A Bibliometric Analysis of Research on Bacterial Persisters.

Background: In the past two decades, the surge of research on bacterial persisters has been inspired as increasingly concerning about the frequent failure of antibiotics treatment. This study was aimed at presenting a bibliometric and visualized analysis of relative publications on bacterial persisters, which offered insights into the development and research trends of this field. Methods: The Web of Science Core Collection and Ovid MEDLINE databases were utilized to retrieve relevant publications on bacterial persisters from 2001 to 2021. After manual selection, data including titles, authors, journals, author keywords, addresses, the number of citations, and publication years were subsequently extracted. The data analysis and visual mapping were conducted with Excel, SPSS, R studio, and VOSviewer. Results: In this study, 1,903 relevant publications on bacterial persisters were included. During 2001-2021, there was an exponential growth in the quantity of publications. It was found that these studies were conducted by 7,182 authors from 74 different countries. The USA led the scientific production with the highest total number of publications (859) and citation frequency (52,022). The Antimicrobial Agents and Chemotherapy was the most influential journal with 113 relevant publications. The cooccurrence analysis revealed that studies on bacterial persisters focused on four aspects: "the role of persisters in biofilms," "clinical persistent infection," "anti-persister treatment," and "mechanism of persister formation." Conclusion: In the past two decades, the global field of bacterial persisters has significantly increased. The USA was the leading country in this field. Mechanistic studies continued to be the future hotspots, which may be helpful to adopt new strategies against persisters and solve the problem of chronic infection in the clinic.

Cell membrane-camouflaged DOX-loaded ß-glucan nanoparticles for highly efficient cancer immunochemotherapy.

Biomimetics plays an important role in cancer treatment since it can prolong the circulation of nanoparticles, enhance their delivery and retention in target tissues, and reduce the systemic toxicity of drugs and their carriers. In this study, we developed a biomimetic nanosystem consisting of chemotherapeutic and immunotherapeutic agents wrapped in cell membranes. Specifically, the anti-tumor drug doxorubicin (DOX) was loaded into a bacterial-derived immunomodulatory agent (low molecular weight curdlan, lCUR), and the lCUR-DOX was further wrapped in the red blood cell membrane for camouflage and prolonged circulation. The successful preparation of the lCUR-DOX@RBC nanosystem was supported by various optical and morphological characterizations. In vitro studies indicated that the nanosystem can escape uptake by macrophages, inhibit the invasion of tumor cells, and reprogram M2 macrophages with an immunosuppressive phenotype into M1 macrophages with an immunopromoting phenotype via the MAPK signaling pathway while promoting the phagocytosis of macrophages. In vivo studies showed that the nanosystem effectively inhibits tumor growth in the A-375 tumor-bearing mouse model. Taken together, the above results support further development of the lCUR-DOX@RBC platform for cancer immunochemotherapy in clinical applications.

Single-helical formyl ß-glucan effectively deliver CpG DNA with poly(dA) to macrophages for enhanced vaccine effects.

Single helical ß-glucan is a one-dimensional host that can form a hybrid helix with DNAs/RNAs as delivery systems. However, unmodified ß-glucan has a gelling tendency and a single helical conformation is challenging to obtain. Therefore, in this study, we developed a ß-glucan formyl derivative with stable single helical conformation and no gelling tendency. Circular dichroism studies found that the formyl-ß-glucan could form a hybrid helix with DNA CpG-poly(dA). The hybrid helix delivery system showed improved activation on antigen-presenting cells, thereby upregulating the mRNA and protein levels of inflammatory factors, and had an immune-enhancing effect on ovalbumin (OVA) immunized mice. These results indicate that formyl-ß-glucan can be developed as a non-cationic supramolecular DNA delivery platform with low toxicity and high efficiency.

Macrophage-Targeted Berberine-Loaded ß-Glucan Nanoparticles Enhance the Treatment of Ulcerative Colitis.

