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Graphical abstract, Highlights • MRSA infection is a global threat to public health. • Vancomycin is one of the first-line drugs for the treatment of MRSA infections. • MRSA with complete resistance to vancomycin have emerged in recent years. • The total number of VRSA isolates is updated in this paper. • Resistance mechanisms, characteristics of VRSA infections, as well as clinical treatments are reviewed., The infection caused by methicillin-resistant Staphylococcus aureus (MRSA) is a global threat to public health. Vancomycin remains one of the first-line drugs for the treatment of MRSA infections. However, S. aureus isolates with complete resistance to vancomycin have emerged in recent years. Vancomycin-resistant S. aureus (VRSA) is mediated by a vanA gene cluster, which is transferred from vancomycin-resistant enterococcus. Since the first VRSA isolate was recovered from Michigan, USA in 2002, 52 VRSA strains have been isolated worldwide. In this paper, we review the latest progresses in VRSA, highlighting its resistance mechanism, characteristics of VRSA infections, as well as clinical treatments.

Background. Danshen Decoction comprises Salvia miltiorrhiza, Santalum album, and Amomum villosum. It can promote blood circulation and remove blood stasis, and is commonly used in the treatment of gastric and duodenal ulcers, coronary heart disease, angina pectoris, etc. This research is based on network pharmacology and is experimentally verified to explore the potential mechanism of Danshen Decoction in the treatment of ischemic cardiomyopathy (ICM). Methods. The effective components and targets of Danshen Decoction were firstly extracted from Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and Analysis Platform, the drug-component-target-disease network was then constructed, the protein-protein interaction (PPI) network was constructed, the Gene Ontology (GO) enrichment analysis was carried out, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was analyzed in order to find the potential active components and therapeutic mechanisms. Finally, the in vitro hypoxia/reoxygenation model in H9c2 cells was established to verify the predicted active components and therapeutic mechanisms. Results. The results showed that Danshen Decoction has 67 potential active components and 109 therapeutic targets in treating ICM. These targets were rich in a variety of gene functions and different signaling pathways; the main gene targets include TP53, c-Jun, and Akt1. Go enrichment analysis showed that response to drug, membrane raft, and G protein-coupled amine receiver activity rank first in each process, and the main signaling pathways include PI3K-Akt signaling pathway. Through molecular docking and experimental verification of the major active components and core therapeutic targets, the active components of Danshen Decoction demonstrated an ability to reduce the cell damage caused by hypoxia/reoxygenation in H9c2 cells by regulating the core therapeutic target including Akt1, c-Jun, and TP53. Conclusion. Danshen Decoction has the effect of treating ICM in multiple ways, which is consistent with the results of network pharmacology. This laid a foundation for further study in exploring the active principles and pharmacological mechanism of Danshen Decoction.

Background. Our previous studies have demonstrated a protective role of Zhilong Huoxue Tongyu capsule in atherosclerosis (AS); however, the molecular mechanisms are unclear. Methods. Human coronary artery endothelial cells (HCAECs) were induced with oxidized low-density lipoprotein (ox-LDL) to obtain cellular AS models. Then, the medicated serum of Zhilong Huoxue Tongyu capsule was obtained and used for treatment with ox-LDL-induced HCAECs. The cell viability was detected by CCK-8 assay. Besides, the binding between miR-30b-5p and NLRP3 was determined by the dual-luciferase reporter gene system assay. Furthermore, ox-LDL-induced HCAECs were transfected with miR-30b-5p mimic or miR-30b-5p inhibitor. The pyroptosis of HCAECs was assessed by flow cytometry, LDH content detection, and qRT-PCR assays. Results. 10% medicated serum of Zhilong Huoxue Tongyu capsule was the maximum nontoxic concentration and it was used in subsequent assays. The rate of pyroptosis, LDH content, and the mRNA expression level of pyroptosis-related genes including NLRP3, ASC, Caspase 1, IL-1β, and IL-18 were prominently enhanced after HCAECs were induced by ox-LDL, which were markedly rescued with medicated serum of Zhilong Huoxue Tongyu capsule. In addition, the medicated serum of Zhilong Huoxue Tongyu capsule significantly enhanced the ox-LDL-induced reduction of miR-30b-5p level. NLRP3 could bind to miR-30b-5p and was negatively corrected with miR-30b-5p. Moreover, all the rates of pyroptosis, LDH content, and the mRNA expression levels of pyroptosis-related genes including NLRP3, ASC, Caspase 1, IL-1β, and IL-18 were further observably decreased after ox-LDL-induced HCAECs treated with medicated serum were transfected with miR-30b-5p mimic, while these were significantly rescued with transfection of miR-30b-5p inhibitor. Conclusion. Zhilong Huoxue Tongyu capsule alleviated the pyroptosis of vascular endothelial cells induced by ox-LDL through miR-30b-5p/NLRP3.

