Signaling repurposable drug combinations against COVID-19 by developing the heterogeneous deep herb-graph method.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spurred a boom in uncovering repurposable existing drugs. Drug repurposing is a strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication. MOTIVATION: Current works of drug repurposing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are mostly limited to only focusing on chemical medicines, analysis of single drug targeting single SARS-CoV-2 protein, one-size-fits-all strategy using the same treatment (same drug) for different infected stages of SARS-CoV-2. To dilute these issues, we initially set the research focusing on herbal medicines. We then proposed a heterogeneous graph embedding method to signaled candidate repurposing herbs for each SARS-CoV-2 protein, and employed the variational graph convolutional network approach to recommend the precision herb combinations as the potential candidate treatments against the specific infected stage. METHOD: We initially employed the virtual screening method to construct the 'Herb-Compound' and 'Compound-Protein' docking graph based on 480 herbal medicines, 12,735 associated chemical compounds and 24 SARS-CoV-2 proteins. Sequentially, the 'Herb-Compound-Protein' heterogeneous network was constructed by means of the metapath-based embedding approach. We then proposed the heterogeneous-information-network-based graph embedding method to generate the candidate ranking lists of herbs that target structural, nonstructural and accessory SARS-CoV-2 proteins, individually. To obtain precision synthetic effective treatments forvarious COVID-19 infected stages, we employed the variational graph convolutional network method to generate candidate herb combinations as the recommended therapeutic therapies. RESULTS: There were 24 ranking lists, each containing top-10 herbs, targeting 24 SARS-CoV-2 proteins correspondingly, and 20 herb combinations were generated as the candidate-specific treatment to target the four infected stages. The code and supplementary materials are freely available at https://github.com/fanyang-AI/TCM-COVID19.

Association between body mass index and newly diagnosed drug-resistant pulmonary tuberculosis in Shandong, China from 2004 to 2019.

BACKGROUND: Drug-resistant tuberculosis (DR-TB), obesity, and malnutrition are growing public health problems in the world. However, little has discussed the impact of different BMI status on the emergence of TB drug resistance. We aimed to explore the drug-resistant profiles of DR-TB and its clinical predictors among underweight, overweight or obesity population. METHODS: 8957 newly diagnosed TB cases with drug susceptibility results and BMI data in Shandong China, from 2004 to 2019 were enrolled. Multivariable and univariable logistic regression models were applied to investigate the impact of BMI on different drug-resistance. Clinical predicators and drug-resistant profiles of DR-TB among obesity, underweight, normal TB group were also described. RESULTS: Among 8957 TB cases, 6417 (71.64%) were normal weight, 2121 (23.68%) were underweight, 373 (4.16%) were overweight, and 46 (0.51%) were obese. The proportion of drug resistance and co-morbidity among normal weight, underweight, overweight, obese TB groups were 18.86%/18.25%/20.38%/23.91% (DR-TB), 11.19%/11.74%/9.65%/17.39% (mono-resistant tuberculosis, MR-TB), 3.41%/3.06%/5.36%/0.00% (multidrug resistant tuberculosis, MDR-TB), 4.21%/3.39%/5.36%/6.52% (polydrug resistant tuberculosis, PDR-TB), 10.57%/8.44%/19.57%/23.91% (co-morbidity), respectively. Compared with normal weight group, underweight were associated with lower risk of streptomycin-related resistance (OR 0.844, 95% CI 0.726-0.982), but contributed to a higher risk of MR-TB (isoniazid) (odds ratio (OR) 1.347, 95% CI 1.049-1.730; adjusted OR (aOR) 1.31, 95% CI 1.017-1.686), P < 0.05. In addition, overweight were positively associated with MDR-TB (OR 1.603, 95% CI 1.002-2.566; aOR 1.639, 95% CI 1.02-2.633), isoniazid + rifampicin + streptomycin resistance (OR 1.948, 95% confidence interval (CI): 1.061-3.577; aOR 2.113, 95% CI 1.141-3.912), Any isoniazid + streptomycin resistance (OR 1.472, 95% CI 1.013-2.14; aOR 1.483, 95% CI 1.017-2.164), P < 0.05. CONCLUSIONS: The higher risk of MDR-TB, isoniazid + rifampicin + streptomycin resistance, Any isoniazid + streptomycin resistance, and co-morbidity among overweight population implies that routine screening for drug sensitivity and more attention on co-morbidity among overweight TB cases may be necessary. In addition, underweight TB cases have a higher risk of isoniazid resistance. Our study suggests that an in-depth study of the interaction between host metabolic activity and infection of DR-TB may contribute more to novel treatment options or preventive measures, and accelerate the implementation of the STOP TB strategy.

