Synthesis, structure-activity relationship and biological evaluation of indole derivatives as anti-Candida albicans agents.

In this work, we synthesized a series of indole derivatives to cope with the current increasing fungal infections caused by drug-resistant Candida albicans. All compounds were evaluated for antifungal activities against Candida albicans in vitro, and the structure-activity relationships (SARs) were analyzed. The results indicated that indole derivatives used either alone or in combination with fluconazole showed good activities against fluconazole-resistant Candida albicans. Further mechanisms studies demonstrated that compound 1 could inhibit yeast-to-hypha transition and biofilm formation of Candida albicans, increase the activity of the efflux pump, the damage of mitochondrial function, and the decrease of intracellular ATP content. In vivo studies, further proved the anti-Candida albicans activity of compound 1 by histological observation. Therefore, compound 1 could be considered as a novel antifungal agent.

Optimization and antifungal activity of quinoline derivatives linked to chalcone moiety combined with FLC against Candida albicans.

In present work, a series of quinoline derivatives linked to chalcone moiety have been prepared, and their in vitro and in vivo antifungal activities against C. albicans have been evaluated. The results indicated that quinoline combined with fluconazole (FLC) showed good inhibitory activity against C. albicans. Especially, compound PK-10 combined with FLC displayed the best antifungal activity against 14 FLC-resistant C. albicans strains with almost no cytotoxicity. Preliminary mechanistic studies proved that PK-10 combined with FLC could inhibit the hyphae formation of C. albicans, induce the accumulation of reactive oxygen species (ROS), the damage of mitochondrial membrane potential and the decrease of intracellular ATP content, which led to mitochondrial dysfunction. In vivo studies found obvious effects of the co-treatment regimen had obvious effects based on histological analysis, body weight curves, and coefficients of major organs. Therefore, the optimization of quinolone-chalcone derivatives combined with FLC could exert the potent antifungal activity in vitro and in vivo obviously, suggesting them as new agents to treat drug-resistant C. albicans infection.

Antifungal evaluation of quinoline-chalcone derivatives combined with FLC against drug-resistant Candida albicans.

With the widespread clinical use of FLC, the FLC-resistant C. albicans greatly increases the difficulty of treatment, and drug combination becomes an important method to treat C. albicans infection. In this work, we have prepared a series of quinoline-chalcone derivatives in good yields, and in vitro antifungal activity against C. albicans were evaluated. The results indicated that most title compounds combined with FLC showed good antifungal activity against drug-resistant C. albicans. Further mechanism researches demonstrated that 6a and 6c combined with FLC could significantly inhibited growth and biofilm formation of C. albicans, induce ROS accumulation, impair the mitochondrial membrane, and decrease intracellular ATP concentrations.

Polyphyllin I Effects Candida albicans via Inhibition of Virulence Factors.

Paris polyphylla is often used in Chinese medicine to treat conditions such as carbuncles, trauma, snake bites, and mosquito bites. In the present study, we investigated the effect and mechanism of the morphological transition and extracellular phospholipase activity of Candida albicans treated with polyphyllin I (PPI). First, the minimum inhibitory concentration and antifungal activity of PPI were evaluated using the multiple microdilution method and time-killing assays. Then, the effect of PPI on the morphological transition of Candida albicans in Spider liquid medium and Sabouraud-dextrose liquid medium containing 10% fetal bovine serum was observed under an inverted microscope and by scanning electron microscopy. Finally, egg yolk agar plates were used to evaluate extracellular phospholipase activity. Gene expression was detected by real-time quantitative polymerase chain reaction analysis. Our results suggest that PPI inhibited the transition from the yeast to the hyphal stage and decreased secreted aspartyl proteinase activity. We further confirmed that PPI significantly downregulated the expression of extracellular phospholipase genes and cAMP-PKA signaling pathway-related genes. Taken together, our results suggest that PPI exerts anti-Candida albicans activity by inhibiting virulence characteristics, including the yeast-to-hyphal transition and the secretion of aspartyl proteases and phospholipases. The study results also indicated that PPI could be a promising therapeutic strategy for Candida albicans.

