Efficient Electrosynthesis of Urea over Single-Atom Alloy with Electronic Metal Support Interaction.

Urea electrosynthesis from carbon dioxide (CO2) and nitrate (NO3-) is an alternative approach to traditional energy-intensive urea synthesis technology. Herein, we report a CuAu single-atom alloy (SAA) with electronic metal support interaction (EMSI), achieving a high urea yield rate of 813.6 µg h-1 mgcat-1 at -0.94 V versus reversible hydrogen electrode (vs. RHE) and a Faradaic efficiency (FE) of 45.2% at -0.74 V vs. RHE. In-situ experiments and theoretical calculations demonstrated that single-atom Cu sites modulate the adsorption behavior of intermediate species. Bimetallic sites synergistically accelerate C-N bond formation through spontaneous coupling of *CO and *NO to form *ONCO as key intermediates. More importantly, electronic metal support interaction between CuAu SAA and CeO2 carrier further modulates electron structure and interfacial microenvironment, endowing electrocatalysts with superior activity and durability. This work constructs SAA electrocatalysts with EMSI effect to tailor C-N coupling at the atomic level, which can provide guidance for the development of C-N coupling systems.

StoneNet: An Efficient Lightweight Model Based on Depthwise Separable Convolutions for Kidney Stone Detection from CT Images.

Kidney stone disease is one of the most common and serious health problems in much of the world, leading to many hospitalizations with severe pain. Detecting small stones is difficult and time-consuming, so an early diagnosis of kidney disease is needed to prevent the loss of kidney failure. Recent advances in artificial intelligence (AI) found to be very successful in the diagnosis of various diseases in the biomedical field. However, existing models using deep networks have several problems, such as high computational cost, long training time, and huge parameters. Providing a low-cost solution for diagnosing kidney stones in a medical decision support system is of paramount importance. Therefore, in this study, we propose "StoneNet", a lightweight and high-performance model for the detection of kidney stones based on MobileNet using depthwise separable convolution. The proposed model includes a combination of global average pooling (GAP), batch normalization, dropout layer, and dense layers. Our study shows that using GAP instead of flattening layers greatly improves the robustness of the model by significantly reducing the parameters. The developed model is benchmarked against four pre-trained models as well as the state-of-the-art heavy model. The results show that the proposed model can achieve the highest accuracy of 97.98%, and only requires training and testing time of 996.88 s and 14.62 s. Several parameters, such as different batch sizes and optimizers, were considered to validate the proposed model. The proposed model is computationally faster and provides optimal performance than other considered models. Experiments on a large kidney dataset of 1799 CT images show that StoneNet has superior performance in terms of higher accuracy and lower complexity. The proposed model can assist the radiologist in faster diagnosis of kidney stones and has great potential for deployment in real-time applications.

Effects of single-use alfentanil versus propofol on cognitive functions after colonoscopy: A randomized controlled trial.

Purpose: Colonoscopy is often accompanied by short-term postoperative cognitive decline. We aimed to explore whether single-use alfentanil for patients undergoing elective colonoscopy could reduce cognitive impairment at discharge compared with propofol. Patients and methods: 172 adult patients undergoing elective colonoscopy were randomized to receive intravenous propofol at 2 mg/kg (group P) or alfentanil at 10 µg/kg (group A); 40 healthy volunteers were included in the blank group. Cognitive function was considered the primary outcome and was measured using five neuropsychological tests before sedation and discharge. The z-score method was used to determine cognitive dysfunction according to z-score >1.96 in two types of neuropsychological tests. Other outcomes included discharge time, vital signs, associated adverse events during colonoscopy, and the satisfaction level of patients and endoscopic physicians. Results: 164 patients (78 in group A and 86 in group P) completed the study protocol. At discharge, the incidence of cognitive dysfunction in group P was 23% and was significantly lower in the alfentanil group (2.5%), with a relative risk of 0.11 (95% confidence interval: 0.03-0.46, P < 0.001). The incidence of hypotension in group A was lower than that in group P (3.8% vs 22.1%, relative risk = 0.17 [95% confidence interval: 0.05-0.46, P = 0.001]), and the discharge time in group A was shorter than that in group P (5 [(Rutter and et al., 2016; Zhang and et al., 2013; Hirsh and et al., 2006; Zhou and et al., 2021; Singh and et al., 2008; Ko and et al., 2010; Sargin et al., 2019) 3-93-9 vs 13 [(Ekmekci and et al., 2017; Eberl and et al., 2012; Eberl and et al., 2014; N'Kaoua and et al., 2002; Chung et al., 1995; Berger and et al., 2019; Quan and et al., 2019; Deng and et al., 2021; Gualtieri and Johnson, 2006) 10-1810-18 min, P < 0.001). Conclusion: For patients undergoing colonoscopy, single-use alfentanil causes less damage to postoperative cognitive function, less risk of hypotension, and shorter discharge time than propofol.