Corilagin ameliorates the extreme inflammatory status in sepsis through TLR4 signaling pathways.

BACKGROUND: Sepsis is one of the serious disorders in clinical practice. Recent studies found toll-like receptors 4 (TLR4) played an important role in sepsis. In this study, we tried to find the influence of Corilagin on TLR4 signal pathways in vitro and in vivo. METHODS: The cellular and animal models of sepsis were established by LPS and then interfered with Corilagin. Real-time PCR and western blot were employed to detect the mRNA and protein expressions of TLR4, MyD88, TRIF and TRAF6. ELISA was used to determine the IL-6 and IL-1ß levels in supernatant and serum. RESULTS: The survival rate was improved in the LPS + Corilagin group, and the mRNA and protein expressions of TLR4, MyD88, TRIF and TRAF6 were significantly decreased than that in the LPS group both in cellular and animal models (P < 0.01). The pro-inflammatory cytokines IL-6 and IL-1ß were greatly decreased in the LPS + Corilagin group both in supernatant and serum (P < 0.01). CONCLUSIONS: Corilagin exerts the anti-inflammatory effects by down-regulating the TLR4 signaling molecules to ameliorate the extreme inflammatory status in sepsis.

Corilagin ameliorates schistosomiasis hepatic fibrosis through regulating IL-13 associated signal pathway in vitro and in vivo.

Interleukin (IL)-13-associated signal pathway plays an important role in schistosomiasis hepatic fibrosis. In this study we tried to investigate the effects of corilagin to ameliorate schistosomiasis hepatic fibrosis through regulating IL-13-associated signal pathway in vitro and in vivo. Cellular model was set up with hepatic stellate cells-T6 cells stimulated by rIL-13 and male Balb/c mice were infected with Schistosoma japonicum cercariaeas as animal model. Liver histological changes were observed with haematoxylin and eosin staining. Masson staining was employed to observe the change of egg granulomas. Expression of Col (collagen) and Col III were examined with Immunohistochemistry. Western bolt was employed to detect the JAK-1 and IL13Rα1 proteins. The mRNA expression of Col I, Col III, IL-13, JAK-1 and IL13Rα1 were tested by quantitative polymerase chain reaction. As a result, less inflammatory changes were found in all corilagin groups compared with model group and praziquantel group. The mRNA levels of Col I, Col III, IL-13, JAK-1 and IL13Rα1 were significantly decreased after corilagin intervention (P < 0·01). JAK-1 and IL-13Rα1 protein levels were also greatly decreased in the corilagin groups (P < 0·01). In conclusion, corilagin could ameliorate schistosomiasis hepatic fibrosis by down-regulating the expression of IL-13 and signal molecules in IL-13 pathway.

Shenqi fuzheng injection attenuates irradiation-induced brain injury in mice via inhibition of the NF-κB signaling pathway and microglial activation.

AIM: Radiation-induced brain injury (RIBI) is the most common and severe adverse effect induced by cranial radiation therapy (CRT). In the present study, we examined the effects of the traditional Chinese medicine Shenqi Fuzheng Injection (SFI) on RIBI in mice, and explored the underlying mechanisms. METHODS: C57BL/6J mice were subjected to a single dose of 20-Gy CRT. The mice were treated with SFI (20 mL·kg(-1)·d(-1), ip) for 4 weeks. Morris water maze test was used to assess the cognitive changes. Evans blue leakage and a horseradish peroxidase (HRP) assay were used to evaluate the integrity of the blood-brain barrier (BBB). The expression of inflammatory factors and microglial activation in brain tissues were detected using RT-PCR, Western blotting and immunofluorescence staining. RESULTS: CRT caused marked reductions in the body weight and life span of the mice, and significantly impaired their spatial learning. Furthermore, CRT significantly increased the BBB permeability, number of activated microglia, expression levels of TNF-α and IL-1ß, and the levels of phosphorylated p65 and PIDD-CC (the twice-cleaved fragment of p53-induced protein with a death domain) in the brain tissues. Four-week SFI treatment (administered for 2 weeks before and 2 weeks after CRT) not only significantly improved the physical status, survival, and spatial learning in CRT-treated mice, but also attenuated all the CRT-induced changes in the brain tissues. Four-week SFI pretreatment (administered for 4 weeks before CRT) was less effective. CONCLUSION: Administration of SFI effectively attenuates irradiation-induced brain injury via inhibition of the NF-κB signaling pathway and microglial activation.

