Federated Active Learning Framework for Efficient Annotation Strategy in Skin-Lesion Classification.

Federated learning (FL) enables multiple institutes to train models collaboratively without sharing private data. Current FL research focuses on communication efficiency, privacy protection, and personalization and assumes that the data of FL have already been ideally collected. However, in medical scenarios, data annotation demands both expertise and intensive labor, which is a critical problem in FL. Active learning (AL) has shown promising performance in reducing the number of data annotations in medical image analysis. We propose a federated AL framework in which AL is executed periodically and interactively under FL. We exploit a local model in each hospital and a global model acquired from FL to construct an ensemble. We use ensemble entropy-based AL as an efficient data-annotation strategy in FL. Therefore, our federated AL framework can decrease the amount of annotated data and preserve patient privacy while maintaining the performance of FL. To our knowledge, this federated AL framework applied to medical images has not been previously reported. We validated our framework on real-world dermoscopic datasets. Using only 50% of samples, our framework was able to achieve state-of-the-art performance on a skin-lesion classification task. Our framework performed better than several state-of-the-art AL methods under FL and achieved comparable performance with full-data FL.

Discovery of a Novel ASM Direct Inhibitor with a 1,5-Diphenyl-pyrazole Scaffold and Its Antidepressant Mechanism of Action.

Multiple studies have confirmed that acid sphingomyelinase (ASM) activity is associated with depression. The discovery of direct inhibitors against ASM is of great significance for exploring antidepressants and their mechanisms of action. Herein, a series of novel phenylpyrazole analogues were rationally designed and synthesized. Among them, compound 46 exhibited potent inhibitory activity (IC50 = 0.87 µM) and good drug-like properties. In vivo studies demonstrated that compound 46 was involved in multiple antidepressant mechanisms of action, which were associated with a decline of ceramide, including increasing the Bcl-2/Bax ratio and BDNF expression, down-regulating caspase-3 and caspase-9, ameliorating oxidative stress, reducing the levels of proinflammatory cytokines such as TNF-α, IL-1ß, and IL-6, and elevating 5-HT levels in the brains of mice, respectively. These meaningful results reveal for the first time that direct inhibitors exhibit remarkable antidepressant effects in the CUMS-induced mouse model through multiple mechanisms of antidepressant action.

Insight into Cardioprotective Effects and Mechanisms of Dexmedetomidine.

PURPOSE: Cardiovascular disease remains the leading cause of death worldwide. Dexmedetomidine is a highly selective α2 adrenergic receptor agonist with sedative, analgesic, anxiolytic, and sympatholytic properties, and several studies have shown its possible protective effects in cardiac injury. The aim of this review is to further elucidate the underlying cardioprotective mechanisms of dexmedetomidine, thus suggesting its potential in the clinical management of cardiac injury. RESULTS AND CONCLUSION: Our review summarizes the findings related to the involvement of dexmedetomidine in cardiac injury and discusses the results in the light of different mechanisms. We found that numerous mechanisms may contribute to the cardioprotective effects of dexmedetomidine, including the regulation of programmed cell death, autophagy and fibrosis, alleviation of inflammatory response, endothelial dysfunction and microcirculatory derangements, improvement of mitochondrial dysregulation, hemodynamics, and arrhythmias. Dexmedetomidine may play a promising and beneficial role in the treatment of cardiovascular disease.

Dexmedetomidine abates myocardial ischemia reperfusion injury through inhibition of pyroptosis via regulation of miR-665/MEF2D/Nrf2 axis.

The current study intended to delve into the mechanisms of dexmedetomidine (Dex) in regulating myocardial pyroptosis against myocardial ischemia/reperfusion injury (MIRI). The rat MIRI models were induced by ligation/release of the coronary artery in vivo and Langendorff perfusion ex vivo. Hemodynamic parameters, infarction sizes, and histopathological changes were assessed to understand the effects of Dex on MIRI. We explored the mechanisms through functional experiments on an H9c2 cell hypoxia/reoxygenation (H/R) model. Cell viability and apoptosis were evaluated using cell counting kit 8 (CCK-8) and AV/PI dual staining respectively. The expressions of miR-665 and MEF2D mRNA were detected by qRT-PCR. Western blot was employed to determine the expression levels of pyroptosis- and signaling pathway- related proteins. The interplays between miR-665 and MEF2D were validated by Dual-luciferase reporter assays. Our findings indicated that Dex preconditioning dramatically attenuated hemodynamic derangements, infarct size, and histopathological damage in rats undergoing MIRI. Dex markedly augmented cell viability, while suppressing cell apoptosis and expressions of NLRP3, cleaved-caspase-1, ASC, GSDMD, IL-1ß, and IL-18 in H9c2 cells subjected to H/R injury. MiR-665 was significantly upregulated, MEF2D and Nrf2 downregulated following H/R, whereas Dex preconditioning reversed these changes. MEF2D was validated to be a target gene of miR-665. Overexpression of miR-665 decreased the expression of MEF2D and blunted the protective effects of Dex in H9c2 cells. Moreover, the functional rescue experiment further verified that Dex regulated MEF2D/Nrf2 pathway via miR-665. In conclusion, Dex mitigates MIRI through inhibiting pyroptosis via regulating miR-665/MEF2D/Nrf2 axis.