Bleeding risks with novel oral anticoagulants especially rivaroxaban versus aspirin: a meta-analysis.

BACKGROUND: This pairwise meta-analysis determines the difference in bleeding risks associated with the use of novel oral anticoagulants (NOACs) and aspirin. METHODS: PubMed, the Cochrane Library database, clinicaltrial.gov , and related studies were searched for randomized control trials (RCTs) comparing NOAC and aspirin published between January 1, 2000 and May 10, 2021. The primary endpoint was intracranial hemorrhage (ICH). RESULTS: Eleven studies involving 57,645 patients were included. Compared to aspirin, rivaroxaban (5 mg/day) had a similar risk of ICH, major bleeding, and fatal bleeding; rivaroxaban (10 mg/day) had higher risks of gastrointestinal hemorrhage (OR: 1.41; 95% CI: 1.03-1.94; P = 0.032; I2 = 0%) and a similar risk of ICH, major bleeding, and fatal bleeding; and rivaroxaban (15-20 mg/day) had higher risks of ICH (OR: 3.21; 95% CI: 1.36-7.60; P = 0.008; I2 = 0%), major bleeding (OR: 2.64; 95% CI: 1.68-4.16; P < 0.001; I2 = 0%), and fatal bleeding (OR: 2.26; 95% CI: 1.25-4.08; P = 0.007; I2 = 0%) and a similar risk of gastrointestinal hemorrhage. Bleeding outcomes between other NOACs (apixaban and dabigatran etexilate) and aspirin were not different. CONCLUSIONS: The bleeding risks associated with NOACs depend on drug type and dosage. For ≥15 mg/day of rivaroxaban, the risk of ICH was significantly higher than that with aspirin. However, further studies comparing dabigatran etexilate and apixaban versus aspirin are warranted to draw a definite conclusion.

Corrigendum: Acute Myocardial Infarction Detection Using Deep Learning-Enabled Electrocardiograms.

[This corrects the article DOI: 10.3389/fcvm.2021.654515.].

Acute Myocardial Infarction Detection Using Deep Learning-Enabled Electrocardiograms.

Background: Acute myocardial infarction (AMI) is associated with a poor prognosis. Therefore, accurate diagnosis and early intervention of the culprit lesion are of extreme importance. Therefore, we developed a neural network algorithm in this study to automatically diagnose AMI from 12-lead electrocardiograms (ECGs). Methods: We used the open-source PTB-XL database as the training and validation sets, with a 7:3 sample size ratio. Twenty-One thousand, eight hundred thirty-seven clinical 12-lead ECGs from the PTB-XL dataset were available for training and validation (15,285 were used in the training set and 6,552 in the validation set). Additionally, we randomly selected 205 ECGs from a dataset built by Chapman University, CA, USA and Shaoxing People's Hospital, China, as the testing set. We used a residual network for training and validation. The model performance was experimentally verified in terms of area under the curve (AUC), precision, sensitivity, specificity, and F1 score. Results: The AUC of the training, validation, and testing sets were 0.964 [95% confidence interval (CI): 0.961-0.966], 0.944 (95% CI: 0.939-0.949), and 0.977 (95% CI: 0.961-0.991), respectively. The precision, sensitivity, specificity, and F1 score of the deep learning model for AMI diagnosis from ECGs were 0.827, 0.824, 0.950, and 0.825, respectively, in the training set, 0.789, 0.818, 0.913, and 0.803, respectively, in the validation set, and 0.830, 0.951, 0.951, and 0.886, respectively, in the testing set. The AUC for automatic AMI location diagnosis of LMI, IMI, ASMI, AMI, ALMI were 0.969 (95% CI: 0.959-0.979), 0.973 (95% CI: 0.962-0.978), 0.987 (95% CI: 0.963-0.989), 0.961 (95% CI: 0.956-0.989), and 0.996 (95% CI: 0.957-0.997), respectively. Conclusions: The residual network-based algorithm can effectively automatically diagnose AMI and MI location from 12-lead ECGs.

