Mechanism of annexin A1/N-formylpeptide receptor regulation of macrophage function to inhibit hepatic stellate cell activation through Wnt/ß-catenin pathway.

BACKGROUND: Hepatic fibrosis is a common pathological process of chronic liver diseases with various causes, which can progress to cirrhosis. AIM: To evaluate the effect and mechanism of action annexin (Anx)A1 in liver fibrosis and how this could be targeted therapeutically. METHODS: CCl4 (20%) and active N-terminal peptide of AnxA1 (Ac2-26) and N-formylpeptide receptor antagonist N-Boc-Phe-Leu-Phe-Leu-Phe (Boc2) were injected intraperitoneally to induce liver fibrosis in eight wild-type mice/Anxa1 knockout mice, and to detect expression of inflammatory factors, collagen deposition, and the role of the Wnt/ß-catenin pathway in hepatic fibrosis. RESULTS: Compared with the control group, AnxA1, transforming growth factor (TGF)-ß1, interleukin (IL)-1ß and IL-6 expression in the liver of mice with hepatic fibrosis induced by CCl4 was significantly increased, which promoted collagen deposition and expression of α-smooth muscle actin (α-SMA), collagen type I and connective tissue growth factor (CTGF), and increased progressively with time. CCl4 induced an increase in TGF-ß1, IL-1ß and IL-6 in liver tissue of AnxA1 knockout mice, and the degree of liver inflammation and fibrosis and expression of α-SMA, collagen I and CTGF were significantly increased compared with in wild-type mice. After treatment with Ac2-26, expression of liver inflammatory factors, degree of collagen deposition and expression of a-SMA, collagen I and CTGF were decreased compared with before treatment. Boc2 inhibited the anti-inflammatory and antifibrotic effects of Ac2-26. AnxA1 downregulated expression of the Wnt/ß-catenin pathway in CCl4-induced hepatic fibrosis. In vitro, lipopolysaccharide (LPS) induced hepatocyte and hepatic stellate cell (HSC) expression of AnxA1. Ac2-26 inhibited LPS-induced RAW264.7 cell activation and HSC proliferation, decreased expression of α-SMA, collagen I and CTGF in HSCs, and inhibited expression of the Wnt/ß-catenin pathway after HSC activation. These therapeutic effects were inhibited by Boc2. CONCLUSION: AnxA1 inhibited liver fibrosis in mice, and its mechanism may be related to inhibition of HSC Wnt/ß-catenin pathway activation by targeting formylpeptide receptors to regulate macrophage function.

Post-Myocardial Infarction Ventricular Septal Defect Successfully Treated with Impella as Bridge to Cardiac Transplantation.

A 63-year-old female presented late with anterior ST-elevation myocardial infarction and cardiogenic shock. This was complicated by acute ventricular septal defect with large left-to-right shunt. An Impella CP was inserted on day seven with rapid haemodynamic improvement. This facilitated bridge to cardiac transplant on day twelve post-MI.

Arene-Ruthenium(II)/Osmium(II) Complexes Potentiate the Anticancer Efficacy of Metformin via Glucose Metabolism Reprogramming.

Targeting metabolic reprogramming to treat cancer could increase overall survival and reduce side effects. Here, we put forward a strategy using arene-ruthenium(II)/osmium(II) complexes to potentiate the anticancer effect of metformin (Met.) via glucose metabolism reprogramming. Complexes 1-6 with oxoglaucine derivatives as ligands were synthesized and their anti-tumor activities were tested under hypoglycemia. Results indicated that 2 and 5 potentiated the anticancer effects of Met. under hypoglycemia, exhibiting lower toxicity, slower blood glucose decline and inhibition of early tumor liver metastasis. Combination of 5 with Met. could be used as a new strategy to treat cancer under hypoglycemia through glucose metabolism reprogramming.

Genesis of improved quality in imaging through a national Australian echocardiography registry.

