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Qingqing Meng,1,* Aiping Wang,1,2,* Hongchen Hua,1 Ying Jiang,1 Yiyun Wang,1 Hongjie Mu,1 Zimei Wu,1 Kaoxiang Sun1 1School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, People’s Republic of China; 2State Key Laboratory of Long-Acting and Targeting Drug Delivery System, Shandong Luye Pharmaceutical Co., Ltd, Yantai, People’s Republic of China *These authors contributed equally to this work Background: Safe and effective delivery of therapeutic drugs to the brain is important for successful therapy of Alzheimer’s disease (AD).Purpose: To develop Huperzine A (HupA)-loaded, mucoadhesive and targeted polylactide-co-glycoside (PLGA) nanoparticles (NPs) with surface modification by lactoferrin (Lf)-conjugated N-trimethylated chitosan (TMC) (HupA Lf-TMC NPs) for efficient intranasal delivery of HupA to the brain for AD treatment.Methods: HupA Lf-TMC NPs were prepared using the emulsion–solvent evaporation method and optimized using the Box–Behnken design. The particle size, zeta potential, drug entrapment efficiency, adhesion and in vitro release behavior were investigated. The cellular uptake was investigated by fluorescence microscopy and flow cytometry. MTT assay was used to evaluate the cytotoxicity of the NPs. In vivo imaging system was used to investigate brain targeting effect of NPs after intranasal administration. The biodistribution of Hup-A NPs after intranasal administration was determined by liquid chromatography–tandem mass spectrometry.Results: Optimized HupA Lf-TMC NPs had a particle size of 153.2±13.7 nm, polydispersity index of 0.229±0.078, zeta potential of +35.6±5.2 mV, drug entrapment efficiency of 73.8%±5.7%, and sustained release in vitro over a 48 h period. Adsorption of mucin onto Lf-TMC NPs was 86.9%±1.8%, which was significantly higher than that onto PLGA NPs (32.1%±2.5%). HupA Lf-TMC NPs showed lower toxicity in the 16HBE cell line compared with HupA solution. Qualitative and quantitative cellular uptake experiments indicated that accumulation of Lf-TMC NPs was higher than nontargeted analogs in 16HBE and SH-SY5Y cells. In vivo imaging results showed that Lf-TMC NPs exhibited a higher fluorescence intensity in the brain and a longer residence time than nontargeted NPs. After intranasal administration, Lf-TMC NPs facilitated the distribution of HupA in the brain, and the values of the drug targeting index in the mouse olfactory bulb, cerebrum (with hippocampus removal), cerebellum, and hippocampus were about 2.0, 1.6, 1.9, and 1.9, respectively.Conclusion: Lf-TMC NPs have good sustained-release effect, adhesion and targeting ability, and have a broad application prospect as a nasal drug delivery carrier. Keywords: Huperzine A, lactoferrin, N-trimethyl chitosan, nose-to-brain, nanoparticles, Alzheimer’s disease

Immunotherapy for esophageal squamous cell carcinoma (ESCC) exhibits notable variability in efficacy. Concurrently, recent research emphasizes circRNAs' impact on the ESCC tumor microenvironment. To further explore the relationship, we leveraged circRNA, microRNA, and mRNA sequence datasets to construct a comprehensive immune-related circRNA-microRNA-mRNA network, revealing competing endogenous RNA (ceRNA) roles in ESCC. The network comprises 16 circular RNAs, 13 microRNAs, and 1,560 mRNAs. Weighted gene co-expression analysis identified immune-related modules, notably cancer-associated fibroblast (CAF) and myeloid-derived suppressor cell modules, correlating significantly with immune and stemness scores. Among them, the CAF module plays a crucial role in extracellular matrix function and effectively discriminates ESCC patients. Four hub collagen family genes within CAF correlated robustly with CAF, macrophage infiltration, and T-cell exclusion. In-house sequencing and RT-qPCR validated their elevated expression. We also identified CAF module-targeting drugs as potential ESCC treatments. In summary, we established an immune-related circRNA-miRNA-mRNA network that not only illuminates ceRNA functionality but also highlights circRNAs' involvement in the CAF through collagen gene targeting. These findings hold promise to predict ESCC immune landscapes and therapy responses, ultimately aiding in more personalized and effective clinical decision-making.

The Paeonia ostii , also known as "Feng Dan" have a crucial role in folk medicine to treat lumbar muscles strain, knee osteoarthritis and cervical spondylosis. In this study, four new phenolic compounds, specifically Paeoniaostiph A-E ( 1 - 4 ) phenolic compounds were characterised through spectroscopic techniques, including 1D and 2D NMR, HRESIMS, UV, IR, and electronic circular dichroism computations to explore their structures. Cytotoxicity and NO production inhibition of the new phenolic compounds were also studied. The results of the cytotoxicity experiment showed that compound 1 is cytotoxic to two human cancer cell lines with IC 50 values ranging from 13.3 to 13.5 μM. Compounds 1 and 2 showed certain inhibitory activity on NO production. This is the first report on isolating the components from natural sources.

The incompletely eliminated Treponema pallidum ( T. pallidum ) during primary syphilis chancre infection can result in the progression of secondary, tertiary, or latent syphilis in individuals, suggesting that T. pallidum has successfully evaded the immune response and spread to distant sites. The mechanism underlying the dissemination of T. pallidum is unclear. Here, a syphilitic rabbit model dorsal-injected with recombinant Tp0136 protein or Tp0136 antibody subcutaneously was used to demonstrate the role of Tp0136 protein in promoting the dissemination of T. pallidum to the testis and angiogenesis in vivo ; vascular endothelial cell line HMEC-1 was employed to display that Tp0136 protein enhances the angiogenesis. Furthermore, the three-dimensional microfluidic angiogenesis system showed that the angiogenesis would heighten vascular permeability. Then transcriptome sequencing analysis, in conjunction with cell-level validation, elucidated the critical role of the PI3K-AKT signaling pathway in the promotion of angiogenesis by Tp0136 protein, resulting in heightened permeability. These findings elucidate the strategy employed by T. pallidum in evading immune clearance.

The evasive tactics of Treponema pallidum pose a major challenge in combating and eradicating syphilis. Natural killer (NK) cells mediate important effector functions in the control of pathogenic infection, preferentially eliminating targets with low or no expression of major histocompatibility complex (MHC) class I. To clarify T. pallidum's mechanisms in evading NK-mediated immunosurveillance, experiments were performed to explore the cross-talk relations among T. pallidum , NK cells, and platelets. T. pallidum adhered to, activated, and promoted particle secretion of platelets. After preincubation with T. pallidum , platelets expressed and secreted high levels of MHC class I, subsequently transferring them to the surface of T. pallidum , potentially inducing an immune phenotype characterized by the "pseudo-expression" of MHC class I on the surface of T. pallidum (hereafter referred to a "pseudo-expression" of MHC class I). The polA mRNA assay showed that platelet-preincubated T. pallidum group exhibited a significantly higher copy number of polA transcript than the T. pallidum group. The survival rate of T. pallidum mirrored that of polA mRNA, indicating that preincubation of T. pallidum with platelets attenuated NK cell lethality. Platelets pseudo-expressed the MHC class I ligand on the T. pallidum surface, facilitating binding to killer cell immunoglobulin-like receptors with two immunoglobulin domains and long cytoplasmic tail 3 (KIR2DL3) on NK cells and initiating dephosphorylation of Vav1 and phosphorylation of Crk, ultimately attenuating NK cell lethality. Our findings elucidate the mechanism by which platelets transfer MHC class I to the T. pallidum surface to evade NK cell immune clearance.

