Identification of Fasudil as a collaborator to promote the anti-tumor effect of lenvatinib in hepatocellular carcinoma by inhibiting GLI2-mediated hedgehog signaling pathway.

Lenvatinib is a frontline tyrosine kinase inhibitor for patients with advanced hepatocellular carcinoma (HCC). However, just 25% of patients benefit from the treatment, and acquired resistance always develops. To date, there are neither effective medications to combat lenvatinib resistance nor accurate markers that might predict how well a patient would respond to the lenvatinib treatment. Thus, novel strategies to recognize and deal with lenvatinib resistance are desperately needed. In the current study, a robust Lenvatinib Resistance index (LRi) model to predict lenvatinib response status in HCC was first established. Subsequently, five candidate drugs (Mercaptopurine, AACOCF3, NU1025, Fasudil, and Exisulind) that were capable of reversing lenvatinib resistance signature were initially selected by performing the connectivity map (CMap) analysis, and fasudil finally stood out by conducting a series of cellular functional assays in vitro and xenograft mouse model. Transcriptomics revealed that the co-administration of lenvatinib and fasudil overcame lenvatinib resistance by remodeling the hedgehog signaling pathway. Mechanistically, the feedback activation of EGFR by lenvatinib led to the activation of the GLI2-ABCC1 pathway, which supported the HCC cell's survival and proliferation. Notably, co-administration of lenvatinib and fasudil significantly inhibited IHH, the upstream switch of the hedgehog pathway, to counteract GLI2 activation and finally enhance the effectiveness of lenvatinib. These findings elucidated a novel EGFR-mediated mechanism of lenvatinib resistance and provided a practical approach to overcoming drug resistance in HCC through meaningful drug repurposing strategies.

Identification of potential DNA methylation biomarkers related to diagnosis in patients with bladder cancer through integrated bioinformatic analysis.

BACKGROUND: Bladder cancer (BLCA) is one of the most common malignancies among tumors worldwide. There are no validated biomarkers to facilitate such treatment diagnosis. DNA methylation modification plays important roles in epigenetics. Identifying methylated differentially expressed genes is a common method for the discovery of biomarkers. METHODS: Bladder cancer data were obtained from Gene Expression Omnibus (GEO), including the gene expression microarrays GSE37817( 18 patients and 3 normal ), GSE52519 (9 patients and 3 normal) and the gene methylation microarray GSE37816 (18 patients and 3 normal). Aberrantly expressed genes were obtained by GEO2R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed using the DAVID database and KOBAS. Protein-protein interactions (PPIs) and hub gene networks were constructed by STRING and Cytoscape software. The validation of the results which was confirmed through four online platforms, including Gene Expression Profiling Interactive Analysis (GEPIA), Gene Set Cancer Analysis (GSCA), cBioProtal and MEXPRESS. RESULTS: In total, 253 and 298 upregulated genes and 674 and 454 downregulated genes were identified for GSE37817 and GSE52519, respectively. For the GSE37816 dataset, hypermethylated and hypomethylated genes involving 778 and 3420 genes, respectively, were observed. Seventeen hypermethylated and low expression genes were enriched in biological processes associated with different organ development and morphogenesis. For molecular function, these genes showed enrichment in extracellular matrix structural constituents. Pathway enrichment showed drug metabolic enzymes and several amino acids metabolism, PI3K-Akt, Hedgehog signaling pathway. The top 3 hub genes screened by Cytoscape software were EFEMP1, SPARCL1 and ABCA8. The research results were verified using the GEPIA, GSCA, cBioProtal and EXPRESS databases, and the hub hypermethylated low expression genes were validated. CONCLUSION: This study screened possible aberrantly methylated expression hub genes in BLCA by integrated bioinformatics analysis. The results may provide possible methylation-based biomarkers for the precise diagnosis and treatment of BLCA in the future.