BMRI-NET: A Deep Stacked Ensemble Model for Multi-class Brain Tumor Classification from MRI Images.

Brain tumors are one of the most dangerous health problems for adults and children in many countries. Any failure in the diagnosis of brain tumors may lead to shortening of human life. Accurate and timely diagnosis of brain tumors provides appropriate treatment to increase the patient's chances of survival. Due to the different characteristics of tumors, one of the challenging problems is the classification of three types of brain tumors. With the advent of deep learning (DL) models, three classes of brain tumor classification have been addressed. However, the accuracy of these methods requires significant improvements in brain image classification. The main goal of this article is to design a new method for classifying the three types of brain tumors with extremely high accuracy. In this paper, we propose a novel deep stacked ensemble model called "BMRI-NET" that can detect brain tumors from MR images with high accuracy and recall. The stacked ensemble proposed in this article adapts three pre-trained models, namely DenseNe201, ResNet152V2, and InceptionResNetV2, to improve the generalization capability. We combine decisions from the three models using the stacking technique to obtain final results that are much more accurate than individual models for detecting brain tumors. The efficacy of the proposed model is evaluated on the Figshare brain MRI dataset of three types of brain tumors consisting of 3064 images. The experimental results clearly highlight the robustness of the proposed BMRI-NET model by achieving an overall classification of 98.69% and an average recall, F1-score and MCC of 98.33%, 98.40, and 97.95%, respectively. The results indicate that the proposed BMRI-NET model is superior to existing methods and can assist healthcare professionals in the diagnosis of brain tumors.

Targeting inhibition of prognosis-related lipid metabolism genes including CYP19A1 enhances immunotherapeutic response in colon cancer.