Objectives: To evaluate the diagnostic performance of different brands of immunochromatographic test (ICT) reagents for Chlamydia trachomatis using homogenized samples to provide a reference for reagent quality control., Methods: Eight commercially available ICT reagents were evaluated, of which three used the latex method and five used the colloidal gold method. Analytical performance evaluation using a pure culture broth of C. trachomatis , as well as clinical application validation using cervical epithelial cell samples acquired from the research subjects, were conducted. The concentration of C. trachomatis was quantified using a nucleic acid amplification test., Results: The limit of detection (LOD) of different ICT reagents in the analytical performance evaluation varied from 9.5 × 10 3 to 1 × 10 5 IFU/mL, and only one reagent met the LOD specified in the manufacturer's instructions. Likewise, only one reagent in the clinical application validation achieved the analytical LOD, four reagents were 2.1-4.2-fold of the analytical LODs, and three reagents failed to detect positive results in clinical samples., Conclusions: The diagnostic performance of different methods and different brands of ICT reagents in clinical practice was different from the manufacturer's instructions and the results of laboratory evaluation. The diagnostic performance of reagents should be evaluated before they are actually used in clinical practice., Competing Interests: 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., (© 2024 The Authors. Published by Elsevier B.V.)

Glycolysis is a key pathway in cellular glucose metabolism for energy supply and regulates immune cell activation. Whether glycolysis is involved in the activation of NOD-like receptor family protein 3 (NLRP3) inflammasomes during Treponema pallidum (T. pallidum) infection is unclear. In this study, the effect of T. pallidum membrane protein Tp47 on NLRP3 inflammasome activation in rabbit peritoneal macrophages was analysed and the role of glycolysis in NLRP3 inflammasome activation was explored. The results showed that Tp47 promoted NLRP3, caspase-1, and IL-1β mRNA expression in macrophages, enhanced glycolysis and glycolytic capacity of macrophage, and promoted the production of macrophage glycolytic metabolites citrate, phosphoenolpyruvate, and lactate. The M2 pyruvate kinase (PKM2) inhibitor shikonin down-regulated the Tp47-promoted NLRP3, caspase-1, and IL-1β mRNA expression in macrophages, and suppressed the Tp47-enhanced glycolysis and glycolytic capacity. Similarly, si-PKM2 significantly inhibited Tp47-promoted NLRP3, caspase-1, and IL-1β mRNA expression and the Tp47-enhanced glycolysis and glycolytic capacity in macrophages. In conclusion, Tp47 activated NLRP3 inflammasomes via PKM2-dependent glycolysis and provided a new perspective on the effect of T. pallidum infection on host macrophages, which would contribute to the understanding of the infection mechanism and host immune mechanism of T. pallidum., 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 © 2023 Elsevier B.V. All rights reserved.)

The aim of this study was to assess the effects of local wound infiltration anaesthesia on postoperative wound pain in patients undergoing open liver resection. The Cochrane Library, PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM) and Wanfang databases were searched. The search period spanned from database creation to December 2022. All relevant studies on local wound infiltration anaesthesia for analgesia after hepatectomy were included. Two investigators independently screened the literature, extracted data and evaluated the quality of each study. Review Manager (RevMan) 5.4 software (Cochrane Collaboration) was used for the meta-analysis, in which 12 studies with 986 patients were included. The results show that local wound infiltration anaesthesia effectively reduced surgical site wound pain at 4 h (mean difference [MD]: -1.26, 95% confidence intervals [CIs]: -2.15 to -0.37, P = .005), 12 h (MD: -0.84, 95% CIs: -1.26 to -0.42, P < .001), 24 h (MD: -0.57, 95% CIs: -1.01 to -0.14, P = .009) and 48 h (MD: -0.54, 95% CIs: -0.81 to -0.26, P < .001) postoperatively; however, there was no significant difference in analgesia at 72 h postoperatively (MD: -0.10, 95% CIs: -0.80 to 0.59, P = .77). These findings suggest that local wound infiltration anaesthesia administered to patients undergoing open liver resection provides good postoperative wound analgesia at the surgical site., (© 2023 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Objective: To analyze the level of chromosome aberration in lymphocytes of medical radiation workers and its influencing factors. Methods: From July to September 2020, 252 medical workers in a tertiary hospital were selected as the study subjects and 107 preserviceworkers were selected as the control group. The Chromosomal aberrations of peripheral blood lymphocytes were measured using conventional cytogenetic analysis method, and the differences were analyzed. Results: The frequencies of dicentric puls centric ring, total chromosome-type aberrations, and abnormal detection rate in the radiation group were significantly higher than those in the control group ( Z =2.59, 3.74, 9.99, P <0.05). There was significant difference in the frequencies of dicentric plus centric ring and total chromosome-type aberrations among different types of work (χ(2)=8.59, 8.17, 11.39, P <0.05), and the frequencies of dicentric plus centric ring were significantly higher in the interventional radiology group than those in diagnostic radiology (χ(2)=2.90, P <0.05), While the rates of acentric fragment and total chromosome-type aberrations were significantly higher in the nuclear medicine group than those in diagnostic radiology (χ(2)=2.81, 3.19, P <0.05). The difference in the abnormal detection rate of chromosome aberrations between different types of work was statistically significant ( P <0.05), and the rate in the interventional radiology group was significantly higher than that in the diagnostic radiology group (χ(2)=7.66, P <0.05). There was no significant difference in chromosome aberration level and abnormal detection rate among different working ages ( P >0.05). Poisson regression analysis indicated that the type of work is a risk factor for chromosomal aberration [ IRR =2.31 (nuclear medicine group), 1.66 (Radiation therapy), and 1.78 (interventional group) ; P <0.05]. Conclusion: Ionizing radiation causes certain radiation damage to medical radiology workers, and the frequencies of chromosome aberration in the radiation workers of nuclear medicine and interventional radiology groups are relatively high, so radiation protection should be strengthened to ensure the health of relevant workers.

To improve the utilization efficiency of nutrients and water and determine the best drip irrigation frequency for long-season tomato cultivation in solar greenhouses, we cultivated tomato grafted seedlings in soil using an integrated water and fertilizer technology: drip irrigation under mulch. Seedlings drip-irrigated with balanced fertilizer (containing 20% N, 20% P 2 O 5 , and 20% K 2 O) and high-K fertilizer (containing 17% N, 8% P 2 O 5 , and 30% K 2 O) once every 12 days were set as control (CK) and that with water once every 12 days as CK 1 , while other seedling groups, drip-irrigated with a nutrient solution of Yamazaki (1978) formula for tomato, were set as treatments (T 1 -T 4 ). There were four drip-irrigation frequencies, i.e ., once every 2 days (T 1 ), 4 days (T 2 ), 6 days (T 3 ), or 12 days (T 4 ), who received the same total amounts of fertilizer and water over the 12 experimental days. The results showed that, with the decreases of drip irrigation frequency, tomato yield, the accumulation of N, P and K in plant dry matter, the fertilizer partial productivity, and the nutrient utilization rate first increased and then decreased, peaking at the T 2 treatment. Compared with CK, under the T 2 treatment, plant dry matter accumulation and the accumulation of N, P and K increased by 4.9%, 8.0%, 8.0%, 16.8%, the partial productivity of fertilizer and the utilization efficiency of water increased by 142.8% and 12.2%, the use efficiency of N, P and K was better than CK by 241.4%, 466.6% and 235.9%, respectively, and the tomato yield increased by 12.2%. Under the experimental conditions, drip irrigation with the Yamazaki nutrient solution at a frequency of 4 days could increase the tomato yield, as well as the use efficiency of nutrients and water. Under long-season cultivation, these trends would result in considerable saving of water and fertilizer. Overall, our findings provided a basis for improving the scientific management of water and fertilizers under long-season tomato cultivation in protected facilities.

The ethnobotanical plant Marsdenia tenacissima has been used for hundreds of years for Dai people in Yunnan Province, China. Previously, chemical investigations on this plant have revealed that pregnane glycosides were the main biological constituents. Nine new pregnane glycosides, marsdeosides A-I ( 1 - 9 ), were isolated from cultivated dried stems of the medicinal plant Marsdenia tenacissima in this study. The structures were analyzed by extensive spectroscopic analysis, including 1D, 2D NMR, HRESIMS, and IR spectroscopic analysis. The absolute configurations of the sugar moieties were identified by comparing the R f values and specific optical rotations with those of the commercially available standard samples and the data reported in the literature. Marsdeosides A ( 1 ) featured an unusual 8,14- seco -pregnane skeleton. Compounds 1 , 8 , and 9 showed activity against nitric oxide production in lipopolysaccharide-activated macrophage RAW264.7, with IC 50 values of 37.5, 38.8, and 42.8 μM (L-NMMA was used as a positive control, IC 50 39.3 μM), respectively. This study puts the knowledge of the chemical profile of the botanical plant M. tenacissima one step forward and, thereby, promotes the sustainable utilization of the resources of traditional folk medicinal plants.

