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Magnolia bark is a traditional Chinese medicine used for hypoglycaemia. With the widespread use of Magnolia bark, its resources are facing a serious shortage. To address this issue, a strategy based on high-coverage mass spectrometry (HCMS) and multidimensional chemical-biological analysis (MCBA) was proposed for the comprehensive exploration of Magnolia officinalis which is the main source of Magnolia bark. The strategy is divided into three main steps. In the first step, the stem bark, stem xylem, root bark, root xylem, leaf and rootlet of Magnolia officinalis were comprehensively analyzed using high-coverage mass spectrometry. In the second step, multivariate statistical analysis was used to explore the heterogeneity of the six parts and detect differential chemical components. In the third step, a combination of experimental screening and molecular docking was used to explore α-glucosidase inhibitors from Magnolia officinalis. Multidimensional chemical-biological analysis (MCBA) of Magnolia officinalis was achieved by combining the last two steps. Finally, a total of 103 compounds were identified from the whole plant of Magnolia officinalis. Differential components of stem bark, stem xylem, leaf, root bark, root xylem and rootlet were systematically revealed. A pair of positional isomers, namely magnolol and honokiol, were found to be α-glucosidase inhibitors. The activity of their combination is superior to that of each single compound, indicating that magnolol and honokiol are in a synergistic relationship. This strategy contributes to comprehensive exploitation of functional plants and effective alleviation of resource shortage. This study also provides a research paradigm for other similar traditional Chinese medicinal plants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background & Aims: As the first approved medication for metabolic dysfunction-associated steatohepatitis (MASH), the thyroid hormone receptor-β (THR-β) agonist MGL-3196 (resmetirom) has garnered much attention as a liver-directed, bioactive oral drug. However, studies on MGL-3196 have also identified remarkable heterogeneity of individual clinical efficacy and its interference with gut microbiota in host hepatoenteral circulation remains to be elucidated., Methods: We compared MASH attenuation by MGL-3196 and its derivative drug HSK31679 between germ-free (GF) and specific-pathogen free (SPF) mice to evaluate the role of gut microbiota. Then cross-omics analyses of microbial metagenome, metabolome and single-cell RNA-sequencing were applied to a randomized, double-blind, placebo-controlled multiple ascending dose cohort receiving HSK31679 treatment (n = 32) or placebo (n = 8), to comprehensively investigate the altered gut microbiota metabolism and circulating immune signatures., Results: HSK31679 outperformed MGL-3196 in ameliorating MASH diet-induced steatohepatitis of SPF mice but not GF mice. In the multiple ascending dose cohort of HSK31679, the relative abundance of B. thetaiotaomicron was significantly enriched, impairing glucosylceramide synthase (GCS)-catalyzed monoglucosylation of microbial Cer(d18:1/16:0) and Cer(d18:1/24:1). In contrast to the non-inferior effect of MGL-3196 and HSK31679 on MASH resolution in GF BTΔGCS mice, HSK31679 led to superior benefit on steatohepatitis in GF BTWT mice, due to its steric hindrance of R123 and Y401 of gut microbial GCS. For participants with high fecal GCS activity, the administration of 160 mg HSK31679 induced a shift in peripheral compartments towards an immunosuppressive niche, characterized by decreased CD8α + dendritic cells and MINCLE + macrophages., Conclusions: This study provided novel insights into the gut microbiota that are key to the efficacy of HSK31679 treatment, revealing microbial GCS as a potential predictive biomarker in MASH, as well as a new target for further microbiota-based treatment strategies for MASH., Impact and Implications: Remarkable heterogeneity in individual clinical efficacy of thyroid hormone receptor-β agonists and their interferences with the microbiome in host hepatoenteral circulation are poorly understood. In our current germ-free mouse models and a randomized, double-blind, multiple-dose cohort study, we identified microbial glucosylceramide synthase as a key mechanistic node in the resolution of metabolic dysfunction-associated steatohepatitis. Microbial glucosylceramide synthase activity could be a predictive biomarker of response to HSK31679 treatment or a new target for microbiota-based therapeutics in metabolic dysfunction-associated steatohepatitis., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Zanthoxyli radix is a popular tea among the elderly, and it is believed to have a positive effect on Alzheimer's disease. In this study, a highly effective three-step strategy was proposed for comprehensive analysis of the active components and biological functions of Zanthoxylum nitidum (ZN), including high-resolution LC-Q-TOF mass spectrometry (HRMS), multivariate statistical analysis for heterogeneity (MSAH), and experimental and virtual screening for bioactivity analysis (EVBA). A total of 117 compounds were identified from the root, stem, and leaf of ZN through HRMS. Bioactivity assays showed that the order of acetylcholinesterase (AChE) inhibitory activity from strong to weak was root > stem > leaf. Nitidine, chelerythrine, and sanguinarine were found to be the main differential components of root, stem, and leaf by OPLS-DA. The IC 50 values of the three compounds are 0.81 ± 0.02, 0.14 ± 0.01, and 0.48 ± 0.01 μM respectively, indicating that they are potent and high-quality AChE inhibitors. Molecular docking showed that pi-pi T-shaped interactions and pi-lone pairs played important roles in AChE inhibition. This study not only explains the biological function of Zanthoxyli radix in alleviating Alzheimer's disease to some extent, but also lays the foundation for the development of stem and leaf of ZN.

Alzheimer's disease (AD) is a common age-associated progressive neurodegenerative disorder that is implicated in the aberrant regulation of numerous circular RNAs (circRNAs). Here, we reported that circ-Bptf, a conserved circRNA derived from the Bptf gene, showed an age-dependent decrease in the hippocampus of APP/PS1 mice. Overexpression of circ-Bptf significantly reversed dendritic spine loss and learning and memory impairment in APP/PS1 mice. Moreover, we found that circ-Bptf was predominantly localized to the cytoplasm and upregulated p62 expression by binding to miR-138-5p. Furthermore, the miR-138-5p mimics reversed the decreased expression of p62 induced by the silencing of circ-Bptf. Together, our findings suggested that circ-Bptf ameliorated learning and memory impairments via the miR-138-5p/p62 axis in APP/PS1 mice. It may act as a potential player in AD pathogenesis and therapy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: It is unclear whether Saccharomyces boulardii (S. boulardii) supplementation in standard triple therapy (STT) is effective in eradicating Helicobacter pylori (H. pylori) infection in children. We therefore conducted a meta-analysis of randomized controlled trials (RCTs) to assess the effect of S. boulardii supplementation on H. pylori eradication in children., Methods: We conducted electronic searches in PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure and Wanfang database from the beginning up to September 2023. A random-effects model was employed to calculate the pooled relative risk (RR) with 95% confidence intervals (CI) through a meta-analysis., Results: Fifteen RCTs (involving 2156 patients) were included in our meta-analysis. Results of the meta-analysis indicated that S. boulardii in combination with STT was more effective than STT alone (intention-to-treat analysis : 87.7% vs. 75.9%, RR = 1.14, 95% CI: 1.10-1.19, P < 0.00001; per-protocol analysis : 88.5% vs. 76.3%, RR = 1.15, 95% CI: 1.10-1.19, P < 0.00001). The S. boulardii supplementation group had a significantly lower incidence of total adverse events (n = 6 RCTs, 9.2% vs. 29.2%, RR = 0.32, 95% CI: 0.21-0.48, P < 0.00001), diarrhea (n = 13 RCTs, 14.7% vs. 32.4%, RR = 0.46, 95% CI: 0.37-0.56, P < 0.00001), and nausea (n = 11 RCTs, 12.7% vs. 21.3%, RR = 0.53, 95% CI: 0.40-0.72, P < 0.0001) than STT group alone. Similar results were also observed in the incidence of vomiting, constipation, abdominal pain, abdominal distention, epigastric discomfort, poor appetite and stomatitis., Conclusions: Current evidence indicated that S. boulardii supplementing with STT could improve the eradication rate of H. pylori, and concurrently decrease the incidence of total adverse events and gastrointestinal adverse events in children., (© 2023. The Author(s).)

