Safety, tolerability, pharmacokinetics and neutrophil elastase inhibitory effects of Sivelestat: A randomized, double-blind, placebo-controlled single- and multiple-dose escalation study in Chinese healthy subjects.

BACKGROUND AND OBJECTIVE: Neutrophil elastase has been identified as a potential therapeutic target for acute lung injury or acute respiratory distress syndrome, and Sivelestat is a selective, reversible and competitive neutrophil elastase inhibitor. This study was designed to investigate the safety, tolerability, pharmacokinetics and neutrophil elastase inhibitory effects of Sivelestat in healthy Chinese subjects. METHODS: A randomized, double-blind, placebo-controlled single- and multiple-dose escalation clinical trial was carried out. Briefly, healthy volunteers in twelve cohorts with 8 per cohort received 1.0-20.2 mg/kg/h Sivelestat or placebo in an intravenous infusion manner for two hours, and healthy volunteers in four cohorts received two hours intravenous infusion of 2.0-5.0 mg/kg/h Sivelestat or placebo with an interval of twelve hours for seven times. The safety and tolerability were evaluated and serial blood samples were collected for pharmacokinetics and neutrophil elastase inhibitory effects analysis at the specified time-point. RESULTS: A total of 128 subjects were enrolled and all participants completed the study except one. Sivelestat exhibited satisfactory safety and tolerability up to 20.2 mg/kg/h in single-dose cohorts and 5.0 mg/kg/h in multiple-dose cohorts. Even so, more attention should be paid to the safety risks when using high doses. The Cmax and AUC of Sivelestat increased in a dose dependent manner, and Tmax was similar for different dose cohorts. In multiple-dose cohorts, the plasma concentrations reached steady state 48 h after first administration and the accumulation of Cmax and AUC was not obvious. Furthermore, the Cmin_ss of 5.0 mg/kg/h dose cohort could meet the needs of clinical treatment. For some reason, the pharmacodynamics data revealed that the inhibitory effect of Sivelestat on neutrophil elastase content in healthy subjects was inconclusive. CONCLUSION: Sivelestat was safe and well tolerated with appropriate pharmacokinetic parameters, which provided support for more diverse dosing regimen in clinical application. CLINICAL TRIAL REGISTRATION: www.chinadrugtrials.org.cn identifier is CTR20210072.

Itaconic Acid-Based Organic-Polymer Monolithic Column for Hydrophilic Capillary Electrochromatography and Its Application in Pharmaceutical Analysis.

Itaconic acid is an excellent hydrophilic monomer owing to the dicarboxylic group possessing strong polarity. This study reports on the preparation of a new organic-polymer monolithic column poly(itaconic acid-co-3-(acryloyloxy)-2-hydroxypropyl methacrylate) (poly(IA-co-AHM)) featuring excellent hydrophilic chromatography ability and its application in pharmaceutical analysis. The monolithic column was successfully synthesized by using the monomer itaconic acid and the cross-linker AHM through an in situ copolymerization method. Optical microscopy, scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR) were employed for the characterization of the poly(IA-co-AHM) monolithic column, and all of these demonstrated that the prepared itaconic acid-based monolithic column exhibited satisfactory permeability and a homogeneous porous structure. Owing to the carboxylic groups of itaconic acid, a cathodic electroosmotic flow (EOF) was generated on the itaconic acid-based monolithic column among the pH ranges of the mobile phase from 4.0 to 9.0. Depending on the powerful hydrophilic interactions, different kinds of polar substances, including thioureas, nucleoside drugs, sulfonamides, and polypeptides, were separated efficiently by the itaconic acid-based monoliths poly(IA-co-AHM). The separations of polar compounds were successfully realized, even at a lower level of 50% acetonitrile content on this monolithic column. The highest column efficiencies corresponding to N,N'-dimethylthiourea and idoxuridine were 102 720 and 124 267 N/m, respectively. The poly(IA-co-AHM) monolithic column displayed excellent repeatability, whose relative standard deviations (RSDs) of the retention time and peak area were both lower than 5.0%. All experimental results demonstrated that the new itaconic acid-functionalized monolithic column was greatly appropriate to separate the polar compounds under the HILIC mode.

Prevalence, contemporary trends and associated factors of potentially inappropriate prescription of edoxaban in real-world clinical practice: A subanalysis of the SUNSHINE registry.