BACKGROUND: Despite rapid technological advances and growth, quality in imaging has not received the focus seen elsewhere in cardiovascular medicine, resulting in significant gaps between guidelines and practice. Contemporary echocardiography practice requires comprehensive real-time data collection to allow dynamic auditing and benchmarking of key performance indices. The American College of Cardiology (ACC) proposed additional data standardisation, structured reporting identifying key data elements and imaging registries. In the absence of an Australian echocardiography registry, we developed a national clinical quality registry (GenesisCare Cardiovascular Outcomes Echo Registry). We hypothesised that measurement and local reporting of data would improve compliance of echo studies with quality guidelines and hence their clinical value. METHODS AND RESULTS: We prospectively collected data on 4 099 281 echocardiographic studies entered directly into a central electronic database from 63 laboratories across four Australian states between 2010 and 2021. Real-time auditing of key data elements and introduction of quality improvement pathways were performed to maximise completeness and uniformity of data acquisition and reporting. We compared completeness of key data element acquisition (AV peak velocity, left ventricular ejection fraction, E/e', LA area, rhythm, RVSP) by time and state using de-identified data. Key performance outcomes benchmarked against the aggregated study cohort and international standards were reported to individual sites to drive quality improvement. Between 2010 and 2014 there were significant improvements in data completeness (72.0%+/-26.8% vs 86.8%+/-13.5%, p=0.02), which were maintained to 2020. In addition, interstate variability fell for both EF and E/e' (p<0.002). CONCLUSIONS: This large-scale collaboration provides a platform for the development of major quality improvement initiatives in echocardiography. Introduction of local quality assurance programmes via a unified national data set significantly improved the completeness of reporting of key echo quality measures. This in turn significantly improved the quality of, and reduced the interstate variability of, echo data. Developing a centralised database allowed rapid adoption nationally of local quality improvements.

Topological boundary states of two-dimensional restricted isosceles triangular photonic crystals.

We propose an all-media photonic crystal (PC) composed of isosceles triangle dielectric cylinders that realizes the topological phase transition by simply rotating the isosceles triangular dielectric cylinders. Additionally, the topological phase transition is closely linked with the size parameters and rotation angle of the isosceles triangle. The topological boundary states with lossless transmission are constructed on the interface of two different topological structures, and the optical quantum spin Hall effect is simulated. Further, we verified that the boundary state is unidirectional and immune to disorder, cavity, and sharp bend defects. By rotating the angle of the triangle to control the transmission path of the pseudo-spin state, we realize diverse transport pathways of light, such as the "straight line" shape, "Z" shape, "U" shape, and "Y" shape. This topological system shows a higher degree of freedom, which can promote the research on topological boundary states and the development of topological insulators in practical applications.

Synthetic cajaninstilbene acid derivatives eradicate methicillin-resistant Staphylococcus aureus persisters and biofilms.

The Staphylococcus aureus can switch to a transient genotype-invariant dormancy, known as a persister, to survive treatment with high doses of antibiotics. This transient persister is an important reason underlying its resistance. There is an urgent need to find new antibacterial agents capable of eradicating methicillin-resistant S. aureus (MRSA) persisters. In this study, 37 new derivatives of cajaninstilbene acid (CSA) were designed and synthesized, and their biological activity against MRSA persisters was evaluated. Most of the newly synthesized derivatives exhibit more potent antimicrobial properties against S. aureus and MRSA than CSA itself, and 23 of the 37 derivatives show a tendency to eradicate MRSA persisters. A representative compound (A6) was demonstrated to target bacterial cell membranes. It eradicated the adherent biofilm of MRSA in a concentration dependent manner, and showed a synergistic antibacterial effect with piperacilin. In a model mouse abscess caused by MRSA persisters, A6 effectively reduced the bacterial load in vivo. These results indicate that A6 is a potential candidate for treatment of MRSA persister infections.

Colchicine in Patients with Chronic Coronary Disease.

