Publications by authors named "Kun Wan"

50 Publications

Mechanistic insight of simultaneous removal of tetracycline and its related antibiotic resistance bacteria and genes by ferrate(VI).

Sci Total Environ 2021 May 3;786:147492. Epub 2021 May 3.

College of the Environment and Ecology, Xiamen University, Xiamen 361102, China. Electronic address:

The emergence of antibiotics and their corresponding antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) have posed great challenges to the public health. The paper demonstrates the removal of co-existing tetracycline (TC), its resistant Escherichia coli (E. coli), and ARGs (tetA and tetR) in a mixed system by applying ferrate(VI) (FeO, Fe(VI)) at pH 7.0. TC was efficiently degraded by Fe(VI), and the rapid inactivation of the resistant E. coli was found with the complete loss of culturability. The results of flow cytometry suggested that the damage of membrane integrity and respiratory activity were highly correlated with the Fe(VI) dosages. Moreover, high-dose Fe(VI) eliminates 6 log viable but non-culturable (VBNC) cells and even breaks the cells into fragments. ARGs in extracellular form (e-ARGs) exhibited a high sensitivity of 4.44 log removal to Fe(VI). Comparatively, no removal of intracellular ARGs (i-ARGs) was observed due to the multi-protection of cellular structure and rapid decay of Fe(VI). The oxidized products of TC were assessed to be less toxic than the parent compound. Overall, this study demonstrated the superior efficiency and great promise of Fe(VI) on simultaneous removal of antibiotics and their related ARB and ARGs in water.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147492DOI Listing
May 2021

Melamine-induced formation of carbon nanotubes assembly on metal-organic framework-derived Co/C composites for lightweight and broadband microwave absorption.

Dalton Trans 2021 May;50(18):6222-6231

Huaian Engineering Research Center of Soft Magnetic Powder Cores and Devices, Jiangsu Red Magnetic Materials Incorporation, Huaian, 211700, China and Anhui Red Magneto-electric Technology Co., Ltd., Wuhu, 241002, China.

Extending effective absorption bandwidth at a low filling ratio is still a challenge for metal-organic framework-derived microwave absorbing materials. Herein, varied complex structures based on CNTs have been built on Co/C particles derived from ZIF-67 via melamine-involved annealing routes. It was found that cobalt nanoparticles derived from ZIF-67 act as catalysts for the growth of CNTs, effectively promoting and controlling the content of melamine. Due to the effective control of the CNT-containing complex structure, excellent microwave absorption performance was achieved at a rather low filling ratio of 20 wt%, which can be attributed to improved attenuation ability and ameliorated impedance matching. Results show that highly graphitic CNTs benefit the formation of the electron transport network and enhancement of conduction loss. Unique one-dimensional complex structure and abundant Co/C interfaces strengthen the polarization loss. When the dielectric loss was optimized at different frequencies, appropriate impedance matching was also gained to realize a broad effective absorption bandwidth of 5.6 and 4.4 GHz in Ku and X bands, respectively. This work may provide novel insights into the synthesis and design of CNT-containing metal-organic framework-derived materials with lightweight features and wide frequency response.
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http://dx.doi.org/10.1039/d1dt00655jDOI Listing
May 2021

RIPK3 Induces Cardiomyocyte Necroptosis via Inhibition of AMPK-Parkin-Mitophagy in Cardiac Remodelling after Myocardial Infarction.

Oxid Med Cell Longev 2021 27;2021:6635955. Epub 2021 Mar 27.

Department of Respiratory and Critical Care Medicine, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China.

Receptor-interacting protein 3- (RIPK3-) modulated necroptosis plays a critical role in cardiac remodelling after myocardial infarction (MI). However, the precise regulatory mechanism is not fully elucidated yet. In the present study, we showed that RIPK3 expression was upregulated in myocardial tissue after MI in a mouse model by coronary artery ligation, as well as in the cardiomyocytes following hypoxic injury . The increase of RIPK3 expression was found to be accompanied by severe cardiac remodelling, cardiac dysfunction, and higher mortality. Elevated RIPK3 expression subsequently abrogated the AMPK pathway that was accompanied by inhibition of Parkin-mediated mitophagy. Loss of mitophagy increased the opening of mitochondrial permeability transition pore (mPTP), which ultimately induced the cardiomyocyte necroptosis. In contrast, genetic ablation of induced the AMPK/Parkin-mitophagy pathway, favouring a prosurvival state that eventually inhibited mPTP opening and induced the necroptosis of cardiomyocytes in the post-MI cardiac remodelling. In conclusion, our results revealed a key mechanism by which necroptosis could be mediated by RIPK3 via the AMPK/Parkin-mitophagy/mPTP opening axis, which provides a potential therapeutic target in the management of heart failure after MI.
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http://dx.doi.org/10.1155/2021/6635955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019651PMC
March 2021

Expression pattern of mitogen-activated protein kinase kinase 4 and regulation to antibacterial factor ABF-1/2 in response to bacterial challenge from Artemia parthenogenetica.

Fish Shellfish Immunol 2021 Mar 27. Epub 2021 Mar 27.

