In Situ Infrared Spectroscopic Evidence of Enhanced Electrochemical CO2 Reduction and C-C Coupling on Oxide-Derived Copper.

The reaction mechanism of CO2 electroreduction on oxide-derived copper has not yet been unraveled even though high C2+ Faradaic efficiencies are commonly observed on these surfaces. In this study, we aim to explore the effects of copper anodization on the adsorption of various CO2RR intermediates using in situ surface-enhanced infrared absorption spectroscopy (SEIRAS) on metallic and mildly anodized copper thin films. The in situ SEIRAS results show that the preoxidation process can significantly improve the overall CO2 reduction activity by (1) enhancing CO2 activation, (2) increasing CO uptake, and (3) promoting C-C coupling. First, the strong *COO- redshift indicates that the preoxidation process significantly enhances the first elementary step of CO2 adsorption and activation. The rapid uptake of adsorbed *COatop also illustrates how a high *CO coverage can be achieved in oxide-derived copper electrocatalysts. Finally, for the first time, we observed the formation of the *COCHO dimer on the anodized copper thin film. Using DFT calculations, we show how the presence of subsurface oxygen within the Cu lattice can improve the thermodynamics of C2 product formation via the coupling of adsorbed *CO and *CHO intermediates. This study advances our understanding of the role of surface and subsurface conditions in improving the catalytic reaction kinetics and product selectivity of CO2 reduction.

D-histidine combated biofilm formation and enhanced the effect of amikacin against Pseudomonas aeruginosa in vitro.

Pseudomonas aeruginosa is an opportunistic gram-negative pathogenic microorganism that poses a significant challenge in clinical treatment. Antibiotics exhibit limited efficacy against mature biofilm, culminating in an increase in the number of antibiotic-resistant strains. Therefore, novel strategies are essential to enhance the effectiveness of antibiotics against Pseudomonas aeruginosa biofilms. D-histidine has been previously identified as a prospective anti-biofilm agent. However, limited attention has been directed towards its impact on Pseudomonas aeruginosa. Therefore, this study was undertaken to explore the effect of D-histidine on Pseudomonas aeruginosa in vitro. Our results demonstrated that D-histidine downregulated the mRNA expression of virulence and quorum sensing (QS)-associated genes in Pseudomonas aeruginosa PAO1 without affecting bacterial growth. Swarming and swimming motility tests revealed that D-histidine significantly reduced the motility and pathogenicity of PAO1. Moreover, crystal violet staining and confocal laser scanning microscopy demonstrated that D-histidine inhibited biofilm formation and triggered the disassembly of mature biofilms. Notably, D-histidine increased the susceptibility of PAO1 to amikacin compared to that in the amikacin-alone group. These findings underscore the efficacy of D-histidine in combating Pseudomonas aeruginosa by reducing biofilm formation and increasing biofilm disassembly. Moreover, the combination of amikacin and D-histidine induced a synergistic effect against Pseudomonas aeruginosa biofilms, suggesting the potential utility of D-histidine as a preventive strategy against biofilm-associated infections caused by Pseudomonas aeruginosa.

Anti-Biofilm Enzymes-Assisted Antibiotic Therapy against Burn Wound Infection by Pseudomonas aeruginosa.

Pseudomonas aeruginosa can form biofilms at the site of burn wound, leading to infection and the failure of treatment regimens. The previous in vitro study demonstrated that a combination of the quorum-quenching enzyme AidHA147G and the extracellular matrix hydrolase PslG was effective in inhibiting biofilm and promoting antibiotic synergy. The aim of the present study was to evaluate the efficacy of this combination of enzymes in conjunction with tobramycin in treating burn wound infected with P. aeruginosa. The results showed that this treatment was effective in quorum-quenching and biofilm inhibition on infected wounds. Compared with the tobramycin treatment only, simultaneous treatment with the enzymes and antibiotics significantly reduced the severity of tissue damage, decreased the bacterial load, and reduced the expression of the inflammatory indicators myeloperoxidase (MPO) and malondialdehyde (MDA). Topical application of the enzymes also reduced the bacterial load and inflammation to some extent. These results indicate that the combined-enzyme approach is a potentially effective treatment for P. aeruginosa biofilm infections of burn wounds.