BACKGROUND: Evidence from a recent trial has shown that the antiinflammatory effects of colchicine reduce the risk of cardiovascular events in patients with recent myocardial infarction, but evidence of such a risk reduction in patients with chronic coronary disease is limited. METHODS: In a randomized, controlled, double-blind trial, we assigned patients with chronic coronary disease to receive 0.5 mg of colchicine once daily or matching placebo. The primary end point was a composite of cardiovascular death, spontaneous (nonprocedural) myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization. The key secondary end point was a composite of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke. RESULTS: A total of 5522 patients underwent randomization; 2762 were assigned to the colchicine group and 2760 to the placebo group. The median duration of follow-up was 28.6 months. A primary end-point event occurred in 187 patients (6.8%) in the colchicine group and in 264 patients (9.6%) in the placebo group (incidence, 2.5 vs. 3.6 events per 100 person-years; hazard ratio, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P<0.001). A key secondary end-point event occurred in 115 patients (4.2%) in the colchicine group and in 157 patients (5.7%) in the placebo group (incidence, 1.5 vs. 2.1 events per 100 person-years; hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.007). The incidence rates of spontaneous myocardial infarction or ischemia-driven coronary revascularization (composite end point), cardiovascular death or spontaneous myocardial infarction (composite end point), ischemia-driven coronary revascularization, and spontaneous myocardial infarction were also significantly lower with colchicine than with placebo. The incidence of death from noncardiovascular causes was higher in the colchicine group than in the placebo group (incidence, 0.7 vs. 0.5 events per 100 person-years; hazard ratio, 1.51; 95% CI, 0.99 to 2.31). CONCLUSIONS: In a randomized trial involving patients with chronic coronary disease, the risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than among those who received placebo. (Funded by the National Health Medical Research Council of Australia and others; LoDoCo2 Australian New Zealand Clinical Trials Registry number, ACTRN12614000093684.).

Synthesis, structural characterization and antitumor activity of six rare earth metal complexes with 8-hydroxyquinoline derivatives.

The rare earth metal Gd(III), Yb(III), Lu(III), Eu(III), Tb(III) and Ho(III) complexes 1-6 with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol (H-L) as ligands were synthesized. The in vitro cytotoxicity assay indicated that the cytotoxicity of 1 was equivalent to cisplatin and higher than that of H-L and other complexes towards T24 tumor cells. The mechanism study indicated that 1 caused significant up-regulation of the proteins p27, p21 and p53 in T24 cells and cell cycle arrest in G2 phase. In addition, 1 induced effective T24 cells apoptosis via mitochondrial dysfunction pathway, which was indicated by changes in mitochondrial membrane potential (Δψ), reactive oxygen species (ROS), intracellular Ca2+ and the mitochondria-related proteins (including cytochrome C (Cyt C), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated x (Bax) and apoptotic protease activating factor-1 (Apaf-1)). Moreover, 1 could activate caspase-3/8/9 in T24 cells. Therefore, complex 1 is a promising and potent anticancer drug candidate.

Cajaninstilbene acid analogues as novel quorum sensing and biofilm inhibitors of Pseudomonas aeruginosa.

Biofilm formation and virulence factor secretion in opportunistic pathogen Pseudomonas aeruginosa are essential for establishment of chronic and recurrent infection, which are regulated by quorum sensing (QS) system. In this study, a set of cajaninstilbene acid analogues were designed and synthesized, and their abilities to inhibit QS and biofilm formation were investigated. Among all the compounds, compounds 3g, 3m and 3o showed potent anti-biofilm activity, especially 3o exhibited promising biofilm inhibitory activity with biofilm inhibition ratio of 49.50 ± 1.35% at 50 µM. Three lacZ reporter strains were constructed to identify the effects of compound 3o on different QS systems. Compound 3o showed the suppression on the expression of lasB-lacZ and pqsA-lacZ as well as on the production of their corresponding virulence factors. Therefore, compound 3o is expected to be generated as a lead compound with inhibition of biofilm formation and QS of Pseudomonas aeruginosa.

Local adaptive evolution of two distinct clades of Beijing and T families of Mycobacterium tuberculosis in Chongqing: a Bayesian population structure and phylogenetic study.