The International Centre for Precision Environmental Health and Governance, College of Life Sciences, Hebei University, 071002, Baoding, PRChin. Electronic address:

Mitogen-activated protein kinase kinase 4, MKK4, is a key upstream kinase in the JNK/p38 MAPK pathway that has been reported to participate in multiple immune responses. In this study, the gene that encodes ApMKK4 was isolated and identified from Artemia parthenogenetica. It was found to contain a 1134 bp open reading frame encoding 378 amino acids. The predicted protein contains D domain, DVD domain and kinase domain. Homology analysis revealed that ApMKK4 shares 38-69% identity with MKK4 homologs from other species. Results revealed that ApMKK4 was mainly expressed during early development of which highest at the gastrula stage. After challenged by Vibrio harveyi and Micrococcus lysodeikticus, ApMKK4 was remarkably upregulated at 10 and 10 cfu/mL bacterial concentrations, respectively. Through siRNAi, the transcript level of ApMKK4 was significantly decreased by 46-67%. Intriguingly, when the ApMKK4-knockdown nauplii faced with bacterial stimulation, the expression of ApMKK4 was completely restored in a short time. Moreover, this phenomenon also occurred in related antimicrobial peptide genes, ABF-1 and ABF-2. Our research reveals that ApMKK4 plays a pivotal role during early development and immune responses against bacterial infections.
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http://dx.doi.org/10.1016/j.fsi.2021.03.008DOI Listing
March 2021

Structural simplification of evodiamine: Discovery of novel tetrahydro-β-carboline derivatives as potent antitumor agents.

Bioorg Med Chem Lett 2021 May 17;40:127954. Epub 2021 Mar 17.

School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address:

Natural products (NPs) have played a crucial role in the discovery and development of antitumor drugs. However, the high structural complexity of NPs generally results in unfavorable physicochemical profiles and poor drug-likeness. A powerful strategy to tackle this obstacle is the structural simplification of NPs by truncating nonessential structures. Herein, a series of tetrahydro-β-carboline derivatives were designed by elimination of the D ring of NP evodiamine. Structure-activity relationship studies led to the discovery of compound 45, which displayed highly potent antitumor activity against all the tested cancer cell lines and excellent in vivo antitumor activity in the HCT116 xenograft model with low toxicity. Further mechanistic research indicated that compound 45 acted by dual Top1/2 inhibition and induced caspase-dependent cell apoptosis coupled with G/M cell cycle arrest. This proof-of-concept study validated the effectiveness of structural simplification in NP-based drug development, discovered compound 45 as a potent antitumor lead compound and enriched the structure-activity relationships of evodiamine.
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http://dx.doi.org/10.1016/j.bmcl.2021.127954DOI Listing
May 2021

Cytokine release syndrome in COVID-19: a major mechanism of morbidity and mortality.

Int Rev Immunol 2021 Feb 22:1-14. Epub 2021 Feb 22.

The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.

The coronavirus disease 2019 (COVID-19) triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) erupted in Hubei Province of China in December 2019 and has become a pandemic. Severe COVID-19 patients who suffer from acute respiratory distress syndrome (ARDS) and multi-organ dysfunction have high mortality. Several studies have shown that this is closely related to the cytokine release syndrome (CRS), often loosely referred to as cytokine storm. IL-6 is one of the key factors and its level is positively correlated with the severity of the disease. The molecular mechanisms for CRS in COVID-19 are related to the effects of the S-protein and N-protein of the virus and its ability to trigger NF-κB activation by disabling the inhibitory component IκB. This leads to activation of immune cells and the secretion of proinflammatory cytokines such as IL-6 and TNF-α. Other mechanisms related to IL-6 include its interaction with GM-CSF and interferon responses. The pivotal role of IL-6 makes it a target for therapeutic agents and studies on tocilizumab are already ongoing. Other possible targets of treating CRS in COVID-19 include IL-1β and TNF-α. Recently, reports of a CRS like illness called multisystem inflammatory syndrome in children (MIS-C) in children have surfaced, with a variable presentation which in some cases resembles Kawasaki disease. It is likely that the immunological derangement and cytokine release occurring in COVID-19 cases is variable, or on a spectrum, that can potentially be governed by genetic factors. Currently, there are no approved biological modulators for the treatment of COVID-19, but the urgency of the pandemic has led to numerous clinical trials worldwide. Ultimately, there is great promise that an anti-inflammatory modulator targeting a cytokine storm effect may prove to be very beneficial in reducing morbidity and mortality in COVID-19 patients.
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http://dx.doi.org/10.1080/08830185.2021.1884248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919105PMC
February 2021

An Outbreak of Botulinum Types A, B, and E Associated With Vacuum-Packaged Salted Fish and Ham.

J Emerg Med 2021 Jan 28. Epub 2021 Jan 28.

Department of Poisoning and Treatment, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.

Background: Botulinum toxin is a neurotoxin generated during the growth of Clostridium botulinum and can lead to a rare but life-threatening disease with neurologic symptoms. Relatively little is known about the many types of botulinum toxins in China. The clinical symptoms of the different types of botulism toxin-induced illnesses appear after an incubation period and vary greatly by the serotype and degree of exposure to the toxin.