Targeting proteasomal deubiquitinases USP14 and UCHL5 with b-AP15 reduces 5-fluorouracil resistance in colorectal cancer cells.

5-Fluorouracil (5-FU) is the first-line treatment for colorectal cancer (CRC) patients, but the development of acquired resistance to 5-FU remains a big challenge. Deubiquitinases play a key role in the protein degradation pathway, which is involved in cancer development and chemotherapy resistance. In this study, we investigated the effects of targeted inhibition of the proteasomal deubiquitinases USP14 and UCHL5 on the development of CRC and resistance to 5-FU. By analyzing GEO datasets, we found that the mRNA expression levels of USP14 and UCHL5 in CRC tissues were significantly increased, and negatively correlated with the survival of CRC patients. Knockdown of both USP14 and UCHL5 led to increased 5-FU sensitivity in 5-FU-resistant CRC cell lines (RKO-R and HCT-15R), whereas overexpression of USP14 and UCHL5 in 5-FU-sensitive CRC cells decreased 5-FU sensitivity. B-AP15, a specific inhibitor of USP14 and UCHL5, (1-5 µM) dose-dependently inhibited the viability of RKO, RKO-R, HCT-15, and HCT-15R cells. Furthermore, treatment with b-AP15 reduced the malignant phenotype of CRC cells including cell proliferation and migration, and induced cell death in both 5-FU-sensitive and 5-FU-resistant CRC cells by impairing proteasome function and increasing reactive oxygen species (ROS) production. In addition, b-AP15 inhibited the activation of NF-κB pathway, suppressing cell proliferation. In 5-FU-sensitive and 5-FU-resistant CRC xenografts nude mice, administration of b-AP15 (8 mg·kg-1·d-1, intraperitoneal injection) effectively suppressed the growth of both types of tumors. These results demonstrate that USP14 and UCHL5 play an important role in the development of CRC and resistance to 5-FU. Targeting USP14 and UCHL5 with b-AP15 may represent a promising therapeutic strategy for the treatment of CRC.

Noninvasive prenatal testing of Duchenne muscular dystrophy in a twin gestation.

PURPOSE: Haplotype-based assay has been proved efficient in noninvasive prenatal testing for various monogenic disorders in singleton pregnancies. However, its application in twin pregnancies is still blank. Here we provide a novel algorithmic approach to noninvasively assess fetal genotypes in a dizygotic twin pregnancy at risk for Duchenne muscular dystrophy (DMD). METHODS: One pregnant woman carrying a dizygotic twin gestation was recruited as she was a heterozygote of DMD gene duplication and has delivered an affected son. Construction of parental haplotypes was achieved by target sequencing of DNA samples from the parent and the proband. Single nucleotide polymorphisms within target regions were classified into six categories according to parental haplotypes. Individual fetal fractions were calculated using paternal heterozygous. Maternal-inherited haplotype was deduced using relative haplotype dosage through a two-step Bayesian model. RESULTS: One male fetus with a lower fetal fraction of 4.6% and one female fetus with a higher fetal fraction of 10.1% were observed. The male fetus was predicted to be a DMD pathogenic variant carrier, while the female fetus was predicted to be homozygous normal. Noninvasive prenatal testing (NIPT) results were concordant with the findings of invasive prenatal diagnosis. CONCLUSIONS: This study is the first report of the use of NIPT for the assessment of DMD in a twin pregnancy. The algorithm provided could expand the use of NIPT to monogenic disorders in dizygotic twin pregnancies.

A Novel Outdoor Positioning Technique Using LTE Network Fingerprints.

