Ubenimex suppresses glycolysis mediated by CD13/Hedgehog signaling to enhance the effect of cisplatin in liver cancer.

Background: Liver cancer ranks third in fatalities among all cancer-related deaths. As a traditional chemotherapy drug, the application of cis-Diamminedichloroplatinum (II) (cisplatin, CDDP) for the treatment of liver cancer is greatly limited by its side effects and high drug resistance. Therefore, we are in urgent need of a more effective and less toxic CDDP therapeutic regimen. Our research aimed to clarify the possible mechanism of ubenimex in enhancing the effect of CDDP on liver cancer. Methods: The underlying mechanism was determined using Cell Counting Kit-8 (CCK-8) assay, flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), transwell assay, wound healing assay and western blot assay. Results: The data indicated that ubenimex suppressed the expression levels of glycolysis-related proteins by decreasing the expression levels of cluster of differentiation 13 (CD13), while overexpression of CD13 could restore the activity of glycolysis. The glycolysis inhibitor 2-deoxy-D-glucose enhanced the antiproliferative effect of ubenimex and CDDP. In addition, the inhibition of the activity levels of the Hedgehog (Hh) pathway members was accompanied by a decrease in CD13 expression, which was reversed following CD13 overexpression. Moreover, ubenimex inhibited the production of lactic acid and adenosine triphosphate (ATP), as well as the expression of key proteins involved in glycolysis, which was similar to the effects caused by the Hh inhibitor cyclopamine. However, the effects of ubenimex were mediated by targeting CD13, while cyclopamine exhibited no effects on CD13, suggesting that Hh signaling occurred in the downstream of CD13. The inhibition of glycolysis by cyclopamine was reduced following CD13 overexpression, which further indicated that ubenimex targeted the CD13/Hh pathway to inhibit glycolysis. Finally, wound healing and transwell assays and cell proliferation and apoptosis analysis demonstrated that ubenimex inhibited glycolysis by alleviating the CD13/Hh pathway, which in turn enhanced the effects of CDDP on inhibiting the progression of liver cancer. Conclusions: Ubenimex inhibits glycolysis by targeting the CD13/Hh pathway, thus playing an anti-tumor role together with CDDP. This study demonstrated the adjuvant effect of ubenimex from the perspective of Hh signal-dependent glycolysis regulation.

Hierarchical Dual Single-Atom Catalysts with Coupled CoN4 and NiN4 Moieties for Industrial-Level CO2 Electroreduction to Syngas.

Renewable-driven electrochemical CO2 reduction reaction (CO2RR) to syngas is an encouraging alternative strategy to traditional fossil fuel-based syngas production, and the development of industrial-level electrocatalysts is vital. Herein, based on theoretical optimization of metal species, hierarchical CoxNi1-x-N-C dual single-atom catalyst (DSAC) with individual NiN4 (CO preferential) and CoN4 (H2 preferential) moieties was constructed by a two-step pyrolysis route. The Co0.5Ni0.5-N-C exhibits a stable CO Faradaic efficiency of 50 ± 5% and an industrial-level current density of 101-365 mA cm-2 in an ultrawide potential window of -0.5 to -1.1 V. The CO/H2 ratio of syngas can be conveniently tuned by regulating the Co/Ni ratio. The coupled effect of NiN4 and CoN4 moieties under a local high-pH microenvironment is responsible for the regulation of the CO/H2 selectivity and yield for the CoxNi1-x-N-C catalyst, which is not present in the mixed Co-N-C and Ni-N-C catalyst. This study provides a promising DSAC strategy for achieving industrial-level syngas production via CO2RR.

Loss-free pulverization by confining copper oxide inside hierarchical nitrogen-doped carbon nanocages toward superb potassium-ion batteries.