Case Report: We describe 4 patients who consumed vacuum-packaged salted fish and ham and then presented with severe gastrointestinal symptoms, resulting in vomiting and one death. Blood serum and urine samples tested by the botulinum neurotoxin Endopep-MS assay were positive for botulinum toxin types A, B, and E. The patient who consumed the largest amount of fish and ham died after 36 h, and the other patients were treated with botulism antitoxin after being diagnosed with a botulinum toxin-induced illness and recovered after 1 month. These cases illustrate the importance of early diagnosis and early treatment of botulism type E, in particular, because of the risk of respiratory failure and treatment delays, which can result in increased mortality and poorer overall outcomes. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Our cases illustrate the importance of early diagnosis and especially the treatment of illnesses related to botulism type E because of the risk of respiratory failure and because treatment delays can result in increased mortality and worsened overall outcomes.
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http://dx.doi.org/10.1016/j.jemermed.2020.12.006DOI Listing
January 2021

Clinical characteristics of re-hospitalized COVID-19 patients with recurrent positive SARS-CoV-2 RNA: a retrospective study.

Eur J Clin Microbiol Infect Dis 2021 Jan 15. Epub 2021 Jan 15.

The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China.

At present, it has been noticed that some patients recovered from COVID-19 present a recurrent positive RNA test of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) after being discharged from hospitals. The purpose of the current study was to characterize the clinical features of re-hospitalized patients with recurrent SARS-CoV-2 positive results. From January 12 to April 1 of 2020, our retrospective study was conducted in China. The exposure history, baseline data, laboratory findings, therapeutic schedule, and clinical endpoints of the patients were collected. All the patients were followed until April 10, 2020. Among all COVID-19 patients included in the current study, there were 14 re-hospitalized patients due to recurrent positive tests of SARS-CoV-2 RNA. Fever (11 [78.6%]), cough (10 [71.4%]), and fatigue (7 [50.0%]) were the most common symptoms on the patient's first admission, and less symptoms were found on their second admission. The average duration from the onset of symptoms to admission to hospital was found to be 8.4 days for the first admission and 2.6 days for the second admission (P = 0.002). The average time from the detection of RNA (+) to hospitalization was 1.9 days for the first admission and 2.6 days for the second admission (P = 0.479), and the average time from RNA (+) to RNA (-) was 11.1 days for the first admission and 6.3 days for the second admission (P = 0.030). Moreover, the total time in hospital was 18.6 days for the first admission and 8.0 days for the second admission (P = 0.000). It may be necessary to increase the isolation observation time and RT-PCR tests should be timely performed on multiple samples as soon as possible.
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http://dx.doi.org/10.1007/s10096-020-04151-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808928PMC
January 2021

Accumulation of antibiotic resistance genes in full-scale drinking water biological activated carbon (BAC) filters during backwash cycles.

Water Res 2021 Feb 15;190:116744. Epub 2020 Dec 15.

College of the Environment and Ecology, Xiamen University, Xiamen 361102, China. Electronic address:

Biological activated carbon (BAC) filtration, a process widely used in drinking water treatment, was recently reported to harbor antibiotic resistance genes (ARGs). This emerging contamination is poorly understood. This study was conducted to investigate the occurrence of ARGs and bacterial community in full-scale BAC filters during the backwash cycle using high-throughput qPCR and high-throughput sequencing. A total of 178 ARGs were detected in all biofilm samples, with relative abundance ranging from 0.1 to 1.37 copies per 16S rRNA and absolute abundance ranging from 4.48 × 10 to 3.09 × 10 copies/g carbon. Biofilms sampled from different filters shared most detected ARGs and dominant genera including Bryobacter, Pedomicrobium, Reyranella, and Terrimonas, though their bacterial community structure differed significantly. After backwashing, the relative ARGs abundance increased by 1.5- to 3.8-folds and the absolute ARGs abundance increased by 0.90- to 1.12-logs in all biofilm samples during filter ripening, indicating that ARGs accumulated in filters during this period. Redundancy analysis suggested that such ARGs accumulation was mainly driven by horizontal gene transfer in winter, but highly correlated with the increasing relative abundance of genera Bryobacter and Acidibacter in summer. It was observed that 80.6 %-89.3% of the detected ARGs persisted in the filters despite of the backwashing. Given the high richness and relative abundance of ARGs in BAC filter and the ineffectiveness of backwashing in ARG removal, more stringent downstream disinfection strategies are deserved and more research is necessary to assess potential human health risks due to the persistence of ARGs in drinking water.
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http://dx.doi.org/10.1016/j.watres.2020.116744DOI Listing
February 2021

Detection and distribution of vbnc/viable pathogenic bacteria in full-scale drinking water treatment plants.

J Hazard Mater 2021 Mar 20;406:124335. Epub 2020 Oct 20.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China; College of Environment & Ecology, Xiamen University, Xiamen 361102, China. Electronic address:

Viable but non-culturable (VBNC) bacteria have attracted widespread attention since they are inherently undetected by traditional culture-dependent methods. Importantly, VBNC bacteria could resuscitate under favorable conditions leading to significant public health concerns. Although the total number of viable bacteria has been theorized to be far greater than those that can be cultured, there have been no reports quantifying VBNC pathogenic bacteria in full-scale drinking water treatment plants (DWTPs). In this work, we used both culture-dependent and quantitative PCR combination with propidium monoazide (PMA) dye approaches to characterize cellular viability. Further, we established a method to quantify viable pathogens by relating specific gene copies to viable cell numbers. Ratios of culturable bacteria to viable 16S rRNA gene copies in water and biological activated carbon (BAC) biofilms were 0-4.75% and 0.04-56.24%, respectively. The VBNC E. coli, E. faecalis, P. aeruginosa, Salmonella sp., and Shigella sp. were detected at levels of 0-10 cells/100 mL in source water, 0-10 cells/100 mL in chlorinated water, and 0-10 cells/g in BAC biofilms. In addition, differences between the total and viable community structures after ozonation and chlorination were investigated. The relative abundance of opportunistic pathogens such as Mycobacterium, Sphingomonas, etc. increased in final water, likely due to their chlorine resistance. In summary, we detected significant quantities of viable/VBNC opportunistic pathogens in full-scale DWTPs, confirming that traditional, culture-dependent methods are inadequate for detecting VBNC bacteria. These findings suggest a need to develop and implement rapid, accurate methods for the detection of VBNC pathogenic bacteria in DWTPs to ensure the safety of drinking water.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124335DOI Listing
March 2021

Association between acute severe mercury poisoning and multiple organ failure.

Am J Transl Res 2020 15;12(8):4347-4353. Epub 2020 Aug 15.

Poisoning Treatment Department, Fifth Medical Center of PLA General Hospital Beijing 100039, China.

Acute mercury poisoning, involving a number of organs, leads to severe dysfunctions, such as acute renal failure (ARF), and even threatens patients' lives. A case of acute severe mercuric chloride (HgCl) poisoning with multiple organ failure was reported in this study. A 38-year-old woman orally took about 50 g HgCl powder in 2015, and showed nausea, emesis, clouding of consciousness, lip and nail cyanosis, and dark red bloody fluid from bilateral nostrils. Based on chest and abdominal CT examinations, gastroscopy, and colonoscopy, the patient was found to suffer oral mucosal hyperemia and ulceration, gastrointestinal bleeding (haematemesis and hemafecia), ARF, metabolic acidosis, collapse and shock. Despite assisted respiration and relevant active treatments, the patient's condition deteriorated gradually and she was dead eventually. The study suggests that the best treatments for acute HgCl poisoning accompanied with ARF are early blood purification and mercury elimination on the basis of conventional therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476145PMC
August 2020

Changes in aerobic fermentation and microbial community structure in food waste derived from different dietary regimes.

Bioresour Technol 2020 Dec 2;317:123948. Epub 2020 Aug 2.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China. Electronic address:

This study aimed to analyze the relationship between food components and food waste aerobic fermentation efficiency. Different food wastes were designed to be reflective of different dietary regimes, including formulated (R1), high oil/fat and salt (R2), high oil/fat and sugar (R3), and vegetarian (R4) diets, after which the physicochemical properties, enzyme activity, and structural characteristics of food waste microbial communities were examined to explore the potential mechanisms of food waste degradation under different dietary regimes. The main results of this study demonstrated that the physicochemical properties and hydrolase activity of different food waste were significantly different. The species richness in R2 and R3 food waste was higher than that of R1 and R4, whereas the community diversity of R1 and R4 food waste was higher than that of R2 and R3. At the genus level, the dominant bacteria in the four food waste types were Bacillus, Thermoactinomyces, Paenibacillus, and Cohnella.
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http://dx.doi.org/10.1016/j.biortech.2020.123948DOI Listing
December 2020

Inactivation of antibiotic resistant Escherichia coli and degradation of its resistance genes by glow discharge plasma in an aqueous solution.

Chemosphere 2020 Aug 16;252:126476. Epub 2020 Mar 16.

Key Lab of Urban Environment & Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, 361021, P. R. China; College of the Environment & Ecology, Xiamen University, Xiamen, 361005, P. R. China. Electronic address:

Emerging contaminants such as antibiotic resistance bacteria (ARB) and antibiotic resistance genes (ARGs) are becoming a global environmental problem. In this study, the glow discharge plasma (GDP) was applied for degrading antibiotic resistant Escherichia coli (E. coli) with resistance genes (tetA, tetR, aphA) and transposase gene (tnpA) in 0.9% sterile saline. The results showed that GDP was able to inactivate the antibiotic resistant E. coli and remove the ARGs and reduce the risk of gene transfer. The levels of E. coli determined by 16S rRNA decreased by approximately 4.7 logs with 15 min of discharge treatment. Propidium monoazide - quantitative polymerase chain reaction (PMA-qPCR) tests demonstrated that the cellular structure of 4.8 more logs E. coli was destroyed in 15 min. The reduction of tetA, tetR, aphA, tnpA genes was increased to 5.8, 5.4, 5.3 and 5.5 logs with 30 min discharge treatment, respectively. The removal of ARGs from high salinity wastewater was also investigated. The total abundance of ARGs was reduced by 3.9 logs in 30 min. Scavenging tests indicated that hydroxyl radicals (·OH) was the most probable agents for bacteria inactivation and ARGs degradation. In addition, the active chlorine (Cl· and Cl) which formed during the discharge may also contribute to the inactivation and degradation.
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http://dx.doi.org/10.1016/j.chemosphere.2020.126476DOI Listing
August 2020

Comparative analysis of two brine shrimps revealed differential expression pattern and functional characterization of CK2α under bacterial stimulation from different geographical distribution.

Fish Shellfish Immunol 2020 Apr 27;99:631-640. Epub 2020 Feb 27.

