Three-dimensional bioprinted GelMA/GO composite hydrogel for stem cell osteogenic differentiation both in vitro and in vivo.

In this study, we evaluated the use of graphene oxide (GO) mixed with methyl methacrylate gelatin (GelMA) for the construction of a microenvironmental implant to repair bone defects in orthopedic surgery. A scaffold containing a GelMA/GO composite with mesenchymal stem cells (MSCs) was constructed using three-dimensional bioprinting. The survival and osteogenic capacity of MSCs in the composite bioink were evaluated using cell viability and proliferation assays, osteogenesis-related gene expression analysis, and implantation under the skin of nude mice. The printing process had little effect on cell viability. We found that GO enhanced cell proliferation but had no significant effect on cell viability. In vitro experiments suggested that GO promoted material-cell interactions and the expression of osteogenesis-related genes. In vivo experiments showed that GO decreased the degradation time of the material and increased calcium nodule deposition. In contrast to pure GelMA, the addition of GO created a suitable microenvironment to promote the differentiation of loaded exogenous MSCs in vitro and in vivo, providing a basis for the repair of bone defects.

Domperidone inhibits cell proliferation via targeting MEK and CDK4 in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of digestive system tumor related death in the world. Unfortunately, effective chemopreventive agent is lack for patients with ESCC in clinical practice, which leads to the extremely high mortality rate. METHODS: A library of prescribed drugs was screened for finding critical anti-tumor properties in ESCC cells. The phosphoproteomics, kinase array, pulldown assay and drug affinity responsive target stabilization assay (DARTS) were applied to explore mechanisms and searched for synergistic targets. Established models of PDX in mice were used to determine the therapeutic effect of domperidone. RESULTS: After screening a library of prescribed drugs, we discovered that domperidone has anti-tumor properties. Domperidone, acting as a gastroprokinetic agent, has been widely used in clinic for gastrointestinal motility disorders. Despite limited research, there are indications that domperidone may have anti-tumor properties. In this study, we determined that domperidone significantly inhibited ESCC proliferation in vitro and in vivo. We employed phosphoproteomics to reveal p-ERK, and p-SMAD3 down-regulation upon domperidone treatment. Then, the results of kinase assay and pulldown assay further validated that domperidone directly combined with MEK1/2 and CDK4, leading to the inhibition of their kinase activity. Furthermore, our results revealed that MEK/ERK and CDK4/SMAD3 signal pathway were major pathways in domperidone against ESCC. CONCLUSION: Collectively, these findings suggest that domperidone serves as an effective "multi-target" inhibitor of MEK1/2 and CDK4, offering potential benefits for the chemoprevention of ESCC.

Software Tools for 2D Cell Segmentation.

Cell segmentation is an important task in the field of image processing, widely used in the life sciences and medical fields. Traditional methods are mainly based on pixel intensity and spatial relationships, but have limitations. In recent years, machine learning and deep learning methods have been widely used, providing more-accurate and efficient solutions for cell segmentation. The effort to develop efficient and accurate segmentation software tools has been one of the major focal points in the field of cell segmentation for years. However, each software tool has unique characteristics and adaptations, and no universal cell-segmentation software can achieve perfect results. In this review, we used three publicly available datasets containing multiple 2D cell-imaging modalities. Common segmentation metrics were used to evaluate the performance of eight segmentation tools to compare their generality and, thus, find the best-performing tool.

Effects of ulinastatin combined with dexmedetomidine on cognitive dysfunction and emergence agitation in elderly patients who underwent total hip arthroplasty.