Background: Asparaginase (ASP) is an important drug in combined chemotherapy regimens for pediatric acute lymphoblastic leukemia (ALL); ASP-associated pancreatitis (AAP) is the main adverse reaction of ASP. Recurrent pancreatitis is a complication of AAP, for which medication is ineffective., Aim: To evaluate the efficacy and safety of endoscopic retrograde cholangiopancreatography (ERCP) in treating recurrent pancreatitis due to AAP., Methods: From May 2018 to August 2021, ten children (five males and five females; age range: 4-13 years) with AAP were treated using ERCP due to recurrent pancreatitis. Clinical data of the ten children were collected, including their sex, age, weight, ALL risk grading, clinical symptoms at the onset of pancreatitis, time from the first pancreatitis onset to ERCP, ERCP operation status, and postoperative complications. The symptomatic relief, weight change, and number of pancreatitis onsets before and after ERCP were compared., Results: The preoperative symptoms were abdominal pain, vomiting, inability to eat, weight loss of 2-7 kg, and 2-9 pancreatitis onsets. After the operation, nine of ten patients did not develop pancreatitis, had no abdominal pain, could eat normally; the remaining patient developed three pancreatitis onsets due to the continuous administration of ASP, but eating was not affected. The postoperative weight gain was 1.5-8 kg. There was one case of post ERCP pancreatitis and two cases of postoperative infections; all recovered after medication., Conclusion: ERCP improved clinical symptoms and reduced the incidence of pancreatitis, and was shown to be a safe and effective method for improving the management of recurrent pancreatitis due to AAP., Competing Interests: Conflict-of-interest statement: All the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

To explore the effects of single or combined application of chlorine-and sulfur-based fertilizers on rice bioavailability of Cd in soils, pot experiments with reddish clayey soil (developed from quaternary red clay parent materials) under three exogenous Cd levels (0, 0.5, and 2.0 mg·kg -1 ) were conducted. Meanwhile, chlorine-based fertilizers (KCl, NH 4 Cl) and sulfur-based fertilizers[K 2 SO 4 , (NH 4 ) 2 SO 4 ] were added in different proportions. The soil pH, Cd morphology, and Cd accumulation in rice at different growth stages were analyzed. The results revealed that both chlorine-and sulfur-based fertilizers could acidify the soil; however, the effect of chlorine-based fertilizers was more significant. During the filling stage of rice, the soil pH value of the treatment of applying single chlorine-based fertilizer decreased by 0.28 on average compared with that of applying single sulfur-based fertilizer. At the maturity stage of rice, chlorine-based fertilizer could activate the residual Cd, whereas sulfur-based fertilizer passivated the acid-extracted Cd to its residual state. Compared with the single application of the same fertilizer, the combined application of chlorine-and sulfur-based fertilizers was more likely to promote the accumulation of Cd in rice plants. The highest Cd accumulation of brown rice was 0.21 mg·kg -1 (2.0 mg·kg -1 exogenous Cd level) in the 1:1 (mole ratios of Cl:S) treatment of chlorine-and sulfur-based fertilizers, which was 16.4% higher than that of single chlorine-based fertilizer and 113.3% higher than that of single sulfur-based fertilizer. Therefore, the combined application of chlorine-fertilizers and sulfur-based fertilizers will increase the concentration of Cd in brown rice. To ensure food quality and safety, it is more advisable to apply single sulfur-based fertilizer for rice planting.

Background: Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Currently, there is no suitable treatment for post-ERCP pancreatitis (PEP) prophylaxis. Few studies have prospectively evaluated interventions to prevent PEP in children., Aim: To assess the efficacy and safety of the external use of mirabilite to prevent PEP in children., Methods: This multicenter, randomized controlled clinical trial enrolled patients with chronic pancreatitis scheduled for ERCP according to eligibility criteria. Patients were randomly divided into the external use of mirabilite group (external use of mirabilite in a bag on the projected abdominal area within 30 min before ERCP) and blank group. The primary outcome was the incidence of PEP. The secondary outcomes included the severity of PEP, abdominal pain scores, levels of serum inflammatory markers [tumor necrosis factor-alpha (TNF-α) and serum interleukin-10 (IL-10)], and intestinal barrier function markers [diamine oxidase (DAO), D-lactic acid, and endotoxin]. Additionally, the side effects of topical mirabilite were investigated., Results: A total of 234 patients were enrolled, including 117 in the external use of mirabilite group and the other 117 in the blank group. The pre-procedure and procedure-related factors were not significantly different between the two groups. The incidence of PEP in the external use of mirabilite group was significantly lower than that in the blank group (7.7% vs 26.5%, P < 0.001). The severity of PEP decreased in the mirabilite group ( P = 0.023). At 24 h after the procedure, the visual analog scale score in the external use of mirabilite group was lower than that in the blank group ( P = 0.001). Compared with those in the blank group, the TNF-α expressions were significantly lower and the IL-10 expressions were significantly higher at 24 h after the procedure in the external use of mirabilite group ( P = 0.032 and P = 0.011, respectively). There were no significant differences in serum DAO, D-lactic acid, and endotoxin levels before and after ERCP between the two groups. No adverse effects of mirabilite were observed., Conclusion: External use of mirabilite reduced the PEP occurrence. It significantly alleviated post-procedural pain and reduced inflammatory response. Our results favor the external use of mirabilite to prevent PEP in children., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The number of pediatric cases of infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has increased. Here, we describe the clinical characteristics of children in a tertiary children's medical center in Shanghai., Methods: A total of 676 pediatric coronavirus disease 2019 (COVID-19) cases caused by the Omicron variant who were admitted to the Shanghai Children's Medical Center from March 28 to April 30, 2022 were enrolled in this single-center, prospective, observational real-world study. Patient demographics and clinical characteristics, especially COVID-19 vaccine status, were assessed., Results: Children of all ages appeared susceptible to the SARS-CoV-2 Omicron variant, with no significant difference between sexes. A high SARS-CoV-2 viral load upon admission was associated with leukocytopenia, neutropenia, and thrombocytopenia (P = 0.003, P = 0.021, and P = 0.017, respectively) but not with physical symptoms or radiographic chest abnormalities. Univariable linear regression models indicated that comorbidities (P = 0.001) were associated with a longer time until viral clearance, and increasing age (P < 0.001) and two doses of COVID-19 vaccine (P = 0.001) were associated with a shorter time to viral clearance. Multivariable analysis revealed an independent effect of comorbidities (P < 0.001) and age (P = 0.003). The interaction effect between age and comorbidity showed that the negative association between age and time to virus clearance remained significant only in patients without underlying diseases (P < 0.001)., Conclusion: This study describes the clinical characteristics of children infected with the Omicron variant of SARS-CoV-2 and calls for additional studies to evaluate the effectiveness and safety of vaccination against COVID-19 in children., (© 2022. Children's Hospital, Zhejiang University School of Medicine.)

Objective: To investigate the changes of nocturnal erectile function and functional connectivity (FC) of bilateral thalami in insomniac ED patients with yin deficiency and fire syndrome., Methods: We enrolled 30 healthy controls and 87 ED patients with yin deficiency and fire syndrome, 41 with and the other 46 without insomnia. Using IIEF-5 and Pittsburgh Sleep Quality Index (PSQI), we evaluated the nocturnal erectile function and sleep quality of the patients and compared the clinical indicators between the two groups. Then we collected and preprocessed the MRI data on the cerebral function of the 15 ED patients with insomnia, another 15 without insomnia and the 30 healthy controls. With the thalamus as the region of interest (ROI), we calculated and compared the FC values of brain regions between the ED patients (with or without insomnia) and healthy controls, and corrected the results for multiple comparisons using the AlphaSim method., Results: Compared with the patients without insomnia, those with insomnia had a lower duration of erectile episode and tumescence and rigidity activity units in the tip of the penis. With the left thalamus as the ROI, the right middle frontal gyrus and inferior parietal were shown to be the differential brain regions among the three groups. Compared with the healthy controls, the patients without insomnia showed decreased FC values between the left thalamus and left orbital part of the middle frontal gyrus, insula, putamen and right thalamus, while those with insomnia exhibited decreased FC values between the left thalamus and bilateral middle frontal gyri, inferior parietal, calcarine fissure, parahippocampal gyrus, left superior parietal gyrus, right precuneus and inferior temporal gyrus, and they also exhibited decreased FC values between the left thalamus and middle frontal gyrus in comparison with those without insomnia. With the right thalamus as the ROI, the left medial superior frontal gyrus, bilateral calcarine fissure and right thalamus were found to be the differential brain regions among the three groups. Compared with the healthy controls, the patients without insomnia showed decreased FC values between the right thalamus (including the right thalamus itself) and left medial orbital superior frontal gyrus, superior temporal gyrus (temporal pole), middle temporal gyrus, insula and right orbital part of the inferior frontal gyrus, while those with insomnia manifested decreased FC values between the right thalamus and middle frontal gyrus, inferior parietal, left superior parietal gyrus and calcarine fissure, and they also manifested increased FC values between the right thalamus and medial superior frontal gyrus, and decreased FC values between the right thalamus and left calcarine fissure in comparison with those without insomnia., Conclusion: ED patients with insomnia have more serious clinical symptoms, with FC changes in the thalamocortical loop, which might be the pathological mechanisms of ED with insomnia.