Background and Objectives: EUS has recently gained attraction in mainland China. This study aimed to evaluate the development of EUS from results of two national surveys., Methods: EUS-related information, including infrastructure, personnel, volume, and quality indicator, was extracted from the Chinese Digestive Endoscopy Census. Data from 2012 and 2019 were compared, and differences among various hospitals and regions were analyzed. The EUS rates (EUS annual volume per 100,000 inhabitants) between China and developed countries were also compared., Results: The number of hospitals performing EUS in mainland China increased from 531 to 1236 (2.33-fold), and 4025 endoscopists performed EUS in 2019. The volumes of all EUS and interventional EUS increased from 207,166 to 464,182 (2.24-fold) and 10,737 to 15,334 (1.43-fold), respectively. The EUS rate in China was lower than that in developed countries but showed a higher growth rate. EUS rate varied substantially among different provincial regions (in 2019: 4.9-152.0 per 100,000 inhabitants) and showed significant positive association with gross domestic product per capita (in 2019: r = 0.559, P = 0.001). The EUS-FNA-positive rate in 2019 was comparable between hospitals in terms of annual volume (≥50 or < 50: 79.9% vs. 71.6%, P = 0.704) and practice duration (starting EUS-FNA before or after 2012: 78.7% vs. 72.6%, P = 0.565)., Conclusion: EUS has developed considerably in China in recent years but still needs substantial improvement. More resources are in demand for hospitals in less-developed regions and with low EUS volume., Competing Interests: None

Objective: To study the role of cytokines and lymphocyte subsets in the diagnosis, prognosis and efficacy evaluation of DLBCL patients, and the effects of Tislelizumab on immune function and cytokines in DLBCL patients., Methods: Twenty-three patients with newly diagnosed DLBCL were selected as DLBCL group and 34 patients with megaloblastic anemia as the control group. The levels of peripheral blood cytokines IL-2, IL-4, IL-6, IL-10, TNF- α and IFN-γ by ELISA method. The levels of peripheral blood CD3 + , CD4 + , CD8 + T lymphocytes, B lymphocytes and NK cells， the ratio of CD4 + /CD8 + were detected by flow cytometry. The levels of cytokins and lymphocyto subsets in DLBCL patients with different clinical data and different therapeutic effects were compared., Results: The levels of cytokines IL-2, IL-6 and IL-10 in DLBCL group were significantly higher than those in control group, but there was no significant correlation between cytokine levels and age and gender. The higher IPI score, higher Ann Arbor stage, B symptoms, higher β 2 -MG, LDH and CRP levels, IL-6 and IL-10 levels were significantly higher, and IL-4 was also significantly higher in patients with high LDH levels. Compared with the ineffective group, the levels of IL-6 and IL-10 were significantly lower and the level of CD4 + T cells and the ratio of CD4 + /CD8 + was significantly higher in the effective group before therapy. The levels of IL-6, IL-10 and B lymphocytes in the effective group decreased significantly after therapy compared to those before therapy. After 4 cycles of therapy, the level of IL-2 and the ratio of CD4 + /CD8 + in the Tislelizumab group were significantly higher than those in the non-Tislelizumab group, and the level of CD8 + T cells was significantly lower than that in the non-Tislelizumab group( P <0.05). The level of B lymphocytes in both the Tislelizumab group and the non-Tislelizumab group after therapy was significantly lower than that before therapy., Conclusion: The expression of cytokines and lymphocyte subsets in peripheral blood of patients with DLBCL is abnormal, which is related to the severity, prognosis and therapeutic effect of the disease. Tislelizumab can improve the immune function of patients with DLBCL by affecting cytokines and lymphocyte subsets and strengthen anti-tumor immunity.

Background: Upper gastrointestinal endoscopy is critical for esophageal squamous cell carcinoma (ESCC) detection; however, endoscopists require long-term training to avoid missing superficial lesions., Aim: To develop a deep learning computer-assisted diagnosis (CAD) system for endoscopic detection of superficial ESCC and investigate its application value., Methods: We configured the CAD system for white-light and narrow-band imaging modes based on the YOLO v5 algorithm. A total of 4447 images from 837 patients and 1695 images from 323 patients were included in the training and testing datasets, respectively. Two experts and two non-expert endoscopists reviewed the testing dataset independently and with computer assistance. The diagnostic performance was evaluated in terms of the area under the receiver operating characteristic curve, accuracy, sensitivity, and specificity., Results: The area under the receiver operating characteristics curve, accuracy, sensitivity, and specificity of the CAD system were 0.982 [95% confidence interval (CI): 0.969-0.994], 92.9% (95%CI: 89.5%-95.2%), 91.9% (95%CI: 87.4%-94.9%), and 94.7% (95%CI: 89.0%-97.6%), respectively. The accuracy of CAD was significantly higher than that of non-expert endoscopists (78.3%, P < 0.001 compared with CAD) and comparable to that of expert endoscopists (91.0%, P = 0.129 compared with CAD). After referring to the CAD results, the accuracy of the non-expert endoscopists significantly improved (88.2% vs 78.3%, P < 0.001). Lesions with Paris classification type 0-IIb were more likely to be inaccurately identified by the CAD system., Conclusion: The diagnostic performance of the CAD system is promising and may assist in improving detectability, particularly for inexperienced endoscopists., Competing Interests: Conflict-of-interest statement: Dr. Wang reports grants from The Science and Technology Commission of Shanghai Municipality during the conduct of the study. Other authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