BACKGROUND: With the continuous growth of the modern elderly population, the risk of fracture increases. Hip fracture is a common type of fracture in older people. Total hip arthroplasty (THA) has significant advantages in relieving chronic pain and promoting the recovery of hip joint function. AIM: To investigate the effect of ulinastatin combined with dexmedetomidine (Dex) on the incidences of postoperative cognitive dysfunction (POCD) and emergence agitation in elderly patients who underwent THA. METHODS: A total of 397 patients who underwent THA from February 2019 to August 2022. We conducted a three-year retrospective cohort study in Shaanxi Provincial People's Hospital. Comprehensive demographic data were obtained from the electronic medical record system. We collected preoperative, intraoperative, and postoperative data. One hundred twenty-nine patients who were administered Dex during the operation were included in the Dex group. One hundred fifty patients who were intravenously injected with ulinastatin 15 min before anesthesia induction were included in the ulinastatin group. One hundred eighteen patients who were administered ulinastatin combined with Dex during the operation were included in the Dex + ulinastatin group. The patients' perioperative conditions, hemodynamic indexes, postoperative Mini-Mental State Examination (MMSE) scores, Ramsay score, incidence of POCD, and serum inflammatory cytokines were evaluated. RESULTS: There was a significant difference in the 24 h visual analogue scale score among the three groups, and the score in the Dex + ulinastatin group was the lowest (P < 0.05). Compared with the Dex and ulinastatin group, the MMSE scores of the Dex + ulinastatin group were significantly increased at 1 and 7 d after the operation (all P < 0.05). Compared with those in the Dex and ulinastatin groups, incidence of POCD, levels of serum inflammatory cytokines in the Dex + ulinastatin group were significantly decreased at 1 and 7 d after the operation (all P < 0.05). The observer's assessment of the alertness/sedation score and Ramsay score of the Dex + ulinastatin group were significantly different from those of the Dex and ulinastatin groups on the first day after the operation (all P < 0.05). CONCLUSION: Ulinastatin combined with Dex can prevent the occurrence of POCD and emergence agitation in elderly patients undergoing THA.

Ion-Selective Micropipette Sensor for In Vivo Monitoring of Sodium Ion with Crown Ether-Encapsulated Metal-Organic Framework Subnanopores.

In vivo sensing of the dynamics of ions with high selectivity is essential for gaining molecular insights into numerous physiological and pathological processes. In this work, we report an ion-selective micropipette sensor (ISMS) through the integration of functional crown ether-encapsulated metal-organic frameworks (MOFs) synthesized in situ within the micropipette tip. The ISMS features distinctive sodium ion (Na+) conduction and high selectivity toward Na+ sensing. The selectivity is attributed to the synergistic effects of subnanoconfined space and the specific coordination of 18-crown-6 toward potassium ions (K+), which largely increase the steric hindrance and transport resistance for K+ to pass through the ISMS. Furthermore, the ISMS exhibits high stability and sensitivity, facilitating real-time monitoring of Na+ dynamics in the living rat brain during spreading of the depression events process. In light of the diversity of crown ethers and MOFs, we believe this study paves the way for a nanofluidic platform for in vivo sensing and neuromorphic electrochemical sensing.

Non-Noble-Metal-Doped Carbon Nitride Photocatalysts for Water Splitting Screened Out by Empty Defect States and the d-Band Center.

A rational design of water-splitting photocatalysts from the perspective of the electronic structure is highly desirable for optimizing catalytic activities. However, the structure-activity relationship is still unclear, which impedes the development of efficient catalysts. Herein, by comparing systematically the overall water-splitting capability of 20 kinds of metallic elements anchored at three sites (including cavity, carbon vacancy, and nitrogen vacancy) of graphitic carbon nitride (g-C3N4) through density functional theory calculations, we uncover that availability of in-gap empty defect states and the d-band center position are paramount parameters to determine activities of g-C3N4 on photocatalytic water splitting. In-gap empty states play a role in accommodating electrons from H2O to facilitate its splitting. A lower d-band center weakens the interaction between reaction intermediates and g-C3N4, thereby promoting O2 desorption. Metals embedded at carbon vacancies are found to be superior to those at cavities and nitrogen vacancies because the former not only provides ample in-gap empty states but also has a lower d-band center. We also discover a rule that, for a reaction in which the bond order between the metal and intermediate enlarges (reduces), its reaction difficulty increases (decreases) with the increasing atomic number for elements in the same period. After screening, we find that non-noble metals Co, Ni, and Ga anchored at carbon vacancies possess catalytic performances comparable to Pd- and Pt-doped systems, with the rate-determining barriers less than 0.55 eV. Our findings may provide useful information for designing effective photocatalysts.

Design, Synthesis, and Anti-Osteoporotic Characterization of Arginine N-Glycosylated Teriparatide Analogs via the Silver-catalyzed Solid-Phase Glycosylation Strategy.

In spite of effective antiosteoporosis potency, teriparatide, a bone-building agent approved by the FDA (Food and Drug Administration), was proven to exhibit various side effects. In our previous work, we developed a universal strategy for synthesizing arginine N-glycosylated peptides termed silver-promoted solid-phase glycosylation (SSG) strategy. However, it is unknown whether the SSG strategy can be applied in the peptide drug design. Herein, we first reported the optimization of teriparatide via SSG strategy. Using Arg20 and/or Arg25 as the modifying positions, three series of arginine N-glycosylated teriparatide analogs were successfully synthesized, of which the introduced sugar groups included glucose, galactose, mannose, rhamnose, ribose, 2-acetamino-2-deoxy-glucose, xylose, lactose, and maltose. Among the 27 arginine N-glycosylated derivatives, Arg20-xylose and Arg25-maltose teriparatide analogs, termed PTH-1g and PTH-2i, respectively, indicated enhanced serum stability and significantly improved antiosteoporotic activities in vitro and in vivo compared with the native counterpart. They may serve as effective therapeutic candidates for treating osteoporosis.

