The impact of metformin on mortality in patients with type 2 diabetes mellitus: a prospective cohort study.

BACKGROUND: Metformin, a widely used antihyperglycemic drug, has shown efficacy in treating type 2 diabetes mellitus (T2DM) and is associated with potential benefits beyond glycemic control. This study investigates the impact of metformin on mortality in T2DM patients using a prospective cohort design utilizing data from the National Health and Nutrition Examination Survey (NHANES). METHODS: In NHANES 1999-2014, a total of 5813 representative participants aged 20 and above with T2DM were included in the analysis. We utilized Kaplan-Meier survival curves and multivariate Cox regression analysis to investigate the impact of metformin on both all-cause mortality and cause-specific mortality among patients with T2DM. RESULTS: Kaplan-Meier analysis showed a significant reduction in all-cause and cause-specific mortality in metformin users compared to non-users (p < 0.05). Multivariate Cox regression confirmed these findings, indicating that metformin use was associated with a 18% reduction in all-cause mortality (HR = 0.82, 95% CI = 0.73-0.92, p < 0.001) and 25% reduction in cardiovascular mortality (HR = 0.75, 95% CI = 0.60-0.94, p = 0.01). CONCLUSION: Our results suggest that metformin significantly reduces all-cause and cardiovascular mortality in T2DM patients, highlighting its potential benefits beyond glycemic control. These results contribute to the existing literature by providing robust evidence from a large prospective cohort study. However, further research is needed to validate these findings and elucidate the underlying mechanisms controlling the effects of metformin on mortality outcomes in individuals with T2DM.

Association between the advanced lung cancer inflammation index and all-cause and cardiovascular mortality in patients with RA: Insights from NHANES data analysis.

Background: Rheumatoid arthritis (RA) is associated with significant mortality, which is primarily due to cardiovascular complications. Despite advancements in RA treatment, mortality rates remain high, highlighting the need for reliable prognostic markers. The advanced lung cancer inflammation index (ALI), which integrates inflammatory and nutritional biomarkers, has shown promise in predicting outcomes in various medical conditions. However, its role in RA prognosis remains unclear. Methods: This study aimed to investigate the associations between the ALI and all-cause mortality, as well as cardiovascular mortality, in RA patients using data from the National Health and Nutrition Examination Survey (NHANES). A total of 1568 RA patients were included, and the ALI was calculated using body mass index (BMI), serum ALB, and the neutrophil-to-lymphocyte ratio. Comprehensive demographic, lifestyle, and metabolic data from the NHANES enabled adjustments for potential confounders. Multivariate Cox regression and sensitivity analyses were conducted to assess the associations between the ALI and mortality outcomes. Results: Our findings demonstrate an inverse association between the ALI and both all-cause and cardiovascular mortality in RA patients. Furthermore, a nonlinear relationship was observed, with mortality risk increasing significantly below a certain ALI threshold. Stratified analyses revealed a protective effect of the ALI across various demographic and clinical subgroups, underscoring its potential as a prognostic marker in patients with RA. Conclusion: The ALI holds promise as a valuable prognostic marker for identifying high-risk individuals and guiding personalized management strategies for patients with RA. However, further validation in prospective studies is warranted to confirm its clinical utility. Nonetheless, the potential implications of the ALI for improving the prognosis of patients with RA underscore the importance of its continued investigation in clinical practice.

Relative efficacy and safety of mesenchymal stem cells for osteoarthritis: a systematic review and meta-analysis of randomized controlled trials.

Introduction: The aim of this meta-analysis was to evaluate the efficacy and safety of mesenchymal stem cells (MSCs) for the treatment of knee osteoarthritis (OA). Methods: The PubMed, Embase, Cochrane Central Register of Controlled Trials, Scopus and Web of Science databases were searched from inception to May 6, 2024 to identify randomized controlled trials that compared MSCs and placebo or other nonsurgical approaches for treating OA. Two investigators independently searched the literature and extracted data, and conventional meta-analyses were conducted with Review Manager 5.3. The outcomes included pain relief, functional improvement, and risk of adverse events (AEs). Results: A total of 18 articles were included. Overall, MSCs were superior to placebo in terms of relieving pain and improving function at the 12-month follow-up. However, the differences in treatment-related AEs were not significant. Conclusion: MSCs may relieving pain and improving function of OA. The limitations of this study include the high heterogeneity of the included studies. Additionally, the follow-up time in the included studies was relatively short, so more clinical trials are needed to predict the long-term efficacy and safety of MSCs. Systematic review registration: https://doi.org/10.17605/OSF.IO/5BT6E, identifier CRD42022354824.

