Publications by authors named "Shaoyan Zhang"

88 Publications

Linggan Wuwei Jiangxin formula ameliorates airway hyperresponsiveness through suppression of IL-1β and IL-17A expression in allergic asthmatic mice especially with diet-induced obesity.

Ann Transl Med 2021 Apr;9(8):682

Institute of Respiratory Disease, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Background: Obese asthma represents a disease phenotype, which is associated with worse disease control and unresponsiveness to standard anti-inflammatory regimens, including inhaled corticosteroids. Obesity-related innate airway hyperresponsiveness (AHR) plays a role in this asthma phenotype via activation of the IL-1β/innate lymphoid cell 3 (ILC3)/IL-17A pathway. Linggan Wuwei Jiangxin (LGWWJX) formula may be a promising therapeutic option for obese asthma according to traditional Chinese medicine theory, clinical experience and related research.

Methods: The murine model of allergic asthma with obesity was induced by ovalbumin (OVA) sensitization and challenge in combination with a high fat diet (HFD). LGWWJX formula intervention was oral administrated. AHR and bronchoalveolar lavage fluid (BALF) cellularity were measured. Lung and liver histopathology assessment was performed by haematoxylin and eosin (H&E) staining. IL-1β and IL-17A in BALF and serum were evaluated by ELISA. Additionally, the influence of different concentrations of LGWWJX formula on IL-1β stimulated IL-17A mRNA expression in ILC3 cells was evaluated in vitro.

Results: LGWWJX treatment significantly reduced AHR and allergic airway inflammatory responses in asthmatic mice, as measured by pulmonary histopathology and BALF cellularity, and these effects were more pronounced in obese asthmatic mice. While eosinophil infiltration in BALF was suppressed with LGWWJX treatment in non-obese asthmatic mice, neutrophils and basophils were significantly decreased in obese asthmatic mice. Notably, LGWWJX also demonstrated remarkable efficacy for weight loss and improvements in hepatic steatosis in mice fed with a HFD. Furthermore, the protein levels of IL-1β in both serum and BALF, as well as those of BALF IL-17A, declined with LGWWJX intervention in both obese and non-obese asthmatic mice, and results from ex-vivo experiments found that LGWWJX significantly attenuated the expression of IL-17A in ILC3 cells with or without stimulation by IL-1β.

Conclusions: LGWWJX may exert a protective effect on asthmatic individuals, especially those with concurrent obesity, most likely through mechanisms including the inhibition of the IL-1β/ILC3/IL-17A/AHR axis, anti-inflammatory effects, weight loss, and the regulation of lipid metabolism. This suggests a promising role of LGWWJX, alone or in combination with anti-inflammatory agents, for the treatment of obese asthma.
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http://dx.doi.org/10.21037/atm-21-1189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106025PMC
April 2021

LPS decreases CFTR open probability and mucociliary transport through generation of reactive oxygen species.

Redox Biol 2021 Jul 30;43:101998. Epub 2021 Apr 30.

Department of Otolaryngology Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, AL, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Lipopolysaccharide (LPS) serves as the interface between gram-negative bacteria (GNB) and the innate immune response in respiratory epithelial cells (REC). Herein, we describe a novel biological role of LPS that permits GNB to persist in the respiratory tract through inducing CFTR and mucociliary dysfunction. LPS reduced cystic fibrosis transmembrane conductance regulater (CFTR)-mediated short-circuit current in mammalian REC in Ussing chambers and nearly abrogated CFTR single channel activity (defined as forskolin-activated Cl currents) in patch clamp studies, effects of which were blocked with toll-like receptor (TLR)-4 inhibitor. Unitary conductance and single-channel amplitude of CFTR were unaffected, but open probability and number of active channels were markedly decreased. LPS increased cytoplasmic and mitochondrial reactive oxygen species resulting in CFTR carbonylation. All effects of exposure were eliminated when reduced glutathione was added in the medium along with LPS. Functional microanatomy parameters, including mucociliary transport, in human sinonasal epithelial cells in vitro were also decreased, but restored with co-incubation with glutathione or TLR-4 inhibitor. In vivo measurements, following application of LPS in the nasal cavities showed significant decreases in transepithelial Cl secretion as measured by nasal potential difference (NPD) - an effect that was nullified with glutathione and TLR-4 inhibitor. These data provide definitive evidence that LPS-generated reactive intermediates downregulate CFTR function in vitro and in vivo which results in cystic fibrosis-type disease. Findings have implications for therapeutic approaches intent on stimulating Cl secretion and/or reducing oxidative stress to decrease the sequelae of GNB airway colonization and infection.
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http://dx.doi.org/10.1016/j.redox.2021.101998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129928PMC
July 2021

Study of antagonism between some intestinal bacteria with high-speed micellar electrokinetic chromatography.

Electrophoresis 2021 Jun 25;42(11):1196-1201. Epub 2021 Feb 25.

Ministry of Education Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection for Food Safety, School of Chemistry, Fuzhou University, Fuzhou, P. R. China.

In this work, high-speed micellar electrokinetic chromatography with LIF detection was applied to study the antagonism between three intestinal bacteria, Escherichia coli (E. coli), Bacillus licheniformis (B. licheniformis) and Bacillus subtilis (B. subtilis). The fluorescent derivatization for the bacteria was performed by labeling the bacteria with FITC. In a high-speed capillary electrophoresis (HSCE) device, the three bacteria could be completely separated within 4 min under the separation mode MEKC. The BGE was 1 × TBE containing 30 mM SDS and 1.5 × 10  g/mL polyethylene oxide. The limits of detection for E. coli, B. licheniformis and B. subtilis were 2.80 × 10 CFU/mL, 1.60 × 10 CFU/mL and 1.90 × 10 CFU/mL respectively. Lastly, the method was applied to investigate the antagonism between the three bacteria. The bacteria were mixed and cultured for 7 days. The samples were separated and determined every day to study the interaction between bacteria. The results showed that B. licheniformis and B. subtilis could not inhibit each other, but they could effectively inhibit the reproduction of E. coli. The method developed in this work was quick, sensitive and convenient, and it had great potential in the application of antagonism study for bacteria.
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http://dx.doi.org/10.1002/elps.202000372DOI Listing
June 2021

Korean Red Ginseng aqueous extract improves markers of mucociliary clearance by stimulating chloride secretion.

J Ginseng Res 2021 Jan 13;45(1):66-74. Epub 2019 Sep 13.

Department of Otolaryngology Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States.

Background: Abnormal chloride (Cl) transport has a detrimental impact on mucociliary clearance in both cystic fibrosis (CF) and non-CF chronic rhinosinusitis. Ginseng is a medicinal plant noted to have anti-inflammatory and antimicrobial properties. The present study aims to assess the capability of red ginseng aqueous extract (RGAE) to promote transepithelial Cl secretion in nasal epithelium.

Methods: Primary murine nasal septal epithelial (MNSE) [wild-type (WT) and transgenic CFTR], fisher-rat-thyroid (FRT) cells expressing human WT CFTR, and TMEM16A-expressing human embryonic kidney cultures were utilized for the present experiments. Ciliary beat frequency (CBF) and airway surface liquid (ASL) depth measurements were performed using micro-optical coherence tomography (μOCT). Mechanisms underlying transepithelial Cl transport were determined using pharmacologic manipulation in Ussing chambers and whole-cell patch clamp analysis.