Taking the advantages of hierarchical nitrogen-doped carbon nanocages (hNCNCs) with nanocavities for encapsulation and multiscale micro-meso-macropores/high conductivity for mass/electron synergistic transportation, a conversion-type CuO anode material is confined inside hNCNCs for potassium storage. The so-obtained yolk-shelled CuO@hNCNC hybrids have tunable CuO contents in the range of 11.7-63.7 wt%. The unique architecture leads to the loss-free pulverization of the active components during charge/discharge, which increases the surface-controlled charge storage, shortens the K+ solid diffusion lengths with an enlarged K+ diffusion coefficient, and meanwhile enhances the rate capability and durability. Consequently, the optimized CuO@hNCNC delivers a high specific capacity of 498 mA h g-1 at 0.1 A g-1 and 194 mA h g-1 at 10.0 A g-1 based on the total mass of CuO@hNCNC, and a long-term stability. The capacity based on the CuO active component reaches a record-high 522 mA h g-1 at 1.0 A g-1 after 2000 cycles, which is ca. 2.5 times the state-of-the-art value in the literature. The evolution of the cycling performance with CuO loading is well understood based on the loss-free pulverization. This study demonstrates a new strategy to turn the generally harmful pulverization of active components into a beneficial factor for K+ storage, which paves the way for exploring high-performance anodes for rechargeable batteries.

pH-Responsive Polymer Films Based on Click Polymerization for Food Freshness Monitoring: Non-Toxic, Non-Leaking, and Antibacterial.

With the requirements for food safety and quality, there has been increasing attention on intelligent food packaging, especially pH-responsive intelligent packaging. However, the toxicity of indicators and the vulnerability of composite films to leakage tend to change the composition of food and endanger human health. In this study, 2-allyoxy-1-hydroxy-anthraquinone (AhAQ), a pH-responsive plant dye that was modified from alizarin (AI), was grafted onto the pH-responsive intelligent film (AhAQF) via click polymerization. The obtained AhAQF film shows color change in response to ammonia vapor and exhibits adequate reversibility after treatment with volatile acetic acid. The obtained AhAQF exhibits zero leakage, owing to the covalent immobilization of AhAQ. Thus, the prepared pH-responsive films are non-toxic and antibacterial and show promising application prospects in visual food intelligent packaging and gas-sensitive labels.

Exploration and Practice of Medicine Pathway for Perioperative VTE Prophylactic Anticoagulant Treatment.

OBJECTIVE: Using perioperative VTE prophylactic anticoagulant pathway delicacy management, we aimed to explore the role of clinical pharmacists in perioperative VTE prophylactic anticoagulant treatment and the effect of the clinical medicine pathway implementation. METHODS: In compliance with evidence-based medicine, combined with clinical practice, clinical pharmacists participated in the formulation of the perioperative anticoagulant clinical medicine pathway. The PDCA cycle was strictly implemented. Urologic Department, Affiliated Hospital of Qingdao University, Qingdao Shandong, China, served as a pilot department for the evaluation of the effect of drug clinical pathway implementation. RESULTS: The anticoagulant clinical medicine pathway for the urologic department was formulated and implemented from October 2020 to August 2021. The entry rate gradually increased, and the accuracy of thrombosis risk assessment improved. The proportion of drugs in the department and the per capita drug cost decreased significantly. CONCLUSION: The perioperative VTE prophylactic anticoagulant pathway showed significant achievements in the rational use of urologic anticoagulant drugs, lowering the cost of medical care. Therefore, it could be considered a novel long-term mechanism for rational analgesia drug use.

Anti-inflammatory Mechanism of Action of Benzoylmesaconine in Lipopolysaccharide-Stimulated RAW264.7 Cells.

Background: Benzoylmesaconine (BMA), the most abundant monoester alkaloid in Aconitum plants, has some biological activities and is a potential therapeutic agent for inflammation-related diseases. However, the potential anti-inflammatory mechanisms of BMA have not been clarified. Purpose: This study aimed to investigate the underlying molecular mechanisms of the anti-inflammatory action of this compound using lipopolysaccharide (LPS)-activated RAW264.7 macrophages. Methods: The release of pro-inflammatory cytokines and mediators were detected by nitric oxide (NO) assays, reactive oxygen species (ROS) assays, and enzyme-linked immunosorbent assays (ELISA) in LPS-activated RAW264.7 macrophage cells. Quantitative real-time PCR was used to measure the gene expression of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Cell viability was determined using a cell counting kit-8 (CCK-8) assay. The expression of iNOS, COX-2, mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB)-related proteins were detected by western blot, and nuclear translocation of p65 was observed by immunofluorescence. Results: BMA significantly decreased the production of IL-1ß, IL-6, TNF-α, PGE2, NO, and ROS and inhibited the protein and mRNA levels of COX-2 and iNOS in LPS-activated RAW264.7 macrophages. Moreover, LPS-induced phosphorylation of IκBα, JNK, p38, and ERK; degradation of IκBα; and nuclear translocation of p65 were significantly suppressed by BMA treatment. Conclusion: These findings demonstrate that the anti-inflammatory effect of BMA was through the suppression of the NF-κB and MAPK signaling pathways and that it may be a therapeutic agent targeting specific signal transduction events required for inflammation-related diseases.