Two antibodies show broad, synergistic neutralization against SARS-CoV-2 variants by inducing conformational change within the RBD.

Continual evolution of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus has allowed for its gradual evasion of neutralizing antibodies (nAbs) produced in response to natural infection or vaccination. The rapid nature of these changes has incited a need for the development of superior broad nAbs (bnAbs) and/or the rational design of an antibody cocktail that can protect against the mutated virus strain. Here, we report two angiotensin-converting enzyme 2 competing nAbs-8H12 and 3E2-with synergistic neutralization but evaded by some Omicron subvariants. Cryo-electron microscopy reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the receptor-binding domain to avoid steric clashing. Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5. Together, these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.

Comparison of blinatumomab and CAR T-cell therapy in relapsed/refractory acute lymphoblastic leukemia: a systematic review and meta-analysis.

OBJECTIVES: This study evaluated the benefits and risks of patients with refractory or relapsed acute lymphocytic leukemia (R/R ALL) treated with anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and blinatumomab. METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were searched for relevant studies. RESULTS: The pooled complete remission (CR) rate and minimal residual disease (MRD) negative rate were 48%, 31% for blinatumomab, and 86% and 80% for CAR T-cell therapy. CONCLUSIONS: The CAR T-cell therapy group exhibited a higher likelihood of CR rate than the blinatumomab group in every analysis regardless of adjustment subgroups. CAR T-cell therapy was associated with a significantly prolonged overall survival (OS) and relapse-free survival (RFS) compared with blinatumomab (2-year OS 55% vs 25%; 2-year RFS 40% vs 22%). CAR T-cell therapy was more effective for achieving CR and bridging to allogeneic hematopoietic stem cell transplantation (allo-SCT) than blinatumomab (2-year OS 75% vs. 57%). An emerging role for blinatumomab is as a bridging agent pre-SCT, and for patients who achieve an MRD-negative state pre-SCT, post-SCT outcomes are expected to be the same as CAR-T. For adverse effects (AEs), blinatumomab was associated with a lower rate of grade ≥3 hematological toxicity, CRS, and neurological events.

Corynoline inhibits esophageal squamous cell carcinoma growth via targeting Pim-3.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive and deadly malignancy characterized by late-stage diagnosis, therapy resistance, and a poor 5-year survival rate. Finding novel therapeutic targets and their inhibitors for ESCC prevention and therapy is urgently needed. METHODS: We investigated the proviral integration site for maloney murine leukemia virus 3 (Pim-3) protein levels using immunohistochemistry. Using Methyl Thiazolyl Tetrazolium and clone formation assay, we verified the function of Pim-3 in cell proliferation. The binding and inhibition of Pim-3 by corynoline were verified by computer docking, pull-down assay, cellular thermal shift assay, and kinase assay. Cell proliferation, Western blot, and a patient-derived xenograft tumor model were performed to elucidate the mechanism of corynoline inhibiting ESCC growth. RESULTS: Pim-3 was highly expressed in ESCC and played an oncogenic role. The augmentation of Pim-3 enhanced cell proliferation and tumor development by phosphorylating mitogen-activated protein kinase 1 (MAPK1) at T185 and Y187. The deletion of Pim-3 induced apoptosis with upregulated cleaved caspase-9 and lower Bcl2 associated agonist of cell death (BAD) phosphorylation at S112. Additionally, binding assays demonstrated corynoline directly bound with Pim-3, inhibiting its activity, and suppressing ESCC growth. CONCLUSIONS: Our findings suggest that Pim-3 promotes ESCC progression. Corynoline inhibits ESCC progression through targeting Pim-3.

Rational design of a cross-type HPV vaccine through immunodominance shift guided by a cross-neutralizing antibody.