Results: RGAE (at 30μg/mL of ginsenosides) significantly increased Cl transport [measured as change in short-circuit current (ΔI = μA/cm)] when compared with control in WT and CFTR MNSE (WT vs control = 49.8±2.6 vs 0.1+/-0.2, CFTR = 33.5±1.5 vs 0.2±0.3, p < 0.0001). In FRT cells, the CFTR-mediated ΔI attributed to RGAE was small (6.8 ± 2.5 vs control, 0.03 ± 0.01, p < 0.05). In patch clamp, TMEM16A-mediated currents were markedly improved with co-administration of RGAE and uridine 5-triphosphate (8406.3 +/- 807.7 pA) over uridine 5-triphosphate (3524.1 +/- 292.4 pA) or RGAE alone (465.2 +/- 90.7 pA) (p < 0.0001). ASL and CBF were significantly greater with RGAE (6.2+/-0.3 m vs control, 3.9+/-0.09 m; 10.4+/-0.3 Hz vs control, 7.3 ± 0.2 Hz;  < 0.0001) in MNSE.

Conclusion: RGAE augments ASL depth and CBF by stimulating Cl secretion through CaCC, which suggests therapeutic potential in both CF and non-CF chronic rhinosinusitis.
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http://dx.doi.org/10.1016/j.jgr.2019.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790903PMC
January 2021

Bottleneck, Isolate, Amplify, Select (BIAS) as a mechanistic framework for intracellular population dynamics of positive-sense RNA viruses.

Virus Evol 2020 Jul 12;6(2):veaa086. Epub 2020 Nov 12.

Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki-aoba, Aoba-ku, Sendai 980-0845, Japan.

Many positive-sense RNA viruses, especially those infecting plants, are known to experience stringent, stochastic population bottlenecks inside the cells they invade, but exactly how and why these populations become bottlenecked are unclear. A model proposed ten years ago advocates that such bottlenecks are evolutionarily favored because they cause the isolation of individual viral variants in separate cells. Such isolation in turn allows the viral variants to manifest the phenotypic differences they encode. Recently published observations lend mechanistic support to this model and prompt us to refine the model with novel molecular details. The refined model, designated Bottleneck, Isolate, Amplify, Select (BIAS), postulates that these viruses impose population bottlenecks on themselves by encoding bottleneck-enforcing proteins (BNEPs) that function in a concentration-dependent manner. In cells simultaneously invaded by numerous virions of the same virus, BNEPs reach the bottleneck-ready concentration sufficiently early to arrest nearly all internalized viral genomes. As a result, very few (as few as one) viral genomes stochastically escape to initiate reproduction. Repetition of this process in successively infected cells isolates viral genomes with different mutations in separate cells. This isolation prevents mutant viruses encoding defective viral proteins from hitchhiking on sister genome-encoded products, leading to the swift purging of such mutants. Importantly, genome isolation also ensures viral genomes harboring beneficial mutations accrue the cognate benefit exclusively to themselves, leading to the fixation of such beneficial mutations. Further interrogation of the BIAS hypothesis promises to deepen our understanding of virus evolution and inspire new solutions to virus disease mitigation.
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http://dx.doi.org/10.1093/ve/veaa086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733609PMC
July 2020

The MADS-box transcription factor regulates secondary metabolism in .

Mycologia 2021 Jan-Feb;113(1):12-19. Epub 2020 Oct 21.

Shandong Provincial Key Laboratory of Agricultural Microbiology, College of Plant Protection, Shandong Agricultural University , Tai'an 271018, China.

MADS-box transcription factors play crucial roles in regulating development processes and biosynthesis of secondary metabolites in eukaryotes. However, the role of MADS-box transcription factors vary among fungal species, and their function remains unclear in the medicinally and economically important fungus . In this study, we characterized a MADS-box gene, , in . Analyses using quantitative real-time polymerase chain reaction (qRT-PCR) showed that expression levels were up-regulated from the mycelia to the primordia stage. In order to further evaluate the effect of MADS-box transcription factors on secondary metabolism, we utilized RNA interference (RNAi) to silence in . Ganoderic acid (GA) and flavonoid contents were enhanced in -silenced strains, suggesting that negatively regulates GA and flavonoid accumulation.
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http://dx.doi.org/10.1080/00275514.2020.1810515DOI Listing
October 2020

Zinc Chelator N,N,N',N'-Tetrakis(2-Pyridylmethyl)Ethylenediamine Reduces the Resistance of to Imipenem.

Infect Drug Resist 2020 18;13:2883-2890. Epub 2020 Aug 18.

Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People's Republic of China.

Purpose: Imipenem is one of the very few effective options for treating () infections; the development of imipenem resistance is a major health concern.

Materials And Methods: The susceptibility of 194 clinical isolates to imipenem was determined. The ability of imipenem to synergize with N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a zinc chelator and a metallo-β-lactamases (MBLs) inhibitor, to inhibit growth was also assessed.

Results: exhibited an elevated resistance to imipenem (MIC = 16 mg/L, MIC = 64 mg/L). A combination of TPEN and imipenem synergized to inhibit the growth of 100% of imipenem-resistant and 79.2% of imipenem-resistance intermediate isolates; no synergy was observed treating imipenem-sensitive isolates. A remarkable decrease in the MIC (from 16 to 4 mg/L) and MIC (from 64 to 8 mg/L) of imipenem was observed when it was combined with TPEN; the portion of imipenem-resistant isolates also decreased (from 48.4% to 0%). Consistent with these results demonstrating synergy, a time-kill assay showed the addition of TPEN significantly improved the bactericidal activity of imipenem toward . Similarly, EDTA (a potent MBLs inhibitor) promoted the anti- activity of imipenem in a disk assay, corroborating the effect of TPEN and supporting the role of MBLs in imipenem resistance exhibited by some isolates.

Conclusion: These findings demonstrate that TPEN can reduce the resistance of to imipenem and suggest that the inhibition of MBLs activity is the underlying mechanism.
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http://dx.doi.org/10.2147/IDR.S267552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445496PMC
August 2020

Contribution of Short Chain Fatty Acids to the Growth of in Rhinosinusitis.

Front Cell Infect Microbiol 2020 11;10:412. Epub 2020 Aug 11.

Department of Otolaryngology Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, AL, United States.