The increased drug resistance and metastasis of melanoma resulted in poor prognosis of patients. Here, we designed and synthesized a novel hemicyanine-based fluorescent probe ZWZ-3, and investigated its application for melanoma imaging and treatment both in vitro and in vivo. ZWZ-3 preferentially accumulated in melanoma cells via a process that depended on the organic anion-transporting polypeptide (OATP), which targeted mitochondria on the hemicyanine cationic nitrogen. In addition, we investigated the effect and molecular mechanism of ZWZ-3 in melanoma. In vitro studies showed that ZWZ-3 promoted the generation of reactive oxygen species and induced mitochondrial-mediated cell apoptosis by upregulating Bax and activating caspase-3, caspase-9, and PARP. Importantly, ZWZ-3 also induced autophagy by upregulating LC-3II and Atg5 and downregulating P62. It significantly suppressed tumor growth of A375 xenograft tumor in mice without notable side effects. Histological and immunohistochemical analyses revealed that ZWZ-3 induced apoptosis and inhibited tumor cell proliferation. Thus, ZWZ-3 represents a novel theranostic agent that can be used to effectively targeting, detecting, and treating melanoma. It could also help monitoring disease progression and response to treatment.

Life is indeed continuously going through the irreversible and inevitable process of aging. The rate of aging process depends on various factors and varies individually. These factors include various environmental stimuli including exposure to toxic chemicals, psychological stress whereas suffering with various illnesses specially the chronic diseases serve as endogenous triggers. The basic underlying mechanism for all kinds of stresses is now known to be manifested as production of excessive ROS, exhaustion of ROS neutralizing antioxidant enzymes and proteins leading to imbalance in oxidation and antioxidant processes with subsequent oxidative stress induced inflammation affecting the cells, tissues, organs and the whole body. All these factors lead to conventional cell death either through necrosis, apoptosis, or autophagy. Currently, a newly identified mechanism of iron dependent regulated cell death called ferroptosis, is of special interest for its implication in pathogenesis of various diseases such as cardiovascular disease, neurological disorders, cancers, and various other age-related disorders (ARD). In ferroptosis, the cell death occur neither by conventional apoptosis, necrosis nor by autophagy, rather dysregulated iron in the cell mediates excessive lipid peroxidation of accumulated lethal lipids. It is not surprising to assume its role in aging as previous research have identified some solid cues on the subject. In this review, we will highlight the factual evidences to support the possible role and implication of ferroptosis in aging in order to declare the need to identify and explore the interventions to prevent excessive ferroptosis leading to accelerated aging and associated liabilities of aging.

This study aims to screen potential anticoagulant components from leeches, a representative animal-sourced traditional Chinese medicine using thrombin (THR)-targeted ultrafiltration combined with ultrahigh performance liquid chromatography and high-resolution Orbitrap mass spectrometry (UPLC-HR-Orbitrap-MS). As a result, five small molecules in leech extract were discovered to interact with THR for the first time. Among them, two new compounds were isolated and their structures were identified by IR, HR-MS and NMR data. Furthermore, their THR inhibitory activity was confirmed with IC50 values of 4.74 and 8.31 μM, respectively. In addition, molecular docking analysis showed that the active (catalytic) site of THR might be the possible binding site of the two hits. Finally, reverse screening analysis indicated that LTA4-H, ACE and ALOX5AP were potential anticoagulant targets of the two new compounds. This study will broaden our understanding of the medicinal substance basis in leeches and further contribute to the discovery and development of clinical anticoagulant drugs from leeches.