In vaccine development, broadly or cross-type neutralizing antibodies (bnAbs or cnAbs) are frequently targeted to enhance protection. Utilizing immunodominant antibodies could help fine-tune vaccine immunogenicity and augment the precision of immunization strategies. However, the methodologies to capitalize on the attributes of bnAbs in vaccine design have not been clearly elucidated. In this study, we discovered a cross-type neutralizing monoclonal antibody, 13H5, against human papillomavirus 6 (HPV6) and HPV11. This nAb exhibited a marked preference for HPV6, demonstrating superior binding activity to virus-like particles (VLPs) and significantly higher prevalence in anti-HPV6 human serum as compared to HPV11 antiserum (90% vs. 31%). Through co-crystal structural analysis of the HPV6 L1 pentamer:13H5 complex, we delineated the epitope as spanning four segments of amino acids (Phe42-Ala47, Gly172-Asp173, Glu255-Val275, and Val337-Tyr351) on the L1 surface loops. Further interaction analysis and site-directed mutagenesis revealed that the Ser341 residue in the HPV6 HI loop plays a critical role in the interaction between 13H5 and L1. Substituting Ser341 with alanine, which is the residue type present in HPV11 L1, almost completely abolished binding activity to 13H5. By swapping amino acids in the HPV11 HI loop with corresponding residues in HPV6 L1 (Ser341, Thr338, and Thr339), we engineered chimeric HPV11-6HI VLPs. Remarkably, the chimeric HPV11-6HI VLPs shifted the high immunodominance of 13H5 from HPV6 to the engineered VLPs and yielded comparable neutralization titers for both HPV6 and HPV11 in mice and non-human primates. This approach paves the way for the design of broadly protective vaccines from antibodies within the main immunization reservoir.

The clinical value of the Duke Anesthesia Resistance Scale in predicting postoperative delirium after hip fracture surgery: a retrospective study.

Aim: This study aims to investigate the clinical value of the Duke Anesthesia Resistance Scale (DARS) in predicting postoperative delirium (POD) after hip fracture surgery. Methods: A retrospective study was conducted. Clinical data were collected from the patients who had hip fracture and underwent elective total hip arthroplasty in Shaanxi Provincial People's Hospital, Third Affiliated Hospital of Xi'an Jiaotong University between January 2022 and June 2023. The Consciousness Fuzzy Assessment Scale was used to evaluate the occurrence of POD on postoperative day 3 (POD 3). The enrolled patients were divided into the POD group (n = 26) and the non-POD group (n = 125). Baseline characteristics, surgical data, postoperative information, and laboratory test results were collected. DARS scores were calculated using the minimum alveolar concentration, end-tidal concentration average (ETAC), and bispectral index (BIS). Multivariate logistic regression analysis was conducted to recognize the independent risk factors for POD after hip fracture surgery. Receiver operating characteristic (ROC) curve was plotted to evaluate the value of DARS in POD prediction. Results: The average age of POD group was significantly higher, comparing to non-POD group (P < 0.05). DARS scores were statistically lower in the POD group compared to non-POD group (P < 0.05). Multivariate logistic regression analysis found that age and DARS scores were factors impacting post-operative delirium occurrence after hip fracture surgery (P < 0.05). ROC showed that the area under the curve for DARS in predicting POD after hip fracture surgery was 0.929 (95% CI [0.861-0.997]). The optimal cutoff value was 30. The sensitivity was 95.45%, while the specificity was 84.09%. Conclusion: DARS score demonstrates good predictive value in hip fracture patients and is feasible in clinical practice, making it suitable for clinical application and promotion.

A novel Fc-enhanced humanized monoclonal antibody targeting B7-H3 suppresses the growth of ESCC.

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor of the digestive tract with a low 5-year survival rate due to the lack of effective treatment methods. Although therapeutic monoclonal antibodies (mAbs) now play an important role in cancer therapy, effective targeted mAbs are still lacking for ESCC. B7-H3 is highly expressed in a variety of tumors and has emerged as a promising therapeutic target. Several mAbs against B7-H3 have advanced to clinical trials, but their development has not yet been pursued for ESCC. Here, we developed a humanized and Fc-engineered anti-B7H3 mAb 24F-Hu-mut2 and systematically evaluated its anti-tumor activity in vitro and in vivo. The 24F-Hu-mut2 was humanized and modified in Fc fragment to obtain stronger antibody-dependent cell-mediated cytotoxicity(ADCC) activity and nanomolar affinity. Furthermore, both of ESCC cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mice models indicated that 24F-Hu-mut2 displayed potent in vivo anti-tumor activity. In addition, a computational docking model showed that the mAb bound to IgC1 and IgC2 domain of B7-H3, which is closer to the cell membrane. Consistently, our ELISA results verified the binding of 24F-Hu-WT and IgC1 and IgC2. Our results indicate that 24F-Hu-mut2 has significant anti-ESCC activity both in vitro and in vivo, and this monoclonal antibody may be a promising antibody against ESCC and other B7-H3 overexpressing tumors.