Chronic rhinosinusitis (CRS) is characterized by complex bacterial infections with persistent inflammation. Based on our rabbit model of sinusitis, blockage of sinus ostia generated a shift in microbiota to a predominance of mucin degrading microbes (MDM) with acute inflammation at 2 weeks. This was followed by conversion to chronic sinus inflammation at 3 months with a robust increase in pathogenic bacteria (e.g., ). MDMs are known to produce acid metabolites [short chain fatty acids (SCFA)] that have the potential to stimulate pathogen growth by offering a carbon source to non-fermenting sinus pathogens (e.g., ). The objective of this study is to evaluate the concentrations of SCFA within the mucus and its contribution to the growth of . Healthy and sinusitis mucus from the rabbit model were collected and co-cultured with the PAO1 strain of for 72 h and colony forming units (CFUs) were determined with the targeted quantification of three SCFAs (acetate, propionate, butyrate). Quantification of SCFAs in healthy and sinusitis mucus from patients with was also performed via high performance liquid chromatography. To provide evidence of fermentative activity, SCFAs were quantified within the mucus samples from rabbits with and without sinusitis. Acetate concentrations were significantly greater in sinusitis mucus compared to controls (4.13 ± 0.53 vs. 1.94 ± 0.44 mM, < 0.01). After 72 h of co-culturing mucus samples with PAO1 in the presence of mucin medium, the blue-green pigment characteristic of was observed throughout tubes containing sinusitis mucus. CFUs were higher in cultures containing mucus samples from sinusitis (8.4 × 10 ± 4.8 × 10) compared to control (1.4 × 10 ± 2.0 × 10) or no mucus (1.5 × 10 ± 2.1 × 10) ( < 0.0001). To provide evidence of fermentative activity in human CRS with , the presence of SCFAs in human mucus was analyzed and all SCFAs were significantly higher in CRS with compared to controls ( < 0.05). Given that SCFAs are solely derived from bacterial fermentation, our evidence suggests a critical role for mucin-degrading bacteria in generating carbon-source nutrients for pathogens. MDM may contribute to the development of recalcitrant CRS by degrading mucins, thus providing nutrients for potential pathogens like .
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http://dx.doi.org/10.3389/fcimb.2020.00412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431473PMC
June 2021

Azithromycin and ciprofloxacin inhibit interleukin-8 secretion without disrupting human sinonasal epithelial integrity in vitro.

Int Forum Allergy Rhinol 2021 Feb 28;11(2):136-143. Epub 2020 Jul 28.

Department of Otolaryngology-Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, AL.

Background: We recently developed a ciprofloxacin and azithromycin sinus stent (CASS) to target recalcitrant infections in chronic rhinosinusitis (CRS). The objective of this study was to evaluate the anti-inflammatory activity of azithromycin released from the CASS and assess the impact on the integrity and function of primary human sinonasal epithelial cells (HSNECs).

Methods: Pseudomonas aeruginosa lipopolysaccharide (LPS)-stimulated HSNECs were treated with azithromycin and/or ciprofloxacin at concentrations attainable from CASS release. Interleukin-8 (IL-8) secretion was quantified by enzyme-linked immunosorbent assay (ELISA). Epithelial integrity (transepithelial resistance [TEER], paracellular permeability [fluorescein isothiocyanate-labeled dextran], lactate dehydrogenase [LDH] assays) and function (ciliary beat frequency [CBF]) were also evaluated.

Results: Azithromycin significantly reduced secreted IL-8 from P. aeruginosa LPS-stimulated HSNECs at all concentrations tested (mean ± standard deviation; control = 5.77 ± 0.39 ng/mL, azithromycin [6 μg/mL] = 4.58 ± 0.40 ng/mL, azithromycin [60 µg/mL] = 4.31 ± 0.06, azithromycin [180 µg/mL] = 4.27 ± 0.26 ng/mL, p < 0.05). Co-incubation with azithromycin (6 µg/mL) and ciprofloxacin (2.4 µg/mL) in LPS-stimulated HSNECs also displayed a significant reduction in secreted IL-8 when compared to P. aeruginosa LPS alone (co-treatment = 4.61 ± 0.29 ng/mL, P. aeruginosa LPS = 7.35 ± 0.89 ng/mL, p < 0.01). The drugs did not negatively impact TEER, paracellular permeability, LDH release, or CBF, indicating retention of cell integrity and function.

Conclusion: Azithromycin decreased P. aeruginosa LPS IL-8 production in HSNECs at drug concentrations attainable with sustained release of azithromycin from the CASS. In addition to antibacterial activity, anti-inflammatory properties of the CASS should provide further benefit for patients with recalcitrant CRS.
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http://dx.doi.org/10.1002/alr.22656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854841PMC
February 2021

Differential Chloride Secretory Capacity in Transepithelial Ion Transport Properties in Chronic Rhinosinusitis.

Am J Rhinol Allergy 2020 Nov 23;34(6):830-837. Epub 2020 Jun 23.

Department of Otolaryngology-Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama.

Background: Epithelial ion transport regulates hydration of airway mucosal surfaces, and thus promotes effective mucociliary clearance (MCC). Decreased transepithelial Cl transport may contribute to epithelial dysfunction by abrogating MCC and increasing mucus viscosity in chronic rhinosinusitis (CRS). The objective of the current study is to evaluate Cl channel transport properties from cultures of human sinonasal epithelia.

Methods: Human sinonasal epithelia (HSNE) from patients undergoing sinus surgery were cultured at an air-liquid interface to confluence and full differentiation. The epithelial monolayers were mounted in Ussing Chambers to investigate pharmacological manipulation of ion transport. Epithelial Na channel (via Amiloride), CFTR (via forskolin), and Ca-activated Cl channel (CaCC, via UTP) transport were investigated among three different patient groups: Control, CRS and CRS with polyposis. CFTR mRNA levels were evaluated with quantitative RT-PCR.

Results: HSNE cultures from 18 patients (Control = 9, CRS = 6, CRS with polyposis = 3) were evaluated in 142 experiments. Summary data from the 18 patients demonstrated that stimulated CFTR-mediated anion transport (Δ I) was significantly lower with CRS (7.58+/-2.24 µA/cm) compared to control (25.86+/-3.44 µA/cm) and CRS with polyposis (20.16+/-4.0 µA/cm) (p = 0.004). No statistically significant difference was found for CaCC anion transport between groups (p = 0.39). Significantly decreased mRNA (relative expression) was noted in CRS cultures (CRS = 40.83+/-1.76 vs. control = 116.2+/-24.27, p = 0.03).

Conclusions: A substantial decrease in the Cl secretory capacity of HSNE monolayers was demonstrated in CRS subjects. Data suggest that CFTR may contribute more to abnormal ion transport in CRS than CaCC.
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http://dx.doi.org/10.1177/1945892420930975DOI Listing
November 2020

AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward .

Antimicrob Agents Chemother 2020 07 22;64(8). Epub 2020 Jul 22.

Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

Therapeutic options for infections are extremely limited. New or repurposed drugs are needed. The anti- activity of AR-12 (OSU-03012), reported to express broad-spectrum antimicrobial effects, was investigated and Antimicrobial susceptibility testing was performed on 194 clinical isolates. Minimum bactericidal concentration and time-kill kinetics assays were conducted to distinguish the bactericidal versus bacteriostatic activity of AR-12. Synergy between AR-12 and five clinically important antibiotics was determined using a checkerboard synergy assay. The activity of AR-12 against intracellular residing within macrophage was also evaluated. Finally, the potency of AR-12 was determined in a neutropenic mouse model that mimics pulmonary infection. AR-12 exhibited high anti- activity , with an MIC of 4 mg/liter (8.7 μM) and an MIC of 8 mg/liter (17.4 μM) for both subsp. and subsp. AR-12 and amikacin exhibited comparable bactericidal activity against extracellular in culture. AR-12, however, exhibited significantly greater intracellular antibacterial activity than amikacin and caused a significant reduction in the bacterial load in the lungs of neutropenic mice infected with No antagonism between AR-12 and clarithromycin, amikacin, imipenem, cefoxitin, or tigecycline was evident. In conclusion, AR-12 is active against and and does not antagonize the most frequently used anti- drugs. As such, AR-12 is a potential candidate to include in novel strategies to treat infections.
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http://dx.doi.org/10.1128/AAC.00236-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526805PMC
July 2020

Translation-Independent Roles of RNA Secondary Structures within the Replication Protein Coding Region of Turnip Crinkle Virus.