A physiologically based pharmacokinetic/pharmacodynamic model to determine dosage regimens and withdrawal intervals of aditoprim against Streptococcus suis.

Introduction: Streptococcus suis (S. suis) is a zoonotic pathogen threatening public health. Aditoprim (ADP), a novel veterinary medicine, exhibits an antibacterial effect against S. suis. In this study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was used to determine the dosage regimens of ADP against S. suis and withdrawal intervals. Methods: The PBPK model of ADP injection can predict drug concentrations in plasma, liver, kidney, muscle, and fat. A semi-mechanistic pharmacodynamic (PD) model, including susceptible subpopulation and resistant subpopulation, is successfully developed by a nonlinear mixed-effect model to evaluate antibacterial effects. An integrated PBPK/PD model is conducted to predict the time-course of bacterial count change and resistance development under different ADP dosages. Results: ADP injection, administrated at 20 mg/kg with 12 intervals for 3 consecutive days, can exert an excellent antibacterial effect while avoiding resistance emergence. The withdrawal interval at the recommended dosage regimen is determined as 18 days to ensure food safety. Discussion: This study suggests that the PBPK/PD model can be applied as an effective tool for the antibacterial effect and safety evaluation of novel veterinary drugs.

Ceftiofur in swine manure contributes to reducing pathogens and antibiotic resistance genes during composting.

Aerobic composting is a common way for the disposal of feces produced in animal husbandry, and can reduce the release of antibiotic resistance genes (ARGs) from feces into the environment. In this study, we collected samples from two distinct treatments of swine manure compost with and without ceftiofur (CEF), and identified the ARGs, mobile genetic elements (MGEs), and bacterial community by metagenomic sequencing. The impacts of CEF on the bacterial community composition and fate of ARGs and MGEs were investigated. With increasing composting temperature and pH, the concentration of CEF in the manure decreased rapidly, with a degradation half-life of 1.12 d and a 100% removal rate after 10 d of aerobic composting. Metagenomics demonstrated that CEF in the manure might inhibit the growth of Firmicutes and Proteobacteria, thereby reducing some ARGs and MGEs hosted by these two bacteria, which was further confirmed by the variations of ARGs and MGEs. A further redundancy analysis suggested that pH and temperature are key environmental factors affecting ARG removal during composting, and intI1 and bacterial communities also have significant influence on ARG abundance. These results are of great significance for promoting the removal of some ARGs from animal manure by controlling some key environmental factors and the type of antibiotics used in animals.

Bacterial Efflux Pump Inhibitors Reduce Antibiotic Resistance.

Bacterial resistance is a growing problem worldwide, and the number of deaths due to drug resistance is increasing every year. We must pay great attention to bacterial resistance. Otherwise, we may go back to the pre-antibiotic era and have no drugs on which to rely. Bacterial resistance is the result of several causes, with efflux mechanisms widely recognised as a significant factor in the development of resistance to a variety of chemotherapeutic and antimicrobial medications. Efflux pump inhibitors, small molecules capable of restoring the effectiveness of existing antibiotics, are considered potential solutions to antibiotic resistance and have been an active area of research in recent years. This article provides a review of the efflux mechanisms of common clinical pathogenic bacteria and their efflux pump inhibitors and describes the effects of efflux pump inhibitors on biofilm formation, bacterial virulence, the formation of bacterial persister cells, the transfer of drug resistance among bacteria, and mismatch repair. Numerous efforts have been made in the past 20 years to find novel efflux pump inhibitors which are known to increase the effectiveness of medicines against multidrug-resistant strains. Therefore, the application of efflux pump inhibitors has excellent potential to address and reduce bacterial resistance.

Biodegradation strategies of veterinary medicines in the environment: Enzymatic degradation.