The industrial Internet of Things (IIoT) can facilitate industrial upgrading, intelligent manufacturing, and lean production. Industrial control system (ICS) is a vital support mechanism for many key infrastructures in the IIoT. However, natural defects in the ICS network security mechanism and the susceptibility of the programmable logic controller (PLC) program to malicious attack pose a threat to the safety of national infrastructure equipment. To improve the security of the underlying equipment in ICS, a model checking method based on timed automata is proposed in this work, which can effectively model the control process and accurately simulate the system state when incorporating time factors. Formal analysis of the ICS and PLC is then conducted to formulate malware detection rules which can constrain the normal behavior of the system. The model checking tool UPPAAL is then used to verify the properties by detecting whether there is an exception in the system and determine the behavior of malware through counter-examples. The chemical reaction control system in Tennessee-Eastman process is taken as an example to carry out modeling, characterization, and verification, and can effectively detect multiple patterns of malware and propose relevant security policy recommendations.

Venenum Bufonis (VB), also called Chan Su in China, has been extensively used as a traditional Chinese medicine (TCM) for treating heart failure (HF) since ancient time. However, the active components and the potential anti-HF mechanism of VB remain unclear. In the current study, the major absorbed components and metabolites of VB after oral administration in rats were first collected from literatures. A total of 17 prototypes and 25 metabolites were gathered. Next, a feasible network-based pharmacological approach was developed and employed to explore the therapeutic mechanism of VB on HF based on the collected constituents. In total, 158 main targets were screened out and considered as effective players in ameliorating HF. Then, the VB components–main HF putative targets–main pathways network was established, clarifying the underlying biological process of VB on HF. More importantly, the main hubs were found to be highly enriched in adrenergic signalling in cardio-myocytes. After verified by molecular docking studies, four key targets (ATP1A1, GNAS, MAPK1 and PRKCA) and three potential active leading compounds (bufotalin, cinobufaginol and 19-oxo-bufalin) were identified, which may play critical roles in cardiac muscle contraction. This study demonstrated that the integrated strategy based on network pharmacology and molecular docking was helpful to uncover the synergistic mechanism of multiple constituents in TCM.

Osteosarcoma is a primary bone malignancy with a high rate of recurrence and poorer prognosis. Therefore, it is of vital importance to explore novel prognostic molecular biomarkers and targets for more effective therapeutic approaches. Previous studies showed that histone demethylase KDM5A can increase the proliferation and metastasis of several cancers. However, the function of KDM5A in the carcinogenesis of osteosarcoma is not clear. In the current study, KDM5A was highly expressed in osteosarcoma than adjacent normal tissue. Knockdown of KDM5A suppressed osteosarcoma cell proliferation and induced apoptosis. Moreover, knockdown of KDM5A could increase the expression level of P27 (cell-cycle inhibitor) and decrease the expression of Cyclin D1. Furthermore, after knockout of KDM5A in osteosarcoma cells by CRISPR/Cas9 system, the tumor size and growth speed were inhibited in tumor-bearing nude mice. RNA-Seq of KDM5A-KO cells indicated that interferon, epithelial–mesenchymal transition (EMT), IL6/JAK/STAT3, and TNF-α/NF-κB pathway were likely involved in the regulation of osteosarcoma cell viability. Taken together, our research established a role of KDM5A in osteosarcoma tumorigenesis and progression.

Since the sudden epidemic of coronavirus disease 2019 (COVID-19), the State Administration of Traditional Chinese Medicine immediately organized experts to formulate and screen the effective prescriptions of traditional Chinese medicine according to the characteristics of the novel coronavirus infection. Qingfei Paidu decoction (QFPDD) has been proven to be effective in multi-provincial clinical trials, and has been selected as a general prescription for the treatment of COVID-19 in different stages that was later promoted to be used nationwide. This review highlights the latest advances of QFPDD, focusing on the TCM theory, mechanism analysis, clinical application of QFPDD and its future perspectives. Moreover, an in-depth discussion of some valuable issues and possible development for future research on QFPDD is also discussed, aiming to provide a novel guide to combat the global epidemic COVID-19.