A nomogram for predicting death for infants born at a gestational age of <28 weeks: a population-based analysis in 18 neonatal intensive care units in northern China.

Background: In China, the number of preterm infants is the second largest globally. Compared with those in developed countries, the mortality rate and proportion of treatment abandonment for extremely preterm infants (EPIs) are higher in China. It would be valuable to conduct a multicenter study and develop predictive models for the mortality risk. This study aimed to identify a predictive model among EPIs who received complete care in northern China in recent years. Methods: This study included EPIs admitted to eighteen neonatal intensive care units (NICUs) within 72 hours of birth for receiving complete care in northern China between January 1, 2015, and December 31, 2018. Infants were randomly assigned into a training dataset and validation dataset with a ratio of 7:3. Univariate Cox regression analysis and multiple regression analysis were used to select the predictive factors and to construct the best-fitting model for predicting in-hospital mortality. A nomogram was plotted and the discrimination ability was tested by an area under the receiver operating characteristic curve (AUROC). The calibration ability was tested by a calibration curve along with the Hosmer-Lemeshow (HL) test. In addition, the clinical effectiveness was examined by decision curve analysis (DCA). Results: A total of 568 EPIs were included and divided into the training dataset and validation dataset. Seven variables [birth weight (BW), being inborn, chest compression in the delivery room (DR), severe respiratory distress syndrome, pulmonary hemorrhage, invasive mechanical ventilation, and shock] were selected to establish a predictive nomogram. The AUROC values for the training and validation datasets were 0.863 [95% confidence interval (CI): 0.813-0.914] and 0.886 (95% CI: 0.827-0.945), respectively. The calibration plots and HL test indicated satisfactory accuracy. The DCA demonstrated that positive net benefits were shown when the threshold was >0.6. Conclusions: A nomogram based on seven risk factors is developed in this study and might help clinicians identify EPIs with risk of poor prognoses early.

Structural basis for broad neutralization of human antibody against Omicron sublineages and evasion by XBB variant.

IMPORTANCE: The ongoing COVID-19 pandemic has been characterized by the emergence of new SARS-CoV-2 variants including the highly transmissible Omicron XBB sublineages, which have shown significant resistance to neutralizing antibodies (nAbs). This resistance has led to decreased vaccine effectiveness and therefore result in breakthrough infections and reinfections, which continuously threaten public health. To date, almost all available therapeutic nAbs, including those authorized under Emergency Use Authorization nAbs that were previously clinically useful against early strains, have recently been found to be ineffective against newly emerging variants. In this study, we provide a comprehensive structural basis about how the Class 3 nAbs, including 1G11 in this study and noted LY-CoV1404, are evaded by the newly emerged SARS-CoV-2 variants.

Integrated Metabolome and Transcriptome Analysis of Petal Anthocyanin Accumulation Mechanism in Gloriosa superba 'Rothschildiana' during Different Flower Development Stages.

Flower color is a key ornamental trait in plants. The petals of Gloriosa superba 'Rothschildiana' petals undergo a color transformation from yellow to red during their development, but the molecular mechanism of this process remains unexplored. This study examines the anthocyanin profiles and gene expression patterns of 'Rothschildiana' petals across four developmental stages: bud (S1), initial opening (S2), half opening (S3), and full opening stage (S4). A total of 59 anthocyanins were identified with significant increases in cyanidin-3,5-O-diglucoside, cyanidin-3-O-glucoside, pelargonidin-3-O-glucoside, and pelargonidin-3,5-O-diglucoside levels observed during petal maturation. Transcriptome analysis revealed 46 differentially expressed genes implicated in flavonoid and anthocyanin biosynthesis. Additionally, three gene modules were found to be associated with anthocyanin accumulation throughout flower development. Expression levels of genes associated with auxin, abscisic acid, brassinosteroid signaling, and transcription factors such as NACs and WRKYs underwent significant changes and exhibited strong correlations with several flavonoid and anthocyanin biosynthetic genes in these modules. These findings offer novel insights into the molecular underpinnings of flower color variation and lay the groundwork for the improvement of G. superba.

A Metal-Organic Framework-Incorporated Hydrogel for Delivery of Immunomodulatory Neobavaisoflavone to Promote Cartilage Regeneration in Osteoarthritis.