BACKGROUND: Lipid metabolic reprogramming in colon cancer shows a potential impact on tumor immune microenvironment and is associated with response to immunotherapy. Therefore, this study aimed to develop a lipid metabolism-related prognostic risk score (LMrisk) to provide new biomarkers and combination therapy strategies for colon cancer immunotherapy. METHODS: Differentially expressed lipid metabolism-related genes (LMGs) including cytochrome P450 (CYP) 19A1 were screened to construct LMrisk in TCGA colon cancer cohort. The LMrisk was then validated in three GEO datasets. The differences of immune cell infiltration and immunotherapy response between LMrisk subgroups were investigated via bioinformatic analysis. These results were comfirmed by in vitro coculture of colon cancer cells with peripheral blood mononuclear cells, human colon cancer tissue microarray analysis, multiplex immunofluorescence staining and mouse xenograft models of colon cancer. RESULTS: Six LMGs including CYP19A1, ALOXE3, FABP4, LRP2, SLCO1A2 and PPARGC1A were selected to establish the LMrisk. The LMrisk was positively correlated with the abundance of macrophages, carcinoma-associated fibroblasts (CAFs), endothelial cells and the levels of biomarkers for immunotherapeutic response including programmed cell death ligand 1 (PD-L1) expression, tumor mutation burden and microsatellite instability, but negatively correlated with CD8+ T cell infiltration levels. CYP19A1 protein expression was an independent prognostic factor, and positively correlated with PD-L1 expression in human colon cancer tissues. Multiplex immunofluorescence analyses revealed that CYP19A1 protein expression was negatively correlated with CD8+ T cell infiltration, but positively correlated with the levels of tumor-associated macrophages, CAFs and endothelial cells. Importantly, CYP19A1 inhibition downregulated PD-L1, IL-6 and TGF-ß levels through GPR30-AKT signaling, thereby enhancing CD8+ T cell-mediated antitumor immune response in vitro co-culture studies. CYP19A1 inhibition by letrozole or siRNA strengthened the anti-tumor immune response of CD8+ T cells, induced normalization of tumor blood vessels, and enhanced the efficacy of anti-PD-1 therapy in orthotopic and subcutaneous mouse colon cancer models. CONCLUSION: A risk model based on lipid metabolism-related genes may predict prognosis and immunotherapeutic response in colon cancer. CYP19A1-catalyzed estrogen biosynthesis promotes vascular abnormality and inhibits CD8+ T cell function through the upregulation of PD-L1, IL-6 and TGF-ß via GPR30-AKT signaling. CYP19A1 inhibition combined with PD-1 blockade represents a promising therapeutic strategy for colon cancer immunotherapy.

Safety and tolerability of esketamine in propofol based sedation for endoscopic variceal ligation with or without injection sclerotherapy: Randomized controlled trial.

OBJECTIVES: Esketamine is an S (+) enantiomer of ketamine with greater potency and similar psychomimetic effects compared to racemic ketamine. We aimed to explore the safety of esketamine in different doses as an adjuvant to propofol in patients undergoing endoscopic variceal ligation (EVL) with or without injection sclerotherapy. METHODS: One hundred patients were randomized to receive sedation with propofol 1.5 mg/kg in combination with sufentanil 0.1 µg/kg (group S), esketamine 0.2 mg/kg (group E0.2), esketamine 0.3 mg/kg (group E0.3), or esketamine 0.4 mg/kg (group E0.4) for EVL (n = 25 each). Hemodynamic and respiratory parameters were recorded during the procedure. The primary outcome was the incidence of hypotension; secondary outcomes included the incidence of desaturation, positive and negative syndrome scale (PANSS) after the procedure, pain score after the procedure, and secretion volume. RESULTS: The incidence of hypotension was significantly lower in groups E0.2 (36%), E0.3 (20%), and E0.4 (24%) than in group S (72%). The incidence of SpO2 ≤94% was significantly lower in group E0.4 (4%) than in group S (32%). No significant intergroup difference was found in the PANSS assessment. CONCLUSIONS: Combining 0.4 mg/kg esketamine with propofol sedation was optimal to facilitate EVL with stable hemodynamic status and better respiratory function during the procedure, without significant psychomimetic side-effects. TRIAL REGISTRATION: Chinese Clinical Trial Registry (Trial ID: ChiCTR2100047033, http://www.chictr.org.cn/showproj.aspx?proj=127518).

CYP4F2-Catalyzed Metabolism of Arachidonic Acid Promotes Stromal Cell-Mediated Immunosuppression in Non-Small Cell Lung Cancer.

SIGNIFICANCE: The identification of a role for CYP4F2-dependent metabolism in driving immune evasion in non-small cell lung cancer reveals a strategy to improve the efficacy of immunotherapy by inhibiting CYP4F2. See related article by Van Ginderachter, p. 3882.

Effects of Intravenous Analgesia Using Tramadol on Postoperative Depression State and Sleep Quality in Women Undergoing Abdominal Endoscopic Surgery: A Randomized Controlled Trial.