An herbal prescription is usually composed of several herbal medicines. The complex and diverse components bring great challenges to its bioactivity study. To comprehensively analyze the bioactivity of an herbal prescription, a new strategy based on peak-by-peak cutting and knock-out chromatography was proposed. In this strategy, active compounds were screened out via peak-by-peak cutting from an herbal extract, and the influence of a compound on the overall activity of the herbal extract was evaluated by knock-out chromatography. Qiliqiangxin capsule is an herbal prescription composed of 11 herbal medicines for the treatment of chronic heart failure. A total of 71 peaks were collected through peak-by-peak cutting, and each peak was identified by a high-resolution mass spectrum. The bioassay against 1,1-diphenyl-2-picrylhydrazyl showed that two types of compounds namely salvianolic acids and caffeoylquinic acids were potent scavengers. Knock-out chromatography suggested that the removal of one single compound had no obvious influence on the overall activity of the Qiliqiangxin capsule. After all the main peaks in the Qiliqiangxin capsule were knocked out, the remaining part still exhibited a potent activity, indicating high activity stability of the Qiliqiangxin capsule. The proposed strategy is helpful for the comprehensive analysis of the bioactivity of other herbal prescriptions., (© 2022 Wiley-VCH GmbH.)

Background: Thymosin-α1 has been implicated into the treatment of novel respiratory virus Coronavirus Disease 2019 (COVID-19), but the underlying mechanisms are still disputable., Aim: Herein we aimed to reveal a previously unrecognized mechanism that thymosin-α1 prevents COVID-19 by binding with angiotensin-converting enzyme (ACE), which was inspired from the tool of network pharmacology., Methods: KEGG pathway enrichment of thymosin-α1 treating COVID-19 was analyzed by Database of Functional Annotation Bioinformatics Microarray Analysis, then core targets were validated by ligand binding kinetics assay and fluorometric detection of ACE and ACE2 enzymatic activity. The production of angiotensin I, angiotensin II, angiotensin (1-7) and angiotensin (1-9) were detected by enzyme linked immunosorbent assay., Results: We found that thymosin-α1 impaired the expressions of angiotensin-converting enzyme 2 and angiotensin (1-7) of human lung epithelial cells in a dose-dependent way ( p < 0.001). In contrast, thymosin-α1 had no impact on their ACE and angiotensin (1-9) expressions but significantly inhibited the enzymatic activity of ACE ( p > 0.05)., Conclusion: The bioinformatic findings of network pharmacology and the corresponding pharmacological validations have revealed that thymosin-α1 treatment could decrease ACE2 expression in human lung epithelial cells, which strengthens the potential clinical applications of thymosin-α1 to prevent severe acute respiratory syndrome coronavirus 2 infection., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the authors, as the current findings are incomplete and need to be validated. The reasons include that the results are not comparable to the diagnostic performance of three bacteria species in 5-fluorouracil resistance in CRC from the clinical studies which are conducted to detect each type of bacteria separately. Additional results of quantifying three bacteria species in the same colorectal cancer group are required to validate the conclusion., (Copyright © 2022. Published by Elsevier Ltd.)

Purpose: Drug delivery to posterior ocular tissues via topical eye drop administration is arduous due to the unique anatomy and physiology of the eye. Therefore, treatments for posterior eye disease have to be administered via intravitreal injection or systemic route, both of which have their drawbacks. Herein, the objective of this work was to demonstrate that a specially designed eye drop formulation could effectively deliver small-molecule vascular endothelial growth factor (VEGF) inhibitor to posterior ocular tissues for antiangiogenic therapy., Methods: The unique eye drop formulation, termed ITRI AXN eye drops, was obtained from self-assembly of (2-hydroxypropyl)-β-cyclodextrin with a VEGF tyrosine kinase inhibitor, a hydrophilic polymer, hypromellose, and a complex stabilizer, caffeine. In vivo ocular pharmacokinetics studies were performed with New Zealand White (NZW) rabbits and Non Human Primates (NHP). The antiangiogenesis effect was evaluated on the Long-Evans rat with laser-induced choroidal neovascularization and pigmented Dutch-Belted rabbits with VEGF-induced retinal neovascularization., Results: The successful drug transport from ocular surface to posterior ocular cavity was indicated by a drug biodistribution pattern in pharmacokinetic studies. Excellent drug exposure in the choroid and retina with the concentrations of 900- and 750-fold greater than drug IC50 0.5 hours post the eye drop administration (drug level: 0.8%) was observed on the NHP study. The obtained formulation also demonstrated a comparable antiangiogenic outcome with the intravitreal injection of anti-VEGF antibody on rat and rabbit disease models., Conclusions: Our eye drop formulation has demonstrated great promise in antiangiogenic therapy against retinal and choroidal neovascularization in animal models. The results suggest that the aim of this work can be successfully achieved by the novel eye drop formulation., Translational Relevance: The preclinical results provide evidence that ITRI AXN eye drops could effectively deliver therapeutics to the choroid and retina for antiangiogenic therapy.

Fibroblast migration is closely regulated by the mechanical characteristics in surrounding microenvironment. While increased interstitial hydrostatic pressure (HP) is a hallmark in many pathological and physiological conditions, little is known about how the HP affects fibroblast motility. Using cell-culture chips with elevated HP conditions, we showed that 20 cmH 2 O HP significantly accelerated fibroblast migration. The HP-induced migration acceleration was dependent on the augmentation of transforming growth factor-β 1 , and correlated with the activation of filamin A via the phosphorylation of p38 mitogen-activated protein kinase. Our results suggest that interstitial HP elevation associated with various pathological states could significantly regulate fibroblast migration., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Inflammatory cytokines were involved in pathological conditions of osteoporosis (OP). However, the specific OP-associated inflammatory cytokines are still awaiting to be detected by using a systemic method. Herein, we adopted an extreme sampling scheme and examined inflammatory cytokines between subjects with low and high bone mineral density (BMD) through protein microarray. First, 8 candidate cytokines including B lymphocyte chemoattractant (BLC), osteopontin (OPN) and insulin-like growth factor-binding protein 4 (IGFBP4) were identified in the discovery extreme sampling subgroup. Then, the different expressions for BLC, OPN and IGFBP4 were validated and replicated in two independent extreme sampling subgroups. Further functional experiments showed that the cytokine BLC was involved in bone metabolism by inhibiting bone formation and promoting bone resorption. Together, this study further revealed that inflammatory cytokines were closely related with OP, and that they highlighted critical roles of BLC in the pathogenesis of OP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aberrant sphingolipid metabolism has been implicated in chemoresistance, but the underlying mechanisms are still poorly understood. Herein we revealed a previously unrecognized mechanism of 5-fluorouracil (5-FU) resistance contributed by high SphK2-upregulated dihydropyrimidine dehydrogenase (DPD) in colorectal cancer (CRC), which is evidenced from human CRC specimens, animal models, and cancer cell lines. TMA samples from randomly selected 60 CRC specimens firstly identified the clinical correlation between high SphK2 and increased DPD (p < 0.001). Then the regulatory mechanism was explored in CRC models of villin-SphK2 Tg mice, SphK2 -/- mice, and human CRC cells xenografted nude mice. Assays of ChIP-Seq and luciferase reporter gene demonstrated that high SphK2 upregulated DPD through promoting the HDAC1-mediated H3K56ac, leading to the degradation of intracellular 5-FU into inactive α-fluoro-β-alanine (FBAL). Lastly, inhibition of SphK2 by SLR080811 exhibited excellent inhibition on DPD expression and potently reversed 5-FU resistance in colorectal tumors of villin-SphK2 Tg mice. Overall, this study manifests that SphK2 high conferred 5-FU resistance through upregulating tumoral DPD, which highlights the strategies of blocking SphK2 to overcome 5-FU resistance in CRC.