In recent years, wireless-based fingerprint positioning has attracted increasing research attention owing to its position-related features and applications in the Internet of Things (IoT). In this paper, by leveraging long-term evolution (LTE) signals, a novel deep-learning-based fingerprint positioning approach is proposed to solve the problem of outdoor positioning. Considering the outstanding performance of deep learning in image classification, LTE signal measurements are converted into location grayscale images to form a fingerprint database. In order to deal with the instability of LTE signals, prevent the gradient dispersion problem, and increase the robustness of the proposed deep neural network (DNN), the following methods are adopted: First, cross-entropy is used as the loss function of the DNN. Second, the learning rate of the proposed DNN is dynamically adjusted. Third, this paper adopted several data enhancement techniques. To find the best positioning fingerprint and method, three types of fingerprint and five positioning models are compared. Finally, by using a deep residual network (Resnet) and transfer learning, a hierarchical structure training method is proposed. The proposed Resnet is used to train with the united fingerprint image database to obtain a positioning model called a coarse localizer. By using the prior knowledge of the pretrained Resnet, feed-forward neural network (FFNN)-based transfer learning is used to train with the united fingerprint database to obtain a better positioning model, called a fine localizer. The experimental results convincingly show that the proposed DNN can automatically learn the location features of LTE signals and achieve satisfactory positioning accuracy in outdoor environments.

Maternal high-fat diet alters angiotensin II receptors and causes changes in fetal and neonatal rats†.

Maternal high-fat diet (HFD) during pregnancy is linked to cardiovascular diseases in postnatal life. The current study tested the hypothesis that maternal HFD causes myocardial changes through angiotensin II receptor (AGTR) expression modulation in fetal and neonatal rat hearts. The control group of pregnant rats was fed a normal diet and the treatment group of pregnant rats was on a HFD (60% kcal fat). Hearts were isolated from embryonic day 21 fetuses (E21) and postnatal day 7 pups (PD7). Maternal HFD decreased the body weight of the offspring in both E21 and PD7. The ratio of heart weight to body weight was increased in E21, but not PD7, when compared to the control group. Transmission electron microscopy revealed disorganized myofibrils and effacement of mitochondria cristae in the treatment group. Maternal HFD decreased S-phase and increased G1-phase of the cellular cycle for fetal and neonatal cardiac cells. Molecular markers of cardiac hypertrophy, such as Nppa and Myh7, were found to be increased in the treatment group. There was an associated increase in Agtr2 mRNA and protein, whereas Agtr1a mRNA and AGTR1 protein were decreased in HFD fetal and neonatal hearts. Furthermore, maternal HFD decreased glucocorticoid receptors (GRs) binding to glucocorticoid response elements at the Agtr1a and Agtr2 promoter, which correlated with downregulation of GR in fetal and neonatal hearts. These findings suggest that maternal HFD may promote premature termination of fetal and neonatal cardiomyocyte proliferation and compensatory hypertrophy through intrauterine modulation of AGTR1 and AGTR2 expression via GR dependent mechanism.

Superaerophobic RuO2 -Based Nanostructured Electrode for High-Performance Chlorine Evolution Reaction.

Constructing a nanostructured electrode with superaerophobic surface property (i.e., superlow adhesion to gas bubbles) has been strikingly highlighted as an advanced technology to minimize the energy loss during various electrochemical gas evolution reactions. Herein, aiming at enhancing the performance of chlorine evolution reaction (ClER), which holds the key for chlor-alkali industry as well as water treatment, a nanostructured RuO2 @TiO2 electrode is demonstrated to overcome the bubble shielding effect, thereby maximizing the working area and offering a robust working condition. Benefitting from the direct growing architecture and the superaerophobic surface property, this nanostructured RuO2 @TiO2 electrode exhibits an excellent ClER performance, reaching 50 mA cm-2 at a low potential of 1.10 V (vs SCE) with a Faradaic efficiency over ≈90%. Moreover, a prominent stability (250 mA cm-2 for 10 h) is observed for this nanostructured electrode, probably due to the small vibrations and scratching forces from gas product.

High-efficiently utilizing micro-nano ozone bubbles to enhance electro-peroxone process for rapid removal of trace pharmaceutical contaminants from hospital wastewater.