Oxytocin ameliorates high glucose- and ischemia/reperfusion-induced myocardial injury by suppressing pyroptosis via AMPK signaling pathway.

The present study aimed to explore the role of oxytocin (OT) in myocardial injury induced by ischemia/reperfusion (I/R) and hyperglycemia and its underlying mechanisms. In this study, the isolated rat hearts underwent I/R in Langendorff perfusion model and H9c2 cells were subjected to hypoxia/reoxygenation (H/R) to establish an in vitro model. I/R injury was induced by exposing the rat hearts to 40 min of global ischemia followed by 60 min of reperfusion. H9c2 cells were cultured under the normoglycemic or hyperglycemic condition with or without pretreatment of OT, and then exposed to 4 h of hypoxia and 2 h of reoxygenation. Measurement indicators included myocardial infarct size assessed by triphenyltetrazolium chloride (TTC) staining and hemodynamic parameters in the ex vivo model as well as cell viability detected by cell counting kit 8 (CCK-8), apoptotic rate evaluated by flow cytometry, and the protein expressions by Western blot. The findings demonstrated that OT attenuated myocardial I/R injury. First, OT preconditioning significantly reduced hemodynamic disorders and myocardial infarct sizes. In addition, OT increased cell viability, decreased cell apoptosis and the expressions of IL-18, IL-1ß, cleaved-caspase-1, NLRP3, and GSDMD following H/R. NLRP3 activator nigericin eliminated the beneficial effects of OT in H9c2 cells. Furthermore, OT also activated AMPK and decreased the expressions of pyroptosis-related proteins. Administration of AMPK inhibitor compound C blunted OT-induced AMPK phosphorylation and elevated the expressions of pyroptosis-related proteins in H9c2 cells subjected to H/R with hyperglycemia. OT alleviates myocardial I/R injury with hyperglycemia by inhibiting pyroptosis via AMPK/NLRP3 signaling pathway.

Dexmedetomidine attenuates myocardial ischemia/reperfusion-induced ferroptosis via AMPK/GSK-3ß/Nrf2 axis.

The present study aimed to investigate whether dexmedetomidine (Dex) exerts cardioprotection effect through inhibiting ferroptosis. Myocardial ischemia/reperfusion injury (MIRI) was induced in Sprague-Dawley rats in Langendorff preparation. The hemodynamic parameters were recorded. Triphenyltetrazolium chloride (TTC) staining was used to determine infarct size. In the in vitro study, the model of hypoxia/reoxygenation (HR) was established in H9c2 cells. Cell viability and apoptosis were detected using cell counting kit 8 (CCK-8), and AV/PI dual staining respectively. Lipid peroxidation as measured by the fluorescence of the fatty acid analog C11-BODIPY581/591 probe and intracellular ferrous iron levels were measured by fluorescence of Phen Green SK (PGSK) probe, whereas immunofluorescence and transmission electron microscopy were also used to examine ferroptosis. Protein levels were investigated by Western blot. The interactions of AMPK/GSK-3ß signaling with Nrf2 were also assessed through AMPK inhibition and GSK-3ß overexpression. Our findings indicated that Dex significantly alleviated myocardial infarction, improved heart function, and decreased HR-induced accumulation of Fe2+ and lipid peroxidation in cardiomyocytes. Dex significantly increased the expression levels of Nrf2, SLC7A11, and GPX4. However, inhibition of Nrf2 by ML385 blunted the protective effect of Dex in HR-treated H9c2 cells. Inhibition of AMPK with a specific inhibitor or siRNA decreased the expression levels of phosphorylation of GSK-3ß and Nrf2 induced by Dex. Overexpression of GSK-3ß resulted in lower levels of nuclear Nrf2, whereas depression of GSK-3ß enhanced expressions of nuclear Nrf2. In conclusion, Dex protects hearts against MIRI-induced ferroptosis via activation of Nrf2 through AMPK/GSK-3ß signaling pathway.