BACKGROUND: Beijing sub-pedigree 2 (BSP2) and T sub-lineage 6 (TSL6) are two clades belonging to Beijing and T family of Mycobacterium tuberculosis (MTB), respectively, defined by Bayesian population structure analysis based on 24-loci mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR). Globally, over 99% of BSP2 and 89% of TSL6 isolates were distributed in Chongqing, suggesting their possible local adaptive evolution. The objective of this paper is to explore whether BSP2 and TSL6 originated by their local adaptive evolution from the specific isolates of Beijing and T families in Chongqing. METHODS: The genotyping data of 16 090 MTB isolates were collected from laboratory collection, published literatures and SITVIT database before subjected to Bayesian population structure analysis based on 24-loci MIRU-VNTR. Spacer Oligonucleotide Forest (Spoligoforest) and 24-loci MIRU-VNTR-based minimum spanning tree (MST) were used to explore their phylogenetic pathways, with Bayesian demographic analysis for exploring the recent demographic change of TSL6. RESULTS: Phylogenetic analysis suggested that BSP2 and TSL6 in Chongqing may evolve from BSP4 and TSL5, respectively, which were locally predominant in Tibet and Jiangsu, respectively. Spoligoforest showed that Beijing and T families were genetically distant, while the convergence of the MIRU-VNTR pattern of BSP2 and TSL6 was revealed by WebLogo. The demographic analysis concluded that the recent demographic change of TSL6 might take 111.25 years. CONCLUSIONS: BSP2 and TSL6 clades might originate from BSP4 and TSL5, respectively, by their local adaptive evolution in Chongqing. Our study suggests MIRU-VNTR be combined with other robust markers for a more comprehensive genotyping approach, especially for families of clades with the same MIRU-VNTR pattern.

Biological evaluation and chemoproteomics reveal potential antibacterial targets of a cajaninstilbene-acid analogue.

Methicillin-resistant Staphylococcus aureus and the formation of persistent nongrowing subpopulations (persisters) is a serious threat to human. Our previous studies have proved that two cajaninstilbene acid (CSA) analogues, compound 5b and 5j display remarkable antibacterial activities, especially overcoming drug resistance of methicillin-resistant Staphylococcus aureus (MRSA). Present study found that 5b and 5j are capable of eradicating MRSA persisters. However, their underlying antibacterial mechanism is still obscure. In this study, biological evaluation was performed by transmission electron micrograph, membrane permeability and membrane depolarization experiment to reveal the effects of drugs on bacteria. Further, affinity-based protein profiling and transcriptional profiling were performed to characterise the protein targets in bacterial. Biological evaluation suggested that 5b has an effect on bacterial membrane, affinity-based protein profiling identified that 5b targets membrane associated protein PgsA and verified by in vitro labelling profile. Transcriptional profiling indicated that 5b interferes in phosphatidylglycerol (PG) synthesis pathway. This study identified a novel antibacterial target PgsA and it might be a potential target to combat the resistant bacteria.

Novel benzyl phenyl sulfide derivatives as antibacterial agents against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) infection is a major threat to human health due to its resistance to almost all classes of antibiotics. Discovery of novel antibacterial agents with new structures which combat the pathogens responsible for MRSA is urgent. In this study, three series of benzyl phenyl sulfide derivatives were designed and synthesized, and their antibacterial activity against eleven MRSA strains were evaluated. The results showed that two series of the synthetic compounds (5a-5l and 12p-12u) exhibit potent antibacterial activity against S. aureus and MRSA, with minimum inhibitory concentrations of 2-64 µg/mL. The structure-activity relationships are discussed and the mechanism of the antibacterial activity was shown to involve the destruction of the bacterial cell membrane. Finally, the MTT assay results suggest that the toxicity of compounds 5f and 5h is selective between bacteria and mammalian cells.

Left Atrial Intramural Hematoma Post-Ablation of Supraventricular Tachycardia: A Rare Complication Treated Successfully.

We report successful management of left atrial hematoma after ablation of supraventricular tachycardia. A 43-year-old female patient experienced chest pain immediately after radiofrequency ablation of a symptomatic left posterolateral accessory pathway. Transthoracic echocardiography demonstrated a large mass occupying the left atrium. Computed tomography and transesophageal echocardiography results were consistent with posterolateral intramural hematoma. She became hemodynamically unstable, requiring emergent surgery. The mass resolved completely by 6 weeks. (Level of Difficulty: Beginner.).