AIM: As the direct oral anticoagulant most recently approved in China, data pertaining to clinical edoxaban use are still scarce. This study investigated the prevalence of and contemporary trends in edoxaban prescription among Chinese patients as well as factors associated with its inappropriate use in a multicentre registry of patients treated in real-world clinical practice. METHODS: This real-world, prospective, multicentre and non-interventional study included 1005 inpatients treated with edoxaban. According to National Medical Products Administration and European Heart Rhythm Association guidelines, edoxaban therapy was determined to be appropriate or inappropriate in each case. RESULTS: The median patient age was 70.0 years (interquartile range 61.0-78.0 years) and 46.3% were women. Overall, 456 (45.4%) patients received inappropriate edoxaban therapy, and common issues included an inappropriately low dosage (183, 18.2%) or wrong drug selection (109, 10.8%), high dosage (73, 7.3%), unreasonable off-label use (49, 4.9%), contraindicated medication combinations (27, 2.7%) and incorrect administration timing (16, 1.6%). Several factors, such as age ≥75 years (odds ratio [OR] = 1.921, 95% confidence interval [CI] 1.355-2.723, P < 0.001), weight >60 kg (OR = 2.657, 95%CI 1.970-3.583, P < 0.001), severe renal insufficiency (OR = 1.988, 95% CI 1.043-3.790, P = 0.037), current anaemia (OR = 1.556, 95% CI 1.151-2.102, P = 0.004) and history of bleeding (OR = 2.931, 95% CI 1.605-5.351, P < 0.001) were associated with an increased risk of inappropriate edoxaban therapy, whereas factors associated with cardiovascular specialties, such as admission to a cardiovascular department (OR = 0.637, 95% CI 0.464-0.873, P = 0.005), dronedarone use (OR = 0.065, 95% CI 0.026-0.165, P < 0.001) and amiodarone use (OR = 0.365, 95% CI 0.209-0.637, P < 0.001) decreased this risk. CONCLUSION: In this real-world study, 45.4% of patients received an inappropriate treatment with edoxaban. Multiple clinical characteristics can help identify patients who should receive edoxaban. Further development and implantation of educational activities and management strategies are needed to ensure the correct use of edoxaban.

Long Non-Coding RNA MALAT1 Protects Against Spinal Cord Injury via Suppressing microRNA-125b-5p Mediated Microglial M1 Polarization, Neuroinflammation, and Neural Apoptosis.

Our previous studies have discovered that long non-coding RNA (lncRNA) MALAT1 and its target microRNA-125b-5p (miR-125b-5p) are implicated in neurological diseases via regulating neuroinflammation and neuronal injury. This study aimed to further explore the relationship between lncRNA MALAT1 and miR-125b-5p, as well as their effect on microglial activation, neuroinflammation, and neural apoptosis in spinal cord injury (SCI). Primary microglia from Sprague Dawley rats were stimulated with lipopolysaccharide (LPS). Then, microglia were transfected with lncRNA MALAT1 overexpression or knock-down adenovirus-associated virus with or without miR-125b-5p mimic. The culture medium of microglia was incubated with primary neurons. SCI rats were established for in vivo validation. LncRNA MALAT1 expression was reduced by LPS treatment in a dose-dependent manner. LncRNA MALAT1 overexpression suppressed the microglial M1 polarization (decreased iNOS but increased ARG1), neuroinflammation (declined PTGS2, TNF-α, IL-1ß, and IL-6), and microglia-induced neural apoptosis (lower TUNEL positive cells and C-caspase3 but higher BCL2) under LPS treatment; its knock-down displayed the opposite trend. Moreover, lncRNA MALAT1 directly bound to and negatively regulated miR-125b-5p. MiR-125b-5p mimic promoted microglial M1 polarization, neuroinflammation, and microglia-induced neural apoptosis following LPS treatment; also, it could attenuate the effect of lncRNA MALAT1. Further in vivo study displayed that lncRNA MALAT1 overexpression elevated the Basso-Beattie-Bresnahan motor function score and improved neural injury. Also, in vivo validation indicated a similar effect of lncRNA MALAT1 on microglial polarization and neuroinflammation as in vitro. LncRNA MALAT1 improves SCI recovery via miR-125b-5p mediated microglial M1 polarization, neuroinflammation, and neural apoptosis.

Effectiveness of Medication Reconciliation in a Chinese Hospital: A Pilot Randomized Controlled Trial.