Nanomaterial Technology and Soft Tissue Sarcomas.

Soft tissue sarcomas (STSs) are relatively rare heterogeneous solid tumors of the mesenchymal origin. They account for approximately 1% of all malignant tumors in adults and have more than 70 histological subtypes. Consequently, the rarity and heterogeneity of STSs make their diagnosis and treatment very challenging. Nanotechnology has attracted increasing attention from researchers due to the unique physicochemical and biological properties of nanomaterials with potential medical applications as nanoprobes, drug delivery systems, photosensitizers, radioenhancers, antitumor agents, and their combinations for cancer diagnosis and treatment. This review discusses the progress made in the use of nanotechnology for the diagnosis and treatment of STSs and highlights future prospects of the STS multimodality therapy.

Research Progress in Exosome-Based Nanoscale Drug Carriers in Tumor Therapies.

Current antitumor treatment methods have several reported limitations, including multidrug resistance and serious adverse reactions. Targeted drug delivery systems are effective alternatives that can help healthcare providers overcome these limitations. Exosomes can serve as a natural nanoscale drug delivery system, with the advantages of high biocompatibility, low immunogenicity, and efficient tumor targetability. In this paper, we discuss the biological characteristics of exosomes, summarize the drug-carrying mechanisms of exosome-based drug delivery systems, and examine the potential role and applicability of exosomes in clinical tumor treatment approaches. This review can be used as a guideline for the future development of exosome-based delivery systems in clinical precision tumor treatment.

Risk Factors and Incidence of Malignancy After Kidney Transplant in Mainland China: A Single-Center Analysis.

OBJECTIVES: Malignancy is a common cause of death in renal transplant patients. The aim of this study was to investigate incidence, risk factors, and survival rates associated with posttransplant malignancy in kidney transplant recipients. MATERIALS AND METHODS: Between January 2015 and December 2020, 1154 patients underwent kidney transplant at the Affiliated Hospital of Qingdao University. Patients with a history of malignancy or other organ transplant(liver, pancreas, heart, orlungs) were excluded from this study. Patients with incomplete follow-up records were also excluded. Ultimately, our study comprised 811 kidney transplant recipients. The patient characteristics and incidence, type, and risk factors associated with posttransplant malignancy were examined. We also analyzed the overall survival of recipients with posttransplant malignancy. RESULTS: A total of 811 renal transplant recipients were followed up, with a median follow-up period of 3.0 years. Fourteen kidney recipients developed posttransplant malignancy (1.7%), with a mean time to malignancy diagnosis of 2.7 years. The 3-year and 5-year overall survival rates were 91.7% and 91.7%, respectively, in recipients with malignancy and 99.2% and 98.8%, respectively, in recipients without malignancy. The overall survival rate was significantly higher in recipients without malignancy than in those with malignancy (P = .03). Female sex, older recipient age, and history of prior kidney transplant were significant predictors of malignancy development. CONCLUSIONS: Postoperative malignancy in kidney transplantrecipients was associated with lower overall survival rates. Malignancy screening is important for kidney transplant patients, especially for older women and patients with a history of prior kidney transplant.

STAT1: a novel candidate biomarker and potential therapeutic target of the recurrent aphthous stomatitis.