Hybrid Path Planning for Unmanned Surface Vehicles in Inland Rivers Based on Collision Avoidance Regulations.

In recent years, with the continuous advancement of the construction of the Yangtze River's intelligent waterway system, unmanned surface vehicles have been increasingly used in the river's inland waterways. This article proposes a hybrid path planning method that combines an improved A* algorithm with an improved model predictive control algorithm for the autonomous navigation of the "Jinghai-I" unmanned surface vehicle in inland rivers. To ensure global optimization, the heuristic function was refined in the A* algorithm. Additionally, constraints such as channel boundaries and courses were added to the cost function of A* and the planned path was smoothed to meet the collision avoidance regulations for inland rivers. The model predictive control algorithm incorporated a new path-deviation cost while imposing a cost constraint on the yaw angle, significantly minimizing the path-tracking error. Furthermore, the improved model predictive control algorithm took into account the requirements of rules in the cost function and adopted different collision avoidance parameters for different encounter scenarios, improving the rationality of local path planning. Finally, the proposed algorithm's effectiveness was verified through simulation experiments that closely approximated real-world navigation conditions.

Scutellarin-mediated autophagy activates exosome release of rat nucleus pulposus cells by positively regulating Rab8a via the PI3K/PTEN/Akt pathway.

To provide a basis for promising exosome-based therapies against intervertebral disc degeneration (IDD), our present research aimed to identify a mechanism underlying the vesicle release from nucleus pulposus cells (NPCs). Scutellarin (SC) is a natural chemotherapeutic agent isolated from Erigeron breviscapus with a variety of biological activities. Here, we observed the significantly elevated autophagy levels in rat NPCs under the stimulation of SC, leading to a concomitant enhancement of intracellular vesicle release, which could be attributed to the inactivation of the phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/protein kinase B (Akt) pathway. To ensure that exosome release was driven by SC via the autophagic pathway, we implemented gain-of-function and loss-of-function studies by additionally using insulin-like growth factor-1 (IGF-1) and small-interfering RNA of autophagy-related gene 5 (ATG5), and the exosome secretion decreased in the case of attenuated autophagy. Evidently, the treatment with SC exerted the remarkable upregulation of Rab8a through the overexpression of ATG5. After the respective knockdown of ATG5 and Rab8a, the increased release of exosomes induced by SC was reversed, whereas the number of intracellular vesicles was restored. Overall, it can be concluded that SC contributes to the autophagy activation in NPCs by acting on the PI3K/PTEN/Akt pathway, which upregulates the expression of Rab8a and promotes the release of exosomes, inspiring novel therapeutic strategies in preventing IDD that might be fruitfully investigated.

Taqman-MGB FQ-PCR for Human GPIIIa, GP1BA and PEAR1 SNPs.

BACKGROUND: A reliable operation-convenient Taqman-MGB probe fluorescence quantity polymerase chain reaction (FQ-PCR) for detection human GPIIIa, GP1BA, and PEAR1 polymorphism were designed, and the performances were assessed. METHODS: Four sets of probes and primers for target alleles included rs5918 (176T>C), rs6065 (5792C>T), rs1204133 (2266G>A), and ß-actin were designed, the reaction systems were optimized. Both artificial plasmids and clinical samples were tested by the research system and Sanger sequencing. The results were compared to assess the performance of the reaction system. RESULTS: The results shown the Taqman-MGB FQ-PCR could test as low as 5 ng/mL. There was no impact even if the concentration of DNA reached 170 ng/mL. The accuracy was 100% by detection of DNA samples and artificial plasmids. The coefficient of variation (CV) of 40 tests lasting 20 days was < 5% at low, medium, and high concentrations, respectively. Compared with Sanger sequencing, the AUC and Youden's index of the reaction system were 0.991, 0.953 and 0.998, 0.993 for C/T allele of rs5918; 0.997, 0.976 and 0.997, 0.989 for T/C of rs6065; 0.998, 0.964, and 0.998, 0.976 for A/G of rs12041331, respectively. Eight kinds of biological ingredients in blood samples had no influence on the reaction system. The similar sequences and other mutant sites of three target gene sites would not impact or cross react with the reaction system. The performance of the system was stable for 11 months under -20℃ ± 5℃. The 275 clinical blood samples were tested by the research system and Sanger sequencing, the consistencies were 100%. CONCLUSIONS: The research reaction system met the requirement in daily routine testing of laboratory medicine. This study was very meaningful for clinical rapid detection and personalized treatment.