A review of the ethnopharmacology, phytochemistry and pharmacology of Cynanchumatratum.

ETHNOPHARMACOLOGICAL RELEVANCE: The dried roots and rhizomes of Cynanchum atratum Bunge is named 'Baiwei' according to traditional Chinese medicine theory. It is also named Cynanchi atrati Radix in Chinese Pharmacopoeia. Cynanchi atrati Radix is famous for its medicinal value of clearing away heat, relieving drenching, detoxifying and treating abscesses. It was commonly used in some Asian countries for the treatment of fever, vasoconstrictive syncope, lymphangitis and other diseases, obviously due to the effect of C21 steroidal glycosides. THE AIM OF THE REVIEW: The review concentrates on the botany, ethnopharmacology, phytochemistry, pharmacology and toxicology of Cynanchum atratum. We also discuss expectations for prospective research and implementation of this herb. MATERIALS AND METHODS: Relevant information about C. atratum was gained from ancient books and records, Doctoral and master's Theses, Science Direct, Pubmed, Wiley, CNKI, WanFang DATA, Google Scholar and other domestic and foreign literature. Some electronic databases have been included. RESULTS: As a member of the Apocynaceae family, C. atratum possesses its up-and-coming biological characteristics. It is widely reported for treating of postpartum fatigue, vomiting, urine drops, nephritis, urinary tract infection, edema, bronchitis and rheumatic low back pain. By now, over 100 compounds have been identified from C. atratum, including C21 steroidal glycosides, acetophenones, alkaloids, volatile oil and other ingredients. Activities such as anti-inflammatory, anti-tumor, anti-virus, antibacterial, anti-forgetful and others have been corroborated in vivo and in vitro. In addition, many of the active ingredients, such as Cynatratoside A, Cynanversicoside A, B, D, G, p-hydroxyacetophenone, 2,4-dihydroxyacetophenone and some volatile oils have been used as quality markers. CONCLUSION: All kinds of research conducted on C.atratum, especially in field of ethnopharmacological use, phytochemicals and pharmacology have been reviewed. The herb has been used over the years in treating nephritis, urinary tract infection, bronchitis and rheumatic lumbocrural pain. Many studies have been carried out to identify compounds that play a leading role in drug activity. However, the mechanism of drug therapy remains unclear. The evidence used to prove the quality standard of medicinal materials is obviously inadequate. Besides, safety evaluation is necessary for clinical medication. Similarly, the separation of steroidal saponins and the development of new drugs will also need further discussion.

Oxytocin Protects Against Isoproterenol-Induced Cardiac Hypertrophy by Inhibiting PI3K/AKT Pathway via a lncRNA GAS5/miR-375-3p/KLF4-Dependent Mechanism.

Cardiac hypertrophy is caused by cardiac volume or pressure overload conditions and ultimately leads to contractile dysfunction and heart failure. Oxytocin (OT), an endocrine nonapeptide, has been identified as a cardiovascular homeostatic hormone with anti-hypertrophic effects. However, the underlying mechanism remains elusive. In this study, we aimed to investigate the role and mechanism of OT in cardiac hypertrophy. The rats with cardiac hypertrophy induced by isoproterenol (ISO) were treated with or without oxytocin. Cardiac functional parameters were analyzed by echocardiography. The changes in cell surface area were observed using wheat germ agglutinin (WGA) or immunofluorescence staining. The expressions of cardiac hypertrophy markers (B-Natriuretic Peptide, BNP and ß-myosin heavy chain, ß-MHC), long non-coding RNA Growth (LcRNA) Arrest-Specific transcript 5 (lncRNA GAS5), miR-375-3p, and Kruppel-like factor 4 (Klf4) were detected by qRT-PCR. KLF4 protein and PI3K/AKT pathway related proteins were detected by Western blot. The interactions among lncRNA GAS5, miR-375-3p, and Klf4 were verified by dual-luciferase reporter assays. The findings showed that OT significantly attenuated cardiac hypertrophy, increased expressions of lncRNA GAS5 and KLF4, and decreased miR-375-3p expression. In vitro studies demonstrated that either knock-down of lncRNA GAS5 or Klf4, or over-expression of miR-375-3p blunted the anti-hypertrophic effects of OT. Moreover, down-regulation of lncRNA GAS5 promoted the expression of miR-375-3p and inhibited KLF4 expression. Similarly, over-expression of miR-375-3p decreased the expression of KLF4. Dual-luciferase reporter assays validated that lncRNA GAS5 could sponge miR-375-3p and Klf4 was a direct target gene of miR-375-3p. In addition, OT could inactivate PI3K/AKT pathway. The functional rescue experiments further identified OT regulated PI3K/AKT pathway through lncRNA GAS5/miR-375-3p/KLF4 axis. In summary, our study demonstrates that OT ameliorates cardiac hypertrophy by inhibiting PI3K/AKT pathway via lncRNA GAS5/miR-375-3p/KLF4 axis.