The cytokinesis-block micronucleus assay has proven to be a reliable technique for biological dosimetry. This study aimed to establish the dose-response curve for X-ray-induced micronucleus. Peripheral blood samples from three healthy donors were irradiated with various doses and scoring criteria by the micronuclei (MN) in binucleated cells. The results showed that the frequency of MN increased with the elevation of radiation dose. CABAS and Dose Estimate software were used to fit the MN and dose into a linear quadratic model, and the results were compared. The linear and quadratic coefficients obtained by the two software were basically the same and were comparable with published curves of similar radiation quality and dose rates by other studies. The dose-response curve established in this study can be used as an alternative method for in vitro dose reconstruction and provides a reliable tool for biological dosimetry in accidental or occupational radiation exposures., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Ethnopharmacological Relevance: Marsdenia tenacissima is a medicinal plant, used as a raw material for cancer treatment in China. In our previous studies, 11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B (MT2), the main steroid aglycone isolated from M. tenacissima, was found to significantly enhance the antitumor activity of paclitaxel (PTX) in vivo. However, it is unclear whether MT2 reverses multidrug resistance (MDR) in tumors., Aim of the Study: To determine the role and mechanism of MT2 in reversing tumor MDR., Materials and Methods: MDR cell line HeLa/Tax was established from the human cervical carcinoma cell line HeLa by long-term exposure to subtoxic concentrations of PTX and was used to evaluate the ability of MT2 to restore chemosensitivity of cells both in vitro and in a nude mouse model. The expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) was determined using western blotting and immunohistochemistry. The substrate transport function was assessed using an MDR function assay kit. The binding modes of MT2 and P-gp were determined using the conformation-sensitive anti-P-gp antibodies. The permeability and transport properties of MT2 were analyzed in Caco-2 cell monolayers., Results: Compared to parental cells, HeLa/Tax cells overexpress P-gp and MRP2 and are approximately 100-360 fold more resistant to the anticancer drugs PTX, docetaxel, and vinblastine. MT2 at 5 or 10 μmol/L significantly increased the sensitivity of HeLa/Tax to these three anticancer drugs (18-56-fold decrease in IC 50 value) and suppressed the expression of P-gp and MRP2. Knockdown of P-gp with small interfering RNA partially reversed MT2-induced sensitivity to PTX in HeLa/Tax cells. Moreover, MT2 directly inhibited P-gp-mediated substrate transport while interacting with membrane P-gp in non-substrate ways. MT2 was highly permeable and could not be transported in the Caco-2 cell monolayers. In nude mice bearing HeLa/Tax xenografts, the combination treatment with MT2 and PTX exerted a synergistic inhibitory effect on the growth of tumors and the expression of P-gp and MRP2 without increasing toxicity., Conclusion: MT2 is a potential agent for reversing MDR. It impedes membrane drug efflux pumps by suppressing P-gp and MRP2 expression, and directly inhibiting the transport function of P-gp., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Colorectal cancer remains a considerable challenge in healthcare nowadays. Approximately 60%-80% of colorectal cancer is caused by intestinal polyps, and resection of intestinal polyps has been proved to reduce the incidence of colorectal cancer. The vast majority of intestinal polyps can be found during colonoscopy and removed endoscopically. Therefore, more attention has been paid to the development of endoscopic resection of intestinal polyps. In this study, we compared the efficacy and safety of cold snare polypectomy (CSP) and hot snare polypectomy (HSP)., Aim: To investigate the efficacy and safety of CSP and HSP for colorectal polyps., Methods: Between January and December 2020, 301 patients with colorectal polyps 4-9 mm in diameter were treated with endoscopic therapy in our hospital, and were divided into the CSP group ( n = 154) and HSP group ( n = 147). The operating time, incidence of bleeding and perforation, use of titanium clips, and complete resection rate were compared between the two groups., Results: We included 249 patients (301 polyps). No differences in gender, age, and polyp size, location, shape and type were observed between the CSP and HSP groups, and the resection rates in these two groups were 93.4% and 94.5%, respectively, with no significant difference. The use of titanium clips was 15.6% and 95.9%, the operating time was 3.2 ± 0.5 min and 5.6 ± 0.8 min, the delayed bleeding rate was 0% and 2.0%, and delayed perforation was 0% and 0.7%, in the CSP and HSP groups, respectively., Conclusion: For sessile colorectal polyps < 10 mm, CSP had the same resection rate of impaired tissue integrity as traditional HSP had. The rate of complications was lower in the CSP group. CSP is a safe and effective method for polypectomy., Competing Interests: Conflict-of-interest statement: Meng QQ, Rao M, Gao PJ are employees of the First Hospital of Jilin University., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Tumoral calcinosis (TC) is a rare disease characterized by periarticular soft tissue calcification. Some cases were reported in Africa and the Middle East. We report an 11-year-old Chinese girl presenting with recurrent multiple subcutaneous masses around the right elbow and hip regions. Although we found abnormalities in FGF23, a protein associated with phosphate metabolism, no positive results were observed in gene sequencing and analysis. The imaging features, laboratory examination, and pathology results confirmed our diagnosis. By using oral phosphorus-lowering drugs (acetazolamide) combined with complete surgical excision, good results were achieved, and no recurrence was reported during the follow-up of 18 months. We report a case of primary hyperphosphatemic TC. The combined use of oral phosphorus-lowering drugs (acetazolamide) and complete surgical excision produced good results, and no recurrence was reported during the follow-up of 18 months., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Background: Artificial intelligence in colonoscopy is an emerging field, and its application may help colonoscopists improve inspection quality and reduce the rate of missed polyps and adenomas. Several deep learning-based computer-assisted detection (CADe) techniques were established from small single-center datasets, and unrepresentative learning materials might confine their application and generalization in wide practice. Although CADes have been reported to identify polyps in colonoscopic images and videos in real time, their diagnostic performance deserves to be further validated in clinical practice., Aim: To train and test a CADe based on multicenter high-quality images of polyps and preliminarily validate it in clinical colonoscopies., Methods: With high-quality screening and labeling from 55 qualified colonoscopists, a dataset consisting of over 71000 images from 20 centers was used to train and test a deep learning-based CADe. In addition, the real-time diagnostic performance of CADe was tested frame by frame in 47 unaltered full-ranged videos that contained 86 histologically confirmed polyps. Finally, we conducted a self-controlled observational study to validate the diagnostic performance of CADe in real-world colonoscopy with the main outcome measure of polyps per colonoscopy in Changhai Hospital., Results: The CADe was able to identify polyps in the test dataset with 95.0% sensitivity and 99.1% specificity. For colonoscopy videos, all 86 polyps were detected with 92.2% sensitivity and 93.6% specificity in frame-by-frame analysis. In the prospective validation, the sensitivity of CAD in identifying polyps was 98.4% (185/188). Folds, reflections of light and fecal fluid were the main causes of false positives in both the test dataset and clinical colonoscopies. Colonoscopists can detect more polyps (0.90 vs 0.82, P < 0.001) and adenomas (0.32 vs 0.30, P = 0.045) with the aid of CADe, particularly polyps < 5 mm and flat polyps (0.65 vs 0.57, P < 0.001; 0.74 vs 0.67, P = 0.001, respectively). However, high efficacy is not realized in colonoscopies with inadequate bowel preparation and withdrawal time ( P = 0.32; P = 0.16, respectively)., Conclusion: CADe is feasible in the clinical setting and might help endoscopists detect more polyps and adenomas, and further confirmation is warranted., Competing Interests: Conflict-of-interest statement: Wu JR, Chen LZ, Chang J and Song P were staff of Tencent Healthcare (Shenzhen) Co. LTD, which supported the work with provision of research grants, prototype software, prototype PC and GPU units. The other authors have no conflicts of interest to declare. The sponsor had no involvement in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, and approval of the manuscript; or the decision to submit the manuscript for publication., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

The differentiation of human pluripotent stem cells (hPSCs) to neural stem cells (NSCs) is the key initial event in neurogenesis and is thought to be dependent on the family of Wnt growth factors, their receptors and signaling proteins. The delineation of the transcriptional pathways that mediate Wnt-induced hPSCs to NSCs differentiation is vital for understanding the global genomic mechanisms of the development of NSCs and, potentially, the creation of new protocols in regenerative medicine. To understand the genomic mechanism of Wnt signaling during NSCs development, we treated hPSCs with Wnt activator (CHIR-99021) and leukemia inhibitory factor (LIF) in a chemically defined medium (N2B27) to induce NSCs, referred to as CLNSCs. The CLNSCs were subcultured for more than 40 passages in vitro; were positive for AP staining; expressed neural progenitor markers such as NESTIN , PAX6 , SOX2 , and SOX1 ; and were able to differentiate into three neural lineage cells: neurons, astrocytes, and oligodendrocytes in vitro. Our transcriptome analyses revealed that the Wnt and Hedgehog signaling pathways regulate hPSCs cell fate decisions for neural lineages and maintain the self-renewal of CLNSCs. One interesting network could be the deregulation of the Wnt/β-catenin signaling pathway in CLNSCs via the downregulation of c-MYC, which may promote exit from pluripotency and neural differentiation. The Wnt-induced spinal markers HOXA1-4 , HOXA7 , HOXB1-4, and HOXC4 were increased, however, the brain markers FOXG1 and OTX2 , were absent in the CLNSCs, indicating that CLNSCs have partial spinal cord properties. Finally, a CLNSC simple culture condition, when applied to hPSCs, supports the generation of NSCs, and provides a new and efficient cell model with which to untangle the mechanisms during neurogenesis.