Covalent Modification of MoS2 with Poly(N-vinylcarbazole) for Solid-State Broadband Optical Limiters.

New soluble MoS2 nanosheets covalently functionalized with poly(N-vinylcarbazole) (MoS2-PVK) were in situ synthesized for the first time. In contrast to MoS2 and MoS2 /PVK blends, both the solution of MoS2 -PVK in DMF and MoS2-PVK/poly(methyl methacrylate) (PMMA) film show superior nonlinear optical and optical limiting responses. The MoS2-PVK/PMMA film shows the largest nonlinear coefficients (ßeff) of about 917 cm GW(-1) at λ=532 nm (cf. 100.69 cm GW(-1) for MoS2/PMMA and 125.12 cm GW(-1) for MoS2/PVK/PMMA) and about 461 cm GW(-1) at λ=1064 nm (cf. -48.92 cm GW(-1) for MoS2/PMMA and 147.56 cm GW(-1) for MoS2/PVK/PMMA). A larger optical limiting effect, with thresholds of about 0.3 GW cm(-2) at λ=532 nm and about 0.5 GW cm(-2) at λ=1064 nm, was also achieved from the MoS2-PVK/PMMA film. These values are among the highest reported for MoS2-based nonlinear optical materials. These results show that covalent functionalization of MoS2 with polymers is an effective way to improve nonlinear optical responses for efficient optical limiting devices.

[Detection of ROS1 gene rearrangement by FISH and analysis of its clinical features in non-small cell lung cancer patients].

OBJECTIVE: To detect the frequency of ROS1 gene rearrangement in non-small cell lung cancer ( NSCLC) patients by FISH, and to analyze the relationship between ROS1 gene rearrangement and clinical features (including age, sex, stage, histology, smoking history) with NSCLC. METHODS: The ROS1 gene rearrangement in histological sections of 1 652 NSCLC tissues was detected by FISH. The extracted RNA was amplified and the sequences were analyzed by Sanger sequencing for ROS1-positive samples. RESULTS: ROS1 rearrangement was identified in 53 specimens (3.2%) from the 1 652 NSCLC tissues. Among these positive cases, 15 were CD74-ROS1, 13 were SLC34A2-ROS1, 13 were SDC4-ROS1 and 12 were TPM3-ROS1. The frequency of ROS1 rearrangement was significantly higher in never-smoking patients (49 cases) than in smokers (4 cases) (P < 0.05). Patients with ROS1-positive NSCLC tended to be younger and there was no significant difference in sex (P > 0.05). All of the ROS1-positive samples were adenocarcinomas, with a tendency toward higher clinical stage (P < 0.05). CONCLUSIONS: ROS1 rearrangement has diversity, and may be defined as a new molecular subtype of NSCLC. ROS1 rearrangement tends to occur in younger, and never-smoker lung adenocarcinoma patients.

[Construction of a repeat-free dual color fluorescent in situ hybridization probe for ROS1 gene in non-small cell lung cancer diagnosis].