Classification of field wheat varieties based on a lightweight G-PPW-VGG11 model.

Introduction: In agriculture, especially wheat cultivation, farmers often use multi-variety planting strategies to reduce monoculture-related harvest risks. However, the subtle morphological differences among wheat varieties make accurate discrimination technically challenging. Traditional variety classification methods, reliant on expert knowledge, are inefficient for modern intelligent agricultural management. Numerous existing classification models are computationally complex, memory-intensive, and difficult to deploy on mobile devices effectively. This study introduces G-PPW-VGG11, an innovative lightweight convolutional neural network model, to address these issues. Methods: G-PPW-VGG11 ingeniously combines partial convolution (PConv) and partially mixed depthwise separable convolution (PMConv), reducing computational complexity and feature redundancy. Simultaneously, incorporating ECANet, an efficient channel attention mechanism, enables precise leaf information capture and effective background noise suppression. Additionally, G-PPW-VGG11 replaces traditional VGG11's fully connected layers with two pointwise convolutional layers and a global average pooling layer, significantly reducing memory footprint and enhancing nonlinear expressiveness and training efficiency. Results: Rigorous testing showed G-PPW-VGG11's superior performance, with an impressive 93.52% classification accuracy and only 1.79MB memory usage. Compared to VGG11, G-PPW-VGG11 showed a 5.89% increase in accuracy, 35.44% faster inference, and a 99.64% reduction in memory usage. G-PPW-VGG11 also surpasses traditional lightweight networks in classification accuracy and inference speed. Notably, G-PPW-VGG11 was successfully deployed on Android and its performance evaluated in real-world settings. The results showed an 84.67% classification accuracy with an average time of 291.04ms per image. Discussion: This validates the model's feasibility for practical agricultural wheat variety classification, establishing a foundation for intelligent management. For future research, the trained model and complete dataset are made publicly available.

Anti-inflammatory and anti-oxidative effects of corilagin in a rat model of acute cholestasis.

BACKGROUND: Nowadays, treatments for cholestasis remain largely nonspecific and often ineffective. Recent studies showed that inflammatory injuries and oxidative stress occur in the liver with cholestasis. In this study, we would use corilagin to treat the animal model of acute cholestasis in order to define the activity to interfere with inflammation-related and oxidative stress pathway in cholestatic pathogenesis. METHODS: Rats were administrated with alpha-naphthylisothiocyanate to establish model of cholestasis and divided into corilagin, ursodeoxycholic acid, dexamethasone, model and normal groups with treatment of related agent. At 24h, 48h and 72h time points after administration, living condition, serum markers of liver damage, pathological changes of hepatic tissue, nuclear factor (NF)-kappaB, myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide (NO) were examined and observed. RESULTS: Compared to model group, corilagin had remarkable effect on living condition, pathological manifestation of liver tissue, total bilirubin, direct bilirubin, (P<0.01), but no effect on alanine aminotransferase (ALT) and aspartate aminotransferase (AST). With corilagin intervention, levels of MPO, MDA and translocation of NF-κB were notably decreased, and levels of SOD and NO were markedly increased (P<0.05 or P<0.01). CONCLUSIONS: It is shown that corilagin is a potential component to relieve cholestasis through inflammation-related and oxidation-related pathway.

Th17 cells contribute to viral replication in coxsackievirus B3-induced acute viral myocarditis.