One Health closely integrates healthy farming, human medicine, and environmental ecology. Due to the ecotoxicity and risk of transmission of drug resistance, veterinary medicines (VMs) are regarded as emerging environmental pollutants. To reduce or mitigate the environmental risk of VMs, developing friendly, safe, and effective removal technologies is an important means of environmental remediation for VMs. Many previous studies have proved that biodegradation has significant advantages in removing VMs, and biodegradation based on enzyme catalysis presents higher operability and specificity. This review focused on biodegradation strategies of environmental pollutants and reviewed the enzymatic degradation of VMs including antimicrobial drugs, insecticides, and disinfectants. We reviewed the sources and catalytic mechanisms of peroxidase, laccase, and organophosphorus hydrolases, and summarized the latest research status of immobilization methods and bioengineering techniques in improving the performance of degrading enzymes. The mechanism of enzymatic degradation for VMs was elucidated in the current research. Suggestions and prospects for researching and developing enzymatic degradation of VMs were also put forward. This review will offer new ideas for the biodegradation of VMs and have a guide significance for the risk mitigation and detoxification of VMs in the environment.

Association of baseline serum cholesterol with benefits of intensive blood pressure control.

BACKGROUND: Intensive systolic blood pressure (SBP) control improved outcomes in the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial. Whether baseline serum lipid parameters influence the benefits of intensive SBP control is unclear. METHODS: The STEP trial was a randomized controlled trial that compared the effects of intensive (SBP target of 110 to <130 mmHg) and standard (SBP target of 130 to <150 mmHg) SBP control in Chinese patients aged 60 to 80 years with hypertension. The primary outcome was a composite of cardiovascular disease events. A total of 8283 participants from the STEP study were included in this post hoc analysis to examine whether the effects of the SBP intervention differed by baseline low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) concentrations. RESULTS: Regardless of the randomized SBP intervention, baseline LDL-C and non-HDL-C concentrations had a J-shaped association with the hazard of the primary outcome. However, the effects of the intensive SBP intervention on the primary outcome were not influenced by baseline LDL-C level ( P for interaction = 0.80) and non-HDL-C level ( P for interaction = 0.95). Adjusted subgroup analysis using tertiles in LDL-C1 (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.52-1.13; P = 0.18), LDL-C2 (HR, 0.81; 95% CI, 0.55-1.20; P = 0.29), and LDL-C3 (HR, 0.68; 95% CI, 0.47-0.98; P = 0.04) was provided, with an interaction P value of 0.49. Similar results were showed in non-HDL-C1 (HR, 0.87; 95% CI, 0.59-1.29; P = 0.49), non-HDL-C2 (HR, 0.70; 95% CI, 0.48-1.04; P = 0.08), and non-HDL-C3 (HR, 0.67; 95% CI, 0.47-0.95; P = 0.03), with an interaction P -value of 0.47. CONCLUSION: High baseline serum LDL-C and non-HDL-C concentrations were associated with increased risk of primary cardiovascular disease outcome, but there was no evidence that the benefit of the intensive SBP control differed by baseline LDL-C and non-HDL-C concentrations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03015311.

CTRP12 alleviates cardiomyocyte ischemia­reperfusion injury via regulation of KLF15.

Myocardial ischemia­reperfusion (I/R) serves a crucial role in myocardial infarction. C1q/TNF­related protein 12 (CTRP12) is a secretory protein involved in metabolism. It has been reported that CTRP12 participates in the regulation of numerous cardiovascular diseases. However, its role in myocardial I/R injury remains unclear. In the present study, the left anterior descending coronary artery in mice was ligated to establish a mouse I/R model. A myocardial hypoxia­reoxygenation (H/R) cell model was also established. Cardiomyocyte injury was evaluated using hematoxylin and eosin staining, Cell Counting Kit­8 and a lactate dehydrogenase (LDH) kit. The expression levels of CTRP12 and Krueppel­like factor 15 (KLF15) in murine myocardial tissues and H9c2 cells were determined using reverse transcription­quantitative PCR and western blotting, as KLF15 was previously reported to protect against I/R­induced cardiomyocyte damage. Furthermore, inflammatory factors TNF­α, IL­1ß and IL­6 were analyzed using ELISA while apoptosis was assessed using TUNEL assays and western blotting. Moreover, the activity of the CTRP12 promoter was determined using a dual­luciferase reporter assay. The results demonstrated that I/R surgery markedly exacerbated myocardial tissue damage, whereas H/R treatment significantly reduced cell viability and significantly increased LDH activity as well as the release of inflammatory factors and apoptosis. I/R and H/R induction significantly reduced the expression levels of CTRP12 and KLF15. CTRP12 overexpression significantly alleviated H/R­induced cell injury and significantly inhibited inflammation and apoptosis. Further analysis demonstrated that KLF15 could significantly promote the activity of the CTRP12 promoter. However, following CTRP12 knockdown, KLF15 overexpression exacerbated cell injury, inflammation and apoptosis. In conclusion, the present study demonstrated that CTRP12 may mitigate inflammation and apoptosis in H/R­induced cardiomyocytes, possibly via the regulation of KLF15, which provided a theoretical basis for the potential treatment of I/R­induced myocardial infarction.