Aim: This study focuses on constructing of an anti-inflammatory drug delivery system by encapsulation of berberine in the ß-glucan nanoparticles and evaluates its effect on treating ulcerative colitis. Methods: ß-Glucan and the anti-inflammatory drug berberine (BER) are self-assembled into nanoparticles to construct a drug delivery system (GLC/BER). The interaction between the drug and the carrier was characterized by circular dichroism, ultraviolet-visible spectroscopy, and dynamic light scattering. The anti-inflammatory effect of the GLC/BER was evaluated through a lipopolysaccharide (LPS)-induced RAW264.7 macrophage inflammation model and a sodium sulfate (DSS)-induced C57BL/6 mouse ulcerative colitis model. Results: The GLC/BER nanoparticles have a particle size of 80-120 nm and a high encapsulation efficiency of 37.8±4.21%. In the LPS-induced RAW264.7 macrophage inflammation model, GLC/BER significantly promoted the uptake of BER by RAW264.7 cells. RT-PCR and ELISA assay showed that it could significantly inhibit the inflammatory factors including IL-1ß, IL-6 and COX-2. Furthermore, GLC/BER shows inhibiting effect on the secretion of pro-inflammatory factors such as IL-1ß and IL-6, down-regulating the production of nitrite oxide; in animal studies, GLC/BER was found to exert a relieving effect on mice colitis. Conclusion: The study found that GLC/BER has an anti-inflammatory effect in vitro and in vivo, and the GLC carrier improves the potency and bioavailability of BER, providing a new type of nanomedicine for the treatment of colitis.

The top 100 cited studies on bacterial persisters: A bibliometric analysis.

Background: Bacterial persisters are thought to be responsible for the recalcitrance and relapse of persistent infections, and they also lead to antibiotic treatment failure in clinics. In recent years, researches on bacterial persisters have attracted worldwide attention and the number of related publications is increasing. The purpose of this study was to better understand research trends on bacterial persisters by identifying and bibliometrics analyzing the top 100 cited publications in this field. Methods: The Web of Science Core Collection was utilized to retrieve the highly cited publications on bacterial persisters, and these publications were cross-matched with Google Scholar and Scopus. The top 100 cited publications were identified after reviewing the full texts. The main information of each publication was extracted and analyzed using Excel, SPSS, and VOSviewer. Results: The top 100 cited papers on bacterial persisters were published between 1997 and 2019. The citation frequency of each publication ranged from 147 to 1815 for the Web of Science Core Collection, 153 to 1883 for Scopus, and 207 to 2,986 for Google Scholar. Among the top 100 cited list, there were 64 original articles, 35 review articles, and 1 editorial material. These papers were published in 51 journals, and the Journal of Bacteriology was the most productive journal with 8 papers. A total of 14 countries made contributions to the top 100 cited publications, and 64 publications were from the United States. 15 institutions have published two or more papers and nearly 87% of them were from the United States. Kim Lewis from Northeastern University was the most influential author with 18 publications. Furthermore, keywords co-occurrence suggested that the main topics on bacterial persisters were mechanisms of persister formation or re-growth. Finally, "Microbiology" was the most frequent category in this field. Conclusion: This study identified and analyzed the top 100 cited publications related to bacterial persisters. The results provided a general overview of bacterial persisters and might help researchers to better understand the classic studies, historical developments, and new findings in this field, thus providing ideas for further research.

Laminarin acetyl esters: Synthesis, conformational analysis and anti-viral effects.

Chemical modification of polysaccharides is important for expanding their applications and gaining new insights into their structure-property relationships. Here we reported the synthesis, characterization, and anti-viral activities of laminarin acetyl derivatives. The chemical structure and chain conformation of acetylated laminarin were characterized by FT-IR, H1 NMR, AFM, UV-vis spectrum, and induced circular dichroism based on a modified Congo Red assay (ICD-CR assay). The inhibition effect of laminarin and its acetyl derivatives on HSV-1 was evaluated by viral plaque assay and virus-associated DNA/protein change. Acetylation modification was found to trigger the conformation transition of laminarin from triple helix to single helix, and the extent of transition can be tuned by the degree of substitution. The single helical acetylated laminarins were found to be stable in neutral aqueous solution and exhibited no cytotoxicity. However, the acetylated laminarin exhibited declined antiviral activity after modification.

Selective and sensitive detection and detoxification of Pd2+ in living cells with a water-soluble fluorescent probe.