Viruses 2020 03 22;12(3). Epub 2020 Mar 22.

Department of Plant Pathology, The Ohio State University, Wooster, OH 44691, USA.

RNA secondary structures play diverse roles in positive-sense (+) RNA virus infections, but those located with the replication protein coding sequence can be difficult to investigate. Structures that regulate the translation of replication proteins pose particular challenges, as their potential involvement in post-translational steps cannot be easily discerned independent of their roles in regulating translation. In the current study, we attempted to overcome these difficulties by providing viral replication proteins in . Specifically, we modified the plant-infecting turnip crinkle virus (TCV) into variants that are unable to translate one (p88) or both (p28 and p88) replication proteins, and complemented their replication with the corresponding replication protein(s) produced from separate, non-replicating constructs. This approach permitted us to re-examine the p28/p88 coding region for potential RNA elements needed for TCV replication. We found that, while more than a third of the p88 coding sequence could be deleted without substantially affecting viral RNA levels, two relatively small regions, known as RSE and IRE, were essential for robust accumulation of TCV genomic RNA, but not subgenomic RNAs. In particular, the RSE element, found previously to be required for regulating the translational read-through of p28 stop codon to produce p88, contained sub-elements needed for efficient replication of the TCV genome. Application of this new approach in other viruses could reveal novel RNA secondary structures vital for viral multiplication.
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http://dx.doi.org/10.3390/v12030350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150753PMC
March 2020

Efflux Pumps Contribute to Intrinsic Clarithromycin Resistance in Clinical, Isolates.

Infect Drug Resist 2020 12;13:447-454. Epub 2020 Feb 12.

Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People's Republic of China.

Purpose: The emergence of clarithromycin resistance is a challenge in treating infections. Known mechanisms that contribute to intrinsic clarithromycin resistance focus on gene-related mutations, but resistant clinical isolates often exhibit an inconsistent genotype.

Patients And Methods: In this study, 194 clinical isolates were collected from patients with lung infections and the whole genome of each isolate was sequenced. A comprehensive examination of the molecular mechanisms underlying intrinsic clarithromycin resistance was performed, combining MIC determination, comparative genome sequence analysis and qRT-PCR.

Results: Of the 194 isolates, 13 (6.7%) were clarithromycin resistant; only seven of these harbored a 2270/2271 mutation. The remaining six resistant isolates did not exhibit a specific resistance-associated mutation in the clarithromycin target-site genes, and , or in the modification gene (41). qRT-PCR analysis showed that the increased expression of the efflux pump genes, MAB_2355c, MAB_1409c and MAB_1846, as well as their positive regulatory gene , consistently correlated with increased clarithromycin resistance. The presence of efflux pump inhibitors significantly decreased the MIC of clarithromycin for nonsusceptible isolates, especially the intrinsic resistant isolates that exhibited no 2270/2271 mutation.

Conclusion: These findings indicate that efflux pumps play a prominent role in the intrinsic resistance of to clarithromycin, complementing other known resistance mechanisms.
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http://dx.doi.org/10.2147/IDR.S239850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024787PMC
February 2020

Association between Plasma Urotensin II and Risk of Hypertension: Findings from a Prospective Study.

Int J Hypertens 2020 30;2020:3284769. Epub 2020 Jan 30.

Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou 215123, China.

Up to date, human urotensin II (UII) is the most potent vasoconstrictor in mammalian animals. To explore whether UII played an important role in the development of hypertension, we conducted a prospective study in Changshu city, China. The baseline investigation was carried out in 2007, and the first follow-up investigation was conducted in 2013. From the participants, we randomly obtained 2000 normotensive subjects aged 40 years and older without any severe disease at baseline and examined plasma UII and endothelin-1 (ET-1) with their blood samples at baseline. Logistic models were used to analyze the association between baseline UII, baseline ET-1, and newly occurring hypertension. In 1,819 subjects with complete data, 723 subjects developed into hypertensive in about five years. After adjusting some potential confounders, the odds ratio (95% confidence interval) for risk of hypertension comparing the highest with the lowest quartile of baseline UII was 0.888 (0.689-1.144). The role of UII in the development of hypertension was not found in the current study; therefore, further research studies should be conducted to explore the relationship between UII and hypertension.
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http://dx.doi.org/10.1155/2020/3284769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013293PMC
January 2020

The impact of Lactococcus lactis (probiotic nasal rinse) co-culture on growth of patient-derived strains of Pseudomonas aeruginosa.

Int Forum Allergy Rhinol 2020 04 10;10(4):444-449. Epub 2020 Jan 10.

Department of Otolaryngology-Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, AL.

Background: The Lactococcus strain of bacteria has been introduced as a probiotic nasal rinse for alleged salubrious effects on the sinonasal bacterial microbiome. However, data regarding interactions with pathogenic bacteria within the sinuses are lacking. The purpose of this study is to assess the interaction between L. lactis and patient-derived Pseudomonas aeruginosa, an opportunistic pathogen in recalcitrant chronic rhinosinusitis (CRS).

Methods: Commercially available probiotic suspension containing L. lactis W136 was grown in an anaerobic chamber and colonies were isolated. Colonies were co-cultured with patient-derived P. aeruginosa strains in the presence of porcine gastric mucin (mimicking human mucus) for 72 hours. P. aeruginosa cultures without L. lactis served as controls. Colony forming units (CFUs) were compared.

Results: Six P. aeruginosa isolates collected from 5 CRS patients (3 isolates from cystic fibrosis [CF], 1 mucoid strain) and laboratory strain PAO1 were co-cultured with L. lactis. There was no statistical difference in CFUs of 5 P. aeruginosa isolates grown with L. lactis compared to CFUs without presence of L. lactis. CFU counts were much higher when the mucoid strain was co-cultured with L. lactis (CFU = 1.9 × 108 ± 1.44 × 107, CFU = 1.3 × 108 ± 8.9 × 106, p = 0.01, n = 7). L. lactis suppressed the growth of 1 P. aeruginosa strain (CFU = 2.15 × 108 ± 2.9 × 107, CFU = 3.95 × 108 ± 4.8 × 106, p = 0.03, n = 7).

Conclusion: L. lactis suppressed the growth of 1 patient P. aeruginosa isolate and induced growth of another (a mucoid strain) in in vitro co-culture setting in the presence of mucin. Further experiments are required to assess the underlying interactions between L. lactis and P. aeruginosa.
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http://dx.doi.org/10.1002/alr.22521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058912PMC
April 2020

Superinfection Exclusion by p28 of Turnip Crinkle Virus Is Separable from Its Replication Function.