Background: Implementing medication reconciliation (MR) was complex and challenging because of the variability in the guidance provided for conducting. The processes of MR adopted in China were different from that recommended by the World Health Organization. A pilot study to inform the design of a future randomized controlled trial to determine the effectiveness of these two workflows was undertaken. Methods: Patients taking at least one home/regular medication for hypertension, diabetes, or coronary heart disease were recruited at admission, and then were randomized using a computer-generated random number in a closed envelope. In the study group, the pharmacist reviewed electronic medical record systems before communication with patients. In the control group, pharmacists communicated with patients at patient's admission. The time investment of pharmacists for MR process, the number of unintended medication discrepancies, and physician acceptance were tested as outcome measures. Results: One hundred and forty adult patients were randomized, of which 66 patients in the intervention received MR within 24 hours, while 58 patients in control received MR at some point during admission. The most common condition in the study group was hypertension (coronary heart disease in the control group). The workflow of the study group can save an average 7 minutes per patient compared with the WHO recommended process [17.5 minutes (IQR 14.00, 28.25) vs 24.5 minutes (IQR17.75, 35.25), p = 0.004]. The number of unintended discrepancies was 42 in the study group and 34 in the control group (p = 0.33). Physicians' acceptance in the study and control groups were 87.5% and 92.3%, respectively (p = 0.87). Conclusion: The results suggest that changes in outcome measures were in the appropriate direction and that the time limit for implementing MR can be set within 48 hours. A future multi-centre RCT study to determine the effectiveness of MR is feasible and warranted.

GPD1 inhibits the carcinogenesis of breast cancer through increasing PI3K/AKT-mediated lipid metabolism signaling pathway.

Glycerol 3-phosphate dehydrogenase 1 (GPD1) acts as a tumor suppressor in various types of cancer. However, the mechanisms of GPD1 anti-tumor remain unclear in breast cancer. This study aims to explore the function and clinical relevance of GPD1 in breast cancer. We confirmed that GPD1 inhibited the ability of proliferation, migration, and invasion in GPD1 overexpression breast cancer cells by CCK-8, wound healing, and Transwell assays, respectively. We found that GPD1 overexpression activated the lipid synthesis pathway and PI3K/AKT signaling pathway. The inhibitory effect of GPD1 on breast cancer cells was also weakened after treatment with LY294002, a PI3K/AKT pathway inhibitor. These results indicated that GPD1 suppressed the carcinogenesis of breast cancer through increasing PI3K/AKT-mediated lipid signaling pathways. Meanwhile, we detected that the relationship between GPD1 level and survival rate presents a positive correlation in breast cancer patients from the Cancer Genome Atlas (TCGA) database. Therefore, GPD1 can be a prognostic biomarker and target in developing therapeutic strategies for breast cancer patients.

Driving natural killer cell-based cancer immunotherapy for cancer treatment: An arduous journey to promising ground.

Immunotherapy represents one of the most effective strategies for cancer treatment. Recently, progress has been made in using natural killer (NK) cells for cancer therapy. NK cells can directly kill tumor cells without pre-sensitization and thus show promise in clinical applications, distinct from the use of T cells. Whereas, research and development on NK cell-based immunotherapy is still in its infancy, and enhancing the therapeutic effects of NK cells remains a key problem to be solved. An incompletely understanding of the mechanisms of action of NK cells, immune resistance in the tumor microenvironment, and obstacles associated with the delivery of therapeutic agents in vivo, represent three mountains that need to be scaled. Here, we firstly describe the mechanisms underlying the development, activity, and maturation of NK cells, and the formation of NK­cell immunological synapses. Secondly, we discuss strategies for NK cell-based immunotherapy strategies, including adoptive transfer of NK cell therapy and treatment with cytokines, monoclonal antibodies, and immune checkpoint inhibitors targeting NK cells. Finally, we review the use of nanotechnology to overcome immune resistance, including enhancing the anti-tumor efficiency of chimeric antigen receptor-NK, cytokines and immunosuppressive-pathways inhibitors, promoting NK cell homing and developing NK cell-based nano-engagers.

Targeting lncRNA NEAT1 Hampers Alzheimer's Disease Progression.