It was found in this study that long intergenic non-protein coding RNA 346 (LINC00346) was an lncRNA aberrantly expressed in gastric cancer (GC) based on multiple Gene Expression Omnibus (GEO) databases of GC cohorts. The LINC00346 gene was recurrently amplified and upregulated in GC, and its expression was positively correlated with poor pathologic stage, large tumor size, and poor prognosis. In addition, the oncogenic transcription factors KLF5 and MYC could bind to the LINC00346 promoter and enhance its expression. Gene Set Enrichment Analysis (GSEA) in the GEO datasets revealed that cell cycle and focal adhesion genes were enriched in patients with high LINC00346 expression. In vitro and in vivo assays of LINC00346 alterations revealed a complex integrated phenotype affecting cell growth, migration and invasion. Strikingly, high-throughput sequencing analysis after LINC00346 alterations highlighted alterations in cell cycle and focal adhesion pathways in GC cells. Mechanistically, argonaute 2 (Ago2) was recruited by LINC00346, which functioned as a molecular sponge for miR-34a-5p by antagonizing its ability to repress CD44, NOTCH1, and AXL protein translation. Taken together, our findings support a model in which the KLF5, MYC/LINC00346/miR-34a-5p cross-talk served as critical effectors in GC tumorigenesis and progression, suggesting a new therapeutic direction in the treatment of GC.

Background: Endoscopic retrograde cholangiopancreatography (ERCP) has been widely used in pediatric patients with cholangiopancreatic diseases., Aim: To evaluate the efficacy, safety, and long-term follow-up results of ERCP in symptomatic pancreaticobiliary maljunction (PBM)., Methods: A multicenter, retrospective study was conducted on 75 pediatric patients who were diagnosed with PBM and underwent therapeutic ERCP at three endoscopy centers between January 2008 and March 2019. They were divided into four PBM groups based on the fluoroscopy in ERCP. Their clinical characteristics, specific ERCP procedures, adverse events, and long-term follow-up results were retrospectively reviewed., Results: Totally, 112 ERCPs were performed on the 75 children with symptomatic PBM. Clinical manifestations included abdominal pain (62/75, 82.7%), vomiting (35/75, 46.7%), acholic stool (4/75, 5.3%), fever (3/75, 4.0%), acute pancreatitis (47/75, 62.7%), hyperbilirubinemia (13/75, 17.3%), and elevated liver enzymes (22/75, 29.3%). ERCP interventions included endoscopic sphincterotomy, endoscopic retrograde biliary or pancreatic drainage, stone extraction, etc . Procedure-related complications were observed in 12 patients and included post-ERCP pancreatitis (9/75, 12.0%), gastrointestinal bleeding (1/75, 1.3%), and infection (2/75, 2.7%). During a mean follow-up period of 46 mo (range: 2 to 134 mo), ERCP therapy alleviated the biliary obstruction and reduced the incidence of pancreatitis. The overall effective rate of ERCP therapy was 82.4%; seven patients (9.3%) were lost to follow-up, eight (11.8%) re-experienced pancreatitis, and eleven (16.2%) underwent radical surgery, known as prophylactic excision of the extrahepatic bile duct and hepaticojejunostomy., Conclusion: ERCP is a safe and effective treatment option to relieve biliary or pancreatic obstruction in symptomatic PBM, with the characteristics of minor trauma, fewer complications, and repeatability., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest for this article., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

Recently, novel approaches for the delivery of therapeutic antibodies have attracted much attention, especially sustained release formulations. However, sustained release formulations capable of carrying a high antibody load remain a challenge for practical use. In this study, a novel injectable hydrogel composed of maleimide-modified γ-polyglutamic acid (γ-PGA-MA) and thiol end-functionalized 4-arm poly(ethylene glycol) (4-arm PEG-SH) was developed for the subcutaneous delivery of trastuzumab. γ-PGA-MA and 4-arm PEG-SH formed a hydrogel through thiol-maleimide reactions, which had shear-thinning properties and reversible rheological behaviors. Moreover, a high content of trastuzumab (>100 mg/mL) could be loaded into this hydrogel, and trastuzumab demonstrated a sustained release over several weeks through electrostatic attraction. In addition, trastuzumab released from the hydrogel had adequate stability in terms of its structural integrity, binding bioactivity, and antiproliferative effect on BT-474 cells. Pharmacokinetic studies demonstrated that trastuzumab-loaded hydrogel (Her-hydrogel-10, composed of 1.5% γ-PGA-MA, 1.5% 4-arm PEG-SH, and 10 mg/mL trastuzumab) and trastuzumab/Zn-loaded hydrogel (Her/Zn-hydrogel-10, composed of 1.5% γ-PGA-MA, 1.5% 4-arm PEG-SH, 5 mM ZnCl 2 , and 10 mg/mL trastuzumab) could lower the maximum plasma concentration (C max ) than the trastuzumab solution. Furthermore, Her/Zn-hydrogel-10 was better able to release trastuzumab in a controlled manner, which was ascribed to electrostatic attraction and formation of trastuzumab/Zn nanocomplexes. In a BT-474 xenograft tumor model, Her-hydrogel-10 had a similar tumor growth-inhibitory effect as that of the trastuzumab solution. By contrast, Her/Zn-hydrogel-10 exhibited a superior tumor growth-inhibitory capability due to the functionality of Zn. This study demonstrated that this hydrogel has potential as a carrier for the local and systemic delivery of proteins and antibodies. STATEMENT OF SIGNIFICANCE: Recently, novel sustained-release formulations of therapeutic antibodies have attracted much attention. However, these formulations should be able to carry a high antibody load owing to the required high dose, and these formulations remain a challenge for practical use. In this study, a novel injectable chemically cross-linked hydrogel was developed for the subcutaneous delivery of trastuzumab. This novel hydrogel possessed ideal characteristics of loading high content of trastuzumab (>100 mg/mL), sustained release of trastuzumab over several weeks, and maintaining adequate stability of trastuzumab. In vivo studies demonstrated that a trastuzumab-loaded hydrogel possessed the ability of controlled release of trastuzumab and maintained antitumor efficacy same as that of trastuzumab. These results implied that a γ-PGA-MA and 4-arm PEG-SH-based hydrogel has great potential in serving as a carrier for the local or systemic delivery of therapeutic proteins or antibodies., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

To investigate the " drug-guide" effect of Achyranthes bidentata saponins( ABS) and geniposide( GE) in the treatment on adjuvant arthritis( AA) rats. A UHPLC-MS/MS method for the quantitative determination of GE,zingibroside R1,ginsenoside Ro and chikusetsu saponin Ⅳa in rat blood and joint dialysate was established. After single or combined administration with ABS and GE was given to AA rat model,a microdialysis sampling method for rat joint cavity and jugular vein blood vessels was established to collect microdialysis samples. Waters Acquity HSS C&#95;(18) column was used to separate the above four components,with mobile phase as acetonitrile-0. 1% formic acid water as mobile phase for gradient elution. ESI source was adopted for mass spectra in a negative ion scanning mode. Multiple reaction monitoring( MRM) mode was applied to detect the above four components. The methodological results showed that GE,zingibroside R1,ginsenoside Ro and chikusetsu saponin Ⅳa demonstrated a good linear relationship within the concentration ranges of 2-4 000,16-4 096,14-3 584,23-5 888 μg·L-1 respectively. The precision,accuracy,stability and matrix effect of these four ingredients reached the requirements of quantitative analysis of biological samples. The pharmacokinetic results demonstrated that the combined administration of ABS and GE( 60 mg·kg~(-1)+60 mg·kg~(-1)) can increase the degree of GE in joint cavity distribution,and the AUCjoint/AUCplasmwere twice of that of single administration of GE( 60 mg·kg~(-1)),which indicated that ABS might played a vital role in GE's distribution to joint cavity. Moreover,there was no significant difference between the distribution trend of total three ABS and GE in rats. The pharmacodynamics results showed that the combined administration of ABS and GE has stronger effects on paw swelling,arthritis index and synovial pathomorphology of AA rats than single administration of GE,which suggested that ABS might improve GE's anti-inflammatory effect in AA rats. Based on the above results,ABS has a targeting effect in increasing GE's concentration in joint cavity,with a synergy in efficacy.