OBJECTIVE: To establish a repeat-free ROS1 gene fluorescence in situ hybridization (FISH) probe, and to compare its efficacy with those of commercial FISH probes in non-small cell lung cancer. METHODS: The probe was constructed by combining human Cot-1 DNA genome into double-stranded sequence, and then digested by duples specific nuclease to establish a repeat-free sequence. The final repeat-free ROS1 FISH probe was labeled by red and green fluoresceins. RESULTS: Compared with the commercialized probe, repeat-free FISH probe exhibited excellent efficiency and low signal to noise ratio (SNR) in samples. There was statistical significance in the difference between the hybridization rate of these two probes (P < 0.05) , but there was no difference between the accuracy rate (P > 0.05). CONCLUSION: The repeat-free ROS1 FISH probe significantly improves the probe hybridization efficiency and SNR in non-small cell lung cancer (NSCLC), resulting in an increased accuracy of detection.

BNIP3-mediated mitophagy boosts the competitive growth of Lenvatinib-resistant cells via energy metabolism reprogramming in HCC.

An increasing evidence supports that cell competition, a vital selection and quality control mechanism in multicellular organisms, is involved in tumorigenesis and development; however, the mechanistic contributions to the association between cell competition and tumor drug resistance remain ill-defined. In our study, based on a contructed lenvitinib-resistant hepatocellular carcinoma (HCC) cells display obvious competitive growth dominance over sensitive cells through reprogramming energy metabolism. Mechanistically, the hyperactivation of BCL2 interacting protein3 (BNIP3) -mediated mitophagy in lenvatinib-resistant HCC cells promotes glycolytic flux via shifting energy production from mitochondrial oxidative phosphorylation to glycolysis, by regulating AMP-activated protein kinase (AMPK) -enolase 2 (ENO2) signaling, which perpetually maintaining lenvatinib-resistant HCC cells' competitive advantage over sensitive HCC cells. Of note, BNIP3 inhibition significantly sensitized the anti-tumor efficacy of lenvatinib in HCC. Our findings emphasize a vital role for BNIP3-AMPK-ENO2 signaling in maintaining the competitive outcome of lenvitinib-resistant HCC cells via regulating energy metabolism reprogramming; meanwhile, this work recognizes BNIP3 as a promising target to overcome HCC drug resistance.

HSP90a promotes the resistance to oxaliplatin in HCC through regulating IDH1-induced cell competition.

Though burgeoning research manifests that cell competition, an essential selection and quality control mechanism for maintaining tissue or organ growth and homeostasis in multicellular organisms, is closely related to tumorigenesis and development, the mechanism of cell competition associated with tumor drug resistance remains elusive. In the study, we uncovered that oxaliplatin-resistant hepatocellular carcinoma (HCC) cells exhibit a pronounced competitive advantage against their sensitive counterparts, which is related to lipid takeover of resistant cells from sensitive cells. Of note, such lipid takeover is dependent on the existence of isocitrate dehydrogenase 1 (IDH1) in resistant HCC cells. Mechanistically, IDH1 activity is regulated by heat shock protein 90 alpha (HSP90α) through binding with each other, which orchestrates the expressions of lipid metabolic enzymes and lipid accumulation in resistant HCC cells. Our results suggest that HCC cell competition-driven chemoresistance can be regulated by HSP90α/IDH1-mediated lipid metabolism, which may serve as a promising target for overcoming drug resistance in HCC.

G-CSF improving combined whole brain radiotherapy and immunotherapy prognosis of non-small cell lung cancer brain metastases.