Novel virosecurinine bivalent mimetics as potent reversal agents against P-glycoprotein-mediated multidrug resistance.

Multidrug resistance (MDR) is a main cause of chemotherapy failure and patient death. This situation usually involves a glycoprotein (P-gp) mediated drug efflux, resulting in a low cellular drug concentration and insensitivity. Here we report the design, synthesis and evaluation of novel (+/-)-securinine bivalents as P-gp inhibitors in vitro and in vivo. MTT assays reflected that bivalent mimetics of securinine particularly the virosecurinine bivalent mimetic 8C showed promissing MDR reversal potential in both P-gp highly expressed cell line HepG2/DOX and MCF-7/ADM. At a 10 µM concentration, 8C can entirely reverse the resistance of HepG2/DOX to doxorubicin (DOX), and is more effective than the positive control verapamil (VRP). Fluorescence, flow cytometry, and DOX efflux assays demonstrated that 8C can facilitate the accumulation and diminish the efflux of intracellular DOX. Molecular docking analysis and western blot assays indicated that 8C accomplished this by competitively inhibiting the activity of P-gp rather than by affecting its expression. Compound 8C was also observed to reverse drug resistance effectively in xenograft models when combined with DOX. This study lays a foundation for the discovery of (+/-)-securinine ramifications as P-gp inhibitors and provides a promising lead compound 8C as a P-gp mediated MDR reversal agent.

Serum thrombospondin-2 is a candidate diagnosis biomarker for early non-small-cell lung cancer.

Thrombospondin-2 (THBS2) is a secreted protein overexpressed in numerous cancers and may function as a diagnostic tumor marker. The objective of the present study was to investigate the diagnostic performance of serum THBS2 in early stage non-small-cell lung cancer (NSCLC). Serum THBS2 and Cyfra21-1 level were evaluated in blood samples of 112 patients from NSCLC groups and 51 healthy control (HC) groups. Receiver operator characteristic (ROC) curves were used to evaluate the diagnostic significance. Serum THBS2 level was significantly up-regulated in NSCLC patients compared with healthy control subjects (P<0.0001), and the postoperative THBS2 level decreased significantly (P<0.0001). ROC curves analysis demonstrated that THBS2 was a comparable biomarker as Cyfra21-1 to distinguish early stage NSCLC or lung squamous cell carcinoma (SC) from healthy control subjects. And Cyfra21-1 was observed with significantly improved performances by the combination of THBS2 to distinguish early stage NSCLC (P<0.05) as well as SC (P<0.05) from the control subjects. In addition, THBS2 was estimated to perform well in the diagnosis of patients with Cyfra21-1-negative NSCLC (area under the curve [AUC] = 0.73). In summary, the present study suggested that serum THBS2 might be an early diagnostic biomarker for NSCLC.

Design and synthesis of 2-hydroxyl-4-methoxyl-3-(3-methylbut-2-en-1-yl)-6-(4-phenylbenzoylamino)benzoic acid derivatives as antibacterial agents based on cajaninstilbene acid scaffold hopping.

The prevalence of multidrug resistance among clinically significant bacterial pathogens underlines a critical need for the development of new classes of antibacterial agents with novel structural scaffolds. Cajaninstilbene acid (CSA), which is isolated from pigeonpea leaves, has shown potent antibacterial activity. In this study, a series of 2-hydroxyl-4-methoxyl-3-(3-methylbut-2-en-1-yl)-6-(4-phenylbenzoylamino)benzoic acid derivatives derived from CSA were designed and synthesized, and their antibacterial activities were evaluated. Several synthesized compounds exhibit better antibacterial activity than CSA against Staphylococcus aureus, Staphylococcus epidermidis, and two strains of methicillin-resistant S. aureus. Meanwhile, the results of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assays illustrate the good selectivity between bacteria and normal cells of the most active compounds 6u and 6v. Furthermore, well combinations with bacterial RNA polymerase of 6u arising from docking study imply the possible mechanism of antibacterial activity of these synthetic compounds.