The electro-peroxone (EP) process encounters two inherent challenges in wastewater treatment: sluggish O2/O3 transfer and substantial ozone waste. To overcome these limitations, we introduced micro-nano bubbles (MNBs) aeration to enhance O2/O3 dissolution and diffusion, ultimately aiming to improve the removal of trace pharmaceutical contaminants from hospital wastewater. In the MNBs aeration system, the ozone transfer coefficient ranging from 0.536 to 0.265 min-1, significantly surpassing that of conventional aeration (0.220 to 0.090 min-1) by approximately 2 to 4.5 times. Consequently, the EP process under MNBs aeration significantly enhanced ozone-resistant ibuprofen (IBU) removal, achieving a removal rate of 98.4 ± 1.5 %, far exceeding the 47.3 ± 4.7 % observed with conventional aeration. This significant improvement was attributed to the heightened production of hydroxyl radicals (•OH), reaching 0.97 × 10-9 M s, compared to only 0.28 × 10-9 M s in conventional aeration. The mechanism behind the enhanced •OH production in the MNBs-EP process relied primarily on two factors: improved O2/O3 dissolution due to high internal pressure/large surface and enhanced O3/H2O2 activation from high collapse energy. These factors together contributed to the robust oxidation capability of the MNBs-EP system. As a result, over 97 % removal efficiency was achieved for five representative pharmaceutical pollutants (sulfamethoxazole, ribavirin, norfloxacin, tetracycline and ampicillin) in just 1 min. Furthermore, when applied to real hospital wastewater, the MNBs-O3-E treatment system reduced all 15 detected trace pharmaceutical compounds to below 10 ng L-1 and achieved 14 types of pollutants with removal rates of over 85 % within 15 min, resulting in an ultrahigh total removal rate of 98.6 %, from an initial total concentration of 2108 ng L-1 to less than 30 ng L-1. Thus, micro-nano aeration endowed the EP process as a promising advanced oxidation system for rapid and highly-effective removal of trace pharmaceutical contaminants from hospital wastewater.

Quorum-quenching enzyme Est816 assisted antibiotics against periodontitis induced by Aggregatibacter actinomycetemcomitans in rats.

Introduction: Quorum-quenching enzyme Est816 hydrolyzes the lactone rings of N-acyl homoserine lactones, effectively blocking the biofilm formation and development of Gram-negative bacteria. However, its applications in the oral field is limited. This study aimed to evaluate the efficacy of enzyme Est816 in combination with antibiotics against periodontitis induced by Aggregatibacter actinomycetemcomitans in vitro and in vivo. Methods: The antimicrobial efficacy of enzyme Est816 in combination with minocycline, metronidazole, and amoxicillin was determined using the minimum inhibitory concentration test. The anti-biofilm effect of enzyme Est816 was assessed using scanning electron microscopy, live/dead bacterial staining, crystal violet staining, and real-time quantitative PCR. Biocompatibility of enzyme Est816 was assessed in human gingival fibroblasts (HGF) by staining. A rat model of periodontitis was established to evaluate the effect of enzyme Est816 combined with minocycline using micro-computed tomography and histological staining. Results: Compared to minocycline, metronidazole, and amoxicillin treatment alone, simultaneous treatment with enzyme Est816 increased the sensitivity of biofilm bacteria to antibiotics. Enzyme Est816 with minocycline exhibited the highest rate of biofilm clearance and high biocompatibility. Moreover, the combination of enzyme Est816 with antibiotics improved the antibiofilm effects of the antibiotics synergistically, reducing the expression of the virulence factor leukotoxin gene (ltxA) and fimbria-associated gene (rcpA). Likewise, the combination of enzyme Est816 with minocycline exhibited a remarkable inhibitory effect on bone resorption and inflammation damage in a rat model of periodontitis. Discussion: The combination of enzyme Est816 with antibiotics represents a prospective anti-biofilm strategy with the potential to treat periodontitis.

Rational design of PspAlgL to improve its thermostability and anti-biofilm activity against Pseudomonas aeruginosa.