Acute viral myocarditis (AVMC) is characterized by virus-triggered myocardial inflammation, and Coxsackievirus B3 (CVB3) is the primary pathogen. We previously proved that Th17 cells, besides having proinflammatory effects, were involved in AVMC by enhancing humoral response. However, the relationship between Th17 cells and CVB3 replication remains unknown. In this experiment, we infected BALB/c mice with CVB3 for establishing AVMC models and then found that, with the increase of viral replication, the expressions of splenic Th17 cells, serum IL-17, and cardiac IL-17 mRNA were elevated significantly, accompanied by the progressive cardiac injuries of AVMC. Furthermore, on day 5, the peak time for viral replication, correlation was positive between cardiac IL-17 mRNA and CVB3 RNA (correlation index = 0.835; p < 0.01). Although the expressions of Th1 and CD8(+) T cells, which could secrete the antiviral cytokine IFN-γ and damage the heart, were also elevated, along with Th17 cells, in AVMC, the neutralization of IL-17 further upregulated the percentages of splenic Th1 and CD8(+) T cells and the levels of cardiac IFN-γ mRNA. The cardiac pathological changes were obviously improved after neutralization, with reduced viral replication followed by decreases in the cardiac inflammatory cytokines IL-17, TNF-α, and IL-1ß. These data suggest that Th17 cells contribute to CVB3 replication in AVMC, and that IL-17 might be an important target for regulating the balance of antiviral immunities.

Impact of alcohol drinking and tobacco smoking on the drug-resistance of newly diagnosed tuberculosis: a retrospective cohort study in Shandong, China, during 2004-2020.

OBJECTIVES: To investigate the independent and collective impact of alcohol drinking and tobacco smoking on the drug-resistance of newly diagnosed tuberculosis (TB). DESIGN: This was a retrospective cohort study. SETTING: Shandong, China. PARTICIPANTS: Patients with newly diagnosed TB from 1 January 2004 to 31 December 2020 were collected. Exclusive criteria: retreated cases; extrapulmonary tuberculosis; without information on drug susceptibility testing results, smoking or drinking habits; bacteriological identification as non-tuberculous mycobacteria. PRIMARY AND SECONDARY OUTCOME MEASURES: Patients were classified into four groups including smokers only (G1), drinker only (G2), smoker +drinker (G3), non-smoker +non-drinker group (G0). We described the drug-resistant profiles, clinical factors and calculated the ORs of different drug-resistance among G1, G2, G3, compared with G0 through univariate and multivariate logistics regression models. RESULTS: Of the 7996 TB cases enrolled, the proportions of G1, G2, G3 and G0 were 8.25%, 3.89%, 16.46% and 71.40%, respectively. The rates of drug-resistant (DR)-TB, mono-resistant TB, multidrug resistant (MDR)-TB, polydrug resistant TB in G1, G2, G3 and G0 were 19.24%/16.4%/17.33%/19.08%, 11.52%/8.68%/10.94%/11.63%, 3.03%/2.57%/2.96%/3.66% and 4.70%/4.82%/3.34%/ 4.08%, respectively. G3 had a higher risk of MDR1: isoniazid +rifampin (adjusted OR (aOR)=1.91, 95% CI: 1.036 to 3.532), but had a lower risk of DR-TB (aOR=0.84, 95% CI: 0.71 to 0.99), rifampin-related resistance (aOR=0.68, 95% CI: 0.49 to 0.93), streptomycin-related resistance (aOR=0.82, 95% CI: 0.68 to 0.99), ethambutol-related resistance (aOR=0.57, 95% CI: 0.34 to 0.95), MDR3: isoniazid +rifampin+streptomycin (aOR=0.41, 95% CI: 0.19 to 0.85), any isoniazid +streptomycin resistance (aOR=0.85, 95% CI: 0.71 to 1.00). However, there were no significant differences between G1 and G0, G2 and G0 in all drug-resistant subtypes. Those patients with cavity had a higher risk of DR-TB among G3 (OR=1.35, 95% CI: 1.01 to 1.81). CONCLUSION: Although we did not found an independent impact of alcohol drinking or tobacco smoking on TB drug-resistance, respectively, these two habits had a combined effect on TB drug-resistance.

Small RNA interference-mediated gene silencing of heparanase abolishes the invasion, metastasis and angiogenesis of gastric cancer cells.