Ethnopharmacological relevance Cardiovascular and cerebrovascular diseases have become a severe threat for human health worldwide, however, optimal therapeutic options are still developed. Zhilong Huoxue Tongyu capsule (ZL capsule) is mainly composed of Astragalus membranaceus, Leech, Earthworm, Cinnamomum cassia and Sargentodoxa cuneata, having functions of replenishing qi and activating blood, dispelling wind and reducing phlegm. It is an expanded application on the basis of traditional uses of above TCMs, acquiring a satisfactory curative effect on cardiovascular and cerebrovascular diseases over twenty years. Aim of the study To comprehensively summarize the main components of ZL capsule, understand the mechanisms of ZL capsule, and conclude clinical regimens of ZL capsule for cardiovascular and cerebrovascular diseases. Materials and methods We selected network pharmacology technology to analyze main active compounds and predict underlying mechanism of ZL capsule against atherosclerosis. Molecular docking was performed to simulate the interaction pattern between the active components of ZL capsule and putative targets. Further, PubMed, Web of Science, China National Knowledge Infrastructure and Google Scholar were used to search literatures, with the key words of “Zhilong Huoxue Tongyu capsule”, “cardiovascular and cerebrovascular diseases”, “atherosclerosis”, “clinical study” and their combinations, mainly from 2000 to 2020. Results Both network pharmacology analysis, molecular docking and animal experiments studies confirmed that mechanisms of ZL capsule plays the role of anti-inflammatory, anti-apoptosis and promoting angiogenesis in treating cardiovascular and cerebrovascular diseases by multi-components acting on multi-targets via multi-pathways. Over 1000 clinical cases were benefited from the treatment of ZL capsule, suggesting a holistic concept of “the same therapy for different myocardial and cerebral diseases”. Conclusions For the first time, this systematic review may supply meaningful information for further studies to explore material basis and pharmacodynamics of ZL capsule and also provide a basis for sharing the “Chinese patent medicine” for cardiovascular and cerebrovascular diseases.

DEP domain containing 1 (DEPDC1) functions as an oncogene in hepatocellular carcinoma (HCC). However, the underlying mechanism of DEPDC1 remains largely unknown. The present study revealed that DEPDC1 knockdown inhibited HCC cell proliferation, colony formation and invasion in vitro and suppressed the growth of HCC xenografts in vivo. Furthermore, DEPDC1 overexpression promoted HCC cell proliferation, colony formation and invasion. DNA microarray, reverse transcription-quantitative-PCR and western blotting results demonstrated that DEPDC1 knockdown in Huh-7 significantly inhibited the expression of chemokine (C-C motif) ligand 20 (CCL20) and chemokine (C-C motif) receptor 6 (CCR6). In addition, the expression of CCL20 and CCR6 were upregulated in HCC tissues and cell lines, and were positively correlated with DEPDC1 expression. CCL20 or CCR6 knockdown via small interfering RNA reversed the effects of DEPDC1 overexpression in HCC cells. Furthermore, it was revealed that conditioned medium from DEPDC1 upregulated Li-7 and Hep3B cells led to angiogenesis in vitro, whereas CCL20 knockdown in Li-7 and Hep3B cells or CCR6 knockdown in human umbilical vein endothelial cells reversed the angiogenic effect of DEPDC1 overexpression. In conclusion, DEPDC1 facilitated cell proliferation, invasion and angiogenesis via the CCL20/CCR6 pathway in HCC.

miRNAs are crucial regulators of angiogenesis, but there have been no detailed studies on the role of miR-191-5p in cerebral infarct angiogenesis. Here, we investigated the role of miR-191-5p in regulating cerebral infarction angiogenesis.Mice were injected intracerebroventricularly with antagomir negative control (NC-antagomir), miR-191-5p antagomir, or pcDNA-BDNF 2 h before middle cerebral artery occlusion (MCAO), followed by neurobehavioral score and foot-fault test. The cerebral infarct volume was performed by TTC staining. The microvessel density was detected by FITC-dextran. RT-qPCR was used to detect the levels of miR-191-5p and its target gene BDNF. Western blotting was applied to detect the protein levels of BDNF. The luciferase reporter assay verified that miR-191-5p targeted BDNF.We found an increased level of miR-191-5p in the brain tissue of mice to MCAO. Down-regulation of miR-191-5p reduced the infarct volume and ameliorated neurological deficits in MCAO mice. Further investigation showed that miR-191-5p directly targeted BDNF and that the protective effect of miR-191-5p inhibition in angiogenesis was achieved by regulating BDNF.Our results indicated that miR-191-5p disturbed the angiogenesis in the mouse models of cerebral infarction by inhibiting BDNF.