OBJECTIVE: To evaluate the therapeutic advantage of G-CSF to whole brain radiotherapy (WBRT) in combination with immunotherapy as a first-line treatment for non-small cell lung cancer (NSCLC) brain metastases (BMs). METHODS: In this retrospective study, 117 patients (37 in G-CSF group and 80 in no G-CSF group) who underwent first-line WBRT combined with immunotherapy were enrolled. Their survival, intracranial response, BM-related symptoms and toxicity were evaluated. RESULTS: The overall survival (OS) of patients in G-CSF group was significantly improved compared to patients no G-CSF group (median time: 14.8 vs 10.2 months; HR: 0.61, 95 % CI: 0.38-0.97, p = 0.035). However, there were no significant differences in intracranial responses between the two groups (p > 0.05). The G-CSF group exhibited a significantly higher rate of relief from BM-related symptoms compared to the no G-CSF group (91.7 % vs 59.5 %, p = 0.037). Cox proportional hazards regression analyses indicated that after-treatment ALC > 0.9 × 10^9/L (HR 0.57, 95 % CI 0.32-0.99, p = 0.046) and Hb > 110 g/dL (HR 0.41, 95 % CI 0.24-0.71, p = 0.001) were significant potential factors associated with extended OS. The addition of G-CSF was well tolerated and effectively reduced the incidence of neutropenia (0 % vs 5.0 %, p = 0.17). CONCLUSION: Integrating G-CSF with WBRT and immunotherapy as a first-line treatment for NSCLC-BMs has exhibited significant efficacy and favorable tolerability.

Preemptive peritonsillar infiltration with lidocaine for relief of bipolar adult post-tonsillectomy pain: a randomized, double-blinded clinical study.

There are discordant results in the studies of the peritonsillar infiltration in adults undergoing the tonsillectomy. The study is to compare the effect of the preemptive peritonsillar infiltration with lidocaine in bipolar tonsillectomy in adult. 172 adult patients were randomly located into five groups before tonsillectomy: group 0: without the peritonsillar infiltration, group 1: for 3 ml normal saline with 1:200,000 epinephrine per tonsil, group 2: for 3 ml 1 %lidocaine with 1:200,000 epinephrine per tonsil, group 3: for 8 ml normal saline with 1:200,000 epinephrine per tonsil, group 4: for 8 ml lidocaine with 1:200,000 epinephrine per tonsil. The post-operative pain in the following 7 days was assessed by visual analog scale. Operation time and post-operative bleeding were also recorded. No significant differences were found between operative times, post-tonsillectomy hemorrhage between the five groups. The differences between pain scores of the group 0, group 1 and group 2 were not statistically significant (P > 0.05). The differences between pain scores of group 3, group 4 against group 0, group 1, group 2 were statistically significant (P < 0.05). We found the volume of peritonsillar infiltration might contribute to the relief of pain of the bipolar post-tonsillectomy.

HSF1 is involved in immunotherapeutic response through regulating APOJ/STAT3-mediated PD-L1 expression in hepatocellular carcinoma.

Hepatocellular cancer (HCC) is a serious illness with high prevalence and mortality throughout the whole world. For advanced HCC, immunotherapy is somewhat impactful and encouraging. Nevertheless, a substantial proportion of patients with advanced HCC are still unable to achieve a durable response, owing to heterogeneity from clonal variability and differential expression of the PD-1/PD-L1 axis. Recently, heat shock factor 1 (HSF1) is recognized as an important component of tumor immunotherapeutic response as well as related to PD-L1 expression in cancer. However, the mechanism of HSF1 regulating PD-L1 in cancer, especially in HCC, is still not fully clear. In this study, we observed the significantly positive correlation between HSF1 expression and PD-L1 expression in HCC samples; meanwhile combination expressions of HSF1 and PD-L1 served as the signature for predicting prognosis of patients with HCC. Mechanistically, HSF1 upregulated PD-L1 expression by inducing APOJ expression and activating STAT3 signaling pathway in HCC. In addition, we explored further the potential values of targeting the HSF1-APOJ-STAT3 axis against CD8+ T cells-mediated cancer cells cytotoxicity. These findings unveiled the important involvement of HSF1 in regulating PD-L1 expression in HCC as well as provided a novel invention component for improving the clinical response rate and efficacy of PD-1/PD-L1 blockade.

Nucleotide sugar transporter SLC35A2 is involved in promoting hepatocellular carcinoma metastasis by regulating cellular glycosylation.