Purpose: This study aimed to explore the effects of intravenous analgesia using tramadol on postoperative depression, anxiety, and sleep in women undergoing abdominal endoscopic surgery. Patients and Methods: Two hundred female patients (100 in each group) who underwent abdominal endoscopic surgery were recruited to randomly receive intravenous analgesia with sufentanil combined with tramadol (tramadol group) or sufentanil (control group). The primary outcome was the incidence of postoperative depression, which was assessed at 1, 2, and 3 days after surgery using the 13-item Beck Depression Inventory. The secondary outcomes were the incidence of anxiety and sleep quality, which were assessed using the 20-item Self-Rating Anxiety Scale and Richards-Campbell Sleep Questionnaire. Results: The incidence of depression (Beck depression scale≥4) during the 3-day follow-up in the control group was 51%, which was significantly higher than that in the tramadol group of 28% (relative risk [RR]=0.55; 95% confidence interval [CI], 0.38-0.79; P=0.001). No difference was found in the incidence of anxiety state (Self-Rating Anxiety Scale≥40) between the tramadol and control groups (7%vs 5%; RR=1.40; 95% CI, 0.46-4.25; P=0.552). All of the Richards-Campbell sleep scales of patients in the tramadol group at 1 (77.4±15.2 vs 64.2±20.1, P<0.001), 2 (84.1±14.9 vs 71.8±18.8, P<0.001), and 3 days (87.0±12.2 vs 70.3±21.0, P<0.001) after surgery were higher than those in the control group. Conclusion: Intravenous analgesia using tramadol can effectively improve the postoperative depression and sleep status of women undergoing abdominal endoscopic surgery. Tramadol is recommended for use in postoperative analgesia when improving postoperative mood, and sleep is needed in clinical practice.

The Diurnal Profile of Human Basal Pain Sensitivity and Skin Sympathetic Nerve Activity: A Healthy Volunteer Study.

Objective: The diurnal rhythm profile of human basal pain sensitivity and its association with sympathetic nerve activity are not fully understood. This study aimed to examine rhythmic changes in experimental pain sensitivity and skin sympathetic nerve activity in healthy volunteers. Methods: Thirty healthy volunteers were included in the study. Experimental pain sensitivity, including pressure pain threshold and tolerance, cold pain threshold (CPT) and tolerance, skin sympathetic nerve activity, and cardiovascular parameters (including heart rate, cardiac output, and peripheral vascular resistance) at six time points throughout the day (08:00, 12:00, 16:00, 20:00, 00:00, and 04:00) were sequentially measured. Circadian rhythm analysis was performed on the mean values of the different measurements and individual subjects. Results: Significant differences were found in experimental pain sensitivity, skin sympathetic nerve activity, and non-invasive cardiovascular parameters at different time points (P < 0.05). The minimum measured values of all four types of experimental pain sensitivity were consistently observed at 04:00. Rhythmical analysis showed that the mean values of pressure pain threshold (meta2d P = 0.016) and skin sympathetic nerve activity (meta2d P = 0.039) were significant. Significant diurnal rhythms in pain sensitivity and skin sympathetic nerve activity existed in some individuals but not in others. No significant correlation between experimental pain sensitivity and skin sympathetic nerve activity was found at any time point (P > 0.05). Conclusion: Significant diurnal fluctuations were observed in different pain sensitivities and skin sympathetic nerve activity. No significant correlation between experimental pain sensitivity and sympathetic excitability at different times was found; the reasons for these phenomena remain to be further studied. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [ChiCTR2000039709].

Anaerobically Digesting Hazardous Waste Pichia pastoris Associated with Butyric Acid Cleaner Production.