Mol Plant Microbe Interact 2020 Feb 27;33(2):364-375. Epub 2019 Dec 27.

Department of Plant Pathology, Ohio Agricultural Research and Development Center, The Ohio State University, Wooster, OH 44691, U.S.A.

We recently reported that the p28 auxiliary replication protein encoded by turnip crinkle virus (TCV) is also responsible for eliciting superinfection exclusion (SIE) against superinfecting TCV. However, it remains unresolved whether the replication function of p28 could be separated from its ability to elicit SIE. Here, we report the identification of two single amino acid mutations that decouple these two functions. Using an infiltration-based delivery system, we transiently expressed a series of p28 deletion and point mutants, and tested their ability to elicit SIE against a cointroduced TCV replicon. We found that substituting alanine (A) for valine (V) and phenylalanine (F) at p28 positions 181 and 182, respectively, modestly compromised SIE in transiently expressed p28 derivatives. Upon incorporation into TCV replicons, V181A and F182A decoupled TCV replication and SIE diametrically. Although V181A impaired SIE without detectably compromising replication, F182A abolished TCV replication but had no effect on SIE once the replication of the defective replicon was restored through complementation. Both mutations diminished accumulation of p28 protein, suggesting that p28 must reach a concentration threshold in order to elicit a strong SIE. Importantly, the severe reduction of F182A protein levels correlated with a dramatic loss in the number of intracellular p28 foci formed by p28-p28 interactions. Together, these findings not only decouple the replication and SIE functions of p28 but also unveil a concentration dependence for p28 coalescence and SIE elicitation. These data further highlight the role of p28 multimerization in driving the exclusion of secondary TCV infections.
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http://dx.doi.org/10.1094/MPMI-09-19-0258-RDOI Listing
February 2020

Controlled delivery of ciprofloxacin and ivacaftor via sinus stent in a preclinical model of Pseudomonas sinusitis.

Int Forum Allergy Rhinol 2020 04 23;10(4):481-488. Epub 2019 Dec 23.

Department of Otolaryngology-Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, AL.

Background: Pseudomonas aeruginosa is common in chronic rhinosinusitus (CRS) and frequently resistant to antibiotic treatment. We recently described the ciprofloxacin and ivacaftor-releasing biodegradable sinus stent (CISS)-a drug-delivery system that administers ciprofloxacin and the mucociliary activator (ivacaftor) at high local concentrations with prolonged mucosal contact time and sustained delivery. The objective of this study is to evaluate the efficacy of the CISS in a rabbit model of P aeruginosa (PAO1 strain) sinusitis.

Methods: Ciprofloxacin/ivacaftor (double layer) was coated on biodegradable poly-D/L-lactic acid (PLLA). A total of 10 sinus stents (5 bare PLLA stent controls, 5 CISSs) were placed unilaterally in rabbit maxillary sinuses via dorsal sinusotomy after inducing infection for 1 week with PAO1. Animals were assessed 3 weeks after stent insertion with sinus culture, nasal endoscopy, computed tomography scan, histopathology, and in-vivo sinus potential difference (SPD) assay.

Results: Rabbits treated with CISS had significant reductions in computed tomography (∆ Kerschner scale: control, 0.55 ± 0.92; CISS, -5.92 ± 1.69; p = 0.024) and endoscopy (control, 4.0 ± 0.0; CISS, 1.875 ± 0.74; p = 0.003) scores. A 2-log reduction of PAO1 was observed (control, -2.14 ± 0.77; CISS, 1.84 ± 1.52; p = 0.047). SPD revealed significantly increased Cl transport in the CISS group compared with the control group (Cl -free + forskolin ΔPD: control, -4.23 ± 1.04 mV; CISS, -18.36 ± 6.31 mV; p = 0.026). Finally, marked improvements were noted in the histology of the mucosa and submucosa in treated animals.

Conclusion: The CISS had robust clinical efficacy in treating P aeruginosa rabbit sinusitis. The innovative design of double-layered drug coating on the surface of the biodegradable stent may provide therapeutic advantages over current treatment strategies for P aeruginosa sinusitis.
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http://dx.doi.org/10.1002/alr.22514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182488PMC
April 2020

Drug resistance and epidemiology characteristics of multidrug-resistant tuberculosis patients in 17 provinces of China.

PLoS One 2019 21;14(11):e0225361. Epub 2019 Nov 21.

Department of Epidemiology and Biostatistics, School of Public Health, Fudan University, Xuhui District, Shanghai, People's Republic of China.

As China is one of high MDR-TB burden countries, it is important to determine the drug resistant pattern and clinical characteristics of multidrug resistant tuberculosis (MDR-TB). We conducted a comprehensive and nationwide study on MDR-TB in 17 provinces for the period from June 2009 to June 2015, and a total of 1154 cases of MDR-TB were finally investigated. The study sought to assess the clinical features and contrast drug susceptibility profiles of MDR-TB patients in China. Cavitary disease, young age, and long duration of TB disease among MDR-TB patients were important predictors. A high resistance proportion of first-line drugs was observed in Beijing, Shanghai and Tianjin. Resistant proportions of second-line anti-TB drugs in western region for amikacin, aminosalicylic acid, and levofloxacin were higher than eastern and central regions. High levels of drug resistance were seen in earlier cases (before 2011) and outpatients. We found high levels of resistance to 1st- and 2nd-line drugs in all settings, with considerable variabilities in terms of different Directly Observed Treatment Short Course (DOTS) programme, level of economic development(eastern, central and western regions) and patient source (inpatients and outpatients). Timely drug susceptibility testing (DST) and effective management are necessary to ensure an early detection of MDR-TB and its proper treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225361PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874064PMC
March 2020

In-vitro evaluation of a ciprofloxacin and azithromycin sinus stent for Pseudomonas aeruginosa biofilms.

Int Forum Allergy Rhinol 2020 01 6;10(1):121-127. Epub 2019 Nov 6.

Department of Otolaryngology-Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, AL.

Background: Chronic rhinosinusitis (CRS) is a chronic inflammatory disease characterized by persistent inflammation and bacterial infection. Ciprofloxacin and azithromycin are commonly prescribed antibiotics for CRS, but the ability to provide targeted release in the sinuses could mitigate side effects and improve drug concentrations at the infected site. This study was aimed to evaluate the efficacy of the novel ciprofloxacin-azithromycin sinus stent (CASS) in vitro.

Methods: The CASS was created by coating ciprofloxacin (hydrophilic, inner layer) and azithromycin (hydrophobic, outer layer) onto a biodegradable poly-l-lactic acid (PLLA) stent. In-vitro evaluation included: (1) assessment of drug-coating stability within the stent using scanning electron microscopy (SEM); (2) determination of ciprofloxacin and azithromycin release kinetics; and (3) assessment of anti-biofilm activities against Pseudomonas aeruginosa.