Pseudomonas aeruginosa biofilm enhances tolerance to antimicrobials and immune system defenses. Alginate is an important component of biofilm and a virulence factor of P. aeruginosa. The degradation of alginate by alginate lyases has come to serve as an adjunctive therapeutic strategy against P. aeruginosa biofilm, but poor stability of the enzyme limited this application. Thus, PspAlgL, an alginate lyase, can degrade acetylated alginate but has poor thermostability. The 3D structure of PspAlgL was predicted, and the thermostability of PspAlgL was rationally designed by GRAPE strategy, resulting in two variants with better stability. These variants, PspAlgLS270F/E311P and PspAlgLG291S/E311P, effectively degraded the alginate in biofilm. In addition, compared with PspAlgL, these variants were more efficient in inhibiting biofilm formation and degrading the established biofilm of P. aeruginosa PAO1, and they were also able to destroy the biofilm attached to catheters and to increase the sensitivity of P. aeruginosa to the antibiotic amikacin. This study provides one potential anti-biofilm agent for P. aeruginosa infection.

Up-regulation of BRD4 contributes to gestational diabetes mellitus-induced cardiac hypertrophy in offspring by promoting mitochondria dysfunction in sex-independent manner.

Gestational diabetes mellitus (GDM) is associated with cardiovascular disease in postnatal life. The current study tested the hypothesis that GDM caused the cardiac hypertrophy in fetal (ED18.5), postnatal day 7 (PD7), postnatal day 21 (PD21) and postnatal day 90 (PD90) offspring by upregulation of BRD4 and mitochondrial dysfunction. Pregnant mice were divided into control and GDM groups. Hearts were isolated from ED18.5, PD7, PD21 and PD90. GDM increased the body weight (BW) and heart weight (HW) in ED18.5 and PD7, but not PD21 and PD90 offspring. However, HW/BW ratio was increased in all ages of GDM offspring compared to control group. Electron microscopy showed disorganized myofibrils, mitochondrial swelling, vacuolization, and cristae disorder in GDM offspring. GDM resulted in myocardial hypertrophy in offspring, which persisted from fetus to adult in a sex-independent manner. Echocardiography analysis revealed that GDM caused diastolic dysfunction, but had no effect on systolic function. Meanwhile, myocardial BRD4 was significantly upregulated in GDM offspring and BRD4 inhibition by JQ1 alleviated GDM-induced myocardial hypertrophy in offspring. Co-immunoprecipitation showed that BRD4 interacted with DRP1 and there was an increase of BRD4 and DRP1 interaction in GDM offspring. Furthermore, GDM caused the accumulation of damaged mitochondria in hearts from all ages of offspring, including mitochondrial fusion fission imbalance (upregulation of DRP1, and downregulation of MFN1, MFN2 and OPA1) and myocardial mitochondrial ROS accumulation, which was reversed by JQ1. These results suggested that the upregulation of BRD4 is involved in GDM-induced myocardial hypertrophy in the offspring through promoting mitochondrial damage in a gender-independent manner.

A dual-cycle regeneration to recover high-value and high-purity FePO4 from real wastewater for Li-battery application.

The recovery of high-purity and high-value FePO4 raw materials from wastewater has great prospects in LiFePO4 battery industry due to the huge demand for new energy vehicle. However, the conventional in-situ FePO4 precipitation, as well as ex-situ PO43- adsorption-alkali regeneration, was incapable of efficiently obtaining high-purity products. To solve these problems, a dual-cycle regeneration method of Fe-NH2-polyacrylonitrile (PAN) adsorbent and H2SO4 desorbing solution was proposed to ex-situ FePO4 recovery from wastewater for Li-battery application. Benefitted from coordination interaction and electrostatic attraction, the maximum PO43- adsorption capacity of Fe-NH2-PAN reached 73.1 ± 0.4 mg/g. The average PO43- removal rate of continuous flow devices were 88.5% and 91.3% when treating low-P-concentration (0.22 mg/L) municipal wastewater (MW) and high-P-concentration (48.9 mg/L) slaughterhouse wastewater (SW) respectively. Furthermore, high-purity FePO4 analyzed by XRD spectra was achieved from the desorption solution at pH ∼1.6, resulting in the ultrahigh P recovery efficiencies of 91.4 ± 3.2%-96.3 ± 2.5% for SW and 82.7 ± 3.5% for MW. Besides, the LiFePO4/C electrodes made of recycled FePO4 exhibited a better discharge capacity (37.3 - 55.8 mAh/g) than that of commercial FePO4 agent (32.2 - 35.1 mAh/g) from 80 to 132 cycles, which showed the promising feasibility of recovering FePO4 from wastewater for Li-battery application.