Long noncoding RNA nuclear enriched abundant transcript 1 (lnc-NEAT1) is closely implicated in neurological diseases, while its implication in Alzheimer's disease (AD) is rarely reported. This study aimed to investigate the effect of lnc-NEAT1 knockdown on neuron injury, inflammation, and oxidative stress in AD, as well as its interaction with downstream targets and pathways. APPswe/PS1dE9 transgenic mice were injected with negative control or lnc-NEAT1 interference lentivirus. Besides, AD cellular model was constructed by amyloid ß treatment in mice primary neuron cells; then, knockdown of lnc-NEAT1 and microRNA-193a was performed alone or in combination. In vivo experiments revealed that Lnc-NEAT1 knockdown improved cognition in AD mice reflected by Morrison water maze and Y-maze assays. Besides, lnc-NEAT1 knockdown reduced injury and apoptosis, decreased inflammatory cytokine levels, repressed oxidative stress level, and activated adenosine cyclophosphate response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) and nuclear factor erythroid 2-related factor 2 (NRF2)/nicotinamide adenine dinucleotide phosphate dehydrogenase 1 (NQO1) pathways in hippocampi of AD mice. Notably, lnc-NEAT1 down-regulated microRNA-193a both in vitro and in vivo and acted as a decoy of microRNA-193a. In vitro experiments showed that lnc-NEAT1 knockdown decreased apoptosis and oxidative stress, improved cell viability, also activated CREB/BDNF and NRF2/NQO1 pathways in AD cellular model. Meanwhile, microRNA-193a knockdown showed the opposite effects, which also attenuated lnc-NEAT1 knockdown-mediated reduction in injury, oxidative stress, and CREB/BDNF and NRF2/NQO1 pathways of AD cellular model. In conclusion, lnc-NEAT1 knockdown reduces neuron injury, inflammation, and oxidative stress through activating microRNA-193a mediated CREB/BDNF and NRF2/NQO1 pathways in AD.

Outcome and Cost-Effectiveness Analysis of Long-acting G-CSF as Primary Prophylaxis of Neutropenia Induced by Chemotherapy in Breast Cancer Patients, From a Retrospective Study.

PURPOSE: This retrospective analysis aimed to evaluate the clinical outcomes and cost-effectiveness of long-acting granulocyte-colony stimulating factor as primary prophylaxis of neutropenia caused by chemotherapy for breast cancer. METHODS: Patients with breast cancer who received long- or short-acting granulocyte-colony stimulating factor as primary prophylaxis of neutropenia were enrolled in this study, and incidences of neutropenia were compared between two groups. A decision-analytic and a Markov model were used to compare the health benefits and costs of utilizing long- vs short-acting granulocyte-colony stimulating factor as the primary prophylaxis from the perspective of the Chinese health service system. Subsequently, one-way deterministic and probabilistic sensitivity analyses were conducted. The incremental cost-effectiveness ratios were calculated in baseline and sensitivity analyses. RESULTS: Patients receiving long-acting granulocyte-colony stimulating factor as the primary prophylaxis of chemotherapy-induced neutropenia experienced a significant lower incidence of this adverse event, compared with the short-acting one for 2 to 7 days. The outcomes of baseline analysis indicated that long-acting granulocyte-colony stimulating factor had a gain of 0.08 quality-adjusted life years and costed $149 more than the short-acting one, yielding an incremental cost-effectiveness ratio of $1792 per quality-adjusted life year. The sensitivity analysis proved the stability of our models and economic efficiency of long-acting granulocyte-colony stimulating factor. CONCLUSIONS: Patients receiving long-acting granulocyte-colony stimulating factor as primary prophylaxis of neutropenia experienced lower risk of this event compared with those underusing short-acting one. The long-acting granulocyte-colony stimulating factor may be a more cost-effective strategy for primary prophylaxis of neutropenia than short-acting one, considering the Chinese willingness-to-pay threshold of $12158.6 per quality-adjusted life year.

Design, Synthesis and Biological Evaluation of Novel Quinoline Derivatives as Potential Anti-Proliferative Agents Against PC-3 and KG-1 Cells.