Fate and exposure risk of florfenicol, thiamphenicol and antibiotic resistance genes during composting of swine manure.

Livestock manure is an important source of antibiotic resistance genes (ARGs) spreading to the environment, posing a potential threat to human health. Here, we investigated the dissipation of florfenicol (FF) and thiamphenicol (TAP), and their effects on the bacterial community, mobile genetic elements (MGEs), and ARGs during composting. The results indicated that FF and TAP dissipated rapidly in compost, with half-life values of 5.1 and 1.6 d, respectively. However, FF could not be completely removed during composting. The FF and TAP residues in manure could reduce the elimination of ARGs and MGEs during composting, and had a negative effect on the physicochemical factors of the compost. Significant correlations were found between floR and intI1, indicating that floR in manure may more easily diffuse to the soil environment. Meanwhile, the presence of FF in manure could increase the abundance of floR. Network analysis showed that Proteobacteria and Firmicutes were the dominant bacterial communities and important potential pathogen hosts carrying ARGs. The predicted environmental concentration of FF in the soil was over 100 µg kg-1, which indicates that FF poses a potential risk to the natural environment, and we verified this result through field experiments. The results showed that FF dissipated in the soil after it migrated from manure to soil. In contrast, TAP in manure posed lower environmental risk. This study highlights that changed in composting conditions may control the rate of removal of ARGs. Further studies are needed to investigate the best environmental conditions to achieve a faster degradation of FF and a more comprehensive elimination of ARGs during composting.

Hypoxia-Preconditioned Extracellular Vesicles from Mesenchymal Stem Cells Improve Cartilage Repair in Osteoarthritis.

In the past decade, mesenchymal stem cells (MSCs) have been widely used for the treatment of osteoarthritis (OA), and extracellular vesicles (EVs) may play a major role in the efficacy of this treatment. Hypoxia can change the cargo and biological functions of MSC-derived EVs (MSC-EVs). The aim of the present study was to determine whether the effects of hypoxia-preconditioned MSC-EVs on OA cartilage repair are superior to normoxia-preconditioned MSC-EVs. By using in vitro and in vivo OA models, we verified that hypoxia-preconditioned MSC-EVs improved chondrocyte proliferation and migration and suppressed chondrocyte apoptosis to a greater extent than normoxia-preconditioned MSC-EVs. Furthermore, we found that hypoxia altered the microRNA expression in MSC-EVs and identified four differentially expressed microRNAs: hsa-miR-181c-5p, hsa-miR-18a-3p, hsa-miR-376a-5p, and hsa-miR-337-5p. Bioinformatics analysis revealed that hypoxic pretreatment may promote cartilage repair by stimulating chondrocyte proliferation and migration and suppressing chondrocyte apoptosis through the miRNA-18-3P/JAK/STAT or miRNA-181c-5p/MAPK signaling pathway. Therefore, hypoxia-preconditioned EVs may be a novel treatment for OA.

Relative Efficacy and Safety of Tanezumab for Osteoarthritis: A Systematic Review and Meta-analysis of Randomized-Controlled Trials.

OBJECTIVES: The aim of this meta-analysis was to evaluate the efficacy and safety of tanezumab for the treatment of patients with knee or hip osteoarthritis (OA). METHODS: PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched from inception to July 2020. Randomized-controlled trials comparing tanezumab with placebo or nonsteroidal anti-inflammatory drugs in patients with OA. Two investigators identified studies and independently extracted data, and conventional meta-analyses were conducted with Review Manager 5.3. The outcomes were pain relief, functional improvement, and risk of adverse events (AEs). RESULTS: A total of 8 articles, comprising 9 randomized-controlled trials, were included. Overall, tanezumab was superior to placebo for relieving pain and improving function, as well as in the patient's global assessment. Tanezumab also had significant advantages over nonsteroidal anti-inflammatory drugs for relieving pain and improving function, as well as in the patient's global assessment. Significantly more patients discontinued treatment because of AEs after treatment with tanezumab. However, the differences in serious AEs and total joint replacement were not significant. Moreover, tanezumab-treated patients experienced significantly more rapid progression of osteoarthritis. DISCUSSION: Tanezumab can alleviate pain and improve function for patients with OA of the hip or knee. Although tanezumab does not cause serious AEs, rapid progression of OA occurred in a small number of participants, so more clinical trials are needed to explore its safety.