Piperlongumine overcomes imatinib resistance by inducing proteasome inhibition in chronic myelogenous leukemia cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper longum L., an herbal medicine used in India and other Asian countries, is prescribed routinely for a range of diseases, including tumor. Piperlongumine, a natural product isolated from Piper longum L., has received widespread attention due to its various pharmacological activities, such as anti-inflammatory, antimicrobial, and antitumor effects. AIM OF THE STUDY: Chronic myelogenous leukemia (CML) is a hematopoietic disease caused by Bcr-Abl fusion gene, with an incidence of 15% in adult leukemias. Targeting Bcr-Abl by imatinib provides a successful treatment approach for CML. However, imatinib resistance is an inevitable issue for CML treatment. In particular, T315I mutant is the most stubborn of the Bcr-Abl point mutants associated with imatinib resistance. Therefore, it is urgent to find an alternative approach to conquer imatinib resistance. This study investigated the role of a natural product piperlongumine in overcoming imatinib resistance in CML. MATERIALS AND METHODS: Cell viability and apoptosis were evaluated by MTS assay and Annexin V/propidium iodide counterstaining assay, respectively. Levels of intracellular signaling proteins were assessed by Western blots. Mitochondrial membrane potential was reflected by the fluorescence intensity of rhodamine-123. The function of proteasome was detected using 20S proteasomal activity assay, proteasomal deubiquitinase activity assay, and deubiquitinase active-site-directed labeling. The antitumor effects of piperlongumine were assessed with mice xenografts. RESULTS: We demonstrate that (i) Piperlongumine inhibits proteasome function by targeting 20S proteasomal peptidases and 19S proteasomal deubiquitinases (USP14 and UCHL5) in Bcr-Abl-WT and Bcr-Abl-T315I CML cells; (ii) Piperlongumine inhibits the cell viability of CML cell lines and primary CML cells; (iii) Proteasome inhibition by piperlongumine leads to cell apoptosis and downregulation of Bcr-Abl; (iv) Piperlongumine suppresses the tumor growth of CML xenografts. CONCLUSIONS: These results support that blockade of proteasome activity by piperlongumine provides a new therapeutic strategy for treating imatinib-resistant CML.

Superhydrophobic and deacidified cellulose/CaCO3-derived granular coating toward historic paper preservation.

Deacidification and surface self-cleaning are of great significance for the long-term preservation of historic literature. Herein, a superhydrophobic self-cleaning coating, derived from nanocellulose coated with CaCO3 particles is constructed via chemical vapor deposition (CVD) for the first time for the preservation of historic paper. The static contact angle of superhydrophobic paper reached more than 150° and the minimum sliding angle was 6.4°. Deacidification effect was achieved with a desired pH value in the range from 7.50 to 7.77 and the maximum alkali storage was up to 1.235 mol/kg. It is found that the low-cost CaCO3 nanoparticles can not only remove the acid substances, but also gave the paper function of self-cleaning, which is very great significant for the protection of paper-based relics.

The effective removal of Congo Red using a bio-nanocluster: Fe3O4 nanoclusters modified bacteria.