BACKGROUND: Cancer is a major public health problem worldwide, and is the leading cause of death. The discovery and development of cancer therapeutic drugs have become the most urgent measure, which significantly benefited from the usage of small molecule compounds. The quinoline core possessed a vast number of biological activities that were found to be imperative. OBJECTIVE: The aim is to design, synthesize and perform the biological evaluation of novel quinoline derivatives as potential anti-proliferative agents. METHODS: Quinoline as a privileged scaffold was adopted to introduce diverse effective nitrogen heterocycles through different linkers. The synthesized compounds were spectroscopically characterized and evaluated for their anti-proliferative activity using the CCK8 assay. The mechanism of action was investigated by flow cytometry and the inhibitory activity against Pim-1 kinase was measured by mobility shift assay. Molecular docking analysis was performed to rationalize biochemical potency as well. RESULTS: The majority of these quinolines displayed potent growth inhibitory effects, among which compounds 13e, 13f and 13h were the most effective ones, with GI50 values of 2.61/3.56, 4.73/4.88 and 4.68/2.98 µM, respectively. Structure-activity relationships indicated that both appropriate heterocycles at the C4 position of pyridine and suitable substituent at quinoline had a significant impact on improving activity. Compounds 13e and 24d exhibited moderate Pim-1 kinase inhibitory activity. CONCLUSION: In this study, three series of novel molecules bearing quinoline scaffold were designed, synthesized and evaluated for their in-vitro anti-proliferative activity. The most promising candidate, 13e, caused cell cycle arrest in a concentration-dependent manner and further induced apoptosis, which might represent a novel antiproliferative agent working through Pim-1 kinase inhibition to a certain extent.

PR-957 Suppresses Th1 and Th17 Cell Differentiation via Inactivating PI3K/AKT Pathway in Alzheimer's Disease.

PR-957 [low molecular mass polypeptide (LMP)-7 selective inhibitor] regulates T helper (Th) cell differentiation and inflammatory response in multiple neurological diseases. Hence, this study aimed to explore the effect of PR-957 on Th1/Th2/Th17 cell differentiation, therapeutic efficacy and its potential mechanisms in Alzheimer's disease (AD). The LMP7 expressions in peripheral blood mononuclear cells from 30 AD patients and 30 healthy controls (HC) were detected. PR-957 was added for the incubation of naive cluster of differentiation (CD)4+ T cells from AD patients, then SC79 [phosphorylated protein kinase B (pAKT) agonist] was added. LMP7, Th1 cells, and Th17 cells were upregulated, while Th2 cells were downregulated in AD patients compared to HC. Also, LMP7 was positively related to Th1 cells and Th17 cells, but it did not correlate with Th2 cells in AD patients. PR-957 treatment downregulated Th1 cells, Th17 cells, and their secreted cytokines as well as phosphorylated phosphoinositide 3-kinase (pPI3K)/PI3K and pAKT/AKT expressions in AD CD4+ T cells. SC79 addition upregulated pAKT/AKT expression, Th1 cells, and Th17 cells, while downregulated Th2 cells; also SC79 could alleviate the effect of PR-957 on regulating PI3K/AKT pathway and Th1, Th2, and Th17 cell differentiation in AD CD4+ T cells. Furthermore, PR-957 attenuated cognitive impairment and neurofibrillary tangle; also it inhibited Th17 cell differentiation and PI3K/AKT pathway in the brain and spleen of AD mice. In conclusion, PR-957 suppresses Th1 and Th17 cell differentiation, attenuates neural injury and improves cognitive function via inactivating PI3K/AKT pathway in AD.

Canagliflozin, characterized as a HDAC6 inhibitor, inhibits gastric cancer metastasis.

Gastric cancer is a common gastrointestinal cancer. Survival outcome for patients with the recurrence or metastasis remains poor due to the lack of effective targeting drugs. The mechanisms of non-histone acetylation modifications are key epigenetic regulations that participate in various biological processes. HDAC6 is mostly located in the cytoplasm to deacetylate non-histone substrates, which has been identified as a critical promoter of many oncogenic pathways in cancers, including gastric cancer. Nevertheless, its inhibitor has not been applied in gastric cancer clinically. In this study, we identified canagliflozin as an active HDAC6-targeted inhibitor from FDA-approved Drug Library by enzymatic assay. The strong affinity of the compounds with HDAC6 was further verified by surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA). In addition, molecular docking showed that canagliflozin could bind to the active pocket of HDAC6 and form interactions with key residues. Further experiments revealed that canagliflozin could effectively inhibit the migration and epithelial-mesenchymal-transition (EMT) of gastric cancer cells in vitro and in vivo. These results reveal a novel finding that canagliflozin has the potential to be an effective agent in inhibiting gastric cancer metastasis.

Prevalence, risk factors, and prediction of inappropriate use of non-vitamin K antagonist oral anticoagulants in elderly Chinese patients with atrial fibrillation: A study protocol.