Geniposide (GE) is an active component isolated from the fruit of Gardenia jasminoides Ellis that has anti-inflammatory and other pharmacological effects; however, the underlying mechanism of GE action has not been elucidated in rheumatoid arthritis (RA). Previous studies have shown that GE plays a therapeutic role in RA via regulation of the integrin beta 1 (Itgβ1)-mediated Ras-Erk1/2 signalling pathway. However, the specific mechanism of GE action on Itgβ1 has not been clarified. Recent evidence indicates that microRNAs (miRNAs) are involved in the development of RA. In this study, we developed a miRNA-124a-based synoviocyte repair strategy. We demonstrated that miRNA-124a can directly inhibit the expression of the Itgβ1 gene and decrease TNF-α-stimulated cell proliferation in vitro. MH7A cells were obtained from the patient with RA and treated with GE in the presence of TNF-α (10 ng/mL). Additionally, we demonstrated that the expression of miRNA-124a can be regulated by GE. GE upregulated the expression of miRNA-124a and decreased the expression of Itgβ1 at the mRNA and protein levels. The results of the present study are the first to suggest that GE inhibits TNF-α-stimulated cell proliferation and blocks the activation of the Ras-Erk1/2 pathway via the upregulation of miRNA-124a expression. Our study elucidates the role of miRNA-124a as a protected miRNA in RA and may provide a novel strategy for the diagnosis and treatment of RA in the future., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Accumulating data indicate that long noncoding RNAs (lncRNAs) serve as important modulators in biological processes and are dysregulated in diverse tumors. The function of FOXD2-AS1 in gastric cancer (GC) progression and related biological mechanisms remain undefined. A comprehensive analysis identified that FOXD2-AS1 enrichment was upregulated markedly in GC and positively correlated with a large tumor size, a later pathologic stage, and a poor prognosis. Gene-set enrichment analysis (GSEA) in GEO datasets uncovered that cell cycle and DNA replication associated genes were enriched in patients with high FOXD2-AS1 expression. Loss of FOXD2-AS1 function inhibited cell growth via inhibiting the cell cycle in GC, whereas upregulation of FOXD2-AS1 expression promoted cancer progression. The enhancer of zeste homolog 2 (EZH2) and lysine (K)-specific demethylase 1A (LSD1) proteins were found to serve as binding partners of FOXD2-AS1 and mediators of FOXD2-AS1 function. Mechanically, FOXD2-AS1 promoted GC tumorigenesis partly through EZH2 and LSD1 mediated EphB3 downregulation. The present results revealed that FOXD2-AS1 acted as a tumor inducer in GC partly through EphB3 inhibition by direct interaction with EZH2 and LSD1, and may prove to be a potential biomarker of carcinogenesis.

Irisin, a myokine produced by skeletal muscle in response to physical exercise, promotes trans-differentiation of white adipose tissue into brown adipose tissue. Recent evidences suggested that irisin also plays an important role in the control of bone metabolism. This study aimed to ascertain the relationship between plasma irisin and bone mineral density (BMD) in Chinese population by adoption of an extreme sampling method. Based on a large and screened Chinese elderly population (N = 6308), two subgroups with extremely high and low hip BMD were selected for discovery (N = 80, high vs. low BMD = 44:36) and validation (N = 60, high vs. low BMD = 30:30), respectively. Plasma irisin, P1NP, and β-CTx were measured using commercially available ELISA kits. Other metabolic parameters (e.g., blood glucose, total cholesterol and triglycerides) were collected. Student's t test and Spearman correlation analyses were conducted in SPSS. Significant difference was discovered for plasma irisin between females and age-matched males (N = 80, male vs. female = 42:38, P = 0.002). The plasma irisin levels were significantly higher in high BMD subjects than in low BMD subjects, which was observed in both discovery (P = 0.012) and validation samples (P = 0.022). However, such observation was limited to males only. Further correlation analyses in males showed that plasma irisin was correlated with BMD (r = 0.362, P = 0.025) and triglyceride (r = - 0.354, P = 0.032). Plasma irisin levels were associated with hip BMD in Chinese elderly men. This study represented the first effort of investigating the relationship of plasma irisin and BMD in elderly population. The positive correlation between plasma irisin and BMD hints intrinsic communication between muscle and bone.

A simple and effective method of high performance liquid chromatography (HPLC) with diode array detection was established to identify the origin of Achyranthes bidentata Blume and evaluate its quality, based on chromatographic fingerprint combined with the similarity analysis, hierarchical cluster analysis and the quantitative analysis of multi-components by single marker (QAMS). In the chromatographic fingerprint, 16 peaks were selected as the common model to evaluate the similarities among 18 batches (S1-S18) of A. bidentata Blume samples collected from different origins in China. The similarities values for 18 batches of samples were more than 0.75, which compared with control fingerprint. Furthermore, 18 batches of A. bidentata Blume samples were categorized into two groups for quantitative analysis, the quantification of three bioactive constituents (β-ecdysterone, cyasterone and 5-hydroxymethyl furfural) between QAMS and external standard method proved the consistency of the two methods, the three constituents showed good regression (R > 0.9995) within linear ranges, and their recoveries were within the range of 97.6-101.5%. This study demonstrated that the quality of A. bidentata Blume can be successfully evaluated by means of a combination of HPLC chromatographic fingerprint and QAMS approach.

Gelsolin (GSN) protein, expressed in circulating monocytes, was previously reported to be associated with osteoporosis in both Chinese and Caucasian women. This study aims to test if plasma GSN protein level is associated with hip bone mineral density (BMD) in Chinese population. Based on two study Groups containing 6,308 old Chinese, we adopted extreme sampling scheme and selected 3 independent samples (Subgroups 1-3) for discovery, replication, and validation purposes. We tested plasma GSN concentration, and analyzed whether plasma GSN level differs between subjects with extremely low vs. high hip BMD. In Group 1 (N = 1,860), the plasma GSN level increased in the female with low BMD, which was discovered in the Subgroup 1 (N = 42, p = 0.093) and replicated in the Subgroup 2 (N = 39, p = 0.095). With more extreme sampling for the Subgroup 3 from the Group 2 (N = 4,448), the difference of plasma GSN level in the female with low BMD vs. high BMD is more significant (N = 45, p = 0.037). After the subjects were pooled from Subgroups 2 and 3, the difference in plasma GSN between low and high BMD subjects became even more significant (p = 0.016). The plasma GSN level was negatively correlated with total hip BMD (r = -0.26, p = 0.033). We concluded that plasma GSN was associated with hip BMD in Chinese postmenopausal women and plasma GSN might be a potential risk biomarker for osteoporosis., Competing Interests: The authors have declared that no competing interests exist.

Rationale: Microdialysis has been used to detect the concentrations of drugs in tissues. Geniposide (GE), an iridoid glycoside compound, is the main bioactive component of Gardenia jasminoides Ellis fruit. We previously demonstrated that GE could control the activity of cytokines and reduce levels of inflammation in adjuvant arthritis (AA) rats, but the topic of concentration changes over time in the joint synovia of AA has rarely been studied., Methods: In this study, a microdialysis technique combined with ultra-high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (UHPLC/ESI-MS/MS) was set up and confirmed to assay GE in the dialysate of the joint cavity in AA rats. Mass detection was conducted in multiple reaction monitoring (MRM) mode with negative ESI, and paeoniflorin (Pae) was used as an internal standard (IS)., Results: A lower limit of quantitation (LLOQ) of 5 ng/mL was found using this method and with good linearity in the range of 5-4000 ng/mL. All the validation data including accuracy, precision, intra and inter-day repeatability and stability meet the requirements. The relative recoveries of GE were determined at approximately 40.01%., Conclusions: The measurements based on microdialysis combined with UHPLC/ESI-MS/MS provide a method for sampling and rapid sensitive analysis of GE in the dialysate of the joint cavity in AA rats. This method should be considered for future pharmacokinetics studies., (Copyright © 2018 John Wiley & Sons, Ltd.)