Efficacy of extracellular vesicles from mesenchymal stem cells on osteoarthritis in animal models: a systematic review and meta-analysis.

Background: Some studies have reported results from the use of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) to treat osteoarthritis (OA). Objective: To evaluate the efficacy of MSC-EVs as a treatment for OA. Data sources: Databases were searched using the terms 'mesenchymal stem cells', 'osteoarthritis' and 'extracellular vesicles.' Study eligibility criteria: Studies performed in animal models utilizing MSC-EVs to treat OA that described the macroscopic evaluation or histological evaluation were included. Study appraisal: The quality of the studies was examined using the CAMARADES quality checklist. Results: MSC-EVs were superior to the placebo in the macroscopic evaluation and histological evaluation. MSC-EVs were more effective in the early stage of OA and once a week was better than multiple times a week. Limitations: The included studies were highly heterogeneous. Conclusion: MSC-EVs may improve the results of macroscopic and histological evaluations of OA.

Dynamic analysis of circulating tumor DNA to predict prognosis and monitor therapeutic response in metastatic relapsed cervical cancer.

Limited and inefficient treatment options exist for metastatic relapsed cervical cancer (MRCC), and there are currently no reliable indicators to guide therapeutic selection. We performed deep sequencing analyses targeting 322 cancer-related genes in plasma cell-free DNA and matched white blood cells in 173 serial blood samples from 82 locally advanced CC (LACC) or MRCC patients and when possible during treatment. We identified five notable nonsynonymous mutant genes (PIK3CA, BRAF, GNA11, FBXW7 and CDH1) in the MRCC samples as the metastatic relapse significantly mutated (MSG) genes and found that MRCC patients with any detectable MSG mutations had significantly shorter progression-free survival (PFS) (P = .005) and overall survival (OS) (P = .007) times than those without detectable MSG mutations. Additionally, analyses of matched prechemotherapy and postchemotherapy plasma revealed that a reduction in the number of MSG mutations after chemotherapy was significantly associated with partial remission (PR) and stable disease (SD) (P = .007). Among the patients included in the longitudinal tracking ctDNA analysis, an increase in MSG mutations was observed earlier in response to disease progression than radiological imaging. Our results outline the mutation profiles of MRCC. We show how longitudinal monitoring with ctDNA in liquid biopsy samples provides both predictive and prognostic information during treatment.

Targeting HMGB3/hTERT axis for radioresistance in cervical cancer.

BACKGROUND: Radiotherapy is regarded as a milestone for the cure of cervical cancer. However, clinical outcome heavily be hindered by radioresistance. So, exploring the underlying mechanism of radioresistance, and find potential target, well deserve fully emphasis. METHODS: In this study, we developed two novel radiation resistance cervical cancer cell lines, which could mimic clinical radioresistance. In order to find new potential targets, RNA-Seq, database analysis, streptavidin-agarose and LC/MS were used. Pull-down, luciferase and rescue assays were conducted to explore the regulatory mechanisms. To further evaluate the correlation between therapeutic responses and HMGB3/hTERT expression, 172 cervical cancer patients were recruited. RESULTS: Knockdown of HMGB3 significantly inhibit the DNA damage repair and induced more γH2AX foci, leading to enhanced chemo- and radio-sensitivity in vitro and in vivo, whereas HMGB3 overexpression has the opposite effects. HMGB3 promotes cell growth and radioresistance by transcriptionally up-regulating hTERT via the specifical binding of HMGB3 at the hTERT promoter region from - 902 to - 321. HMGB3 knockdown-mediated radiosensitization could be reversed by the overexpressed hTERT in both cervical cancer cell lines and xenograft tumor mouse model. Furthermore, clinical data from 172 cervical cancer patients proved that there was a positive correlation between HMGB3 and hTERT expression, and high expression of HMGB3/hTERT predicted poor response to radiotherapy, worse TNM stages and shorter survival time. CONCLUSION: Here, we have identified HMGB3/hTERT signaling axis as a new target for cervical cancer radioresistance. Our results provide new insights into the mechanism of cervical cancer radioresistance and indicate that targeting the HMGB3/hTERT signaling axis may benefit cervical cancer patients.

Mesenchymal Stem Cell-Derived Extracellular Vesicles in Tissue Regeneration.