The treatment of osteoarthritis (OA)-related cartilage defects is a great clinical challenge due to the complex pathogenesis of OA and poor self-repair ability of cartilage tissue. Combining local and long-term anti-inflammatory therapies to promote cartilage repair is an effective method to treat OA. In this study, a zinc-organic framework-incorporated extracellular matrix (ECM)-mimicking hydrogel platform was constructed for the inflammatory microenvironment-responsive delivery of neobavaisoflavone (NBIF) to promote cartilage regeneration in OA. The NBIF was encapsulated in situ in zeolitic imidazolate frameworks (ZIF-8 MOFs). The NBIF@ZIF-8 MOFs were decorated with polydopamine and incorporated into a methacrylate gelatin/hyaluronic acid hybrid network to form the NBIF@ZIF-8/PHG hydrogel. The hydrogel featured excellent cell/tissue affinity, providing a favorable microenvironment for recruiting cells and cytokines to the defect sites. The hydrogel enabled the on-demand NBIF released in response to a weakly acidic microenvironment at the injured joint site to resolve inflammatory responses during the early stages of OA. Consequently, the cooperativity of the loaded NBIF and hydrogel synergistically modulated the immune response and assisted in cartilage defect repair. In summary, the NBIF@ZIF-8/PHG hydrogel delivery platform represents an effective treatment strategy for OA-related cartilage defects and may attract attentions for applications in other inflammatory diseases.

Evaluation of topical methylene blue nanoemulsion for wound healing in diabetic mice.

CONTEXT: Diabetic wounds (DW) are a complication of diabetes and slow wound healing is the main manifestation. Methylene blue (MB) has been shown to exhibit therapeutic effects on diabetes-related diseases. OBJECTIVE: To investigate the mechanisms of action of MB-nanoemulsion (NE) in the treatment of DW. MATERIALS AND METHODS: The concentration of MB-NE used in the in vivo and in vitro experiments was 0.1 mg/mL. Streptozocin-induced diabetic mice were used as models. The mice were separated into nondiabetic, diabetic, MB-NE treated, and NE-treated groups. Intervention of high glucose-induced human umbilical vein endothelial cells using MB-NE. The mechanism by which MB-NE promotes DW healing is investigated by combining histological analysis, immunofluorescence analysis, TUNEL and ROS assays and western blotting. RESULTS: In diabetic mice, the MB-NE accelerated DW healing (p < 0.05), promoted the expression of endothelial cell markers (α-SMA, CD31 and VEGF) (p < 0.05), and reduced TUNEL levels. In vitro, MB accelerated the migration rate of cells (p < 0.05); promoted the expression of CD31, VEGF, anti-apoptotic protein Bcl2 (p < 0.05) and decreased the expression of the pro-apoptotic proteins cleaved caspase-3 and Bax (p < 0.05). MB upregulated the expression of Nrf2, catalase, HO-1 and SOD2 (p < 0.05). In addition, MB reduced the immunofluorescence intensity of TUNEL and ROS in cells and reduced apoptosis. The therapeutic effect of MB was attenuated after treatment with an Nrf2 inhibitor (ML385). DISCUSSION AND CONCLUSION: This study provides a foundation for the application of MB-NE in the treatment of DW.

Open a new epoch of arsenic trioxide investigation: ATOdb.

Arsenic trioxide (ATO) is a great discovery in the treatment of acute promyelocytic leukemia (APL), which has been used in an increasing number of malignant diseases. Systematic integrative analysis will help to precisely understand the mechanism of ATO and find new combined drugs. Therefore, we developed a one-stop comprehensive database of ATO named ATOdb by manually compiling a wealth of experimentally supported ATO-related data from 3479 articles, and integrated analysis tools. The current version of ATOdb contains 8373 associations among 2300 ATO targets, 80 conditions and 262 combined drugs. Each entry in ATOdb contains detailed information on ATO targets, therapeutic/side effects, systems, cell names, cell types, regulations, detection methods, brief descriptions, references, etc. Furthermore, ATOdb also provides data visualization and analysis results such as the drug similarities, protein-protein interactions, and miRNA-mRNA relationships. An easy-to-use web interface was deployed in ATOdb for users to easily browse, search and download the data. In conclusion, ATOdb will serve as a valuable resource for in-depth study of the mechanism of ATO, discovery of new drug combination strategies, promotion of rational drug use and individualized treatments. ATOdb is freely available at http://bio-bigdata.hrbmu.edu.cn/ATOdb/index.jsp.