9%, being higher than that of typical SCC group (7.1%). CONCLUSION: The presence of multiple, scattered stained spots in iodine-unstained areas was predictive of BLSCC components. Such lesion should be treated actively and subject to a more rigorous follow-up protocol due to a higher likelihood of late recurrence.

LncRNA UCA1 affects epithelial-mesenchymal transition, invasion, migration and apoptosis of nasopharyngeal carcinoma cells.

Objective: In this study, long non-coding RNA urothelial carcinoma associated 1 (lncRNA UCA1) in nasopharyngeal carcinoma (NPC) and its effect on the malignant phenotype of NPC cells was investigated. Methods: Initially, the expression of UCA1 in NPC tissues and cells was detected. NPC cell line that with highest expression of UCA1 was selected for subsequent cell function test. A series of experiments were used to detect proliferation, colony formation, cell cycle distribution, apoptosis, invasion and migration of NPC cells with the interference of UCA1 expression. Western blot analysis was carried out to detect the expression of E-cadherin and vimentin for verifying the effect of UCA1 on epithelial mesenchymal transition (EMT). Results: The expression of UCA1 was found to be upregulated in NPC tissues and cells. The expression of UCA1 in stage Ⅲ + IV of NPC tissues and in patients with lymph node metastasis was significantly higher than that in patients at stage Ⅰ + Ⅱ and in patients without lymph node metastasis. Inhibition of UCA1 repressed proliferation, EMT, colony formation, invasion and migration while stimulating apoptosis of NPC cells. Conclusion: Our study suggests that UCA1 expression was overexpressed in NPC. Additionally, UCA1 suppression could inhibit proliferation, EMT, invasion and migration, and promote apoptosis of NPC cells.

Blastocyst activation engenders transcriptome reprogram affecting X-chromosome reactivation and inflammatory trigger of implantation.

Implantation of the blastocyst into the uterus is the gateway for further embryonic development in mammals. Programming of blastocyst to an implantation-competent state known as blastocyst activation is the determining factor for implantation into the receptive uterus. However, it remains largely unclear how the blastocyst is globally programmed for implantation. Employing a delayed implantation mouse model, we show here that the blastocyst undergoes extensive programming essential for implantation. By analyzing the transcriptional profile of blastocysts with different implantation competency, we reveal the dynamic change in the biosynthesis, metabolism, and proliferation during blastocyst reactivation from diapause. We also demonstrate that reactivation of the X chromosome, one of the most important events during periimplantation of female embryonic development, is not completed even in blastocysts under conditions of dormancy, despite long term suspension in the uterus. Moreover, the mural trophectoderm (TE), but not the polar TE, differentiates to be more invasive through the weakened cell-cell tight junctions and extracellular matrices (ECMs). By analyzing the differentially expressed profile of secretory proteins, we further demonstrate that the blastocyst functions as a proinflammatory body to secrete proinflammatory signals, such as TNFα and S100A9, thereby triggering embryo-uterine attachment reaction during implantation. Collectively, our data systematically and comprehensively disclose the programming of blastocyst reactivation from diapause for implantation and uncover previously undefined roles of blastocyst during implantation.

Spatiotemporal coordination of trophoblast and allantoic Rbpj signaling directs normal placental morphogenesis.

The placenta, responsible for the nutrient and gas exchange between the mother and fetus, is pivotal for successful pregnancy. It has been shown that Rbpj, the core transcriptional mediator of Notch signaling pathway, is required for normal placentation in mice. However, it remains largely unclear how Rbpj signaling in different placental compartments coordinates with other important regulators to ensure normal placental morphogenesis. In this study, we found that systemic deletion of Rbpj led to abnormal chorioallantoic morphogenesis and defective trophoblast differentiation in the ectoplacental cone (EPC). Employing mouse models with selective deletion of Rbpj in the allantois versus trophoblast, combining tetraploid aggregation assay, we demonstrated that allantois-expressed Rbpj is essential for chorioallantoic attachment and subsequent invagination of allantoic blood vessels into the chorionic ectoderm. Further studies uncovered that allantoic Rbpj regulates chorioallantoic fusion and morphogenesis via targeting Vcam1 in a Notch-dependent manner. Meanwhile, we also revealed that trophoblast-expressed Rbpj in EPC facilitates Mash2's transcriptional activity, promoting the specification of Tpbpα-positive trophoblasts, which differentiate into trophoblast subtypes responsible for interstitial and endovascular invasion at the later stage of placental development. Collectively, our study further shed light on the molecular network governing placental development and functions, highlighting the necessity of a spatiotemporal coordination of Rbpj signaling for normal placental morphogenesis.

Inhibition of CD147 expression promotes chemosensitivity in HNSCC cells by deactivating MAPK/ERK signaling pathway.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world. CD147, a transmembrane glycoprotein, has been reported to be correlated with cancer progression, metastasis, and chemoresistance in various cancers. In this study, we aimed to investigate the mechanism of CD147 in regulating drug resistance in HNSCC cells. qRT-PCR were used to evaluated the expression of CD147 in 57 HNSCC tumorous tissues and 2 cell lines. Increased expression of CD147 was found in most HNSCC samples, and the expression level of CD147 was correlated with multidrug resistance. CD147 RNA silencing decreased the chemoresistance of HNSCC cells by deactivating MAPK/ERK signaling pathway. Further investigation revealed that either rescue expression of CD147 or treatment of MAPK/ERK activator phorbol 12-myristate 13-acetate (PMA) in CD147 knockdown CRC cell line attenuated the decreased chemoresistance in CD147 knockdown cells. Taken together, our results suggest that CD147 promotes chemoresistance by activating MAPK/ERK signaling pathway in HNSCC.