The Key Laboratory of Zoological Systematics and Application, College of Life Sciences, Hebei University, 071002, Baoding, PR China. Electronic address:

Understanding how the brine shrimp responds to different geographical populations can provide novel insights on response to bacterial stimulation. In the paper, Artemia sinica from lower altitudes and Artemia parthenogenetica from higher altitudes of the Tibetan Plateau, were used to illustrate different defense against bacteria mechanisms that these organisms used to adapt to different geographical environments. Protein kinase CK2 is a serine/threonine kinase with a multitude of protein substrates. It is a ubiquitous enzyme essential for the viability of eukaryotic cells, where its functions in a variety of cellular processes, including cell cycle progression, apoptosis, transcription, and viral infection. The gene encodes the same mRNA sequence in A. sinica and A. parthenogenetica, named AsCK2α and ApCK2α, respectively. The open reading frame was obtained, a 1047-bp sequence encoding a predicted protein of 349 amino acids. To systematically analyze the expression of AsCK2α and ApCK2α during embryonic development and bacterial challenge, real-time PCR, Western blotting and immunohistochemistry were performed. The results showed that AsCK2α was higher than ApCK2α at different developmental stages. Under bacterial challenge, the expression of ApCK2α was significantly higher than AsCK2α. Protein localization analysis showed that AsCK2α and ApCK2α were mainly distributed in the head and chest. Our research revealed that CK2α plays a vital role in the growth, development and bacterial stimulation of the brine shrimp.
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http://dx.doi.org/10.1016/j.fsi.2020.02.047DOI Listing
April 2020

Domain-adversarial multi-task framework for novel therapeutic property prediction of compounds.

Bioinformatics 2020 05;36(9):2848-2855

Department of Computer Science, UC Santa Barbara, Santa Barbara, CA 93106, USA.

Motivation: With the rapid development of high-throughput technologies, parallel acquisition of large-scale drug-informatics data provides significant opportunities to improve pharmaceutical research and development. One important application is the purpose prediction of small-molecule compounds with the objective of specifying the therapeutic properties of extensive purpose-unknown compounds and repurposing the novel therapeutic properties of FDA-approved drugs. Such a problem is extremely challenging because compound attributes include heterogeneous data with various feature patterns, such as drug fingerprints, drug physicochemical properties and drug perturbation gene expressions. Moreover, there is a complex non-linear dependency among heterogeneous data. In this study, we propose a novel domain-adversarial multi-task framework for integrating shared knowledge from multiple domains. The framework first uses an adversarial strategy to learn target representations and then models non-linear dependency among several domains.

Results: Experiments on two real-world datasets illustrate that our approach achieves an obvious improvement over competitive baselines. The novel therapeutic properties of purpose-unknown compounds that we predicted have been widely reported or brought to clinics. Furthermore, our framework can integrate various attributes beyond the three domains examined herein and can be applied in industry for screening significant numbers of small-molecule drug candidates.

Availability And Implementation: The source code and datasets are available at https://github.com/JohnnyY8/DAMT-Model.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa063DOI Listing
May 2020

Co-selection and stability of bacterial antibiotic resistance by arsenic pollution accidents in source water.

Environ Int 2020 02 30;135:105351. Epub 2019 Nov 30.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China; College of the Environment and Ecology, Xiamen University, Xiamen 361102, China. Electronic address:

Frequent heavy-metal pollution accidents severely deteriorated the source water quality of drinking water treatment plants (DWTP). Limited data have explicitly addressed the impact of these incidents on bacterial antibiotic resistance (BAR). In present study, we investigated the shift of antibiotic resistome caused by heavy metal pollution incidents via simulating an arsenic shock loading [As (III)], along with the associated risks imposed on drinking water systems. The results indicated that a quick co-selection of antibiotic resistant bacteria (ARB) was achieved after exposure to 0.2-1 mg/L As (III) for only 6 h, meanwhile, there was an increase of relative abundance of antibiotic resistance genes (ARGs) and mobile genetic elements. Most of the co-selected BAR could be maintained for at least 4 days in the absence of As (III) and antibiotics, implying that the pollution in source water possibly contributed to the preservation and proliferation of antibiotic resistance determinants in the subsequent DWTP. Bacterial community structure analysis showed a strong correlation between bacterial community shift and BAR promotion, and enrichment of opportunistic bacteria (e.g. Escherichia-Shigella, Empedobacter sp. and Elizabethkingia sp.). The results indicated a potential epidemiological threat to the public due to accident-level arsenic contamination in the source water. This study gave insight into understanding the source water pollution accidents from the perspective of bio-hazard and biological risks, and highlighted a neglected important source of BAR in drinking water systems.
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http://dx.doi.org/10.1016/j.envint.2019.105351DOI Listing
February 2020

Profiling the microbial contamination in aviation fuel from an airport.

Biofouling 2019 09 11;35(8):856-869. Epub 2019 Oct 11.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, People's Republic of China.