Results: The ciprofloxacin nanoparticle suspension in the inner layer was confirmed by zeta potential. Both ciprofloxacin (60 µg) and azithromycin (3 mg) were uniformly coated on the surface of the PLLA stents. The CASS showed ciprofloxacin/azithromycin sustained release patterns, with 80.55 ± 11.61% of ciprofloxacin and 93.85 ± 6.9% of azithromycin released by 28 days. The CASS also significantly reduced P aeruginosa biofilm mass compared with bare stents and controls (relative optical density units at 590-nm optical density: CASS, 0.037 ± 0.006; bare stent, 0.911 ± 0.015; control, 1.000 ± 0.000; p < 0.001; n = 3).

Conclusion: The CASS maintains a uniform coating and sustained delivery of ciprofloxacin and azithromycin, providing anti-biofilm activities against P aeruginosa. Further studies evaluating the efficacy of CASS in a preclinical model are planned.
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http://dx.doi.org/10.1002/alr.22475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942221PMC
January 2020

Ginkgolide B protects human pulmonary alveolar epithelial A549 cells from lipopolysaccharide-induced inflammatory responses by reducing TRIM37-mediated NF-κB activation.

Biotechnol Appl Biochem 2020 Nov 17;67(6):903-911. Epub 2020 Feb 17.

Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.

The treatment options for acute stroke combined with pulmonary infection are limited. Clinically, there are several therapies to promote blood circulation and dissipate blood stasis; these treatment options include ginkgolide B (GB), which has PAF (platelet activating factor)-inhibiting effects. PAF-receptor (PAF-R) antagonists are used to treat a variety of inflammatory diseases; however, the potential of PAF-R antagonists as a treatment for lung infections remains unclear. The aim of the present study is to investigate the protective effect of GB on lipopolysaccharide-induced inflammatory responses in A549 human pulmonary alveolar epithelial cells (HPAEpiC) in vitro. Cell viability and apoptosis were measured by CCK-8 and flow cytometry. TRIM37, Caspase-3, and NF-κBp65 expression levels were measured by real-time PCR and Western blotting. The release of tumor necrosis factor-α and interleukin-1β was measured by ELISA. The data indicates that GB may reduce TRIM37 expression by antagonizing the PAF-R pathway, thereby inhibiting the activation of nuclear factor-κB and alleviating the inflammatory response of alveolar epithelial cells. This study is the first to provide insight into the therapeutic potential of GB and suggests that clinical application of GB in acute stroke combined with pulmonary inflammation may be efficacious.
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http://dx.doi.org/10.1002/bab.1847DOI Listing
November 2020

USP9X promotes LPS-induced pulmonary epithelial barrier breakdown and hyperpermeability by activating an NF-κBp65 feedback loop.

Am J Physiol Cell Physiol 2019 09 19;317(3):C534-C543. Epub 2019 Jun 19.

Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Institutes of Integrative Medicine, Fudan University, Shanghai, China.

NF-κB is a central regulator of inflammatory and immune responses and has been shown to regulate transcription of several inflammatory factors as well as promote acute lung injury. However, the regulation of NF-κB signaling in acute lung injury has yet to be investigated. Human pulmonary alveolar epithelial cells (HPAEpiC) were treated with LPS to establish an acute lung injury model in vitro in which LPS stimulation resulted in pulmonary epithelial barrier breakdown and hyperpermeability. Cell viability was measured by CCK-8, and the transepithelial permeability was examined by measurement of transepithelial electrical resistance (TEER) and the transepithelial flux. Expression of ubiquitin-specific peptidase 9 X-linked (USP9X), zonula occludens (ZO-1), occludin and NF-κBp65, and the secretion of TNF-α and IL-1β were measured by Western blotting and ELISA, respectively. For in vivo studies, mice were intraperitoneally injected with LPS and/or NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC). Lung tissues were harvested for hematoxylin-eosin staining and Western blotting, and bronchoalveolar lavage fluid (BALF) was harvested for ELISA. We found that treatment with LPS in HPAEpiC inhibited cell viability and induced the expression of USP9X. Interestingly, knockdown of USP9X and treatment with PDTC suppressed LPS-induced HPAEpiC injury. USP9X overexpression promoted NF-κB activation, while NF-κB inactivation inhibited USP9X transcription and HPAEpiC injury induced by USP9X overexpression. Furthermore, LPS also induced the expression of USP9X in lungs, which was inhibited by PDTC. Taken together, these results demonstrate a critical role of USP9X-NF-κBp65 loop in mediating LPS-induced acute lung injury and may serve as a potential therapeutic target in acute lung injury.
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http://dx.doi.org/10.1152/ajpcell.00094.2019DOI Listing
September 2019

Enhanced Ganoderic Acids Accumulation and Transcriptional Responses of Biosynthetic Genes in Fruiting Bodies by Elicitation Supplementation.

Int J Mol Sci 2019 Jun 10;20(11). Epub 2019 Jun 10.

Shandong Provincial Key Laboratory of Agricultural Microbiology, College of Plant Protection, Shandong Agricultural University, Tai'an 271018, China.

Ganoderic acids (GAs) are a type of highly oxygenated lanostane-type triterpenoids that are responsible for the pharmacological activities of . They have been investigated for their biological activities, including antibacterial, antiviral, antitumor, anti-HIV-1, antioxidation, and cholesterol reduction functions. Inducer supplementation is viewed as a promising technology for the production of GAs. This study found that supplementation with sodium acetate (4 mM) significantly increased the GAs content of fruiting bodies by 28.63% compared to the control. In order to explore the mechanism of ganoderic acid accumulation, the transcriptional responses of key GAs biosynthetic genes, including the acetyl coenzyme A synthase gene, and the expression levels of genes involved in calcineurin signaling and acetyl-CoA content have been analyzed. The results showed that the expression of three key GAs biosynthetic genes (, , and ) were significantly up-regulated. Analysis indicated that the acetate ion increased the expression of genes related to acetic acid assimilation and increased GAs biosynthesis, thereby resulting in the accumulation of GAs. Further investigation of the expression levels of genes involved in calcineurin signaling revealed that Na supplementation and the consequent exchange of Na/Ca induced GAs biosynthesis. Overall, this study indicates a feasible new approach of utilizing sodium acetate elicitation for the enhanced production of valuable GAs content in , and also provided the primary mechanism of GAs accumulation.
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http://dx.doi.org/10.3390/ijms20112830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600565PMC
June 2019

In-vitro evaluation of a ciprofloxacin- and ivacaftor-coated sinus stent against Pseudomonas aeruginosa biofilms.

Int Forum Allergy Rhinol 2019 05 31;9(5):486-492. Epub 2019 Jan 31.

Department of Otolaryngology-Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, AL.

Background: We recently developed a novel ciprofloxacin-coated sinus stent capable of releasing antibiotics over a sustained period of time. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that has synergistic bactericidal activity with ciprofloxacin and also enhances sinus mucociliary clearance. The objective of this study was to optimize and evaluate the efficacy of a ciprofloxacin- and ivacaftor-releasing biodegradable sinus stent (CISS) in vitro.

Methods: A CISS was created by coating ciprofloxacin/ivacaftor-embedded nanoparticles with an acrylate and ammonium methacrylate copolymer onto a biodegradable poly-L-lactic acid stent. In-vitro evaluation of the CISS included: (1) assessment of drug stability in nanoparticles by zeta potential, and drug-coating stability within the CISS using scanning electron microscopy (SEM); (2) determination of ciprofloxacin- and ivacaftor-release kinetics; and (3) assessment of anti-Pseudomonas aeruginosa biofilm formation by calculating relative optical density units (RODUs) compared with control stents at 590-nm optical density.