Background: We had reported that cajanolactone A (CLA) from Cajanus cajan dose-dependently inhibited ovariectomy-induced obesity and liver steatosis in mice, showing potential to prevent postmenopausal obesity and fatty liver. In this study, the role of CLA in the regulation of energy and lipid homeostasis was investigated., Methods: Ovariectomized mice treated with CLA or vehicle for 12 weeks were performed a 48 h monitoring for energy metabolism and food uptake. After that, hypothalami, perigonadal (pWATs), inguinal (iWATs) and brown (BATs) adipose tissues, livers, sera, and fecal and cecal contents were collected and analyzed., Findings: In CLA-treated mice, we observed reduced food uptake; increased energy expenditure; inhibited expression of orexigenic genes (ORX, ORXR2, pMCH and Gal) in the hypothalami, of lipogenic genes (CD36, SREBP-1c, ChREBP, PPARγ) in the livers, and of lipid storage proteins in the WATs (FSP27, MEST and caveolin-1) and livers (FSP27, Plin2 and Plin5); stimulated expression of metabolism-related proteins (pATGL and Echs1) in the adipose tissues and of thermogenic protein (UCP1) in the inguinal WATs; increased BAT content; increased mitochondria in the pWATs and livers; inhibited angiogenesis in the pWATs; and altered gut microbiome diversity with an increased abundance of Bacteroides., Interpretation: CLA prevents ovariectomy-induced obesity and liver steatosis via regulating energy intake and lipid synthesis/storage, promoting UCP1-dependent heat production, and protecting the mitochondrial function of hepatocytes and adipocytes. The improved gut microecology and inhibited angiogenesis may also contribute to the anti-obese activity of CLA., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ketogenic diet (KD) is popular in diabetic patients but its cardiac safety and efficiency on the heart are unknown. The aim of the present study is to determine the effects and the underlined mechanisms of KD on cardiac function in diabetic cardiomyopathy (DCM). We used db/db mice to model DCM, and different diets (regular or KD) were used. Cardiac function and interstitial fibrosis were determined. T-regulatory cell (Treg) number and functions were evaluated. The effects of ketone body (KB) on fatty acid (FA) and glucose metabolism, mitochondria-associated endoplasmic reticulum membranes (MAMs), and mitochondrial respiration were assessed. The mechanisms via which KB regulated MAMs and Tregs were addressed. KD improved metabolic indices in db/db mice. However, KD impaired cardiac diastolic function and exacerbated ventricular fibrosis. Proportions of circulatory CD4 + CD25 + Foxp3 + cells in whole blood cells and serum levels of IL-4 and IL-10 were reduced in mice fed with KD. KB suppressed the differentiation to Tregs from naive CD4 + T cells. Cultured medium from KB-treated Tregs synergically activated cardiac fibroblasts. Meanwhile, KB inhibited Treg proliferation and productions of IL-4 and IL-10. Treg MAMs, mitochondrial respiration and respiratory complexes, and FA synthesis and oxidation were all suppressed by KB while glycolytic levels were increased. L-carnitine reversed Treg proliferation and function inhibited by KB. Proportions of ST2L + cells in Tregs were reduced by KB, as well as the production of ST2L ligand, IL-33. Reinforcement expressions of ST2L in Tregs counteracted the reductions in MAMs, mitochondrial respiration, and Treg proliferations and productions of Treg cytokines IL-4 and IL-10. Therefore, despite the improvement of metabolic indices, KD impaired Treg expansion and function and promoted cardiac fibroblast activation and interstitial fibrosis. This could be mainly mediated by the suppression of MAMs and fatty acid metabolism inhibition via blunting IL-33/ST2L signaling., Competing Interests: All authors declare no potential conflict of interest., (Copyright © 2021 Jun Tao et al.)

Ethnopharmacological Relevance: Ferula sinkiangensis K. M. Shen is a traditional Chinese medicine that has a variety of pharmacological properties relevant to neurological disorders and inflammations. Kellerin, a novel compound extracted from Ferula sinkiangensis, exerts a strong anti-neuroinflammatory effect by inhibiting microglial activation. Microglial activation plays a vital role in ischemia-induced brain injury. However, the potential therapeutic effect of kellerin on focal cerebral ischemia is still unknown., Aim of the Study: To explore the effect of kellerin on cerebral ischemia and clarify its possible mechanisms, we applied the middle cerebral artery occlusion (MCAO) model and the LPS-activated microglia model in our study., Materials and Methods: Neurological outcome was examined according to a 4-tiered grading system. Brain infarct size was measured using TTC staining. Brain edema was calculated using the wet weight minus dry weight method. Neuron damage and microglial activation were observed by immunofluorescence in MCAO model in rats. In in vitro studies, microglial activation was examined by flow cytometry and the viability of neuronal cells cultured in microglia-conditioned medium was measured using MTT assay. The levels of pro-inflammatory cytokines were measured by qRT-PCR and ELISA. The proteins involved in NF-κB signaling pathway were determined by western blot. Intracellular ROS was examined using DCFH-DA method and NADPH oxidase activity was measured using the NBT assay., Results: We found that kellerin improved neurological outcome, reduced brain infarct size and decreased brain edema in MCAO model in rats. Under the pathologic conditions of focal cerebral ischemia, kellerin alleviated neuron damage and inhibited microglial activation. Moreover, in in vitro studies of LPS-stimulated BV2 cells kellerin protected neuronal cells from being damaged by inhibiting microglial activation. Kellerin also reduced the levels of pro-inflammatory cytokines, suppressed the NF-κB signaling pathway, and decreased ROS generation and NADPH oxidase activity., Conclusions: Our discoveries reveal that the neuroprotective effects of kellerin may largely depend on its inhibitory effect on microglial activation. This suggests that kellerin could serve as a novel anti-inflammatory agent which may have therapeutic effects in ischemic stroke., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background/aims: Single-balloon enteroscopy (SBE) has been widely used in diagnosing small bowel disease. We conducted this study to systematically appraise its technical and clinical performance., Methods: Studies on SBE published by September 2018 were systematically searched. Technical and clinical performance data were collected and analyzed with descriptive or meta-analysis methods., Results: In total, 54 articles incorporating 4,592 patients (6,036 procedures) were included. Regarding technical parameters, the pooled insertion depths (IDs) for anterograde and retrograde SBE were 209.2 cm and 98.1 cm, respectively. The pooled retrograde ID in Asian countries was significantly greater than that in Western countries (129.0 cm vs 81.1 cm, p<0.001). The pooled anterograde and retrograde procedure times were 57.6 minutes and 65.1 minutes, respectively. The total enteroscopy rate was 21.9%, with no significant difference between Asian and Western countries. Clinically, the pooled diagnostic yield of SBE was 62.3%. Obscure gastrointestinal bleeding (OGIB) was the most common indication (50.0%), with a diagnostic yield of 59.5%. Vascular lesions were the most common findings in Western OGIB patients (76.9%) but not in Asian ones (31.0%). The rates of severe and mild adverse events were 0.5% and 2.5%, respectively., Conclusions: SBE is technically efficient and is clinically effective and safe, but total enteroscopy is relatively difficult to achieve with this technique. Etiologies of OGIB in Asian countries differ from those in Western countries.

Background: Osteoporosis is a systemic skeletal disease that leads to a high risk for bone fractures. Morinda officinalis How. has been used as osteoporosis treatment in China. However, its mechanism of action as an anti-osteoporotic herb remains unknown., Methods: A network pharmacology approach was applied to explore the potential mechanisms of action of M. officinalis in osteoporosis treatment. The active compounds of M. officinalis and their potential osteoporosis-related targets were retrieved from TCMSP, TCMID, SwissTargetPrediction, DrugBank, DisGeNET, GeneCards, OMIM, and TTD databases. A protein-protein interaction network was built to analyze the target interactions. The Metascape database was used to carry out GO enrichment analysis and KEGG pathway analysis. Moreover, interactions between active compounds and potential targets were investigated through molecular docking., Results: A total of 17 active compounds and 93 anti-osteoporosis targets of M. officinalis were selected for analysis. The GO enrichment analysis results indicated that the anti-osteoporosis targets of M. officinalis mainly play a role in the response to steroid hormone. The KEGG pathway enrichment analysis showed that M. officinalis prevents osteoporosis through the ovarian steroidogenesis signaling pathway. Moreover, the molecular docking results indicated that bioactive compounds (morindon, ohioensin A, and physcion) demonstrated a good binding ability with IGF1R, INSR, ESR1, and MMP9., Conclusion: M. officinalis contains potential anti-osteoporotic active compounds. These compounds function by regulating the proteins implicated in ovarian steroidogenesis-related pathways that are crucial in estrogen biosynthesis. Our study provides new insights into the development of a natural therapy for the prevention and treatment of osteoporosis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims: The studies on post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in pancreas divisum (PD) patients without chronic pancreatitis (CP) are rare. In this study, we aimed to evaluate the incidence of PEP in PD patients without CP and the risk and protective factors for PEP. Methods: Consecutive patients with symptomatic PD that underwent ERCP from January 2005 to December 2017 were retrospectively analyzed. The patients were divided into PD without CP group and CP group. The basic information and medical records of patients were collected. The risk and protective factors for PEP in PD patients without CP were analyzed by univariate logistic analysis. Results: A total of 89 ERCP procedures were performed in 51 PD patients without CP, and 249 procedures in 136 patients with CP. The incidence of PEP was significantly higher in PD patients without CP than those with CP (15.7% vs. 5.6%, p  = .005). Female gender were independent risk factors for PEP, while dorsal duct stent placement was a protective factor. Conclusion: CP may be a protective factor against PEP in PD patients. Female was a risk factor for PEP in PD patients and dorsal duct stent placement was a preventive factor that reduced the incidence of PEP in PD patients without CP.