Background: Atrial fibrillation (AF) is an arrhythmia that is prevalent globally, and its incidence grows exponentially with aging. Non-vitamin K antagonist oral anticoagulants (NOACs) have been developed in recent years, and it challenges the supremacy of warfarin for thromboembolism prophylaxis in AF. Nevertheless, there are limited data specifically evaluating the real-life use of NOACs in elderly patients with AF in China. Methods: This is a national, multicenter, non-interventional, cross-sectional study that enrolls patients with AF aged 75 years and above from 31 institutions across China. Data were collected using the Hospital Information System. The primary outcomes include (1) profiles of NOAC use in the elderly; (2) frequency of inappropriate NOAC use based on guidelines and approved labeling recommendations; (3) exploring potential risk factors related to NOACs inappropriate use; and (4) creating a prediction tool for inappropriate NOACs use. Conclusion: The results of this study reveal the prevalence, risk factors, and corresponding prediction tool of inappropriate NOACs use in older patients with AF in China, as well as provide valuable insights into the clinical application of NOACs in high-risk populations in the real-world setting. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT05361889.

Synthesis and biological evaluation of antibacterial activity of novel clarithromycin derivatives incorporating 1,2,3-triazole moieties at the 4''- and 11-OH positions.

Bacterial infection is still one of the diseases that threaten human health, and bacterial drug resistance is widespread worldwide. As a result, their eradication now largely relies on antibacterial drug discovery. Here, we reveal a novel approach to the development of 14-membered macrolide antibiotics by describing the design, synthesis, and evaluation of novel clarithromycin derivatives incorporating 1,2,3-triazole moieties at the 4''- and 11-OH positions. Using chemical synthesis, 35 clarithromycin derivatives were prepared, and their antibacterial properties were profiled. We found that compounds 8e-8h, 8l-8o, 8v, and 19d were as potent as azithromycin against Enterococcus faecalis ATCC29212. Furthermore, compounds 8c, 8d, 8n, and 8o showed slightly improved antibacterial activity (2-fold) against Acinetobacter baumannii ATCC19606 when compared with azithromycin and clarithromycin. In addition, compounds 8e, 8f, 8h, 8l, and 8v exhibited excellent antibacterial activity against Staphylococcus aureus ATCC43300, Staphylococcus aureus PR, and Streptococcus pneumoniae ER-2. These compounds were generally 64- to 128-fold more active than azithromycin, and 32- to 128-fold more active than clarithromycin. The results of molecular docking indicated that compound 8f may bind to the nucleotide residue A752 through hydrogen-bonding, hydrophobic, electrostatic, or π-π stacking interactions. The predicted ClogP data suggested that higher values of ClogP (>6.65) enhanced the antibacterial activity of compounds such as 8e, 8f, 8h, 8l, and 8v. The determination of the minimum bactericidal concentration showed that most of the tested compounds were bacteriostatic agents. From this study of bactericidal kinetics, we can conclude that compound 8f had a concentration- and time-dependent effect on the proliferation of Staphylococcus aureus ATCC43300. Finally, the results of the cytotoxicity assay showed that compound 8f exhibited no toxicity at the effective antibacterial concentration.

The role of A-kinase interacting protein 1 in regulating progression and stemness as well as indicating the prognosis in glioblastoma.

BACKGROUND: A-kinase interacting protein 1 (AKIP1) is recently implicated in the pathogenesis of several solid tumors, while its role in glioblastoma multiforme (GBM) is largely unknown. Therefore, the current study aimed to investigate the effect of AKIP1 on GBM cell malignant behaviors, stemness, and its underlying molecular mechanisms. METHODS: U-87 MG and A172 cells were transfected with control or AKIP1 overexpression plasmid; control or AKIP1 siRNA plasmid. Then cell proliferation, apoptosis, invasion, CD133+ cell proportion, and sphere formation assays were performed. Furthermore, RNA-Seq was performed in U-87 MG cells. Besides, AKIP1 expression was detected in 25 GBM and 25 low-grade glioma (LGG) tumor samples. RESULTS: AKIP1 was increased in several GBM cell lines compared to the control cell line. After transfections, it was found that AKIP1 overexpression increased cell invasion, CD133+ cell proportion, and sphere formation ability while less affecting cell proliferation or cell apoptosis in U-87 MG and A172 cells. Moreover, AKIP1 siRNA achieved the opposite effect in these cells, except that it inhibited cell proliferation but induced cell apoptosis to some extent. Subsequent RNA-Seq assay showed several critical carcinogenetic pathways, such as PI3K/AKT, Notch, EGFR tyrosine kinase inhibitor resistance, Ras, ErbB, mTOR pathways, etc. were potentially related to the function of AKIP1 in U-87 MG cells. Clinically, AKIP1 expression was higher in GBM tissues than in LGG tissues, which was also correlated with the poor prognosis of GBM to some degree. CONCLUSIONS: AKIP1 regulates the malignant behaviors and stemness of GBM via regulating multiple carcinogenetic pathways.