Synthesis and Biological Evaluation of Cajaninstilbene Acid and Amorfrutins A and B as Inhibitors of the Pseudomonas aeruginosa Quorum Sensing System.

The quorum sensing (QS) system inhibitors of Pseudomonas aeruginosa are thought to attenuate bacterial pathogenicity and drug resistance by inhibiting biofilm formation and the production of virulence factors. In this study, a synthetic approach to the natural products cajaninstilbene acid (1) and amorfrutins A (2) and B (3) has been developed and was characterized by the Heck reaction, which was used to obtain the stilbene core and a Pinick oxidation to give the O-hydroxybenzoic acid. The biological activities of these compounds against the P. aeruginosa quorum sensing systems were evaluated. Amorfrutin B (3) showed promising antibiofilm activity against P. aeruginosa PAO1 with a biofilm inhibition ratio of 50.3 ± 2.7. Three lacZ reporter strains were constructed to identify the effects of compound 3 on different QS systems. Suppression efficacy of compound 3 on the expression of lasB-lacZ and pqsA-lacZ as well as on the production of their corresponding virulence factors elastase and pyocyanin was observed.

Delayed presentation of pulmonary artery perforation by an Amulet left atrial appendage closure device.

Left atrial appendage occlusion (LAAO) devices offer stroke prevention in atrial fibrillation for patients intolerant of anticoagulation. Device placement leading to bleeding and cardiac tamponade have been reported periprocedurally but delayed presentations have not been reported in the literature. We present the case of an Amulet LAAO device causing erosion and bleeding from the main pulmonary artery that presented with cardiac tamponade 6 months after device placement. The pulmonary artery defect was repaired primarily and buttressed with a pericardial patch with good result.

Design, synthesis and biological evaluation of 2-substituted 3-hydroxy-6-methyl-4H-pyran-4-one derivatives as Pseudomonas aeruginosa biofilm inhibitors.

Drug-resistant bacteria associated with biofilm formation are rapidly on the rise, requiring novel therapeutic options to combat biofilm induced drug-resistance. In this study, a class of 3-hydroxy-2-(phenylhydroxy-methyl)-6-methyl-4H-pyran-4-one derivatives (1a-1e) were found by screening of an in-house compound library to be potential Pseudomonas aeruginosa biofilm inhibitors. Thirty one novel 2-substituted 3-hydroxy-6-methyl-4H-pyran-4-one derivatives were synthesized and assayed for their biofilm inhibitory activity. A promising biofilm inhibitor 6a was identified, and showed an obvious biofilm inhibitory effect even at a concentration of 2.5 µM. Further mechanism studies revealed that 6a only shows inhibitory effects on the expression of pqsA-gfp in a fluorescent reporter strain, and the production of a PQS- regulated virulence factor, pyocyanin. This indicates that this type of compound exercises its anti-biofilm activity specifically through the PQS pathway. Novel chemical biofilm inhibitors are described here and guard against biofilm formation associated with Pseudomonas aeruginosa infections.

[Assessment of Medical Waste Disposal Technologies Based on the AHP].

Five types of medical waste disposal technologies that are currently applied in our country were analyzed and compared such as the rotary kiln incineration method, pyrolysis method, high-temperature steam sterilization method, chemical disinfection method, and microwave disinfection method. The five methods were quantitatively evaluated and screened using an analytical hierarchy process (AHP). Based on this process, the ranking weights of optimal and suboptimal alternatives were studied using sensitivity analysis. The results show that the rotary kiln incineration and pyrolysis methods are presently the most widely used technologies for medical waste disposal in our country. The AHP shows that the comprehensive benefits of high-temperature steam sterilization in medical waste disposal are the best compared with the other four methods in terms of social, environmental, technological, and economic factors, followed by the chemical disinfection method. The sensitivity analysis shows that the change points of the guideline layer factors that lead to the change of the alternatives are the social factors (0.2100), environmental factors (0.3500), technical factors (0.1200), and economic factors (0.2400). Subcriteria factors have less influence on the weight ranking of the alternatives.