Recombinant Pichia pastoris semisolid hazardous waste treatment is difficult and traditional solid waste treatment is not applicable. However, P. pastoris wastes have features of high density and enriched proteins/polysaccharides, which could supply nitrogen/carbon sources for butyric acid production. The waste P. pastoris was first treated using NaOH to form a waste yeast suspension, and then the suspension was mixed with glucose to obtain a starting medium containing 5.6 g DCW/L (dry cell weight) yeast to initiate butyrate fermentation. The suspension was intermediately supplemented to bring the total waste yeast concentration to 26.3 g DCW/L while continuously feeding the concentrated glucose solution. With the proposed strategy, butyrate concentration reached high levels of 51.0-54.0 g/L using Clostridium tyrobutyricum as the strain. Amino acids/oligosaccharides/SO4 2- in the suspension, raw material costs, complicated pretreatment process, and butyric acid cleaner production could be effectively utilized, reduced, eliminated, and realized. However, the apparent waste P. pastoris reduction rate was only 49% per batch, thus a "tanks in-series type's repeated waste treating system" model was developed to theoretically explore the possibility of increasing the waste yeast reduction rate R. The simulation results indicated that when setting the treatment unit numbers at 4, waste solid concentration could decrease from 26.3 to 3.37 g DCW/L and the hazardous waste yeast reduction rate R would increase from 49 to 97%.

High butanol/acetone ratio featured ABE production using mixture of glucose and waste Pichia pastoris medium-based butyrate fermentation supernatant.

In this study, butanol (ABE) fermentations were implemented in a 7 L anaerobic fermentor, by directly using the mixture of glucose solution with the corn/waste Pichia pastoris medium-based butyrate fermentation supernatants (BFS II) as the co-substrate, followed by consecutively feeding of the BFS and concentrated glucose solution. When compared with the major index of ABE fermentation using 150 g/L corn-based medium, butanol concentration could be maintained at high level of 12.7-12.8 g/L, butanol/acetone (B/A) largely increased from ~ 2.0 to 4.4-5.0, butanol yield on total carbon sources increased from 0.32-0.34 to 0.39-0.41 (mol base) with a higher butyrate/glucose consumption ratio of 37%-53%. Efficient utilization of butyrate, SO42-, amino acids, oligosaccharides, etc. in BFS II and the intracellular NADH contributed to the ABE fermentation performance improvement. The proposed strategy could be considered as the second utilization of waste Pichia pastoris, which could save raw materials/operating costs, fully use the oligosaccharides/SO42- in BFS II to relieve the working loads in downstream waste water treatment process, and increase fermentation products diversity/flexibility to deal with the varied marketing prices and requirements.

Prevotellaceae produces butyrate to alleviate PD-1/PD-L1 inhibitor-related cardiotoxicity via PPARα-CYP4X1 axis in colonic macrophages.