Objective: To investigate the effects of transcranial direct current stimulation (tDCS) on the disturbance of brain network dysfunction after sleep deprivation (SD). Methods: The experimental design of self-control was used in the study. All 16 subjects received 2 times of 24 h SD with an interval of 3 weeks. After the first normal sleep, 24 h SD and transcranial electrical stimulation (true or false stimulation) intervention (the current magnitude of true and false stimulation was 1 mA, and the action time was 20 min and 2 s, respectively. The intervention experiment lasted for 20 min. ) and the resting magnetic resonance imaging data were collected after the second transcranial electrical stimulation (sham or true stimulation). The resting fMRI data were collected as baseline before SD, the bilateral posterior cingulate cortex in the default mode network was selected as the seed point, and the functional connectivity between the seed points and the whole brain was calculated. Results: Compared with the rest wakefulness, the functional connectivity among bilateral posterior cingulate cortex, bilateral thalamus and hippocampus was increased ( P ＜0. 01), but connected with the right precuneus, bilateral insula was decreased after 24 h SD ( P ＜0. 01). Compared with the sham tDCS group, the functional connectivity between left posterior cingulate cortex seed point and right precuneus of tDCS group was increased ( P ＜0. 01); but decreased with the bilateral thalamus, insula and right cerebral cortex ( P ＜0. 01). There was a decrease in the functional connectivity among the right posterior cingulate cortex and the bilateral thalamus, right insula, and cerebral cortex( P ＜0. 01). Conclusion: 24-hours sleep deprivation can cause functional connection disorder of bilateral posterior cingulate gyrus, and transcranial electrical stimulation can improve the functional connection disorder after sleep deprivation to some extent.

BACKGROUND Adenocarcinoma of the lung is a type of non-small cell lung cancer (NSCLC). Clinical outcome is associated with tumor grade, stage, and subtype. This study aimed to identify RNA expression profiles, including long noncoding RNA (lncRNA), microRNA (miRNA), and mRNA, associated with clinical outcome in adenocarcinoma of the lung using bioinformatics data. MATERIAL AND METHODS The miRNA and mRNA expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database, and lncRNA expression profiles were downloaded from The Atlas of Noncoding RNAs in Cancer (TANRIC) database. The independent dataset, the Gene Expression Omnibus (GEO) accession dataset, GSE81089, was used. RNA expression profiles were used to identify comprehensive prognostic RNA signatures based on patient survival time. RESULTS From 7,704 lncRNAs, 787 miRNAs, and 28,937 mRNAs of 449 patients, four joint RNA molecular signatures were identified, including RP11-909N17.2, RP11-14N7.2 (lncRNAs), MIR139 (miRNA), KLHDC8B (mRNA). The random forest (RF) classifier was used to test the prediction ability of patient survival risk and showed a good predictive accuracy of 71% and also showed a significant difference in overall survival (log-rank P=0.0002; HR, 3.54; 95% CI, 1.74-7.19). The combined RNA signature also showed good performance in the identification of patient survival in the validation and independent datasets. CONCLUSIONS This study identified four RNA sequences as a prognostic molecular signature in adenocarcinoma of the lung, which may also provide an increased understanding of the molecular mechanisms underlying the pathogenesis of this malignancy.

Objective: This study aimed to evaluate the safety and efficiency of radiofrequency ablation (RFA) in Chinese patients with gastroesophageal reflux disease (GERD)., Methods: This was a single-center, prospective study including 27 Chinese patients with GERD. The outcomes in all patients were evaluated before and at 3, 6, and 12 months after RFA, including their GERD health-related quality of life (GERD-HRQL) score, esophageal acid exposure, DeMeester score, lower esophageal sphincter (LES) resting pressure, and patient's satisfaction with symptom control. Furthermore, rabeprazole sodium (RS) administration, reflux esophagitis (RE), and intraoperative and postoperative complications were also evaluated., Results: RFA treatment significantly reduced the GERD-HRQL score, the percentage of time that esophageal pH < 4, and the DeMeester score, and significantly increased the LES resting pressure in GERD patients. A need for RS administration was reduced and RE symptoms were relieved. Satisfaction rate of 92.6% and 96.3% was reported by these patients at 6 and 12 months post-treatment, respectively. Mild bleeding (<20 mL) occurred in one patient during RFA, and no serious intraoperative and postoperative complications were observed., Conclusion: RFA is safe and effective in the treatment of GERD in Chinese patients., (© 2019 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Persistent inflammation disrupts functional recovery after spinal cord injury (SCI). Peroxisome proliferator-activated receptor gamma (PPAR- γ ) activation promotes functional recovery in SCI rats by inhibiting inflammatory cascades and increasing neuronal survival. We sought to clarify the relationship between PPAR- γ activation and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome suppression, and the role of NF- κ B in activating the NLRP3 inflammasome in neurons. In SCI rats, we found that rosiglitazone (PPAR- γ agonist) inhibited the expression of caspase-1. In in vitro neurons, G3335 (PPAR- γ antagonist) reversed the rosiglitazone-induced inhibition of caspase-1, interleukin 1 (IL-1 β ), and interleukin 6 (IL-6). Rosiglitazone inhibited the expression of NLRP3, caspase-1, IL-1 β , and IL-6. However, the activator of NLRP3 could counteract this inhibition induced by PPAR- γ activation. NF- κ B did not participate in the process of rosiglitazone-induced inhibition of NLRP3. Consistent with our in vitro results, we verified that locomotor recovery of SCI rats in vivo was regulated via PPAR- γ , NLRP3, and NF- κ B. These results suggest that PPAR- γ activation exerts an anti-inflammatory effect by suppressing the NLRP3 inflammasome-but not NF- κ B-in neurons and that PPAR- γ activation is a promising therapeutic target for SCI.

Multi-drug resistance (MDR) to anticancer drugs is the primary impediment to successful treatment of cancer. Hunting for new compounds with potent anti-MDR activity is an effectual approach to conquer cancer drug resistance. In this work, 33 new sulfur-containing 1,4-naphthoquinone oxime derivatives were prepared and investigated for their cytotoxicity against a panel of tumor cell lines and fibroblast normal cell line. Cell-based assay showed that most of target compounds displayed more potent cytotoxic potency than positive controls. Meanwhile, all of compounds were non-toxic to normal cells. More importantly, the cytotoxic activity of these oxime derivatives toward drug-resistant cancer cell lines was found to be much stronger than that toward drug-susceptible cell lines (anti-drug resistance coefficient (ADRC) > 1). Of these, compound 12 m was identified as the most effective molecule with IC50 values in the range of 0.29 ± 0.01 to 1.33 ± 0.05 μM toward MDR sublines. Further mechanism studies demonstrated that 12 m could inhibit colony formation, cause G1 phase arrest and promote cell apoptosis mediated by augmenting Bax/Bcl-2 ratio of Bel7402/5-FU cells. Our findings provide promising start points for development of sulfur-containing 1,4-naphthoquinone oxime derivatives as potential anti-MDR agents., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Tens of millions of gastrointestinal endoscopic procedures are performed every year in China, but the quality varies significantly and related factors are complex. Individual endoscopist- and endoscopy division-related factors may be useful to establish a model to measure and predict the quality of endoscopy., Aim: To establish a model to measure and predict the quality of gastrointestinal endoscopic procedures in mainland China., Methods: Selected data on endoscopy experience, equipment, facility, qualification of endoscopists, and other relevant variables were collected from the National Database of Digestive Endoscopy of China. The multivariable logistic regression analysis was used to identify the potential predictive variables for occurrence of medical malpractice and patient disturbance. Linear and nonlinear regressions were used to establish models to predict incidence of endoscopic complications., Results: In 2012, gastroscopy/colonoscopy-related complications in mainland China included bleeding in 4,359 cases (0.02%) and perforation in 914 (0.003%). Endoscopic-retrograde-cholangiopancreatography-related complications included severe acute pancreatitis in 593 cases (0.3%), bleeding in 2,151 (1.10%), perforation in 257 (0.13%) and biliary infection in 4,125 (2.11%). Moreover, 1,313 (5.0%) endoscopists encountered with medical malpractice, and 5,243 (20.0%) encountered with the disturbance from patients. The length of endoscopy experience, weekly working hours, weekly night shifts, annual vacation days and job satisfaction were predictors for the occurrence of medical malpractice and patient disturbance. However, the length of endoscopy experience and the ratio of endoscopists to nurses were not adequate to establish an effective predictive model for endoscopy complications., Conclusion: The workload and job satisfaction of endoscopists are valuable predictors for medical malpractice or patient disturbance. More comprehensive data are needed to establish quality-predictive models for endoscopic complications., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest arising from this work.