A bio-nanocluster (Fe3O4@bacteria) was prepared by simply mixture using the bacterial suspension and Fe3O4 nanoclusters to remove Congo red (CR) contamination from water resources. The bio-nanocluster was characterized by SEM, TEM and XPS. Adsorption efficiency, adsorption process and adsorption mechanism were comprehensively investigated. The maximum adsorption capacity (Qm) of CR dye onto the Fe3O4@bacteria peaked at 320.1 mg/g, which was 2.88 times that of Fe3O4 under the same condition. Based on the equilibrium and kinetic studies, the Langmuir isotherm theory and pseudo-first-order model is appropriate to describe the adsorption process. The adsorption of CR is spontaneous and exothermic according to the thermodynamics parameters (ΔGθ, ΔHθ and ΔSθ). The adsorption force dominated the Van der Waals force, biofloculation and chemisorption. The Fe3O4@bacteria could be applied potentially as an absorbent with high efficiency and environmentally friendly remediation of dyeing wastewater.

Estrogen normalizes maternal HFD-induced vascular dysfunction in offspring by regulating ATR.

Previous studies have shown that female offspring are resistant to fetal high-fat diet (HFD)-induced programming of heightened vascular contraction; however, the underlying mechanisms remain unclear. The present study tested the hypothesis that estrogen plays a key role in protecting females from fetal programming of increased vascular contraction induced by maternal HFD exposure. Pregnant rats were fed a normal diet (ND) or HFD (60% kcal from fat). Ovariectomy (OVX) and 17ß-estradiol (E2) replacement were performed on 8-week-old female offspring. Aortas were isolated from adult female offspring. Maternal HFD exposure increased angiotensin II (Ang II)-induced contractions of the aorta in adult OVX offspring, which was abrogated by E2 replacement. The AT1 receptor (AT1R) antagonist losartan (10 µM), but not the AT2 receptor (AT2R) antagonist PD123319 (10 µM), completely blocked Ang II-induced contractions in both ND and HFD offspring. In addition, HFD exposure caused a decrease in endothelium-dependent relaxations induced by acetylcholine (ACh) in adult OVX but not OVX-E2 offspring. However, it had no effect on sodium nitroprusside (SNP)-induced endothelium-independent aorta relaxation in any of the six groups. Maternal HFD feeding increased AT1R, but not AT2R, leading to an increased AT1R/AT2R ratio in HFD-exposed OVX offspring, associated with selective decreases in DNA methylation at the AT1aR promoter, which was ameliorated by E2 replacement. Our results indicated that estrogen play a key role in sex differences of maternal HFD-induced vascular dysfunction and development of hypertensive phenotype in adulthood by differently regulating vascular AT1R and AT2R gene expression through a DNA methylation mechanism.

Occurrence and risk assessment of typical PPCPs and biodegradation pathway of ribavirin in wastewater treatment plants.

A large number of pharmaceuticals and personal care products (PPCPs) persist in wastewater, and the consumption of PPCPs for COVID-19 control and prevention has sharply increased during the pandemic. This study investigated the occurrence, removal efficiency, and risk assessment of six typical PPCPs commonly used in China in two wastewater treatment plants (WWTPs). Ribavirin (RBV) is an effective pharmaceutical for severely ill patients with COVID-19, and the possible biodegradation pathway of RBV by activated sludge was discovered. The experimental results showed that PPCPs were detected in two WWTPs with a detection rate of 100% and concentrations ranging between 612 and 2323 ng L-1. The detection frequency and concentrations of RBV were substantially higher, with a maximum concentration of 314 ng L-1. Relatively high pollution loads were found for the following PPCPs from influent: ibuprofen > ranitidine hydrochloride > RBV > ampicillin sodium > clozapine > sulfamethoxazole. The removal efficiency of PPCPs was closely related to adsorption and biodegradation in activated sludge, and the moving bed biofilm reactor (MBBR) had a higher removal capacity than the anoxic-anaerobic-anoxic-oxic (AAAO) process. The removal efficiencies of sulfamethoxazole, ampicillin sodium, ibuprofen, and clozapine ranged from 92.21% to 97.86% in MBBR process and were relatively low, from 61.82% to 97.62% in AAAO process, and the removal of RBV and ranitidine hydrochloride were lower than 42.96% in both MBBR and AAAO processes. The discrepancy in removal efficiency is caused by temperature, hydrophilicity, and hydrophobicity of the compound, and acidity and alkalinity. The transformation products of RBV in activated sludge were detected and identified, and the biodegradation process of RBV could be speculated as follows: first breaks into TCONH2 and an oxygen-containing five-membered heterocyclic ring under the nucleosidase reaction, and then TCONH2 is finally formed into TCOOH through amide hydrolysis. Aquatic ecological risks based on risk quotient (RQ) assessment showed that PPCPs had high and medium risks in the influent, and the RQ values were all reduced after MBBR and AAAO treatment. Ranitidine hydrochloride and clozapine still showed high and medium risks in the effluent, respectively, and thus presented potential risks to the aquatic ecosystem.