BACKGROUND: Immune checkpoint inhibitor-related cardiotoxicity is one of the most lethal adverse effects, and thus, the identification of underlying mechanisms for developing strategies to overcome it has clinical importance. This study aimed to investigate whether microbiota-host interactions contribute to PD-1/PD-L1 inhibitor-related cardiotoxicity. METHODS: A mouse model of immune checkpoint inhibitor-related cardiotoxicity was constructed by PD-1/PD-L1 inhibitor BMS-1 (5 and 10 mg/kg), and cardiomyocyte apoptosis and cardiotoxicity were determined by hematoxylin and eosin, Masson's trichome and TUNEL assays. 16S rRNA sequencing was used to define the gut microbiota composition. Gut microbiota metabolites short-chain fatty acids (SCFAs) were determined by HPLC. The serum levels of myocardial enzymes (creatine kinase, aspartate transaminase, creatine kinase-MB and lactate dehydrogenase) and the production of M1 factors (TNF-α and IL-1ß) were measured by ELISA. The colonic macrophage phenotype was measured by mmunofluorescence and qPCR. The expression of Claudin-1, Occludin, ZO-1 and p-p65 was measured by western blot. The gene expression of peroxisome proliferator-activated receptor α (PPARα) and cytochrome P450 (CYP) 4X1 was determined using qPCR. Statistical analyses were performed using Student's t-test for two-group comparisons, and one-way ANOVA followed by Student-Newman-Keul test for multiple-group comparisons. RESULTS: We observed intestinal barrier injury and gut microbiota dysbiosis characterized by Prevotellaceae and Rikenellaceae genus depletion and Escherichia-Shigella and Ruminococcaceae genus enrichment, accompanied by low butyrate production and M1-like polarization of colonic macrophages in BMS-1 (5 and 10 mg/kg)-induced cardiotoxicity. Fecal microbiota transplantation mirrored the effect of BMS-1 on cardiomyocyte apoptosis and cardiotoxicity, while macrophage depletion and neutralization of TNF-α and IL-1ß greatly attenuated BMS-1-induced cardiotoxicity. Importantly, Prevotella loescheii recolonization and butyrate supplementation alleviated PD-1/PD-L1 inhibitor-related cardiotoxicity. Mechanistically, gut microbiota dysbiosis promoted M1-like polarization of colonic macrophages and the production of proinflammatory factors TNF-α and IL-1ß through downregulation of PPARα-CYP4X1 axis. CONCLUSIONS: Intestinal barrier dysfunction amplifies PD-1/PD-L1 inhibitor-related cardiotoxicity by upregulating proinflammatory factors TNF-α and IL-1ß in colonic macrophages via downregulation of butyrate-PPARα-CYP4X1 axis. Thus, targeting gut microbiota to polarize colonic macrophages away from the M1-like phenotype could provide a potential therapeutic strategy for PD-1/PD-L1 inhibitor-related cardiotoxicity.

Comparison of the edible quality of liquid egg with different cooking methods and their antioxidant activity after in vitro digestion.

The purpose of this study was to compare the edible quality of liquid egg after steaming, baking, frying and microwaving. Texture profile analysis (TPA) and color analysis were used to evaluate the sensory characteristics of cooked eggs. The fat, vitamin A and E, protein and amino acid content of cooked eggs and the antioxidant activity after in vitro digestion were determined to display the variations in nutritional value. TPA results demonstrate that baked egg exhibited a softer and more elasticity texture, with a significant lower hardness of 3234 g than fried and microwaved eggs (p < 0.05). This is also consistent with the results of cohesiveness and chewiness. Consequences from scanning electron microscope showed plentiful honeycomb structure in baked egg, which may be related to the soft and elasticity texture. However, significantly higher contents of fat, vitamins A and E, protein were determined in fried egg (p < 0.05), which may be related to its lower moisture content. The strongest free radical scavenging efficiency for the hydroxyl, the DPPH and the superoxide radical were found in the gastrointestinal digestion of fried egg, with the rate of 95.76%, 81.08%, and 91.08%, respectively. Overall, baked egg showed superior soft and elasticity taste characteristics due to its honeycomb structure, while fried egg exhibited better antioxidant activity because of its high contents in vitamins and amino acids. The above results provide potential approach for the manufacture of pre-cooked eggs and related products using liquid eggs as ingredients.

Targeting the Otub1/c-Maf axis for the treatment of multiple myeloma.

The oncogenic transcription factor c-Maf has been proposed as an ideal therapeutic target for multiple myeloma (MM), but how to achieve it is still elusive. In the present study, we found the Otub1/c-Maf axis could be a potential target. Otub1, an OTU family deubiquitinase, was found to interact with c-Maf by mass spectrometry. Otub1 abrogates c-Maf K48-linked polyubiquitination, thus preventing its degradation and enhancing its transcriptional activity. Specifically, this deubiquitinating activity depends on its Lys71 and the N terminus but is independent of UBE2O, a known E2 of c-Maf. Otub1 promotes MM cell survival and MM tumor growth. In contrast, silence of Otub1 leads to c-Maf degradation and c-Maf-expressing MM cell apoptosis. Therefore, the Otub1/c-Maf axis could be a therapeutic target of MM. In order to explore this concept, we performed a c-Maf recognition element-driven luciferase-based screen against US Food and Drug Administration-approved drugs and natural products, from which the generic cardiac glycoside lanatoside C (LanC) is found to prevent c-Maf deubiquitination and induces its degradation by disrupting the interaction of Otub1 and c-Maf. Consequently, LanC inhibits c-Maf transcriptional activity, induces c-Maf-expressing MM cell apoptosis, and suppresses MM growth and prolongs overall survival of model mice, but without apparent toxicity. Therefore, the present study identifies Otub1 as a novel deubiquitinase of c-Maf and establishes that the Otub1/c-Maf axis is a potential therapeutic target for MM.