Microbial contamination during fuel storage can cause fuel system fouling and corrosion. Characterizing microbial contamination is critical for preventing and solving these problems. In this study, culture-based combing with the culture-independent methods, were used to profile the microbial contamination in aviation fuel. High-throughput sequencing (HTS) modified by propidium monoazide (PMA) revealed a higher diversity of contaminating microorganisms in samples than the culture method. Proteobacteria (47%), Actinobacteria (21%) and Ascomycota (>99%, fungi) were the most abundant phyla, and the neglected archaea was also detected. Additionally, qPCR-based methods revealed all samples contained a heavy level of microbial contamination, which was more accurate than its culturable counterparts, and fungal contamination was still a problem in aviation fuel. The application of a PCR-based method gives deeper insight into microbial contamination in aviation fuel than the conventional culture method, thus using it for regular detection and accurate description of fuel contamination is strongly recommended in the case of explosive microbial growth.
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http://dx.doi.org/10.1080/08927014.2019.1671977DOI Listing
September 2019

High-throughput sequencing reveals biofluid exosomal miRNAs associated with immunity in pigs.

Biosci Biotechnol Biochem 2020 Jan 4;84(1):53-62. Epub 2019 Sep 4.

College of Animal Science and Technology, Chongqing Three Gorges Vocational College, Chongqing, China.

Large numbers of miRNAs are found in biofluid exosomes. We isolated ~50-200 nm diameter exosomes from four types of porcine biofluid (urine, plasma, semen, and bile) using serial centrifugation and ultracentrifugation procedures. A total of 42.15 M raw data were generated from four small RNA libraries. This produced 40.17 M map-able sequences, of which we identified 204 conserved miRNAs, and 190 novel candidate miRNAs. Furthermore, we identified 34 miRNAs specifically expressed in only one library, all with well-characterized immune-related functions. A set of five universally abundant miRNAs (miR-148a-3p, miR-21-5p, let-7f-5p, let-7i-5p, and miR-99a-5p) across all four biofluids was also found. Function enrichment analysis revealed that the target genes of the five ubiquitous miRNAs are primarily involved in immune and RNA metabolic processes. In summary, our findings suggest that porcine biofluid exosomes contain a large number of miRNAs, many of which may be crucial regulators of the immune system.
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http://dx.doi.org/10.1080/09168451.2019.1661767DOI Listing
January 2020

Population and single cell metabolic activity of UV-induced VBNC bacteria determined by CTC-FCM and DO-labeled Raman spectroscopy.

Environ Int 2019 09 21;130:104883. Epub 2019 Jun 21.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China. Electronic address:

The occurrence of viable but non-culturable (VBNC) bacteria will result in significant underestimation of viable bacterial counts in drinking water. Whereas, much is unknown in characterizing their viability. In this study, two environmental isolates (Aeromonas sp. and Pseudomonas sp.) and two model strains (E. coli and S. aureus) were induced into VBNC state by UV irradiation. Then, their metabolic activity was determined by 5-cyano-2,3-ditolyl tetrazolium chloride combination flow cytometry (CTC-FCM) and DO-labeled Raman spectroscopy, respectively, at both population and single cell levels. The results showed that almost all strains could enter VBNC state irradiated by ≥ 5 mJ/cm UV. When determined by CTC-FCM, the population metabolic activity for each strain did not vary significantly (p > 0.05) unless the UV dose reached 200 mJ/cm. Their single cell activity spectrum narrowed slightly, as indicated by changes in the standard deviation of the logarithmic normal distribution (σ) of 0.015-0.033. This minute difference suggested the CTC-FCM method was suitable for assessing the essential viability of VBNC bacteria. With respect to Raman method, an obvious dose-response effect was recorded. With the UV dosages increased from 10 to 200 mJ/cm, the CD/(CD + CH) for the four strains were reduced to between 95.7% and 47.9% of unirradiated controls, depending on strain and UV dose. Meanwhile, the single cellular Raman spectrum showed much more heterogeneously metabolic activity distribution, with some cells even entering metabolic "silence". Considering the ubiquitous participation of water in biochemical processes, the Raman method was more appropriate in assessing the overall metabolic activity. The above findings can not only be a reference for VBNC mechanism studies, but also have the potential in optimizing disinfection and other bacterial removal processes.
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http://dx.doi.org/10.1016/j.envint.2019.05.077DOI Listing
September 2019

Low nutrient levels as drinking water conditions can reduce the fitness cost of efflux pump-mediated ciprofloxacin resistance in Pseudomonas aeruginosa.

J Environ Sci (China) 2019 Sep 1;83:123-132. Epub 2019 Apr 1.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China. Electronic address:

The long-term persistence of antibiotic resistance in the environment, especially in drinking water, is a public health concern. Expression of an efflux pump, an important mechanism of resistance to antibiotics, usually confers a fitness cost in bacteria. In this study, we aimed to determine why antibiotic resistance conferred by overexpression of an efflux pump persisted in low-nutrient environments (TOC < 10 mg/L) such as drinking and source water in which antibiotic selective pressure might be very low or even absent. Competition experiments between wild-type Pseudomonas aeruginosa and ciprofloxacin-resistant mutants revealed that the fitness cost of ciprofloxacin resistance significantly decreased (p < 0.05) under low-nutrient (0.5 mg/L total organic carbon (TOC)) relative to high-nutrient (500 mg/L TOC) conditions. Mechanisms underlying this fitness cost were analyzed. The mexD gene expression in resistant bacteria (cip_3 strain) was significantly lower (p < 0.05) in low-nutrient conditions, with 10 mg/L TOC ((8.01 ± 0.82)-fold), than in high-nutrient conditions, with 500 mg/L TOC ((48.89 ± 4.16)-fold). Moreover, rpoS gene expression in resistant bacteria ((1.36 ± 0.13)-fold) was significantly lower (p < 0.05) than that in the wild-type strain ((2.78 ± 0.29)-fold) under low-nutrient conditions (10 mg/L TOC), suggesting a growth advantage. Furthermore, the difference in metabolic activity between the two competing strains was significantly smaller (p < 0.05) in low-nutrient conditions (5 and 0.5 mg/L TOC). These results suggest that nutrient levels are a key factor in determining the persistence of antibiotic resistance conferred by efflux pumps in the natural environment with trace amounts or no antibiotics.
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http://dx.doi.org/10.1016/j.jes.2019.03.022DOI Listing
September 2019

Organic carbon: An overlooked factor that determines the antibiotic resistome in drinking water sand filter biofilm.