Low bone mineral density (BMD) is a risk factor of osteoporotic fracture (OF). Peripheral blood monocytes (PBM) can differentiate into osteoclasts to resorb bone. It was known that PBM-expressed Anxa2 protein is associated with BMD, and extracellular Anxa2 protein promotes osteoclastogenesis. This study aimed to test 1) whether Anxa2 protein level in PBM differs significantly between subjects with OF and without fracture history (NF); 2) whether Anxa2 level in plasma is associated with BMD; 3) how Anxa2 protein at various concentrations would affect osteoblastic activity in vitro. All the study subjects were Chinese Han elderly. Firstly, Anxa2 protein in PBM was identified and quantitated by LC-MS/MS and compared between 45 OF cases and 42 healthy controls. Secondly, plasma Anxa2 protein level was quantitated by ELISA and compared between unrelated subjects with extremely low vs. high hip BMD (0.63±0.10 vs. 1.05±0.10 g/cm2, n = 75). Furthermore, in vitro functional assay was utilized to test the effects of extracellular Anxa2 protein on osteoblastic growth. We found that Anxa2 protein expression in PBM was significantly up-regulated in OF vs. NF subjects (fold change [FC)] = 1.16, P<0.05). Plasma Anxa2 protein concentration (range: 31.69-227.35ng/ml) was significantly elevated in low vs. high BMD subjects (84.85 vs. 66.15ng/ml, FC = 1.28, P<0.05). Cellular dynamical monitoring demonstrated that the general shape of dose-response relationship is the inverse U-shaped curve. Specifically, lower dose of Anxa2 protein may promote osteoblast growth and the optimal concentration for osteoblastic growth was around 50ng/ml, but even higher concentration could attenuate hFOB1.19 osteoprogenitor cell growth. We concluded that Anxa2 protein could attenuate osteoblast growth and be associated with hip BMD and OF in Chinese elderly.

Geniposide (GE) is the extraction and purification of iridoid glycosides from the Gardenia jasminoides Ellis , which is a promising anti-inflammatory drug, but its mechanism of actions on rheumatoid arthritis (RA) has not been clarified. This study investigated the molecular mechanism behind GE reduced the high permeability of fibroblast-like synoviocytes (FLSs) derived from SD rats with adjuvant arthritis (AA), with the aims of observing the action of GE in AA rats and exploring new therapeutic strategies for RA treatment. The CCK-8 method was used to detect FLSs proliferation. The pro-inflammatory cytokines levels and anti-inflammatory cytokines levels in FLSs were determined by ELISA kits. FLSs permeability assay was performed on Transwell. Immunofluorescence was used to assay the arrangement and morphology of F-actin. The expression of the key molecules related to FLSs permeability (RhoA, p-p38MAPK, NF-κB p-p65 and F-actin) was detected by western blotting. After treatment with lipopolysaccharide (LPS), the proliferation and the permeability of the cells increased significantly (all P < 0.05). The expression of RhoA, p-p38MAPK, NF-κB p-p65 and F-actin in FLSs was higher compared with the control group, and F-actin was redistributed, with the formation of additional stress fibers. But, these conditions were moderated after treatment with GE. We demonstrated that the treatment of different concentrations of GE (25, 50, and 100 μg/mL) had a significant inhibitory effect on the proliferation and permeability of FLSs in vitro . Furthermore, the levels of interleukin (IL)-1β and IL-17 secreted by FLSs were decreased in different doses of GE groups, and the levels of anti-inflammatory cytokines (IL-4, TGF-β1) were increased. Under treatment with GE, low expression of RhoA downregulated expression of p-p38MAPK, NF-κB p-p65, and F-actin while compared with control group, and restored the hyperpermeability of FLSs due to LPS treatment. Taken together, GE might play its anti-inflammatory and immunoregulatory effects via regulating the relative equilibrium of pro-inflammatory cytokines and anti-inflammatory cytokines. GE attenuated the hyperpermeability of FLSs. The down-regulation of the conduction of RhoA/p38MAPK/NF-κB/F-actin signal may play a critical role in the mechanisms of GE on RA. GE could be an effective therapeutic agent for the treatment of RA.

It is widely reported that long non‑coding RNAs (lncRNAs) are involved in regulating cell differentiation, proliferation, apoptosis and other biological processes. Certain lncRNAs have been found to be crucial in various types of tumor. Taurine‑upregulated gene 1 (TUG1) has been shown to be expressed in a tissue‑specific pattern and exert oncogenic or tumor suppressive functions in different types of cancer in humans. According to previous studies, TUG1 is predominantly located in the nucleus and may regulate gene expression at the transcriptional level. It mediates chromosomal remodeling and coordinates with polycomb repressive complex 2 (PRC2) to regulate gene expression. Although the mechanisms of how TUG1 affects the tumor genesis process remain to be fully elucidated, increasing studies have suggested that TUG1 offers potential as a diagnostic and prognostic biomarker, and as a therapeutic target in certain types of tumor. This review aims to summarize current evidence concerning the characteristics, mechanisms and associations with cancer of TUG1.

Rheumatoid arthritis (RA) is a systemic, Th1 cytokine-predominant autoimmune disease result in a chronic and inflammatory disorder. Geniposide (GE), an iridoid glycoside compound that is purified from Gardenia jasminoides Ellis, has antiinflammatory and other immunoregulatory effects, but its exact mechanism of actions on RA is unknown. The aim of this study was to elucidate antiinflammation effects of GE on adjuvant arthritis (AA) rats and its possible immune tolerance mechanisms. Male Sprague-Dawley rats were administered with GE (30, 60, and 120 mg/kg) orally from day 17 to 24 after immunization. Lymphocyte proliferation was assessed by MTT. Levels of interleukin-2 (IL-2), IL-4, and transforming growth factor-β1 were tested by ELISA. The expression of β2-AR, GRK2, and β-arrestin-1 and β-arrestin-2 was detected by western blot. Geniposide was found to relieve the secondary hind paw swelling and arthritis scores, along with attenuating histopathologic changes and decreasing IL-2 and increasing IL-4, transforming growth factor-β1 in mesenteric lymph node (MLN) lymphocytes of AA rats. In addition, GE in vivo increased the expression of β2-AR and decreased the expression of GRK2, β-arrestin-1 and β-arrestin-2, and level of cyclic adenosine monophosphate of MLN lymphocytes in AA rats. From these results, we can infer that GE on immune tolerance effects, β2-AR desensitization, and β2-AR-AC-cyclic adenosine monophosphate transmembrane signal transduction of MLN lymphocytes plays crucial roles in antiinflammatory and immunoregulatory pathogeneses of RA. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Recent evidence indicates that E2F1 transcription factor have pivotal roles in the regulation of cellular processes, and is found to be dysregulated in a variety of cancers. Long non-coding RNAs (lncRNAs) are also reported to exert important effect on tumorigenesis. E2F1 is aberrantly expressed in gastric cancer (GC), and biology functions of E2F1 in GC are controversial. The biological characteristics of E2F1 and correlation between E2F1 and lncRNAs in GC remain to be found. In this study, integrated analysis revealed that E2F1 expression was significantly increased in GC cases and its expression was positively correlated with the poor pathologic stage, large tumor size and poor prognosis. Forced E2F1 expression promotes proliferation, whereas loss of E2F1 function decreased cell proliferation by blocking of cell cycle in GC cells. Mechanistic analyses indicated that E2F1 accelerates GC growth partly through induces TINCR transcription. TINCR could bind to STAU1 (staufen1) protein, and influence CDKN2B mRNA stability and expression, thereby affecting the proliferation of GC cells. Together, our findings suggest that E2F1/TINCR/STAU1/CDKN2B signaling axis contributes to the oncogenic potential of GC and may constitute a potential therapeutic target in this disease.