Circular RNA AXL increases neuron injury and inflammation through targeting microRNA-328 mediated BACE1 in Alzheimer's disease.

OBJECTIVE: Our previous study observed that circular RNA AXL (circ-AXL, access number circ_0002945) was closely correlated with disease risk and severity of Alzheimer's Disease (AD) by microarray and RT-qPCR validation. Then this current study aimed to further investigate the effect of circ-AXL on regulating neuron injury and inflammation in cellular AD models and its underlying molecular mechanism. METHODS: SK-N-SH and SK-SY5Y cell lines were treated by amyloid ß to construct cellular AD models. Then control or circ-AXL overexpression, control or circ-AXL knock-down, microRNA-328 (miR-328) knock-down with or without circ-AXL knock-down, as well as BACE1 overexpression with or without miR-328 overexpression plasmids were transfected into cellular AD models. Furthermore, neuron injury and inflammation were detected. RESULTS: Circ-AXL overexpression increased apoptosis rate and declined neurite outgrowth, as well as elevated inflammatory cytokines in cellular AD models; but circ-AXL knockdown exhibited opposite effects. Additionally, circ-AXL negatively regulated miR-328 but positively modulated BACE1; besides, miR-328 negatively regulated BACE1; further luciferase reporter gene assay presented that circ-AXL directly bound miR-328, and miR-328 directly bound BACE1. Furthermore, miR-328 overexpression decreased apoptosis rate, elevated neurite outgrowth, and declined inflammatory cytokines in cellular AD models; but miR-328 knockdown presented opposite effects. Notably, miR-328 knockdown attenuated the effect of circ-AXL knockdown on cellular AD models. Moreover, BACE1 overexpression aggravated neuron injury and inflammation, as well as attenuated the effect of miR-328 overexpression on these functions in cellular AD models. CONCLUSION: Circ-AXL may serve as a potential treatment target via miR-328 mediated BACE1 in AD.

Etanercept Reduces Neuron Injury and Neuroinflammation via Inactivating c-Jun N-terminal Kinase and Nuclear Factor-κB Pathways in Alzheimer's Disease: An In Vitro and In Vivo Investigation.

Inflammation contributes to amyloid beta (Aß) aggregation and neuron loss in Alzheimer's disease (AD). Meanwhile, tumor necrosis factor-α (TNF-α) inhibitors present strong effect on suppressing inflammation. Thus, this study aimed to investigated the effect and molecular mechanism of etanercept (ETN) (a commonly used TNF-α inhibitor) on neuron injury and neuroinflammation in AD. AD cellular model was constructed by co-culture of primary embryonic neuron cells and microglial cells, followed by Aß treatment. Subsequently, ETN was used to treat AD cellular model. Besides, APPswe/PS1M146V/tauP301L transgenic (AD) mice were respectively treated with saline or ETN by intravenous injection once per 3 days for 10 times. In vitro data revealed that cell viability and neurite outgrowth were increased, but apoptosis and levels of pro-inflammatory cytokines (including TNF-α, interleukin-1ß, Interleukin-6 and C-C motif chemokine ligand 2 (CCL2)) were decreased by ETN treatment in AD cellular model. In vivo experiments found that ETN treatment improved spatial, long-term memory (reflected by Morrison water maze) and working memory (reflected by Y maze) in AD mice. Besides, ETN treatment reduced neuron injury (reflected by Hematoxylin-Eosin (HE) and terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) assays) and levels of pro-inflammatory cytokines (including TNF-α, interleukin-1ß, Interleukin-6 and CCL2) in AD mice. Moreover, ETN repressed the activation of c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) pathways in AD both in vitro and in vivo. In conclusion, ETN exerts neuroprotective function via inactivating JNK and NF-κB pathways in AD, indicating the potential of ETN for improving AD management.

Tissue-based metabolomics reveals metabolic signatures and major metabolic pathways of gastric cancer with help of transcriptomic data from TCGA.