Environ Int 2019 04 1;125:117-124. Epub 2019 Feb 1.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, People's Republic of China. Electronic address:

Biofilter, an essential water treatment process, is reported to be the harbor of bacterial antibiotic resistance genes (ARGs). Due to the oligotrophic characteristic of source water, filter biofilm is largely influenced by the concentration of organic carbon. The objective of this study was to investigate the effect of organic carbon concentration on shaping bacterial antibiotic resistome in filter biofilm. Our study was based on pilot-scale sand filters, and we investigated the antibiotic resistome using high-throughput qPCR. A total of 180 resistance genes from eight categories of antibiotics were detected in 15 biofilm samples of three sand filters. The results indicated that higher concentration of influent organic carbon led to lower diversity of bacterial community and richness of antibiotic resistance genes (ARGs) in biofilm. We discovered a negative correlation (p ≤ 0.01) between the richness of ARGs and the corresponding TOC level. Moreover, the absolute abundance of ARGs was positively correlated (p ≤ 0.05) with the abundance of 16S rRNA gene and was determined by the organic carbon concentration. Sand filters with gradient influent organic carbon concentration led to the formation of different antibiotic resistomes and canonical correspondence analysis (CCA) indicated that difference in bacterial community composition was likely the main reason behind this difference. We also observed a similar trend in the relative abundance of ARGs, which increased with the depth of sand filters. However, this trend was more pronounced in filters with low organic carbon concentrations. Overall, this study revealed that the organic carbon concentration determined the absolute abundance of ARGs and also shaped the diversity and relative abundance of ARGs in drinking water sand filters. These results may provide new insights into the mechanism of persistent bacterial antibiotic resistance in drinking water treatment.
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http://dx.doi.org/10.1016/j.envint.2019.01.054DOI Listing
April 2019

Study of biological up-flow roughing filters designed for drinking water pretreatment in rural areas: using ceramic media as filter material.

Environ Technol 2020 Apr 11;41(10):1256-1265. Epub 2018 Oct 11.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, People's Republic of China.

Roughing filters have been successfully employed as a pretreatment method in rural water supply, but few studies have reported the performance of up-flow roughing filters (URFs) packed with ceramic media. In this study, two pilot-scale URFs filled with ceramic media were designed. Filter performance, height profiles and head loss development were fully investigated. The average DOC, UV absorbance, NH-N and total bacterial counts removal efficiencies of filters were found to be close to 8%, 10%, 70% and 0.6 log (75%), respectively. Both filters could remove about 60-90% of turbidity with influent turbidity ranging from 1 to 500 NTU and high removal efficiencies (∼60%) were achieved when influent turbidity was lower than 2.5 NTU at a hydraulic load up to 2 m h. Height profiles revealed that UV absorbance, NH-N and turbidity were primarily removed in the former part of filter columns and that the separated solids stored within 20 cm of ceramic media layer above the bottom contributed to over 90% of total head loss. Filter run times were estimated to be around 60-80 days with a maximum head loss of 30 cm and an average influent turbidity of 10 NTU. The results indicated that the two URFs, combining low-cost operation and simple maintenance with good performance, were well suited to small waterworks in rural areas.
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http://dx.doi.org/10.1080/09593330.2018.1530304DOI Listing
April 2020

Clinical analysis of 86 botulism cases caused by cosmetic injection of botulinum toxin (BoNT).

Medicine (Baltimore) 2018 Aug;97(34):e10659

Department of Poisoning Treatment, Affiliated Hospital, Academy of Military Medical Science, Poisoning Treatment Center of the Army, Beijing, China.

This study was conducted to analyze the clinical characteristics of and treatment strategies for botulism among patients receiving cosmetic injection of botulinum toxin (BoNT).A total of 86 botulism patients caused by cosmetic injection of BoNT were enrolled in our study. All of the patients were diagnosed according to their history of cosmetic BoNT injection, clinical symptoms and signs, and other auxiliary examinations (including those on renal and liver functions, blood index detection, and chest X-ray). All of the patients received comprehensive treatments and botulinum antitoxin serum injection.The main symptoms of botulism patients included headache, dizziness, insomnia, fatigue, blurred vision, eye opening difficulty, slurred speech, dysphagia, bucking, constipation, and anxiety. These clinical symptoms occurred 0∼36 days after BoNT injection, especially from 2nd to 6th day after the operation. Furthermore, the usage dose of BoNT was negatively related to latent period. Finally, patients all discharged from our hospital 1∼20 days after treatments, and their symptoms relieved or disappeared.Botulism is a severe side effect for BoNT injection. Injecting botulinum antitoxin serum may be an effective approach to improve clinical outcomes of botulism cases.
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http://dx.doi.org/10.1097/MD.0000000000010659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112997PMC
August 2018

Hydrothermal growth of ferrous hydroxide terephthalate as a new positive electrode material for supercapacitors.