The state assessment of automation equipment in smart substations requires not only more accurate evaluation, but also the revision of the evaluation system in the future as technology evolves. According to the comprehensive concept of interval value fuzzy soft set and the analytic hierarchy process, a method for state evaluation of substation automation equipment is proposed. The evaluation index system is established by analyzing the off line status and online status information of the substation automation equipment. The comprehensive concept of interval value fuzzy soft set is introduced, and the index state is evaluated and its weight coefficient is calculated. This establishes an evaluation system with small calculation, high flexibility and strong expandability. The running example analysis shows that the state evaluation method is beneficial to accurately judge the real operating state of the substation automation equipment.

5-hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter in the modulation of the cognitive, behavioral and psychological functions in animals and humans. Among the fourteen subtypes of 5-HT receptor, 5-HT1A receptor has been extensively studied. Tandospirone, an azapirone derivative with strong and selective agonist effect on 5-HT1A receptor, has been used for the treatment of anxiety disorders especially generalized anxiety disorder for decades. Recently, tandospirone showed the efficacy in relieving the syndromes of social anxiety disorder and post-traumatic stress disorder as well as in potentiating the effect of antidepressants in the treatment of depression in both preclinical and clinical studies. More impressively, the beneficial effect of tandospirone has been revealed on improvement of motor dysfunction of Parkinson's disease and cognitive deficits of schizophrenia either in monotherapy or in combination with other drugs. This review discusses the superiority of tandospirone in the treatment of the disorders and associated mechanisms in central nervous system from the literature.

// Yan Shi 1, * , Sijin Yang 2, * , Man Luo 3 , Wei-Dong Zhang 4 and Zun-Ping Ke 5 1 Department of Emergency, The Affiliated Huai′an Hospital of Xuzhou Medical University and The Second People′s Hospital of Huai′an, Huai′an, China 2 Department of Heart Encephalopathy, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China 3 Department of Emergency, Huai′an First People′s Hospital, Nanjing Medical University, Huai′an, China 4 Department of Cardiology, People’s Hospital of Xuyi, Jiangsu, Xuyi, China 5 Department of Cardiology, The Fifth People′s Hospital of Shanghai, Fudan University, Shanghai, China * Co-first authors Correspondence to: Wei-Dong Zhang, email: xyxrmyy@163.com Zun-Ping Ke, email: kzprenmin@163.com Keywords: coronary artery disease, systematic analysis, microarray, gene expression omnibus (GEO), neutrophil degranulation Received: February 13, 2017 Accepted: March 29, 2017 Published: April 26, 2017 ABSTRACT Coronary artery disease caused about 1 of every 7 deaths in the United States and early prevention was potential to decrease the incidence and mortality. We aimed to figure the genes involving in the coronary artery disease using meta-anlaysis. Five datasets of coronary heart disease from GEO series were retrieved and data preprocessing and quality control were carried out. Moderated t-test was used to decide the differentially expressed genes for a single dataset. And the combined p-value using systematic-analysis methods were conducted using MetaDE. The pathway enrichment was carried out using Reactome database. Protein-protein interactions of the identified differentially expressed genes were also analyzed using STRING v10.0 online tool. After removing unidentified or intermediate samples and a total of 238 cases and 189 matched or partially matched control from five microarray datasets were retrieved from GEO. Six different quality control measures were calculated and PCA biplots were plotted in order to visualize the quantitative measure. The first two PCs captured 91% of the variance and we decided to include all of the datasets for systematic analysis. Using the FDR cut-off as 0.1, nine genes, including LFNG, ID3, PLA2G7, FOLR3, PADI4, ARG1, IL1R2, NFIL3 and MGAM, were differentially expressed according to maxP. Their protein-protein interactions showed that they were closely connected and 24 Reactome pathways were related to coronary artery disease. We concluded that pathways related to immune responses, especially neutrophil degranulation, were associated with coronary heart disease.