Background and Aim: Although several randomized controlled trials (RCTs) have reported that supplemental simethicone (SIM) can improve bowel preparation based on polyethylene glycol, there is no consensus as to whether SIM can ultimately increase the adenoma detection rate (ADR) during colonoscopy. A meta-analysis was performed to assess the effect of SIM on ADR during colonoscopy., Methods: Databases including PubMed, EMBASE, and the Cochrane Library were searched to find relevant RCTs. RCTs evaluating the effect of pre-procedure SIM on the ADR during colonoscopy were finally included, and fixed effect models were applied., Results: Six trials involving 1855 patients were finally included. The present meta-analysis suggested that the ADR during colonoscopy was significantly increased by supplemental SIM (27.9% vs 23.3%, P = 0.02), with a relative risk of 1.20 (95% confidence interval 1.03-1.39). Subgroup analysis suggested that supplemental SIM may be more useful to improve ADR during colonoscopy in endoscopic centers with low baseline ADR., Conclusions: Supplemental SIM for bowel preparation based on polyethylene glycol is useful to improve the ADR during colonoscopy., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The aim of this randomized controlled trial was to evaluate the effect of tranexamic acid (TXA) on postoperative blood loss during transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH). A total of 60 patients with BPH and undergoing TURP were randomized into TXA and control groups. Patients were intravenously administered 1 g TXA or placebo (0.9% sodium chloride solution), respectively, after the induction of anesthesia for TURP. Intraoperative and postoperative bladder irrigation volumes and blood loss volumes were compared between the two groups. Coagulation function (measured by prothrombin, activated partial thromboplastin and thrombin time and fibrinogen levels) was measured before the operation and at 4 h post-operation. Complications from thromboembolic events, such as lower-limb and pulmonary embolisms, were also noted. The TXA group had significantly decreased blood loss intraoperatively and at 4 h postoperatively compared with the control group (P<0.05). The 24 h postoperative blood loss and coagulation function of the two groups were not significantly different. No thromboembolic events or other complications occurred in either group. In conclusion, a preoperative single dose of TXA was indicated to reduce perioperative blood loss in TURP without a notable increase in thrombosis risk.

Objectives: This study aimed to investigate the frequency, predictors, and management of relapse of type 1 autoimmune pancreatitis (AIP) after steroid treatment., Methods: One hundred one patients with type 1 AIP receiving steroid as initial treatment were enrolled. Predictors were identified by multivariate analysis using Cox proportional hazards model. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated., Results: Thirty-nine (41.1%) patients experienced relapse after steroid treatment during a median follow-up of 40 months. The cumulative rate of relapse reached a plateau at 57.6% (95% CI, 50.3%-64.9%) at 59 months. Without maintenance therapy (HR, 4.53; 95% CI, 1.35-15.17) and proximal bile duct involvement (HR, 2.10; 95% CI, 1.07-4.14) were identified as risk factors. Repeated steroid treatment with the same initial dose but longer induction and tapering duration was given to 87.2% patients with relapse and obtained response (97.1%) during a short-term follow-up (median, 19 months)., Conclusions: Relapses are common in type 1 AIP after steroid treatment. Without maintenance therapy and proximal bile duct involvement were risk factors. Repeated steroid treatment with longer duration is effective for relapse.

The peroxisome proliferator-activated receptor gamma (PPAR- γ ) agonist rosiglitazone inhibits NF- κ B expression and endogenous neural stem cell differentiation into neurons and reduces the inflammatory cascade after spinal cord injury (SCI). The aim of this study was to explore the mechanisms underlying rosiglitazone-mediated neuroprotective effects and regulation of the balance between the inflammatory cascade and generation of endogenous spinal cord neurons by using a spinal cord-derived neural stem cell culture system as well as SD rat SCI model. Activation of PPAR- γ could promote neural stem cell proliferation and inhibit PKA expression and neuronal formation in vitro. In the SD rat SCI model, the rosiglitazone + forskolin group showed better locomotor recovery compared to the rosiglitazone and forskolin groups. MAP2 expression was higher in the rosiglitazone + forskolin group than in the rosiglitazone group, NF- κ B expression was lower in the rosiglitazone + forskolin group than in the forskolin group, and NeuN expression was higher in the rosiglitazone + forskolin group than in the forskolin group. PPAR- γ activation likely inhibits NF- κ B, thereby reducing the inflammatory cascade, and PKA activation likely promotes neuronal cell regeneration.

As a continuation of our research on developing potent and potentially safe antineoplastic agents, a set of forty five sulfur-containing shikonin oxime derivatives were synthesized and evaluated for their in vitro cytotoxic activity against human colon cancer (HCT-15), gastric carcinoma (MGC-803), liver (Bel7402), breast (MCF-7) cancer cells and human skin fibroblast (HSF) cells. All the synthesized compounds exhibited potent cytotoxic activity selectively towards HCT-15 cells and did not display apparent toxicity to the normal HSF cells, some of which were more or comparatively effective to the parent compound against HCT-15, MGC-803 and Bel7402 cells. The most active agent 9m displayed high potency against human cancer cells with IC 50 ranging from 0.27 ± 0.02 to 9.23 ± 0.12 μM. The structure-activity relationships (SARs) studies suggested that the nature of substituent group in the side chain is important for antitumor potency in vitro. Additionally, nitric oxide release studies revealed that the amount of nitric oxide generated from these oxime derivatives was relatively low. Furthermore, cellular mechanism investigations indicated that compound 9m could arrest cell cycle at G1 phase and induce a strong apoptotic response in HCT-15 cells. Moreover, western blot studies revealed that compound 9m induced apoptosis through the down-regulation of Bcl-2 and up-regulation of Bax, caspase 3 and 9. For all these reasons, compound 9m hold promising potential as antineoplastic agent., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Shikonin, alkannin and their derivatives, the main ingredient of Lithospermum erythrorhizon and Arnebia euchroma (Royle) Johnst native to Inner Mongolian and Northwest of China respectively, hold promising potentials for antitumor effects via multiple-target mechanisms. This review will emphasize the importance of their antitumor activity in apoptosis, necroptosis and immunogenic cell death, and expound the relationship of their antitumor activity and naphthoquinone scaffold that could generate ROS and alkylating agent. Meanwhile, the antitumor mechanisms of naturally-occurring shikonin, alkannin and their derivatives, which were divided into the direct interaction involved in alkylating agent, covalently binding the DNA and protein, as well as the indirect interaction mediated by ROS, nonspecifically influencing the mitochondria or multiple signal pathways, will be systematically summarized and discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

We evaluated the role of IL-10- in IL-33-mediated cholesterol reduction in macrophage-derived foam cells (MFCs) and the mechanism by which IL-33 upregulates IL-10. Serum IL-33 and IL-10 levels in coronary artery disease patients were measured. The effects of IL-33 on intra-MFC cholesterol level, IL-10, ABCA1 and CD36 expression, ERK 1/2, Sp1, STAT3 and STAT4 activation, and IL-10 promoter activity were determined. Core sequences were identified using bioinformatic analysis and site-specific mutagenesis. The serum IL-33 levels positively correlated with those of IL-10. IL-33 decreased cellular cholesterol level and upregulated IL-10 and ABCA1 but had no effect on CD36 expression. siRNA-IL-10 partially abolished cellular cholesterol reduction and ABCA1 elevation by IL-33 but did not reverse the decreased CD36 levels. IL-33 increased IL-10 mRNA production but had little effect on its stability. IL-33 induced ERK 1/2 phosphorylation and increased the luciferase expression driven by the IL-10 promoter, with the highest extent within the -2000 to -1752 bp segment of the 5'-flank of the transcription start site; these effects were counteracted by U0126. IL-33 activated Sp1, STAT3 and STAT4, but only the STAT3 binding site was predicted in the above segment. Site-directed mutagenesis of the predicted STAT3-binding sites (CTGCTTCCTGGCAGCAGAA→︀CTGCCTGGCAGCAGAA) reduced luciferase activity, and a STAT3 inhibitor blocked the regulatory effects of IL-33 on IL-10 expression. Chromatin immunoprecipitation (CHIP) confirmed the STAT3-binding sequences within the -1997 to -1700 and -1091 to -811 bp locus regions. IL-33 increased IL-10 expression in MFCs via activating ERK 1/2 and STAT3, which subsequently promoted IL-10 transcription and thus contributed to the beneficial effects of IL-33 on MFCs.