Multi-walled carbon nanotubes exacerbate doxorubicin-induced cardiotoxicity by altering gut microbiota and pulmonary and colonic macrophage phenotype in mice.

Epidemiologic studies show that the levels of air pollutants and particulate matter are positively associated with the morbidity and mortality of cardiovascular diseases. Here we demonstrate that the intratracheal instillation of multi-walled carbon nanotubes (MWCNTs), a standard fine particle, exacerbate doxorubicin (DOX)-induced cardiotoxicity in mice through altering gut microbiota and pulmonary and colonic macrophage phenotype. MWCNTs (25 µg/kg per day, 5 days a week for 3 weeks) promoted cardiotoxicity and apoptosis in the DOX (2 mg/kg, twice a week for 5 weeks)-treated C57BL/6 mice. MWCNTs exaggerated DOX-induced gut microbiota dysbiosis characterized by the increased abundances of Helicobacteraceae and Coriobacteriaceae. In addition, MWCNTs promoted DOX-induced M1-like polarization of colonic macrophages with an increase in TNF-α, IL-1ß and CC chemokine ligand 2 in peripheral blood. Importantly, treatment with the antibiotics attenuated MWCNTs plus DOX-induced apoptosis of cardiomyocytes and M1-like polarization of colonic macrophages. The fecal microbiota transplantation demonstrated that MWCNTs exaggerated DOX-induced cardiotoxicity with M1-like polarization of colonic macrophages. The conditioned medium from MWCNTs-treated pulmonary macrophages promoted DOX-induced gut microbiota dysbiosis and colonic macrophage polarization. Furthermore, the co-culture of macrophages and fecal bacteria promoted M1-like macrophage polarization and their production of TNF-α and IL-1ß, and thereby exacerbated the effects of MWCNTs. Moreover, IL-1ß and TNF-α blockade, either alone or in combination attenuated MWCNTs-exacerbated cardiotoxicity. In summary, MWCNTs exacerbate DOX-induced cardiotoxicity in mice through gut microbiota and pulmonary and colonic macrophage interaction. Our findings identify a novel mechanism of action of inhaled particle-driven cardiotoxicity.

Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis.

c-Maf is a critical oncogenic transcription factor that contributes to myelomagenesis. Our previous studies demonstrated that the deubiquitinase USP5 stabilizes c-Maf and promotes myeloma cell proliferation and survival; therefore, the USP5/c-Maf axis could be a potential target for myeloma therapy. As a concept of principle, the present study established a USP5/c-Maf-based luciferase system that was used to screen an FDA-approved drug library. It was found that mebendazole, a typical anthelmintic drug, preferentially induced apoptosis in c-Maf-expressing myeloma cells. Moreover, oral administration of mebendazole delayed the growth of human myeloma xenografts in nude mice but did not show overt toxicity. Further studies showed that the selective antimyeloma activity of mebendazole was associated with the inhibition of the USP5/c-Maf axis. Mebendazole downregulated USP5 expression and disrupted the interaction between USP5 and c-Maf, thus leading to increased levels of c-Maf ubiquitination and subsequent c-Maf degradation. Mebendazole inhibited c-Maf transcriptional activity, as confirmed by both luciferase assays and expression measurements of c-Maf downstream genes. In summary, this study identified mebendazole as a USP5/c-Maf inhibitor that could be developed as a novel antimyeloma agent.