PURPOSE: The aim of the present study was to screen differential metabolites of gastric cancer (GC) and identify the key metabolic pathways of GC. METHODS: GC (n=28) and matched paracancerous (PC) tissues were collected, and LC-MS/MS analysis were performed to detect metabolites of GC and PC tissues. Metabolite pathways based on differential metabolites were enriched by MetaboAnalyst, and genes related to metabolite pathways were identified using the KEGGREST function of the R software package. Transcriptomics data from The Cancer Genome Atlas (TCGA) was analyzed to obtain differentially expressed genes (DEGs) of GC. Overlapping genes were acquired from metabonimics and transcriptomics data. Pathway enrichment analysis was performed using String. The protein expression of genes was validated by the Human Protein Atlas (HPA) database. RESULTS: A total of 325 key metabolites were identified, 111 of which were differentially expressed between the GC and PC groups. Seven metabolite pathways enriched by MetaboAnalyst were chosen, and 361 genes were identified by KEGGREST. A total of 2831 DEGs were identified from the TCGA cohort. Of these, 1317 were down-regulated, and 1636 were up-regulated. Twenty-two overlapping genes were identified between genes related to metabolism and DEGs. Glycerophospholipid (GPL) metabolism is likely associated with GC, of which AGPAT9 and ETNPPL showed lower expressed in GC tissues. CONCLUSIONS: We investigated the tissue-based metabolomics profile of GC, and several differential metabolites were identified. GPL metabolism may affect on progression of GC.

Design, synthesis and antibacterial evaluation of novel 3-O-substituted 15-membered azalides possessing 1,2,3-triazole side chains.

The acquired and intrinsic resistance of bacteria to macrolide antibiotics limits the clinical application of these agents, and thus it is particularly important to discover novel macrolide antibiotics that can be administered to counteract the prevalence of bacterial resistance. In this study, we introduced some active 1,2,3-triazole side chains into the azithromycin at position 3-O, thereby obtaining a number of 3-O-substituted 15-membered azalides. Determination of the minimum inhibitory concentration (MIC) of these target compounds revealed that the compound 9g possessed the strongest antibacterial activity (MIC = 8-16 µg/mL) against drug-resistant strains and was generally 16- to 32-fold more active than the azithromycin (MIC ≥ 256 µg/mL). Combined analysis of the results of antibacterial activity together with theoretically calculated lipid/water partition coefficients (ClogP) indicated the importance of the chemical nature of the alkyl groups attached to the 1,2,3-triazole side chain in conferring promising antibacterial activity. The findings of molecular docking analyses indicated that compound 9g may bind to the A752 base of 23S rRNA in bacterial ribosome via hydrophobic or electrostatic interactions, resulting in the excellent antibacterial activity of this compound. Furthermore, the data of minimum bactericidal concentration revealed that compounds 9e, 9f, 9g and 9h are excellent bacteriostatic agents. In addition, the study of bactericidal kinetics confirmed that compound 9g is a time- and concentration-dependent agent.

Antithrombotic Management for Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention or With Acute Coronary Syndrome: An Evidence-Based Update.

Combined antithrombotic regimens for atrial fibrillation (AF) patients with coronary artery disease, particularly for those who have acute coronary syndrome (ACS) and/or are undergoing percutaneous coronary intervention (PCI), presents a great challenge in the real-world clinical scenario. Conventionally, a triple antithrombotic therapy (TAT), which consists of combined oral anticoagulant therapy to prevent systemic embolism or stroke along with dual antiplatelet therapy to prevent coronary arterial thrombosis (CAT), is used. However, TAT has been associated with a significantly increased risk of bleeding. With the emergence of non-vitamin K antagonist oral anticoagulants (NOACs), randomized controlled trials have demonstrated a better risk-to-benefit ratio of dual antithrombotic therapy (DAT) in combination of a NOAC and with a P2Y12 inhibitor than vitamin K antagonist-based TAT. The results of these studies have impacted the recommendations of current international guidelines, which favor a DAT with a NOAC and P2Y12 inhibitor (especially clopidogrel) in this clinical setting. Additionally, aspirin can be administered during the periprocedural period, while the treatment duration of TAT should be as short as possible. In this article, we summarize the up-to-date evidence regarding antithrombotic regimens for AF patients with PCI or ACS, with a specific focus on the optimal approach and critical discussions of key scientific data and future developments for antithrombotic management in these patients.