In this paper; the surface plasmon resonance (SPR) sensor with a porous silica film was studied. The effect of the thickness and porosity of the porous silica film on the performance of the sensor was analyzed. The results indicated that the figure of merit (FOM) of an SPR sensor can be enhanced by using a porous silica film with a low-refractive-index. Particularly; the FOM of an SPR sensor with 40 nm thick 90% porosity porous silica film; whose refractive index is 1.04 was improved by 311% when compared with that of a traditional SPR sensor. Furthermore; it was found that the decrease in the refractive index or the increase in the thickness of the low-refractive-index porous silica film can enlarge the FOM enhancement. It is believed that the proposed SPR sensor with a low-refractive-index porous silica film will be helpful for high-performance SPR sensors development., Competing Interests: The authors declare no conflict of interest.

Objective: To investigate the expression levels of S100A6, Notch1 in multiple myeloma (MM) patients and its clinical significance. Mathods: The expression levels of S100A6, Notch1 in 28 MM cases and 20 healthy controls were determined by real time quantitative PCR (RQ-PCR) , and their relationships with clinical features and outcomes were analyzed. Immunohistochemical was used to analysis the levels of S100A6 and Notch1 in bone marrow biopsy samples and intramedullary metastases soft tissues. RQ-PCR and Western blot were used to test the changes of Notch1 mRNA and Notch1 protein in U266 MM cells after S100A6 silenced by siRNA. Results: ①The expression levels of S100A6, Notch1 in primary MM patients was 2.19±1.25, 2.98±0.64, significantly higher than those in controls (0.71±0.20, 0.58±0.39, P <0.05) and patients in platform status (0.85±0.26, 0.72±0.40, P <0.05) . 8 cases with intramedullary metastasis had significantly higher levels of S100A6 (3.36±1.23) and Notch1 (5.71±3.96) , as compared to those without extra medullary metastases. ②S100A6 expression was positive correlation with Notch1 ( r =0.505, P =0.007) . ③S100A6 and Notch1 proteins were positive in plasma cells of bone marrow biopsy samples and intramedullary metastases soft tissues. ④The Notch1 mRNA and Notch1 expression decreased significantly after 48 hours treatment by S100A6 siRNA in U266 cells. Conclusion: S100A6 and Notch1 were closely associated with MM progress and intramedullary metastasis. They have significant correlation and might be as two prognostic molecular markers in MM.

Aim: To evaluate the numbers of different subsets of monocytes and their associations with the values of clinical measures in mild acute pancreatitis (MAP) patients., Methods: The study included one group of 13 healthy controls and another group of 24 patients with new-onset MAP. The numbers of different subsets of monocytes were examined in these two groups of subjects by flow cytometry. The concentrations of plasma interleukin (IL)-10 and IL-12 were determined by cytometric bead array. The acute physiology and chronic health evaluation (APACHE) II scores of individual patients were evaluated, and the levels of plasma C-reactive protein (CRP) as well as the activities of amylase and lipase were measured., Results: In comparison with that in the controls, significantly increased numbers of CD14+CD163-, CD14+CD163-MAC387+ M1 monocytes, but significantly reduced numbers of CD14+CD163+IL-10+ M2 monocytes were detected in the MAP patients ( P < 0.01 or P < 0.05). Furthermore, significantly higher levels of plasma IL-10 and IL-12 were observed in the MAP patients ( P < 0.01 for all). More importantly, the levels of plasma CRP were positively correlated with the numbers of CD14+CD163- ( R = 0.5009, P = 0.0127) and CD14+CD163-MAC387+ ( R = 0.5079, P = 0.0113) M1 monocytes and CD14+CD163+CD115+ M2 monocytes ( R = 0.4565, P = 0.0249) in the patients. The APACHE II scores correlated with the numbers of CD14+CD163+CD115+ ( R = 0.4581, P = 0.0244) monocytes and the levels of plasma IL-10 ( R = 0.4178, P = 0.0422) in the MAP patients. However, there was no significant association among other measures tested in this population., Conclusion: Increased numbers of CD14+CD163- and CD14+ CD163-MAC387+ monocytes may contribute to the pathogenesis of MAP, and increased numbers of CD14+CD163+CD115+ monocytes may be a biomarker for evaluating the severity of MAP., Competing Interests: Conflict-of-interest statement: The authors declare no financial or commercial conflicts of interest.

Three new limonoid-type triterpenoids, namely toonasins A-C (1-3) with a rare lactam E ring, along with six known compounds (4-9) were isolated from the barks of Toona sinensis. The structures of new compounds were elucidated by interpretation of spectroscopic data, and the relative configuration of compound 1 was further characterized by X-ray crystallographic analyses. The isolated compounds were evaluated for their cytotoxic activities against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480), and compounds 3 and 5 showed weak cytotoxicities., Competing Interests: The authors declare no conflict of interest.

Objective: To investigate the expression level of S100A6 mRNA in MM and to its clinical significance, and to evaluate its significance., Methods: The expression level of S100A6 mRNA in MM patients was determined by real time quantitative PCR(RQ-PCR), and its relationship with the clinical features and outcomes of patients was analyzed by statistic method., Results: S100A6 mRNA was detected in 20 MM patients. Compared with normal persons, the S100A6 mRNA expression in MM patients was higher. In different groups, the S100A6 mRNA expression in MM patients of 3 stages was higer than that in patients of 1 and 2 stages. MM patients with higher S100A6 mRNA expression had poor prognosis and higer extramedullary metastasis rate., Conclusion: The high expression of S100A6 mRNA is associated with poor prognosis and may be a prognostic molecular marker of MM.

The antitumor activity of shikonin derivatives is largely dependent on the generation of superoxide radicals and the alkylation activity of their naphthoquinone moiety. However, our recent study showed that 1,4-dioxime-5,8-dimethoxynaphthalene (DMAKO-05), a novel shikonin derivative, displayed more potential antitumor activity and less toxicity compared to fluorouracil (5-FU) both in vitro and in vivo, even though the hydroxyl and carbonyl groups of its naphthoquinone structure were shielded. To understand the underlying mechanisms, we investigated the metabolism of DMAKO-05 in rat liver microsomes. The kinetic analysis indicated that DMAKO-05 underwent a biphasic metabolism in rat liver microsomes. The inhibition experiments showed that CYP1A and CYP3A were the major enzymes in the metabolism of DMAKO-05, along with partial contribution from CYP2A. In addition, the structures of eight DMAKO-05 metabolites, which were characterized by accurate mass and MS/MS fragmentograms, implied that DMAKO-05 was mainly metabolized through the oxygenation of its naphthoquinone nucleus and the hydrolysis of its side chain, instead of the oxidation of hydroxyimine to ketone. Therefore, DMAKO-05 should not be considered as a traditional naphthoquinone prodrug.

We present an effective method to synthesize 15 nm magnetite nanocrystals with the morphology of square and circular nanoplates, which expose (001) facet and (111) facet, respectively. The magnetic property and electrochemical behavior towards As(III) exhibit strong facet-dependent characteristics. Theoretical calculations confirm the facet-dependent characteristics and provide the corresponding explanations.