Optimization of the Purifying Process for Columbianetin-ß-D-Glucopyranoside from Angelicae Pubescentis Radix and Evaluation of Its Analgesic Activity Using Hot Plate Test.

The objective of this work was to provide an economic and practical method for the purification of columbianetin-ß-D-glucopyranoside from Angelicae Pubescentis Radix extract. In the static adsorption and desorption, the effects of resin type (D101, HP-20, AB-8, GDX-201, and DA201), contact time (10-360 min), and temperature (298-318 K) were assessed on columbianetin-ß-D-glucopyranoside adsorption efficiency in laboratory. GDX-201 resin showed the best adsorption and desorption properties for columbianetin-ß-D-glucopyranoside. The kinetic data revealed that the equilibrium time for columbianetin-ß-D-glucopyranoside adsorption was achieved within 150 min. Moreover, the adsorption kinetic curve was well in accordance with the pseudo-second-order equation (R 2 > 0.99). The rate controlling step of the adsorption process was the intraparticle diffusion. The Langmuir isotherm models (R 2 > 0.99) could describe the whole adsorption process, which was exothermic and spontaneous according to the result of thermodynamics tests. In the dynamic adsorption and desorption process, the optimum loading flow (4, 5, and 6 BV/h), ethanol concentration (0-60%), and elution volume (10-230 mL) were optimized. Under optimal conditions of 4 BV/h loading flow, 6.7 BV loading volume, 25% ethanol, and 14 BV elution volume, the content of columbianetin-ß-D-glucopyranoside in the product was increased 29.61-fold from 0.45% to 13.32 ± 0.64% with yield of 88.03 ± 2.76% by an experiment of lab-scale enlargement. Then, columbianetin-ß-D-glucopyranoside was further purified by PHPLC and its purity was more than 98%. Additionally, the analgesic activity of the columbianetin-ß-D-glucopyranoside was assessed by hot plate test. The experimental results showed that columbianetin-ß-D-glucopyranoside significantly increased the latency of pain response in mice. This study demonstrated columbianetin-ß-D-glucopyranoside could be as a potentially natural analgesic component. It could be summed up that the established method was successfully applied to purifying columbianetin-ß-D-glucopyranoside from Angelicae Pubescentis Radix extract.

Dexmedetomidine preconditioning mitigates myocardial ischemia/reperfusion injury via inhibition of mast cell degranulation.

The degranulation of cardiac mast cells is associated with occurrence and development of myocardial ischemia/reperfusion (I/R) injury. Dexmedetomidine has a cardioprotective effect from I/R injury. The purpose of this study was to investigate whether dexmedetomidine preconditioning induced cardioprotection is related to suppression of degranulation of cardiac mast cell. Both in vivo and in vitro experimental results revealed that hemodynamic disorder, arrhythmia, infarct size, histopathological score, and mast cell degranulation were dramatically increased in I/R injury groups compared with non-I/R groups, and mastocyte secretagogue compound 48/80 aggravated these damages, but it can be improved by dexmedetomidine preconditioning. Similarly, compound 48/80 increased levels of cardiac troponin I (cTnI) and tryptase, cardiomyocytes apoptosis, and expression of high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), and nuclear factor-kappa B p65 (NF-κB p65) in cardiac tissues induced by I/R injury, but it can be partially decreased by dexmedetomidine pretreatment. Compound 48/80 inhibited proliferation of H9C2(2-1) and RBL-2H3, exacerbated apoptosis of H9C2(2-1), and elevated levels of cTnI and tryptase, while both of which were abolished by dexmedetomidine pretreatment. Our data suggest that dexmedetomidine preconditioning alleviates the degranulation of mast cells and the apoptosis of cardiomyocytes caused by I/R injury, and inhibits the activation of inflammatory related factors HMGB1, TLR4, and NF-κB p65.