PURPOSE: Recently, aberrant glycosylation has been recognized to be relate to malignant behaviors of cancer and outcomes of patients with various cancers. SLC35A2 plays an indispensable role on glycosylation as a nucleotide sugar transporter. However, effects of SLC35A2 on malignant behaviors of cancer cells and alteration of cancer cells surface glycosylation profiles are still not fully understood, particularly in hepatocellular carcinoma (HCC). Hence, from a glycosylation perspective, we investigated the effects of SLC35A2 on metastatic behaviors of HCC cells. METHODS: SLC35A2 expression in clinical samples and HCC cells was examined by immunohistochemical staining or Western blot/quantitative PCR and was regulated by RNA interference or vectors-mediated transfection. Effects of SLC35A2 expression alteration on metastatic behaviors and membrane glycan profile of HCC cells were observed by using respectively invasion, migration, cell adhesion assay, in vivo lung metastatic nude mouse model and lectins microarray. Co-location among proteins in HCC cells was observed by fluorescence microscope and detected by an in vitro co-immunoprecipitation assay. RESULTS: SLC35A2 was upregulated in HCC tissues, and is associated with poor prognosis of HCC patients. SLC35A2 expression alteration significantly affected the invasion, adhesion, metastasis and membrane glycan profile and led to the dysregulated expressions or glycosylation of cell adhesion-related molecules in HCC cells. Mechanistically, the maintenance of SLC35A2 activity is critical for the recruitment of the key galactosyltransferase B4GalT1, which is responsible for complex glycoconjugate and lactose biosynthesis, to Golgi apparatus in HCC cells. CONCLUSION: SLC35A2 plays important roles in promoting HCC metastasis by regulating cellular glycosylation modification and inducing the cell adhesive ability of HCC cells.

Bronchial salivary gland-type intraductal carcinoma with KIAA1217::RET gene fusion composed of intercalated and oncocytic components.

Salivary gland-type intraductal carcinoma (IC) is a rare malignant salivary gland neoplasm. Primary salivary gland-type IC has never been described in the lung. Herein, we present a primary pulmonary IC in a 63-year-old woman. The tumor originated in the bronchus wall of the right middle lobe. The tumor consisted of two histological types, intercalated component and oncocytic component. The intercalated component showed tubular/cystic pattern composed of column to cube-shaped cells and scattered mucous cells. The oncocytic component showed solid nests composed of large cells with abundant eosinophilic granular cytoplasm. Immunohistochemically, both histological components were positive for cytokeratin 7 (CK7), S-100 protein, SOX10, and mammaglobin. The rimming myoepithelial cells were highlighted by p63 and smooth muscle actin (SMA). The tumor cells were negative for androgen receptor (AR), HER-2, Dog-1, TTF-1, napsin A, GCDFP-15, and GATA3. In the present case, we detected KIAA1217::RET fusion via DNA-based next-generation sequencing (NGS) and RT-PCR, which established the diagnosis of IC at a molecular level. The present case expands the categories of bronchopulmonary salivary gland-type tumors.

Integrative analysis of clinicopathological features defines novel prognostic models for mantle cell lymphoma in the immunochemotherapy era: a report from The North American Mantle Cell Lymphoma Consortium.

BACKGROUND: Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes. METHODS: The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases. RESULTS: In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p < 0.0001) and progression-free survival (PFS, p < 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p < 0.0001 for OS and p = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort. CONCLUSIONS: The outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL.

Activation of transcriptional activity of HSE by a novel mouse zinc finger protein ZNFD specifically expressed in testis.