Results: The presence of drugs and a uniform coating on the stent were confirmed by zeta potential and SEM. Sustained drug release was observed through 21 days without an initial burst release. Anti-biofilm formation was observed after placing the CISS for 3 days onto a preformed 1-day P aeruginosa biofilm. The CISS significantly reduced biofilm mass compared with bare stents and controls (RODUs at 590-nm optical density; CISS, 0.31 ± 0.01; bare stent, 0.78 ± 0.12; control, 1.0 ± 0.00; p = 0.001; n = 3).

Conclusion: The CISS maintains a uniform coating and sustained delivery of drugs providing a marked reduction in P aeruginosa biofilm formation. Further studies evaluating the efficacy of CISS in a preclinical model are planned.
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http://dx.doi.org/10.1002/alr.22285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491263PMC
May 2019

Controlled synthesis of unique CoS nanostructures with carbon coating as advanced electrode for solid-state asymmetric supercapacitors.

J Colloid Interface Sci 2019 Mar 3;540:389-397. Epub 2019 Jan 3.

Jiangsu Key Laboratory of Electrochemical Energy Storage Technologies, College of Materials Science and Technology, Nanjing University of Aeronautics and Astronautics, Nanjing 210016, PR China; College of Chemical Engineering, Shijiazhuang University, Shijiazhuang, Hebei Province 050035, PR China. Electronic address:

Stimulated by both the rich electrochemical properties and unique structural merits, much attention is directed to construct novel cobalt sulfides nanoarchitectures for energy storage devices. Here, carbon-coated cobalt sulfide nanostructures are fabricated with the assistance of polyvinylpyrrolidone during hydrothermal process. The morphology of carbon-coated cobalt sulfide can evolve from well-defined uniform nanooctahedrons, nanoflowers to nanospheres by simply controlling the polyvinylpyrrolidone amount. Remarkably, the unique carbon-coated cobalt sulfide configuration takes full advantage of the synergistic contributions from both the homogeneous incorporated carbon layer and the ideal hierarchical flowerlike structures, thereby making it to be a suitable electrode for supercapacitors. By virtue of the intriguing structural features of carbon-coated cobalt sulfide, a solid asymmetric supercapacitor based on carbon-coated cobalt sulfide nanoflowers as the positive electrode and active carbon as the negative electrode achieves remarkable cycling stability (around 86% capacitance retention even up to 10,000 times), and outstanding energy density of 40 Wh kg at power density of 850 W kg. The exceptionably electrochemical performance of the asymmetric supercapacitor is related to the enhanced electrical conductivity and increased electrode/electrolyte contact area of carbon-coated cobalt sulfide. Thus, the as-prepared carbon-coated cobalt sulfide nanoflowers is demonstrated to be a promising electrode for asymmetric supercapacitors.
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http://dx.doi.org/10.1016/j.jcis.2019.01.002DOI Listing
March 2019

Herbal dry extract BNO 1011 improves clinical and mucociliary parameters in a rabbit model of chronic rhinosinusitis.

Int Forum Allergy Rhinol 2019 06 18;9(6):629-637. Epub 2019 Jan 18.

Department of Otolaryngology-Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, AL.

Background: Enhancing chloride (Cl ) secretion in sinus epithelia represents a novel therapeutic approach to chronic rhinosinusitis (CRS). Herbal dry extract BNO 1011 enhances mucociliary clearance (MCC) via upregulation of Cl secretion in sinonasal cultures in vitro and murine epithelium in vivo. The objective of this study is to evaluate whether the BNO 1011 improves MCC and clinical parameters in a rabbit model of CRS.

Methods: After the development of CRS in 30 New Zealand white rabbits, animals were randomly assigned to receive oral placebo (n = 10), BNO 1011 (low dose [LD], 25 mg/kg/daily) (n = 10), or BNO1011 (high dose [HD], 125 mg/kg/daily) (n = 10) for 4 weeks. Outcomes included sinus opacification (Kerschner's rabbit sinus CT grade), maxillary epithelial Cl secretion (sinus potential difference [PD] assay), airway surface liquid (ASL) depth using micro-optical coherence tomography (μOCT), and submucosal gland density (SMD) on histopathology. Outcome parameters were analyzed by 2 blinded investigators.

Results: BNO 1011 significantly cleared sinus opacification (HD = 1.21 ± 0.63, LD = 1.26 ± 0.37,) compared to placebo (4.02 ± 0.92) (p = 0.009). BNO 1011 resulted in markedly greater mean sinus PD polarization (HD = -12.23 ± 1.4 mV, LD = -12.0 ± 3.0 mV) when compared to rabbits treated with placebo (-4.1 ± 1.1 mV) (p = 0.03). ASL depth was significantly improved when treated with HD (4.08 ± 0.06 μm) and LD (4.05 ± 0.06 μm) compared to placebo (3.5 ± 0.05 μm) (post hoc analysis, p < 0.0001). Histologically, epithelial thickness (HD = 10.0 ± 0.7 μm; LD = 13.7 ± 0.9 μm; placebo = 21.1 ± 2.3 μm; p < 0.005), subepithelial thickness (HD = 63.1 ± 6.6 μm; LD = 103.2 ± 6.7 μm; placebo = 113.3 ± 6.0 μm; p < 0.001), and SMD (HD = 22.2 ± 2.9%; LD = 31.8 ± 1.1%; placebo = 43.8 ± 1.7%; p < 0.0001) were noticeably better with the HD.

Conclusion: Herbal dry extract BNO 1011 improves radiographic, histologic, and MCC parameters in a rabbit model of CRS.
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http://dx.doi.org/10.1002/alr.22290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555666PMC
June 2019

Higher heart rates increase risk of diabetes and cardiovascular events: A prospective cohort study among Inner Mongolians.

Diabetes Metab 2020 02 11;46(1):20-26. Epub 2019 Jan 11.

Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, PR China. Electronic address:

Aim: The study examined the association between resting heart rate and risk of type 2 diabetes (T2D) and cardiovascular events in an Inner Mongolian population.

Methods: Based on a cross-sectional survey carried out in 2003, 2530 participants were reinvestigated between 2013 and 2014. All participants were classified into four groups (quartiles) according to heart rate. Primary outcomes were hypertension, T2D, major macrovascular events and all-cause deaths. Logistic regression models were used to estimate odds ratios (ORs), and shape-restricted cubic spline regressions were conducted to investigate the associations between resting heart rate and study outcomes.

Results: During the 10-year follow-up, 502 (41.6%) patients developed hypertension, 200 (10.4%) had diabetes, 464 (18.3%) experienced major macro-vascular events and 306 (14.3%) died. Resting heart rate was significantly associated with an increased risk of hypertension, T2D, major macro-vascular events and all-cause deaths: adjusted ORs (95% CI) for the highest vs lowest quartiles of heart rate were 1.51 (1.06-2.15), 2.44 (1.54-3.85), 1.55 (1.14-2.10) and 1.57 (1.05-2.34), respectively. Multivariable-adjusted restricted cubic spline regression models showed a linear association between heart rate and the four outcomes (all P < 0.05 for linearity). The addition of heart rate to basic risk factors improved the prediction of risk of diabetes and all-cause deaths [indices of continuous net reclassification improvement and of integrated discrimination improvement were 21.92% (P = 0.002) and 22.69% (P < 0.001), and 0.72% (P = 0.01) and 0.58% (P = 0.03), respectively].