BACKGROUND: The recurrent aphthous stomatitis (RAS) frequently affects patient quality of life as a result of long lasting and recurrent episodes of burning pain. However, there were temporarily few available effective medical therapies currently. Drug target identification was the first step in drug discovery, was usually finding the best interaction mode between the potential target candidates and probe small molecules. Therefore, elucidating the molecular mechanism of RAS pathogenesis and exploring the potential molecular targets of medical therapies for RAS was of vital importance. METHODS: Bioinformatics data mining techniques were applied to explore potential novel targets, weighted gene co-expression network analysis (WGCNA) was used to construct a co-expression module of the gene chip data from GSE37265, and the hub genes were identified by the Molecular Complex Detection (MCODE) plugin. RESULTS: A total of 16 co-expression modules were identified, and 30 hub genes in the turquoise module were identified. In addition, functional analysis of Hub genes in modules of interest was performed, which indicated that such hub genes were mainly involved in pathways related to immune response, virus infection, epithelial cell, signal transduction. Two clusters (highly interconnected regions) were determined in the network, with score = 17.647 and 10, respectively, cluster 1 and cluster 2 are linked by STAT1 and ICAM1, it is speculated that STAT1 may be a primary gene of RAS. Finally, genistein, daidzein, kaempferol, resveratrol, rosmarinic acid, triptolide, quercetin and (-)-epigallocatechin-3-gallate were selected from the TCMSP database, and both of them is the STAT-1 inhibitor. The results of reverse molecular docking suggest that in addition to triptolide, (-)-Epigallocatechin-3-gallate and resveratrol, the other 5 compounds (flavonoids) with similar structures may bind to the same position of STAT1 protein with different docking score. CONCLUSIONS: Our study identified STAT1 as the potential biomarkers that might contribute to the diagnosis and potential therapeutic target of RAS, and we can also screen RAS therapeutic drugs from STAT-1 inhibitors.

Benzoylaconine Modulates LPS-Induced Responses Through Inhibition of Toll-Like Receptor-Mediated NF-κB and MAPK Signaling in RAW264.7 Cells.

Previous studies have shown that benzoylaconine (BAC), a representative monoester alkaloid, has a potential anti-inflammatory effect. This study investigated the underlying molecular mechanisms using the mode of LPS-activated RAW264.7 macrophage cells. Our findings showed that BAC significantly suppressed the release of pro-inflammatory cytokines and mediators, including IL-6, TNF-α, IL-1ß, ROS, NO, and PGE2. BAC treatment also effectively downregulated the elevated protein levels of iNOS and COX-2 induced by LPS in a dose-dependent manner. In this study, we found that BAC inhibited LPS-induced NF-κB activation by reducing the phosphorylation and degradation of IκBα by western blotting and blocking the nuclear translocation of p65 using an immunofluorescence assay. The elevated protein levels of JNK, p38, and ERK phosphorylation after LPS stimulation were restored effectively by BAC treatment. The protein expression of Toll-like receptor 4 (TLR4) and LPS-induced phosphorylation of TAK1, which is a crucial upstream regulatory factor of TLR-induced MAPK and NF-κB signaling, were inhibited by BAC in activated RAW264.7 macrophages. Moreover, BAC decreased the levels of TAK1 phosphorylation and pro-inflammatory cytokines and mediators associated with MAPK and NF-κB activation, similar to TLR4 inhibitor TAK-242. These findings demonstrated that BAC exhibited an anti-inflammatory effect by the inhibition of TLR-induced MAPK and NF-κB pathways, indicating that it could potentially be used for treating inflammatory diseases.

Ubenimex Suppresses the Ability of Migration and Invasion in Gastric Cancer Cells by Alleviating the Activity of the CD13/NAB1/MAPK Pathway.

BACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors in China. Most GC patients are diagnosed at an advanced stage, for that the prognosis is dismal and metastasis is common. Although there have been increasing numbers of studies indicating that Ubenimex can suppress metastasis in GC, the underlying mechanism is still unknown. METHODS: Herein, the inhibitory effect of Ubenimex on GC metastasis, in which the underlining mechanism was determined using Gene chip analysis, high content screening (HCS), transwell assays, wound healing assays and Western blot assays. RESULTS: The results obtained from wound healing assays and transwell assays indicated that Ubenimex, an inhibitor of CD13, suppressed the migration and invasion of MKN-28, MGC-803, BGC-823 and SGC-790 cells, by downregulating CD13 expression. In addition, the findings acquired from Gene chip analysis and HCS demonstrated that NGFI-A-binding protein 1 (NAB1) was a putative target downstream of CD13. Furthermore, the results obtained from Western blot assays showed that Ubenimex not only inhibits NAB1 expression by targeting CD13, but also inhibits GC metastasis by mitigating the activity of the MAPK signaling pathway. These findings indicated a possible mechanism via the CD13/NAB1/MAPK pathway of which activity was restrained. CONCLUSION: Ubenimex exert the inhibitory effect on GC metastasis by targeting CD13, in which NAB1 expression and the activation of MAPK signaling pathway were both suppressed. This study identified a promising target for the inhibition of GC metastasis.