Geniposide (GE), an iridoid glycoside compound purified from Gardenia jasminoides Ellis, has antiinflammatory and other pharmacological effects, but its mechanism of actions on rheumatoid arthritis (RA) have not been clarified. The purpose of this article was to investigate the pharmacological effects of GE on collagen-induced arthritis (CIA) rats and its feasible mechanisms. Collagen-induced arthritis was induced by injection of chicken type II collagen emulsion. The rats were orally administered with GE (33, 66, and 132 mg/kg) from days 14 to 30 after immunization. The histological examination showed that GE could attenuate histopathologic changes of mesenteric lymph node (MLN) in CIA rats. Geniposide inhibited the production of Interleukin 6 (IL-6) and IL-17, while promoting the production of IL-4 and transforming growth factor-beta 1 in MLN lymphocytes (MLNLs). Moreover, the proliferation capability of MLNLs was increased after the administration of GE. In addition, the treatment with GE in vivo decreased the expressions of P-Raf, P-MEK, and P-Erk1/2 in MLNLs. These results may highlight the antiinflammatory effects and possible mechanisms of GE in MLNLs of RA. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Context: Development of a reliable and selective anti-inflammatory agent of cyclooxygenase-2 (COX-2), induced or up-regulated by inflammatory/injury stimulus such as IL-1β, TNF-α and LPS in the various types of organs, tissues and cells, with low side effects is a long-standing medicinal chemistry problem with significant social implications., Objective: To target druggable enzymome COX-2 by exploiting NSAIDs and genipin (GEP) in anti-inflammatory infection., Materials and Methods: The compound aspirin GEP ester (AGE) was designed by computer-assisted screening, synthesized in the esterification of the acylate derivative and the methylate derivative with Et 3 N, and evaluated with 20, 40 and 60 mg/kg from days 18 to 24 after immunization in collagen-induced arthritis (CIA) rats by the sequential enzymatic experiments, western-blot analysis and pathological observation methods., Results: AGE exhibited higher binding affinity with COX-1 and displayed the lowest estimated free energy with COX-2 than other ligands built by hanging NSAIDs with GEP, and was characterized by 1 H NMR, 13 C NMR and HRMS. AGE was competed against COX-2 with molecule-dependent potencies and selectivity (IC 50 : 0.36 mM; selectivity index: 275) in the sequential enzymatic experiments and decreased the expression of COX-2 in peripheral blood lymphocytes of CIA rats. AGE (40 and 60 mg/kg) could significantly relieve the secondary hind paw swelling and arthritis index, along with observing AGE attenuated histopathological changes of fibroblast like synovial tissue (FLST) and mesenteric lymph node lymphocytes (MLNL) in CIA rats., Discussion and Conclusion: AGE pharmacophore reported herein may be an effective strategy to develop a novel anti-inflammatory agent and potential inhibitor of COX-2.

A model which is capable of capturing the spectral distribution features helps to improve the WDMS(White Dwarf + M Sequence Binaries) classification system running in SDSS-DR10 because the distribution feature of a spectra is one of the most important factors that determine its spectral type. Radial basis function (RBF) neural network is an efficient computational model that is widely used for numerical approximation and object classification. However, due to the reason that the network’s hyper-parameters are usually determined empirically, the performance of the network is limited. In this paper, on the basis of analyzing the distribution features of WDMS in a high dimensional space, an automatic classification model for WDMS ia propose based on RBF neural network. And according to the features, we propose centroids criterion and width criterion to determine hyper-parameters for the network in a more theoretical way, which improves the accuracy of the model. After training and applying the model, a total number of 4 631 WDMS candidates are classified and 25 of them are newly identified, which proves the feasibility of the model and provides further researches on WDMS with more data.

LAMOST-DR1 is the first data released by Guoshoujing telescop, which has the largest number of stellar spectra in the world at present. The data set provides the data source for searching for special and rare celestial objects like cataclysmic variable stars.Meanwhile, it requires more advanced astronomical data processing methods and techniques. A data mining method for cataclysmic variable spectra in massive spectra data is proposed in this paper. Different types of celestial spectra show obvious difference in the feature space constructed with Laplacian Eigenmap method. The parameters of artificial neural network are optimized with particle swarm optimization method and the total LAMOST-DR1 data is processed. 7 cataclysmic variable star spectra are found in the experiment including 2 dwarf nova, 2 nova like variables and a highly polarized AM Her type. The newly found spectra enrich the current cataclysmic variable spectra library. The experiment is the first attempt of searching for cataclysmic variable star spectra with Guoshoujing telescope data and the results show that our approach is feasible in LAMOST data. This method is also applicable for mining other special celestial objects in sky survey telescope data.

The Sloan Digital Sky Survey (SDSS) has released the latest data (DR10) which covers the first APOGEE spectra. The massive spectra can be used for large sample research inscluding the structure and evolution of the Galaxy and multi-wave-band identi cation. In addition, the spectra are also ideal for searching for rare and special objects like white dwarf main-sequence star (WDMS). WDMS consist of a white dwarf primary and a low-mass main-sequence (MS) companion which has positive significance to the study of evolution and parameter of close binaries. WDMS is generally discovered by repeated imaging of the same area of sky, measuring light curves for objects or through photometric selection with follow-up observations. These methods require significant manual processing time with low accuracy and the real-time processing requirements can not be satisfied. In this paper, an automatic and efficient method for searching for WDMS candidates is presented. The method Genetic Algorithm (GA) is applied in the newly released SDSS-DR10 spectra. A total number of 4 140 WDMS candidates are selected by the method and 24 of them are new discoveries which prove that our approach of finding special celestial bodies in massive spectra data is feasible. In addition, this method is also applicable to mining other special celestial objects in sky survey telescope data. We report the identfication of 24 new WDMS with spectra. A compendium of positions, mjd, plate and fiberid of these new discoveries is presented which enrich the spectral library and will be useful to the research of binary evolution models.

In the present paper, an automatic and efficient method for searching for dwarf nova candidates is presented. The methods PCA (principal component analysis) and SVM (support vector machine) are applied in the newly released SDSS-DR9 spectra. The final dimensions of the feature space are determined by the identification accuracy of training samples with different dimensions constrained by SVM. The massive spectra are dimension reduced by PCA at first and classified by the best SVM clas sifier. The final less number of candidates can be identified manually. A total number of 276 dwarf nova candidates are selected by the method and 6 of them are new discoveries which prove that our approach to finding special celestial bodies in massive spectra data is feasible. The new discoveries of this paper are added in the current dwarf nova template library which can contribute to constructing a more accurate feature space. The method proposed in this paper can also be used for special objects searching in other sky survey telescopes like Guoshoujing (Large Sky Area Multi-Object Fiber Spectroscopic Telescope -LAMOST) telescope.

Objective: To explore the transgenic efficiency of non-viral vector Tf-PEG-PEI and the cell specific silencing effect of plasmid pPSMAe/p-shNS-ploy(A) on prostate cancer cells., Methods: Polyethyleneimine (PEI) was modified by using polyethylene glycol and transferrin to synthesize the non-viral vector Tf-PEG-PEI. NS-specific plasmids pPSMAe/p-shNS-ploy(A) and Tf-PEG-PEI were used to transfect prostate cancer LNCap and PC-3 cells. The changes of cell morphology, proliferation ability and cell cycle were studied after down-regulating the NS gene level., Results: Tf-PEG-PEI was successfully modified. After transfection, the PSMA-expressing LNCaP cells became larger and showed more pseudopodia, having a tendency to differentiate. Their cell proliferation ability was reduced, and the detection of cell cycle showed a decrease of S phase and an increase of G(1) phase after knocking down NS gene. These targets were not changed in non-PSMA-expresing PC-3 cells., Conclusions: The non-viral vector Tf-PEG-PEI has a high ability to transfer targeted gene into target cells. The cellular specificity of short-hairpin RNA transcription driven by PSMAe/p is confirmed by silencing NS gene. The use of cell specific promoter may be an effective strategy of gene therapy for prostate cancer.

Degradation of Acid Red 4 (AR4) by photocatalytic processes with TiO(2) nanotube arrays (TNTs) of various dimensions was carried out in this study. TNTs was fabricated by the anodization of titanium foil in electrolyte containing fluoride. The dimension and the induced photocurrent of TNTs were determined by a field-emission scanning electron microscopy and a potentialstat/galvanostat, respectively. The well-defined and highly-ordered TNTs were formed at the anodization voltage ranging from 10 to 40 V in water/glycerol solution (20:80 wt.%) containing 0.5 wt.% NH(4)F. TNTs annealed at 600 degrees C was found to induce the highest photocurrent and to exhibit the preeminent performance of AR4 degradation. The apparent first-ordered reaction rate constant for AR4 degradation was roughly linearly dependent on the induced photocurrent of TNTs, despite the dimension of nanotubes. The depths of incident UV light penetration through the nanotubes and of AR4 diffusion inside nanotubes restricted the degradation of AR4.