Cyclin-dependent kinase 7/9 inhibitor SNS-032 induces apoptosis in diffuse large B-cell lymphoma cells.

Approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) are refractory or relapse to standard chemotherapy, and most of them are activated B cell-like DLBCLs (ABC-DLBCL) and germinal center B cell-like DLBCLs (GCB-DLBCL). SNS-032, a novel and selective CDK7/9 inhibitor, that the first phase clinical trials approved by US FDA for cancer treatment have been completed. In this study, we investigated the anti-tumor effect of SNS-032 in ABC- and GCB-DLBCL subtypes. We report that SNS-032 induced growth inhibition and cell apoptosis in both DLBCL cells in vitro, and inhibited the growth of both DLBCL xenografts in nude mice. Mechanistically, SNS-032 inhibited RNA polymerase II, which led to transcriptional-dependent suppression of NF-κB signaling pathway and its downstream targets involved in cell survival; SNS-032 also downregulates BCL-2 and c-MYC in both mRNA and protein levels. Significantly, these findings provide pre-clinical evidence for application of targeting the CDK7/9 in DLBCL.

Inhibition of proteasomal deubiquitinases USP14 and UCHL5 overcomes tyrosine kinase inhibitor resistance in chronic myeloid leukaemia.

BACKGROUND: Chronic myeloid leukaemia (CML) is a haematological cancer featured by the presence of BCR-ABL fusion protein with abnormal tyrosine kinase activation. Classical tyrosine kinase inhibitor (TKI)-based therapies are available to patients with CML. However, acquired resistance to TKI has been a challenging obstacle, especially stubborn T315I mutation is the most common cause. Therefore, it is especially urgent to find more effective targets to overcome TKI resistance induced by BCR-ABLT315I . Proteasomal deubiquitinases (USP14 and UCHL5) have fundamental roles in the ubiquitin-proteasome system and possess multiple functions during cancer progression. METHODS: The human peripheral blood mononuclear cells were collected to measure the mRNA expression of USP14 and UCHL5, as well as to detect the toxicity effect of b-AP15. We explored the effect of b-AP15 on the activity of proteasomal deubiquitinases. We detected the effects of b-AP15 on BCR-ABLWT and BCR-ABLT315I CML cells in vitro and in the subcutaneous tumour model. We knocked down USP14 and/or UCHL5 by shRNA to explore whether these proteasomal deubiquitinases are required for cell proliferation of CML. RESULTS: In this study, we found that increased expression of the proteasomal deubiquitinase USP14 and UCHL5 in primary cancer cells from CML patients compared to healthy donors. b-AP15, an inhibitor of USP14 and UCHL5, exhibited potent tumour-killing activity in BCR-ABLWT and BCR-ABLT315I CML cell lines, as well as in CML xenografts and primary CML cells. Mechanically, pharmacological or genetic inhibition of USP14 and UCHL5 induced cell apoptosis and decreased the protein level of BCR-ABL in CML cells expressing BCR-ABLWT and BCR-ABLT315I . Moreover, b-AP15 synergistically enhanced the cytotoxic effect caused by TKI imatinib in BCR-ABLWT and BCR-ABLT315I CML cells. CONCLUSION: Collectively, our results demonstrate targeting USP14 and UCHL5 as a potential strategy for combating TKI resistance in CML.