BACKGROUND: Heparanase facilitates the invasion and metastasis of cancer cells, and is over-expressed in many kinds of malignancies. Our studies indicated that heparanase was frequently expressed in advanced gastric cancers. The aim of this study is to determine whether silencing of heparanase expression can abolish the malignant characteristics of gastric cancer cells. METHODS: Three heparanase-specific small interfering RNA (siRNAs) were designed, synthesized, and transfected into cultured gastric cancer cell line SGC-7901. Heparanase expression was measured by RT-PCR, real-time quantitative PCR and Western blot. Cell proliferation was detected by MTT colorimetry and colony formation assay. The in vitro invasion and metastasis of cancer cells were measured by cell adhesion assay, scratch assay and matrigel invasion assay. The angiogenesis capabilities of cancer cells were measured by tube formation of endothelial cells. RESULTS: Transfection of siRNA against 1496-1514 bp of encoding regions resulted in reduced expression of heparanase, which started at 24 hrs and lasted for 120 hrs post-transfection. The siRNA-mediated silencing of heparanase suppressed the cellular proliferation of SGC-7901 cells. In addition, the in vitro invasion and metastasis of cancer cells were attenuated after knock-down of heparanase. Moreover, transfection of heparanase-specific siRNA attenuated the in vitro angiogenesis of cancer cells in a dose-dependent manner. CONCLUSIONS: These results demonstrated that gene silencing of heparanase can efficiently abolish the proliferation, invasion, metastasis and angiogenesis of human gastric cancer cells in vitro, suggesting that heparanase-specific siRNA is of potential values as a novel therapeutic agent for human gastric cancer.

N-butanol Extract from Melilotus Suaveolens Ledeb Affects Pro- and Anti-Inflammatory Cytokines and Mediators.

Melilotus suaveolens Ledeb is a traditional medicinal plant for treating inflammation-related disease. This explores the inner anti-inflammatory mechanism of n-butanol extract from M. suaveolens Ledeb. Inflammatory cellular model was established by lipopolysaccharide intervention on RAW264.7 cell line. Levels of secreted cytokines TNF-α, IL-1ß, IL-6, NO and IL-10 in supernatant, mRNA expression of TNF-α, COX-2, iNOS and HO-1, protein expression of COX-2 and HO-1, activation of NF-κB and ingredients in the extract were assayed by ELISA, real time quantitative PCR, western blot, immunocytochemical test and HPLC fingerprint test, respectively. As a result, the extract could not only markedly reduce the production of pro-inflammatory mediators to different extents by blocking NF-κB activation but also promote the release of anti-inflammatory mediator HO-1 significantly. Each 1 g extract contained 0.023531 mg coumarin and another two high polar ingredients, probably saponins. It can be concluded that the extract has similar effects on antagonizing pro-inflammatory mediators and cytokines like Dexamethasone, and has effects on promoting the production of anti-inflammatory mediators.

In vitro antiviral activity of lutein against hepatitis B virus.

Despite the availability of an effective vaccine, the hepatitis B virus (HBV) infection and its treatment remains one of the foremost public health problems in the world. The present study was performed in order to investigate the anti-HBV activity of lutein in vitro. The antiviral activity of lutein was examined by detecting the levels of HBsAg, HBeAg and extracellular HBV DNA in stable HBV-producing human hepatoblastoma HepG2 2.2.15 cells. It was found that lutein effectively suppressed the secretion of HBsAg from HepG2 2.2.15 cells in a dose-dependent manner, and it also suppressed the amount of extracellular HBV DNA. A luciferase reporter gene assay was used to determine the effects of lutein on the activities of HBV promoters. The results showed that lutein inhibited the activity of HBV full-length promoter (Fp). These data indicate that lutein possesses an anti-HBV activity and exerts its antivirus effects via inhibition of HBV transcription.

Influence of silencing TRAF6 with shRNA on LPS/TLR4 signaling in vitro.

This study investigated the influence of silencing TRAF6 with shRNA on lipopolysaccharide (LPS)/toll-like receptor (TLR)-4 signaling pathway in vitro. Four plasmids (pGCsi-TRAF6-shRNA1, 2, 3, 4) containing different shRNA sequences were designed and synthesized. The proliferation of RAW264.7 cells after transfected with these plasmids was measured by MTT assay. Inflammatory cellular models were established by LPS stimulation. Levels of TNF-alpha, IL-1beta and TGF-beta1 in the supernatants, mRNA expressions of TRAF6, IL-6 and COX-2, protein expression of TRAF6 and translocation of NF-kappaB were assayed by ELISA, real-time quantitative PCR and Western blotting, respectively. The results showed that the TRAF6 gene knockdown by RNAi hardly inhibited the proliferation of RAW264.7 cells within 72 h. The mRNA and protein expression of TRAF6 was lower in the TRAF6-shRNA1, 2 groups than in the TRAF6-shRNA3, 4 groups. Therefore, pGCsi-TRAF6-shRNA1, 2 were selected for the subsequent experiments. Our results still showed that pGCsi-TRAF6-shRNA1, 2 could significantly reduce the production of pro-inflammatory cytokines and mediators including TNF-alpha, IL-1beta, IL-6 and COX-2, and inhibit NF-kappaB nuclear translocation. Moreover, pGCsi-TRAF6-shRNA1, 2 could suppress the release of TGF-beta1 at the protein level. It was concluded that the recombinant plasmid pTRAF6-shRNA can, to some extent, inhibit inflammatory response stimulated by LPS at the initial phase. TRAF6 may become the potential therapeutic target of many inflammation-related diseases.