A photocatalytic membrane supported on a porous ceramic tube was described, in which permeation of solutes through the membrane and tube and photocatalytic reaction occur simultaneously. In this photocatalytic membrane reactor, TiO(2) catalyst was coated on the surface of a porous ceramic tube and all experiments were conducted in one pass dead-end system. The objectives of this study are to demonstrate the predominance of dead-end operation and to determine the reaction kinetics model of the photocatalytic reaction. Acid Red 4 (AR 4) dye was used as a model pollutant. A detailed study of physical parameters including flow configurations (dead-end and cross-flow), flow rate, initial dye concentration, light intensity and catalyst loading has been performed to obtain the reaction kinetics. The simultaneous effect of light intensity and catalyst loading was also determined experimentally. Experiments were also conducted to compare the photocatalytic degradation of AR 4 in the dead-end and cross-flow system. The major findings of this study are: (1) the decomposition ratios for dead-end system were three and five times higher than cross-flow system at flow rates of 6.67x10(-8) and 4.00x10(-7)m(3)/s, respectively. (2) The decomposition ratio increased with increasing catalyst loading and light intensity, but remained constant at higher catalyst loading. (3) The decomposition ratio was found to be decreased with increasing flow rate.

In this study, the full lipL21 gene fragment encoding outer membrane protein LipL21 was cloned from L. interrogans serovar Lai and inserted into eukaryotic expression vector pcDNA3.1(+). The guinea pigs were immunized with pcDNA3.1(+)-lipL21, pcDNA3.1(+) or PBS. Six weeks after the second immunization, the splenocytes were isolated to detect their proliferative ability by lymphocyte transformation experiments. In addition, microscopic agglutination test was used for quantitative detection of specific antibodies. The rest guinea pigs were challenged intraperitoneally with L. interogans sorevar Lai. Then, protective effect was evaluated on the basis of survival and histopathological lesions in the kidneys, lungs, and liver. The lipL21 gene was successfully expressed in COS-7 cells through recombinant pcDNA3.1(+)-lipL21. The titer of specific antibodies substantially increased, and the stimulation index of splenocytes increased significantly. Hence, the pcDNA3.1(+)-lipL21 could protect the immunized guinea pigs from homotypic Leptospira infection. Furthermore, no obvious pathologic changes were observed in the pcDNA3.1(+)-lipL21 immunized guinea pigs. The results showed that the protective effect with pathogenic strains of Leptospira was shared by LipL21 mediated through a plasmid vector. Consequently, these results indicated that the lipL21 DNA vaccine was a promising candidate for the prevention of leptospirosis.

The decomposition of 2-chlorophenol by UV/TiO2 process with the application of external bias voltage was examined in this study. Experiments were conducted in a batch reactor using TiO2-coated titanium sheet as anode and platinum sheet as cathode. The anode photocatalysis of 2-chlorophenol was totally inhibited for experiments conducted with the application of external anodic bias voltage lower than the flat band potential of TiO2. The decomposition rate of 2-chlorophenol was then increased with increasing external anodic bias voltage applied up to 0.0 V (versus SCE). The application of external bias voltage higher than 1.0 V did not markedly promote the photocatalysis of 2-chlorophenol possibly because the photocurrent induced was constant. Experimental results indicated that the decomposition of 2-chlorophenol was more effective for experiments conducted in acidic solutions due to the lower flat band potential of TiO2 and the higher photocurrent induced. The presence of electron scavengers in aqueous solution, such as oxygen molecules, may increase the decomposition rate of 2-chlorophenol. However, the effect of dissolved oxygen was diminished for experiments conducted with applied external bias voltage. The photocatalytic decomposition rate of 2-chlorophenol was enhanced linearly with the increasing UV light intensity when the external bias voltage was applied.

The decomposition of 2-nitrophenol in aqueous solutions by ozone and UV/ozone processes was found to be technically feasible under adequate experimental conditions. Formation of nitrate ions was observed following the decomposition of 2-nitrophenol by ozone and UV/ ozone processes. Increasing ozone dosage and UV light intensity accelerated the decomposition rate of 2-nitrophenol in an aqueous solution. The species distribution of 2-nitrophenol under various solution conditions plays a significant role in determining decomposition behavior. In most experiments conducted in this study, the decomposition of 2-nitrophenol by ozone and UV/ozone processes was favored to occur in alkaline conditions. The addition of 2-butanol accelerated the rate of gaseous ozone transfer to an aqueous phase by reducing the surface tension of aqueous solution and therefore enhancing the decomposition rate of 2-nitrophenol by ozone and UV/ozone processes.

Photocatalytic processes using TiO(2) as a catalyst have attracted extensive attention for decomposition of organic contaminants. The determination of optimum reactor design and operational conditions are the major concerns for the development and potential application of the photocatalytic process. Various photoreactor types, photocatalyst arrangements, light sources, and operation conditions were reported. This study was focused on the application of the ultraviolet light emitting diode (UV-LED) as the UV light source for the photocatalytic decomposition of Reactive Red 22 (RR 22). The temporal behavior of the photocatalytic decomposition of RR 22 in aqueous solution by the UV-LED/TiO(2) with a rectangular planar fixed-film reactor operated in a recirculation mode was studied under various conditions including initial dye concentration, periodic illumination, light intensity, and arrangements of TiO(2) coating. The decomposition of RR 22 in aqueous solution by TiO(2) photocatalytic processes with the UV-LED was found to be technically feasible with a high TiO(2) coated weight (1.135g) and low pH value (pH 2). A Langmuir-Hinshelwood-type kinetic equation was adequate for modeling the photocatalytic decomposition of RR 22 by the UV-LED/TiO(2) photocatalytic processes. The experimental results indicated that the photonic efficiency with periodic illumination was much higher than those with continuous illumination. The photonic efficiencies with the quartz-liquid-catalyst (QLC) arrangement were higher than those with the quartz-catalyst-liquid (QCL) arrangement for experiments conducted at lower applied light intensity; however, the photonic efficiencies for these two arrangements were nearly identical for experiments conducted at higher light intensities.

Objective: To determine the level and the role of beta-endorphin in hypothalamus of rat with trigeminal neuralgia., Methods: The animal model of primary trigeminal neuralgia in rat was established, the contents of beta-endorphin were measured by radioimmunoassay techniques., Results: The beta-endorphin of hypothalamus in experimental group was significantly lower than other groups (P < 0.01)., Conclusions: Beta-endorphin may play important roles in primary trigeminal neuralgia.

It has been reported that arsenic trioxide (As2O3) is an apoptosis inducer and radiation sensitizer for various cancer cell lines. In this study of breast cancer patients, we examined the combined effect of topical As2O3 and radiation therapy on fungating and/or skin-infiltrating lesions of breast cancer. The dermatological, gastrointestinal, hematological, renal and hepatic toxicities of the treatment were also monitored. As2O3 gel (0.05%) was applied to tumor lesions 1 h prior to delivery of each fraction, with the gel removed about 5 min before the irradiation. Superficial radiation was delivered using an electron beam from a linear accelerator. Every week, the tumor lesions were photographed to evaluate effectiveness, and blood was sampled to monitor changes in hemogram and biochemical profile. Seven breast cancer patients with cutaneous metastasis were enrolled in this study. In terms of tumor, the rates for complete, partial response and stable disease were 42.9 (three of seven), 42.9 (three of seven) and 14.3% (one of seven), respectively. The skin pain, assessed by a visual analog scale, and secretion from all of the seven superficial and fungating wounds decreased markedly after treatment. Significant bone marrow suppression or granulocytosis was not noted. Further, changes in renal and hepatic function were also not significant. It seems reasonable to conclude that As2O3 may be an effective and safe radiosensitizer for palliative radiotherapy for skin-infiltrating lesions of breast cancer.