Conclusion: Higher heart rates were associated with an increased risk of hypertension, T2D, major macro-vascular events and all-cause deaths among Inner Mongolians, suggesting that heart rate measurement may be of value as a potential clinical and diagnostic marker.
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http://dx.doi.org/10.1016/j.diabet.2019.01.002DOI Listing
February 2020

Ivacaftor, a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator, Enhances Ciprofloxacin Activity Against Pseudomonas aeruginosa.

Am J Rhinol Allergy 2019 Mar 25;33(2):129-136. Epub 2018 Dec 25.

1 Department of Otolaryngology - Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama.

Background: Methods to improve the clinical efficacy of currently available antibiotics against multidrug resistant bacteria in cystic fibrosis (CF) chronic rhinosinusitis (CRS) are greatly needed. Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, was recently identified as having potentially beneficial off-target effects as a weak inhibitor of bacterial DNA gyrase and topoisomerase IV. The objective of the current study is to evaluate whether ivacaftor enhances the antimicrobial activity of ciprofloxacin against Pseudomonas aeruginosa.

Methods: The planktonic growth of the PAO-1 strain of P. aeruginosa was studied in the presence of ciprofloxacin and/or ivacaftor. Effects were measured according to optical density of cultured PAO-1 at 600 nm. For a static PAO-1 biofilm assay, the PAO-1 strain was inoculated and cultured for 72 h in the presence of the drugs. Formed PAO-1 biofilms were quantified by crystal violet staining and imaged with confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM).

Results: PAO-1 growth was significantly reduced in the presence of ivacaftor (8 or 16 µg/mL) and ciprofloxacin (0.02 or 0.05 µg/mL) compared to ciprofloxacin alone ( P < .001). Similarly, ivacaftor (8 or 16 µg/mL) showed a significant reduction of PAO-1 biofilms when treated with 0.05 µg/mL of ciprofloxacin. Significant synergism was noted between ciprofloxacin and 16 µg/mL of ivacaftor ( P < .0001) in reducing planktonic growth and biofilm formation. Quantitative measurements with crystal violet staining were correlated to CLSM and SEM images.

Conclusion: Ivacaftor enhanced ciprofloxacin's antimicrobial activity against P. aeruginosa. Further studies evaluating the efficacy of ivacaftor/ciprofloxacin combination for P. aeruginosa for CF CRS are warranted.
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http://dx.doi.org/10.1177/1945892418815615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728449PMC
March 2019

Endothelial cell autophagy in chronic intermittent hypoxia is impaired by miRNA-30a-mediated translational control of Beclin-1.

J Cell Biochem 2019 03 5;120(3):4214-4224. Epub 2018 Dec 5.

Department of Respiratory Disease, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.

Chronic intermittent hypoxia (CIH) in obstructive sleep apnea causes damage of aortic endothelial cells, which predisposes the development of many cardiovascular diseases. Recently, both altered expression of microRNAs (miRNAs) and impaired autophagy were found to be associated with endothelial cell dysfunction in CIH. However, the exact molecular regulatory pathway has not been determined. Here, we address this question. In a mouse model of CIH, we detected significant upregulation of miR-30a, a miRNA that targets 3'-untranslated region of autophagy-associated protein 6 (Beclin-1) messenger RNA (mRNA) for suppressing the protein translation, which subsequently attenuated the endothelial cell autophagy against cell death. Indeed, unlike Beclin-1 mRNA, the Beclin-1 protein in endothelial cells did not increase after CIH. Suppression of miR-30a by expression of antisense of miR-30a significantly increased Beclin-1 levels to enhance endothelial cell autophagy in vitro and in vivo, which improved endothelial cell survival against CIH. Together, these data suggest that endothelial cell autophagy in CIH may be attenuated by miR-30a-mediated translational control of Beclin-1 as an important cause of endothelial cell dysfunction and damage.
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http://dx.doi.org/10.1002/jcb.27708DOI Listing
March 2019

Repression of turnip crinkle virus replication by its replication protein p88.

Virology 2019 01 2;526:165-172. Epub 2018 Nov 2.

Department of Plant Pathology, The Ohio State University, Wooster, OH 44691, USA. Electronic address:

We recently reported that p28, one of the two turnip crinkle virus (TCV) replication proteins, trans-complemented a defective TCV lacking p28, yet repressed the replication of another TCV replicon encoding wild-type p28 (Zhang et al., 2017). Here we show that p88, the TCV-encoded RNA-dependent RNA polymerase, likewise trans-complemented a p88-defective TCV replicon, but repressed one encoding wild-type p88. Surprisingly, lowering p88 protein levels enhanced trans-complementation, but weakened repression. Repression by p88 was not simply due to protein over-expression, as deletion mutants missing 127 or 224 N-terminal amino acids accumulated to higher levels but were poor repressors. Finally, both trans-complementation and repression by p88 were accompanied by preferential accumulation of subgenomic RNA2, and a novel class of small TCV RNAs. Our results suggest that repression of TCV replication by p88 may manifest a viral mechanism that regulates the ratio of genomic and subgenomic RNAs based on p88 abundance.
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http://dx.doi.org/10.1016/j.virol.2018.10.024DOI Listing
January 2019

Theoretical Study on the Reaction Mechanism and Kinetics of Criegee Intermediate CHOO with Acrolein.

J Phys Chem A 2018 Nov 30;122(44):8729-8737. Epub 2018 Oct 30.

School of Chemistry and Chemical Engineering, Key Laboratory of Cluster Science of Ministry of Education , Beijing Institute of Technology , Beijing 100081 , P. R. China.

The detailed reaction mechanism and kinetics of Criegee intermediate CHOO with acrolein were investigated. CHOO may add to the C═O or C═C double bond of acrolein to form a five-membered ring adducts, and it may also insert the terminal oxygen atom or insert itself into the C-H bond of acrolein. The addition reactions are more favorable in energy than the insertion reactions. The master equation calculation show that the most competitive reaction channel is the 1,3-cycloaddition of CHOO across the C═O double bond forming the secondary ozonide (SOZ). The lowest energy pathway for SOZ decomposition involves the formation of the singlet biradical intermediate by ring fission, the H-shift isomerization and the dissociation to products. The calculated overall rate constant decreases as the temperature increases from 200 to 500 K, and at 298 K, it is 4.31 × 10 cm molecule s. The branching ratio of collisionally stabilized SOZ increases with the increase of pressure. At low pressure, some of SOZ decompose to HCOOH + acrolein or HCHO + acrylic acid. The pressure dependence of this reaction is in agreement with the previous theoretical and experimental observations for the reaction of CHOO with acetaldehyde.
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http://dx.doi.org/10.1021/acs.jpca.8b06897DOI Listing
November 2018