Trimethylamine N-oxide is associated with coronary atherosclerotic burden in non-ST-segment myocardial infarction patients: SZ-NSTEMI prospective cohort study.

Trimethylamine N-oxide (TMAO) is reported to accelerate atherosclerosis and the development of adverse cardiac outcomes. Relationship between coronary atherosclerotic burden and TMAO has been examined in stable coronary artery disease and ST-segment elevation myocardial infarction, but not in non-ST-segment elevation myocardial infarction (NSTEMI). We examined the association between TMAO and coronary atherosclerotic burden in NSTEMI. In this prospective cohort study, two groups including NSTEMI (n = 73) and age-sex matched Healthy (n = 35) individuals were enrolled between 2019 and 2020. Coronary atherosclerotic burden was stratified based on the number of diseased coronary vessels and clinical risk scores including SYNTAX and GENSINI. Fasting plasma TMAO was measured by isotope dilution high-performance liquid chromatography. The median plasma TMAO levels were significantly higher in the NSTEMI group than in the Healthy group, respectively (0.59 µM; interquartile range [IQR]: 0.43-0.78 versus 0.42 µM; IQR: 0.33-0.64; P = 0.006). Within the NSTEMI group, higher TMAO levels were observed in the multivessel disease (MVD) versus single vessel disease (P = 0.002), and intermediate-high risk (score ≥ 23) versus low risk (score < 23) of SYNTAX (P = 0.003) and GENSINI (P = 0.005). TMAO level remained an independent predictor of MVD (odds ratio [OR]: 5.94, P = 0.005), intermediate-high risk SYNTAX (OR: 3.61, P = 0.013) and GENSINI scores (OR: 4.60, P = 0.008) following adjustment for traditional risk factors. Receiver operating characteristic curve (AUC) analysis for TMAO predicted MVD (AUC: 0.73, 95% confidence interval [Cl]: 0.60-0.86, P = 0.002), intermediate-high SYNTAX score (AUC: 0.70, 95% Cl: 0.58-0.82, P = 0.003) and GENSINI score (AUC: 0.70, 95% Cl: 0.57-0.83, P = 0.005). In all, TMAO levels are independently associated with high coronary atherosclerotic burden in NSTEMI.

The prognostic value of the triglyceride glucose index in patients with chronic heart failure and type 2 diabetes: A retrospective cohort study.

AIMS: The triglyceride glucose (TyG) index is a marker of insulin resistance. However, the prognostic value thereof in patients with chronic heart failure (CHF) and type 2 diabetes remains unclear. METHODS: This study included patients diagnosed with CHF and type 2 diabetes in Fuwai Hospital of Chinese Academy of Medical Sciences, Shenzhen, from January 2017 to July 2019. The primary endpoint was cardiovascular death or rehospitalization for heart failure. RESULTS: The study included 546 patients with CHF and type 2 diabetes. We divided the patients into three groups (T1 [TyG index < 8.55], T2 [TyG index ≥ 8.55 and < 9.06], and T3 [TyG index ≥ 9.06]) according to the TyG index level. The incidence of the primary outcome in the T3 group was significantly higher than that in the T1 group. There was no significant difference between the T1 and T2 groups. The trend test revealed a positive correlation between the TyG index and the incidence of the primary outcome (P = 0.001). CONCLUSIONS: There is a positive correlation between the TyG index and the prognosis of patients with CHF and type 2 diabetes.

Mass spectrometric analysis of enzymatic digestion of denatured collagen for identification of collagen type.

Collagen type II and I from bovine were thermally denatured and digested with trypsin. The digest mixture was analyzed with liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS). Peptides in the digest mixture were identified by mass spectrometry/mass spectrometry (MS/MS) sequencing. The results indicated that the digest mixtures of collagen type II and I contained lots of specific peptides and common peptides. Specific peptides could be used as index for identifying collagen type. Articular cartilage from bovine was pretreated and analyzed with the same method to determine the collagen types. The result indicated that the method developed was effective for identification of collagen types. The research provided a possible approach for collagen identification in particular tissues.