18F-FDG PET/CT SUVmax and serum CEA levels as predictors for EGFR mutation state in Chinese patients with non-small cell lung cancer.

The epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) contribute to an increased response rate, compared with chemotherapy, in patients with inhibitor-sensitive EGFR mutations. The present study evaluated the association between the maximum standardized uptake value (SUVmax) of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT), as well as serum carcinoembryonic antigen (CEA) levels and EGFR mutations prior to treatment, in patients with non-small cell lung cancer (NSCLC). Patients with histologically confirmed NSCLC (n=167), who underwent an 18F-FDG PET/CT scan, EGFR mutation analysis and a serum CEA test participated in the present study. Multivariate logistic regression analysis was used to analyze predictors of EGFR mutations. Receiver-operating characteristic (ROC) curve analysis was performed to determine the efficient cut-off value. Survival rate analysis was evaluated according to SUVmax and EGFR mutation status. A decreased SUVmax and an increased CEA level was observed in patients with EGFR-mutations, compared with patients with wild-type primary lesions and metastatic lymph nodes. The exon 19 EGFR mutation was associated with increased SUVmax, compared with the exon 21 L858R mutation. The ROC analysis indicated that an 18F-FDG PET/CT uptake SUVmax >11.5 may be a predictor of the wild-type EGFR genotype and increased CEA levels (CEA >9.4 ng/ml) were associated with EGFR mutations. Furthermore, patients with no smoking history, low SUVmax of the primary tumor, metastatic lymph nodes and a high CEA level were significantly associated with EGFR mutation status. The results of the present study indicated that patients with advanced NSCLC, particularly Chinese patients, with decreased SUVmax and increased CEA levels are associated with EGFR mutations, which may serve as predictors for the EGFR-TKI therapeutic response.

Hypo-fractionation radiotherapy normalizes tumor vasculature in non-small cell lung cancer xenografts through the p-STAT3/HIF-1 alpha signaling pathway.

BACKGROUND: Hypo-fractionation radiotherapy (HFRT) was considered to be an important treatment for non-small cell lung cancer (NSCLC), but the radiobiological effects of HFRT on NSCLC remain unclear. The aim of this study was to investigate specific biological effect of HFRT on tumor angiogenesis, compared with conventional radiotherapy (CRT). METHODS: The subcutaneous xenograft models and the dorsal skinfold window chamber (DSWC) models of nude mice bearing H460 and HCC827 NSCLC cells were irradiated with doses of 0 Gy (sham group), 22 Gy delivered into 11 fractions (CRT group) or 12 Gy delivered into 1 fraction (HFRT group). At certain time-points after irradiation, the volumes, hypoxic area, coverage rate of pericyte and micro-vessel density (MVD) of the subcutaneous xenograft models were detected, and the tumor vasculature was visualized in the DSMC model. The expressions of phosphorylated signal transducer and activator of transcription (p-STAT3), hypoxia-inducible factor 1-α (HIF-1α), CXCL12 and VEGFA were detected. RESULTS: Compared with the CRT groups, HFRT showed more-efficient tumor growth-suppression, accompanied by a HFRT-induced window-period, during which vasculature was normalized, tumor hypoxia was improved and MVD was decreased. Moreover, during the window-period, the signal levels of p-STAT3/HIF-1α pathway and the expressions of its downstream angiogenic factors (VEGFA and CXCL12) were inhibited by HFRT. CONCLUSION: Compared with CRT, HFRT induced tumor vasculature normalization by rendering the remaining vessels less tortuous and increasing pericyte coverage of tumor blood vessels, thereby ameliorating tumor hypoxia and enhancing the tumor-killing effect. Moreover, HFRT might exert the aforementioned effects through p-STAT3/HIF-1α signaling pathway.