Mesenchymal stem cells (MSCs) are multipotent stem cells that have attracted increasing interest in the field of regenerative medicine. Previously, the differentiation ability of MSCs was believed to be primarily responsible for tissue repair. Recent studies have shown that paracrine mechanisms play an important role in this process. MSCs can secrete soluble molecules and extracellular vesicles (EVs), which mediate paracrine communication. EVs contain large amounts of proteins and nucleic acids, such as mRNAs and microRNAs (miRNAs), and can transfer the cargo between cells. The cargoes are similar to those in MSCs and are not susceptible to degradation due to the protection of the EV bimolecular membrane structure. MSC-EVs can mimic the biological characteristics of MSCs, such as differentiation, maturation, and self-renewal. Due to their broad biological functions and their ability to transfer molecules between cells, EVs have been intensively studied by an increasing number of researchers with a focus on therapeutic applications, especially those of EVs secreted by MSCs. In this review, we discuss MSC-derived EVs and their therapeutic potential in tissue regeneration.

Differences In Gastrointestinal Safety Profiles Among Novel Oral Anticoagulants: Evidence From A Network Meta-Analysis.

BACKGROUND: There is no consensus at present regarding the differences in the risk of GI bleeding across various NOAC regimens. Therefore, we performed a network meta-analysis to compare the risk of gastrointestinal bleeding after different NOAC regimens. METHODS: PubMed, Cochrane, Web of Science, Clinicaltrial.gov and Clinicaltrialresults.org were searched for randomized controlled trials (RCTs) assessing gastrointestinal bleeding of all NOAC regimens from inception to January 2018. The primary endpoint was major gastrointestinal (MGI) bleeding. The meta-regression was performed to access the association between the MGI bleeding events and mortality. The network meta-analysis was carried out with the Bayesian random-effect model. RESULTS: A total of 25 RCTs, including 139,392 patients, were identified. Meta-regression analysis showed that MGI bleeding was correlated with fatal bleeding events (odds ratios [OR], 1.76; 95% confidence interval [CI], 1.13-2.77], P=0.015). The network meta-analysis results showed that compared to the conventional regimens, rivaroxaban was associated with increased risk of MGI bleeding (OR, 1.37; 95% credible interval [CrI], 1.00-1.85), but not the apixaban (OR, 0.77; 95% CrI, 0.53-1.07]), edoxaban (OR, 0.86; 95%CrI, 0.52-1.18) and dabigatran etexilate (OR, 1.22; 95% CrI, 0.82-1.69). Compared to rivaroxaban, apixaban (OR, 0.56; 95% CrI, 0.35-0.88) and edoxaban (OR, 0.62; 95% CrI, 0.35-0.96) showed a significantly lower risk of MGI bleeding. Apixaban had the highest probability of being the safest option with regard to the risk of MGI bleeding (89.1%), followed by edoxaban (77.4%), conventional therapy (51.4%), dabigatran etexilate (23.8%) and rivaroxaban (8.3%). CONCLUSION: The risk of GI bleeding significantly varies among different NOAC regimens, and evidence shows that apixaban and edoxaban had the most favorable MGI bleeding safety profile, while rivaroxaban and dabigatran etexilate were the least safe.

ß-elemene inhibits radiation and hypoxia-induced macrophages infiltration via Prx-1/NF-κB/HIF-1α signaling pathway.

Background: In cancers, tumor-associated macrophages (TAMs) play an important role in the progression, evasion of immunity and sensitivity to therapy. Unfortunately, radiation and hypoxia could induce the M2 macrophages infiltration and polarization. Materials and methods: In this study, we investigated the relevance of macrophage recruitment with radiation and hypoxia by transwell. We also evaluated the effect of ß-elemene on the infiltration of M2 macrophages and explored its underlying molecular mechanism by a series of in vitro and in vivo experiments. Results: Irradiated or hypoxia lung cancer cells recruit macrophages, and the recruitment is MCP-1 dependent. We also found that radiation and hypoxia-induced MCP-1 secretion follows upregulation of Prx-1, which leads to nuclear accumulation of NF-κB and HIF-1α expression. In addition, ß-elemene could effectively suppress this recruitment phenomenon through Prx-1/NF-κB/HIF-1α signaling. Conclusion: Our study showed that radiation and hypoxia significantly promoted the macrophages recruitment. ß-elemene could effectively suppress this recruitment phenomenon and MCP-1 expression via inhibiting Prx-1/NF-κB/HIF-1α pathways.