Flavonoid Compound Icariin Activates Hypoxia Inducible Factor-1α in Chondrocytes and Promotes Articular Cartilage Repair.

Articular cartilage has poor capability for repair following trauma or degenerative pathology due to avascular property, low cell density and migratory ability. Discovery of novel therapeutic approaches for articular cartilage repair remains a significant clinical need. Hypoxia is a hallmark for cartilage development and pathology. Hypoxia inducible factor-1alpha (HIF-1α) has been identified as a key mediator for chondrocytes to response to fluctuations of oxygen availability during cartilage development or repair. This suggests that HIF-1α may serve as a target for modulating chondrocyte functions. In this study, using phenotypic cellular screen assays, we identify that Icariin, an active flavonoid component from Herba Epimedii, activates HIF-1α expression in chondrocytes. We performed systemic in vitro and in vivo analysis to determine the roles of Icariin in regulation of chondrogenesis. Our results show that Icariin significantly increases hypoxia responsive element luciferase reporter activity, which is accompanied by increased accumulation and nuclear translocation of HIF-1α in murine chondrocytes. The phenotype is associated with inhibiting PHD activity through interaction between Icariin and iron ions. The upregulation of HIF-1α mRNA levels in chondrocytes persists during chondrogenic differentiation for 7 and 14 days. Icariin (10-6 M) increases the proliferation of chondrocytes or chondroprogenitors examined by MTT, BrdU incorporation or colony formation assays. Icariin enhances chondrogenic marker expression in a micromass culture including Sox9, collagen type 2 (Col2α1) and aggrecan as determined by real-time PCR and promotes extracellular matrix (ECM) synthesis indicated by Alcian blue staining. ELISA assays show dramatically increased production of aggrecan and hydroxyproline in Icariin-treated cultures at day 14 of chondrogenic differentiation as compared with the controls. Meanwhile, the expression of chondrocyte catabolic marker genes including Mmp2, Mmp9, Mmp13, Adamts4 and Adamts5 was downregulated following Icariin treatment for 14 days. In a differentiation assay using bone marrow mesenchymal stem cells (MSCs) carrying HIF-1α floxed allele, the promotive effect of Icariin on chondrogenic differentiation is largely decreased following Cre recombinase-mediated deletion of HIF-1α in MSCs as indicated by Alcian blue staining for proteoglycan synthesis. In an alginate hydrogel 3D culture system, Icariin increases Safranin O positive (SO+) cartilage area. This phenotype is accompanied by upregulation of HIF-1α, increased proliferating cell nuclear antigen positive (PCNA+) cell numbers, SOX9+ chondrogenic cell numbers, and Col2 expression in the newly formed cartilage. Coincide with the micromass culture, Icariin treatment upregulates mRNA levels of Sox9, Col2α1, aggrecan and Col10α1 in the 3D cultures. We then generated alginate hydrogel 3D complexes incorporated with Icariin. The 3D complexes were transplanted in a mouse osteochondral defect model. ICRS II histological scoring at 6 and 12 weeks post-transplantation shows that 3D complexes incorporated with Icariin significantly enhance articular cartilage repair with higher scores particularly in selected parameters including SO+ cartilage area, subchondral bone and overall assessment than that of the controls. The results suggest that Icariin may inhibit PHD activity likely through competition for cellular iron ions and therefore it may serve as an HIF-1α activator to promote articular cartilage repair through regulating chondrocyte proliferation, differentiation and integration with subchondral bone formation.

Site-specific characterization of the Asp- and Glu-ADP-ribosylated proteome.

Poly(ADP-ribosyl)ation is catalyzed by a family of enzymes known as PARPs. We describe a method to characterize the human aspartic acid- and glutamic acid-ADP-ribosylated proteome. We identified 1,048 ADP-ribosylation sites on 340 proteins involved in a wide array of nuclear functions; among these were many previously unknown PARP downstream targets whose ADP-ribosylation was sensitive to PARP inhibitor treatment. We also confirmed that iniparib had a negligible effect on PARP activity in intact cells.

Study on the proliferation and drug-resistance of human brain tumor stem-like cells.

Brain tumor stem-like cells (BTSLCs) have been implied to play an important role in genesis and development of glioma. However, their characteristics on proliferation and drug-resistance are uncertain thoroughly. In this experiment, some of the biological characteristics about BTSLCs were explored. Twenty cases of different grades of human glioma tissues were obtained from clinic. The primary glioma cells were collected and CD133(+) cells from them were purified by magnetic cell sorting assay. The BTSLCs were identified by testing the expression of CD133, Nestin, NSE, and GFAP, along with the culture process. WST-8 assay kit was used to evaluate the proliferating situation of CD133(+) cells in the different grade gliomas, and to compare the drug-resistance between the CD133(+) and CD133( - ) cells in the medium containing different concentrations of teniposide (VM-26). The results showed that the CD133(+) cells could regenerate by self-renewal, then generate and different into NSE(+) and GFAP(+) cells, respectively. CD133(+) cells in the high grade of gliomas showed the faster generation than the ones in the low grade. The number of survived CD133(+) cells in the medium containing VM-26 was much more than the CD133(-) ones in it. Therefore, it was implied that the CD133(+) BTSLCs existed in the glioma tissues possessed the more tolerant ability to the VM-26, and could proliferate much more easily in the high-grade glioma.