Retraction Note to: MicroRNA-330-3p promotes cell invasion and metastasis in non-small cell lung cancer through GRIA3 by activating MAPK/ERK signaling pathway.

An amendment to this paper has been published and can be accessed via the original article.

Increased expression of galectin-1 is associated with human oral squamous cell carcinoma development.

Galectin-1 (Gal-1) is a newly found immunoregulatory carbohydrate-binding protein in cancer biology. The purpose of this study was to evaluate the effects of Gal-1 on oral squamous cell carcinoma (OSCC) development. Immunohistochemistry, Western blotting and RT-PCR were carried out in 62 primary OSCC, 38 oral leukoplakia (OPL) tissues to detect the Gal-1 expression in both protein and mRNA levels. Ten normal oral mucosa (NOM) tissues were used as control. Gal-1 protein was significantly overexpressed in OSCC cancer cells and OPL prickle cells compared to NOM (P<0.05). In accordance with Gal-1 protein, Gal-1 mRNA was also up-regulated in OSCC tissues and OPL tissues. Furthermore, both the Gal-1 protein and mRNA in OSCC tissues were higher than in OPL tissues (P<0.05). Our data supports the important roles of Gal-1 in OSCC development and suggests that Gal-1 upregulation in the OSCC and OPL tissues might be a predictor of early oral carcinogenesis.

Tea polyphenols exerts anti-hepatitis B virus effects in a stably HBV-transfected cell line.

In this study, the anti-HBV effects of tea polyphenols (TP) were examined. After cells were exposed to TP for 3, 6, 9 days, amounts of HBsAg, HBeAg and HBV-DNA released into the supernatant of the cultured HepG2 2.2.15 cells were detected. TP, to some extent, inhibited the secretion of HBsAg and strongly suppressed the secretion of HBeAg in a dose-dependent (P<0.01) and time-dependent manner, with 50% maximal inhibitory concentration (IC50) value being 7.34 microg/mL on the 9th day, but the time-dependence was not significant (P=0.051). Expression of HBV-DNA in the supernatant of the cell culture also was significantly decreased in a dose-dependent fashion (P<0.01). The IC50 of TP in inhibiting HBV DNA was 2.54 microg/mL. It concluded that TP possessed potential anti-HBV effects and may be used as a treatment alternative for HBV infection.

Selection of optimal antisense accessible sites of uroplakin II mRNA for bladder urothelium.

The optimal antisense accessible sites (AAS) of uroplakin II (UP II) mRNA, a specific gene expressed in bladder urothelium, were selected in order to provide a novel method for targeted therapy of transitional cell carcinoma (TCC) of bladder. The 20 mer random oligonucleotide library was synthesized, hybridized with in vitro transcripted total UP II cRNA, then digested by RNase H. After primer extension and autoradiography, the AAS of UP II were selected. The RNADraw software was used to analyze and choose the AAS with obvious stem-loop structures, according to which the complementary antisense oligonucleotides (AS-ODN) were synthesized. With the AS-ODN(0) designed only by RNADraw as a control, the AS-ODNs were transferred into UP II highly-expressing cell line RT(4). The cellular expression of UP II mRNA was detected by RT-PCR and Western blot. Twelve AAS of UP II mRNA were selected in vitro. Four AAS with stem-loop structures were chosen, locating at 558-577, 552-571, 217-236 and 97-116 bp of UP II mRNA respectively. After transfection with the corresponding AS-ODN (AS-ODN(1), AS-ODN(2), AS-ODN(3) and AS-ODN(4)) for 18 h, the UP II mRNA levels in RT(4) cells were reduced by 29.3%, 82.7%, 71.3% and 70.9%, while UP II protein levels were decreased by 20.2%, 78.5%, 65.2% and 64.4% respectively, which were significantly higher than those of AS-ODN(0) (14.3%, 12.1% respectively) (P<0.01). The AAS of UP II mRNA was effectively selected in vitro by random oligonucletide library/RNase H cleavage method in combination with computer software analysis, which had important reference values for further studying biological functions of UP II gene and targeted therapeutic strategy for TCC of bladder.