Zinc finger proteins (ZFPs) that contain multiple cysteine and/or histidine residues perform important roles in various cellular functions, including transcriptional regulation, cell proliferation, differentiation, and apoptosis. The Cys-Cys-His-His (C(2)H(2)) type of ZFPs are the well-defined members of this super family and are the largest and most complex proteins in eukaryotic genomes. In this study, we identified a novel C(2)H(2) type of zinc finger gene ZNFD from mice which has a 1,002 bp open reading frame and encodes a protein with 333 amino acid residues. The predicted 37.4 kDa protein contains a C(2)H(2) zinc finger domain. ZNFD gene is located on chromosome 18qD1. RT-PCR analysis revealed that the ZNFD gene was specifically expressed in mouse testis but not in other tissues. Subcellular localization analysis demonstrated that ZNFD was localized in the nucleus. Reporter gene assays showed that overexpression of ZNFD in the COS7 cells activates the transcriptional activities of heat shock element (HSE). Overall, these results suggest that ZNFD is a member of the zinc finger transcription factor family and it participates in the transcriptional regulation of HSE. Many heat shock proteins regulated by HSE are involved in testicular development. Therefore, our results suggest that ZNFD may probably participate in the development of mouse testis and function as a transcription activator in HSE-mediated gene expression and signaling pathways.

Total glucosides of peony induce fibroblast-like synovial apoptosis, and ameliorate cartilage injury via blocking the NF-κB/STAT3 pathway.

Background: Rheumatoid arthritis (RA) is one of the most common inflammatory arthritis worldwide. Total glucosides of peony (PG) were isolated from Paeonia lactiflora Pall, which were found to have the capacity to intervene in the progression of arthritis via an anti-inflammatory action. This study aimed to explore the protective effect of PG against RA. Methods: In this study, we further investigated the molecular mechanisms of PG on RA. We constructed RA models by Bovine type II collagen in vitro or complete Freund's adjuvant (FCA) in vivo. The RA-MH7A cells were cultured and treated with different doses (10, 20, 50 µg/mL) of PG. Cell proliferation, apoptosis, and release of inflammatory cytokines were determined. Furthermore, the effect of PG was also explored in vivo using the collagen-induced arthritis rat model. After 30 days, the rats were sacrificed; histological changes, cytokine level, and protein expression were measured. Results: It was revealed that PG dose-dependently inhibited RA-synovial cell growth and induce apoptosis by regulating relative gene level. Besides, PG downregulated the levels of interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and IL-1ß, and upregulated IL-10 level in vitro and in vivo. The regulation contributed to the restoration of cartilage injuries. Furthermore, PG also downregulated the expression of nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) phosphorylation. Conclusions: All these results showed that PG inhibits the excessive proliferation of synovial cells, and ameliorates cartilage injury via blocking the NF-κB/STAT3 pathway. Collectively, this study provides novel insights into the mechanism of PG, laying a foundation for the application of PG in RA.

Prognostic value of nuclear ß-catenin overexpression at invasive front in colorectal cancer for synchronous liver metastasis.

BACKGROUND: ß-catenin plays an important role in colorectal tumorigenesis. Relatively little is known about the relationship between ß-catenin overexpression and liver metastasis. The purpose of this study was to investigate whether nuclear ß-catenin overexpression in colorectal cancer is associated with synchronous liver metastasis. METHODS: The ß-catenin expression in tumor tissue from 486 patients with colorectal cancer was examined by immunohistochemistry. The relationship between nuclear ß-catenin expression in colorectal cancers and liver metastatic lesions and other clinicopathological characteristics was analyzed. Univariate analysis and logistic multivariate regression analysis were adopted to discriminate risk factors of liver metastasis. RESULTS: Nuclear ß-catenin overexpression at the invasive front of the primary tumor in patients with liver metastasis is more evident than that in patients without liver metastasis (71.5% vs. 29.3%; P < 0.001). Nuclear ß-catenin expression in primary tumors had a positive correlation with that in the matched metastatic lesions (r = 0.499, P < 0.001). Univariate and multivariate analyses indicated that overexpression of nuclear ß-catenin at the invasive front in colorectal cancer correlated with liver metastasis. CONCLUSIONS: Overexpression of nuclear ß-catenin at the invasive front in colorectal cancer is strongly associated with liver metastasis and may be a promising predictor of liver metastasis.