miRNA-221 promotes cutaneous squamous cell carcinoma progression by targeting PTEN.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is a common type of skin malignancy. MicroRNA-221 (miRNA-221) is a critical non-coding RNA in tumor initiation and progression. However, the molecular mechanisms of miRNA-221 in the development of CSCC remain unknown. This study investigated the expression of miRNA-221 in CSCC and its potential tumor biological functions. METHODS: MTT assay, colony assay, PCR, and Western blot were adopted. RESULTS: In this study, miRNA-221 expression was significantly higher in CSCC tissues and cell lines than in normal tissues and cells (P < 0.05). Further functional experiments indicated that miRNA-221 knockdown inhibited the proliferation and cell cycle, while upregulation of miRNA-221 presented the opposite role. The dual reporter gene assays indicated that PTEN is a direct target gene of miRNA-221. PTEN protein or mRNA levels were decreased after the cells were transfected with miR-221 mimics. CONCLUSIONS: Taken together, the obtained results indicated that miR-221 plays an oncogenic function in CSCC by targeting PTEN and further suggest that miR-221 may be a potential target for CSCC diagnosis and treatment.

Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis.

Cisplatin (CDDP)-based chemotherapy is a standard treatment for gastric cancer (GC). However, chemoresistance is a major obstacle for CDDP application. Exploring underlying mechanisms of CDDP resistance development in GC and selecting an effective strategy to overcome CDDP resistance remain a challenge. Here, we demonstrate that a transmembrane ectoenzyme, CD13, endows GC patients with insensitivity to CDDP and predicts an undesirable prognosis in GC patients with CDDP treatment. Similarly, CD13 expression is positively related with CDDP resistance in GC cells. A CD13 inhibitor, Ubenimex, reverses CDDP resistance and renders GC cells sensitivity to CDDP, for which CD13 reduction is essential, and epithelial membrane protein 3 (EMP3) is a putative target downstream of CD13. Furthermore, Ubenimex decreases EMP3 expression by boosting its CpG island hypermethylation for which CD13 down-regulation is required. In addition, EMP3 is a presumptive modifier by which CD13 exerts functions in the phosphoinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. Ubenimex inhibits the activation of the CD13/EMP3/PI3K/AKT/NF-κB pathway to overcome CDDP resistance in GC cells by suppressing autophagy and epithelial-mesenchymal transition (EMT). Therefore, CD13 is a potential indicator of CDDP resistance formation, and Ubenimex may serve as a potent candidate for reversing CDDP resistance in GC.

Association of plasminogen activator inhibitor-1 and vitamin D receptor expression with the risk of keloid disease in a Chinese population.

Keloid disease (KD) is a benign fibroproliferative scarring condition of unknown etiopathogenesis. Plasminogen activator inhibitor-1 (PAI-1) and vitamin D receptor (VDR) have been shown to play important roles in the progression of tissue fibrosis; therefore, both these genes are potential susceptibility genes for KD. We aimed to determine whether the gene expression levels of PAI-1 and VDR are altered in Chinese KD patients. We measured the expression of PAI and VDR in human peripheral blood lymphocytes in 236 patients with keloid and 219 age- and sex-matched healthy controls by quantitative real-time polymerase chain reaction. We found that PAI-1 expression in peripheral blood lymphocytes was significantly higher in patients with KD than in control individuals (p < 0.0001), while VDR expression was significantly lower in KD patients than in control individuals (p < 0.0001). High levels of PAI-1 and low levels of VDR expression were significantly associated with an increased risk for KD. PAI-1 and VDR might play important roles in keloid development. Gene expression levels of PAI-1 and VDR may, therefore, be used as potential markers for the prediction of keloid development after scarring.