Due to the cytotoxic potential of even low doses of Pd2+, the development of its detection and detoxification strategies is highly demanding. In this paper, we developed a water-soluble fluorescent probe IMQU-8 with a new scaffold for Pd2+ sensing. IMQU-8 can detect Pd2+ with high selectivity and sensitivity and has a good detection limit of 2.5 nM under physiological conditions. Its sensing mechanism has been revealed through job plot experiments and HRMS, FT-IR, 1H NMR and DFT calculations, which demonstrated that the N atoms of the pyridyl group and imino group are crucial for Pd2+ sensing. Fluorescence lifetime assessment indicated that IMQU-8 and IMQU-8-Pd have almost identical fluorescence lifetimes, implying that IMQU-8 undergoes static quenching toward Pd2+. Additionally, IMQU-8 has been successfully applied to image Pd2+ in living cells. Since IMQU-8 and its coordinated complex IMQU-8-Pd exhibit low toxicity, IMQU-8 has been applied for the detoxification of Pd2+ in living cells.

Antifracture, Antibacterial, and Anti-inflammatory Hydrogels Consisting of Silver-Embedded Curdlan Nanofibrils.

The bacterial exopolysaccharide Curdlan has a unique collagen-like triple helical structure and immune-modulation activities. Although there have been several types of Curdlan gels reported for antibacterial or wound healing purposes, none of them exhibit favorable mechanical properties for clinically applicable wound healing materials. Herein, we present a two-step approach for preparing Ag-embedded Curdlan hydrogels that are highly soft but are very stretchable compared with common polysaccharide-based hydrogels. Ag ions were first reduced in a diluted Curdlan solution to form AgNP-decorated triple helices. Then, the aqueous solution consisting of Curdlan/Ag nanoparticles was mixed with a dimethyl sulfoxide solution consisting of a high concentration of Curdlan. This mixing triggered the conformation transformation of Curdlan random coils into triple helices, and then the helices were further packed into semicrystalline nanofibrils of ∼20 nm in diameter. Due to the presence of semicrystalline fibrils, this novel Curdlan hydrogel exhibits a fracture strain of ∼350% and fracture stress of ∼0.2 MPa at a water content of ∼97%. This nanofibril hydrogel supported the attachment, spreading, and growth of fibroblasts and effectively inhibited the growth of Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. Moreover, the hydrogels downregulated NO production and proinflammatory gene expression levels in lipopolysaccharide (LPS)-stimulated macrophages but did not change the anti-inflammatory gene expression levels in IL-4-stimulated macrophages. In an animal study, these hydrogels accelerated wound healing in a bacteria-infected mice skin wound model. These results validate the further development of Curdlan/AgNPs nanofibril hydrogels in clinical wound management.

Development of chitosan/gelatin hydrogels incorporation of biphasic calcium phosphate nanoparticles for bone tissue engineering.

The chitosan/gelatin hydrogel incorporated with biphasic calcium phosphate nanoparticles (BCP-NPs) as scaffold (CGB) for bone tissue engineering was reported in this article. Such nanocomposite hydrogels were fabricated by using cycled freeze-thawing method, of which physicochemical and biological properties were regulated by adjusting the weight ratio of chitosan/gelatin/BCP-NPs. The needle-like BCP-NPs were dispersed into composites uniformly, and physically cross-linked with chitosan and gelatin, which were identified via Scanning Electron Microscope (SEM) images and Fourier Transform Infrared Spectroscopy (FT-IR) analysis. The porosity, equilibrium swelling ratio, and compressive strength of CGB scaffolds were mainly influenced by the BCP-NPs concentration. In vitro degradation analysis in simulated body fluids (SBF) displayed that CGB scaffolds were degraded up to at least 30 wt% in one month. Also, CCK-8 analysis confirmed that the prepared scaffolds had a good cytocompatibility through in culturing with bone marrow mesenchymal stem cells (BMSCs). Finally, In vivo animal experiments revealed that new bone tissue was observed inside the scaffolds, and gradually increased with increasing months, when implanted CGB scaffolds into large necrotic lesions of rabbit femoral head. The above results suggested that prepared CGB nanocomposites had the potential to be applied in bone tissue engineering.

Improving the pharmacokinetics and tissue distribution of pyrinezolid by self-assembled polymeric micelles.

Antibiotic-resistance by bacteria is a growing global concern within the healthcare field, and it has provided an impetus for continued antimicrobial development. Pyrinezolid (PZ), a novel oxazolidinone compound, can effectively inhibit most gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Though PZ is a promising antimicrobial candidate, the druggability of PZ is limited by its poor water solubility. Therefore, the amphipathic mPEG-PLLA copolymer was used to prepare the pyrinezolid micelles (PZ-M). Herein, we described the preparation, pharmacokinetic properties, tissue distribution, efficacy and toxicity of PZ-M. In vivo studies show that PZ-M possess prolonged blood circulation time and increased oral bioavailability compared with free PZ. Meanwhile, PZ-M increase lung PZ exposure and reduce liver and kidney exposure, which indicates that PZ-M may enhance the efficacy in vivo in MRSA-related pneumonia patients and decrease potential renal and hepatic toxicities.

Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents.

A scaffold-hopping strategy toward Agomelatine based on in silico screening and knowledge analysis was employed to design novel antidepressant agents. A series of 3, 4-dihydroisoquinoline compounds were selected for chemical synthesis and biological assessment. Three compounds (6a-1, 6a-2, 6a-9) demonstrated protective effects on corticosterone-induced lesion of PC12 cells. Compound 6a-1 also displayed low inhibitory effects on the growth of HEK293 and L02 normal cells and it was further evaluated for its potential antidepressant effects in vivo. The forced swim test (FST) results revealed that compound 6a-1 remarkably reduced the immobility time of rats and the open field test (OFT) results indicated a better general locomotor activity of the rats treated with compound 6a-1 than those with Agomelatine or Fluoxetine. Mechanism studies implied that compound 6a-1 can significantly reduce PC12 cell apoptosis by up-regulation of GSH and down-regulation of ROS in corticosterone-induced lesion of PC12 cells. Meanwhile, the down-regulation of calcium ion concentration and up-regulation of BDNF level in PC12 cells may account for the neuroprotective effects. Furthermore, compound 6a-1 can increase cell survival and cell proliferation, promote cell maturation in the rat hippocampus after chronic treatment. The acute toxicity data in vivo indicated compound 6a-1 exhibited less hepatotoxicity than Agomelatine.

The in vivo and in vitro phase I metabolism of FYL-67, a novel oxazolidinone antibacterial drug, studied by LC-MS/MS.

In our previous study, FYL-67, a novel linezolid analogue with the morpholinyl ring replaced by a 4-(pyridin-2-yl)-1H-pyrazol-1-yl group, was demonstrated to own an excellent activity against Gram-positive organisms,such as methicillin-resistant Staphylococcus aureus (MRSA). However, metabolic biotransformation was not investigated. This study was performed to identify the phase I metabolites of FYL-67 using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The chemical structures were confirmed by comparison with corresponding chemical standards obtained internal. Primary elucidation of the metabolic pathway of FYL-67 in vitro was performed using liver preparations (microsomes and hepatocytes) from rats and humans, and SD (Sprague Dawley, rat, rattus norvegicus) rats were used for the study of in vivo approach. To the end, two metabolites (M1 and M2 ) were detected after in vitro as well as in vivo experiments. Based on LC-MS/MS analyses, the metabolites were demonstrated to be 5-(aminomethyl)-3-(3-fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)oxazolidin-2-one (M1 ) and 3-(3-fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one (M2 ). Amide hydrolysis at acetyl group of FYL-67 leading to the formation of M1 was observed and suggested to play a major role in both in vivo and in vitro phase I metabolism of FYL-67. M1 was demonstrated to undergo a further oxidation to form M2 . In addition, the results indicated no species difference existing between rats and humans. The outcomes of our research can be utilized for the development and validation of the analytical method for the quantification of FYL-67 as well as its metabolites in biological samples. Furthermore, it is helpful to conduct studies of pharmacodynamics and toxicodynamics. Copyright © 2015 John Wiley & Sons, Ltd.

Discovery of a Teraryl Oxazolidinone Compound (S)-N-((3-(3-Fluoro-4-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide Phosphate as a Novel Antimicrobial Agent with Enhanced Safety Profile and Efficacies.

A series of novel teraryl oxazolidinone compounds was designed, synthesized, and evaluated for their antimicrobial activity and toxicities. The compounds with aromatic N-heterocyclic substituents at the 4-position of pyrazolyl ring showed better antibacterial activity against the tested bacteria than other compounds with different patterns of substitution. Among all potent compounds, 10f exhibited promising safety profile in MTT assays and in hERG K(+) channel inhibition test. Furthermore, its phosphate was found to be highly soluble in water (47.1 mg/mL), which is beneficial for the subsequent in vivo test. In MRSA systemic infection mice models, 10f phosphate exerted significantly improved survival protection compared with linezolid. The compound also demonstrated high oral bioavailability (F = 99.1%). Moreover, from the results of in vivo toxicology experiments, 10f phosphate would be predicted to have less bone marrow suppression.