Dalton Trans 2018 Sep;47(35):12056-12060

School of Materials Science and Engineering, Nanchang University, Nanchang, Jiangxi 330031, China.

Ferrous hydroxide terephthalate, Fe(OH)(C8H5O4), is first prepared by an in situ hydrothermal growth method on nickel foam, which can be directly used as the positive electrodes for supercapacitors with superior pseudocapacitive behaviors. It displays high specific capacitance of 5.25 F cm-2 (656.3 F g-1) at 10 mA cm-2 (1.25 A g-1).
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http://dx.doi.org/10.1039/c8dt02377hDOI Listing
September 2018

Reduction of the fitness cost of antibiotic resistance caused by chromosomal mutations under poor nutrient conditions.

Environ Int 2018 11 29;120:63-71. Epub 2018 Jul 29.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China. Electronic address:

The prevalence of antibiotic resistance in drinking water system is pressing public health risk. Antibiotic resistance conferred by chromosomal mutations often produces fitness cost, which may affect its spread and persistence. In this study, the rifampin-resistant strains were competed with their wild-type counterparts at different nutrient levels. It was observed that the ratio of the absolute number between resistant and wild-type cells quickly decreased under rich nutrient conditions, but it slowly reduced or remained stable in the poor nutrient medium. This finding suggested that poor nutrient conditions resulted in the reduction of fitness cost of antibiotic resistance, i.e. the resistant bacteria became more competitive. Implying mechanisms analysis found that the differences of metabolic activity between wild-type and rifampin-resistant strains was significant smaller (P < 0.05) at low nutrient levels. Additionally, distinguishable large colony size rifampin-resistant strains were observed during competition assay. DNA sequencing of RNA polymerase subunit genes further revealed that these colonies could be adaptive mutants from wild-type strain in rpoB gene. To our knowledge, this is the first study to reveal that the oligotrophic conditions facilitate the persistence of antibiotic resistance in drinking water by reducing the fitness cost of the resistant strains.
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http://dx.doi.org/10.1016/j.envint.2018.07.035DOI Listing
November 2018

Enzymatic Degradation of Allergen Peptides from Bovine Casein by a Combination of Streptomyces Aminopeptidases.

Appl Biochem Biotechnol 2019 Feb 16;187(2):570-582. Epub 2018 Jul 16.

Okayama Prefectural Technology Center for Agriculture, Forestry, and Fisheries, Research Institute for Biological Sciences (RIBS), 7549-1 Kibichuo-cho, Kaga-gun, Okayama, 716-1241, Japan.

Cow's milk is one of the most common allergenic foods. Cow's milk allergy is mainly an IgE-mediated hypersensitivity reaction, and the major allergens from cow's milk have been found to be caseins, β-lactoglobulin, and α-lactalbumin. Several peptides derived from bovine casein are known allergens in cow's milk. To reduce their allergenicity, these proteins can be degraded by food-grade peptidases. We succeeded in detection of two peptides, VLPVPQK and FFVAPFPEVFGK, from bovine casein-derived allergen peptides by using an ion trap LC-MS apparatus. This study focuses on the synergistic effects of Streptomyces aminopeptidases belonging to the M1, M24, and M28 families on the degradation of the allergen peptides. From these results, we demonstrated that the combination of M1 and M24 aminopeptidases was the most effective for degrading the abovementioned allergenic peptides.
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http://dx.doi.org/10.1007/s12010-018-2839-7DOI Listing
February 2019

Loop of Streptomyces Feruloyl Esterase Plays an Important Role in the Enzyme's Catalyzing the Release of Ferulic Acid from Biomass.

Appl Environ Microbiol 2018 02 17;84(3). Epub 2018 Jan 17.

Research Institute for Biological Sciences, Okayama Prefectural Technology Center for Agriculture, Forestry, and Fisheries, Kaga-gun, Okayama, Japan

Feruloyl esterases (FAEs) are key enzymes required for the production of ferulic acid from agricultural biomass. Previously, we identified and characterized R18, an FAE from NBRC 12852, which showed no sequence similarity to the known FAEs. To determine the region involved in its catalytic activity, we constructed chimeric enzymes using R18 and its homolog (TH2-18) from strain TH-2. Although R18 and TH2-18 showed 74% identity in their primary sequences, the recombinant proteins of these two FAEs (recombinant R18 [rR18] and rTH2-18) showed very different specific activities toward ethyl ferulate. By comparing the catalytic activities of the chimeras, a domain comprised of residues 140 to 154 was found to be crucial for the catalytic activity of R18. Furthermore, we analyzed the crystal structure of rR18 at a resolution of 1.5 Å to elucidate the relationship between its activity and its structure. rR18 possessed a typical catalytic triad, consisting of Ser-191, Asp-214, and His-268, which was characteristic of the serine esterase family. By structural analysis, the above-described domain was found to be present in a loop-like structure (the R18 loop), which possessed a disulfide bond conserved in the genus Moreover, compared to rTH2-18 of its parental strain, the TH2-18 mutant, in which Pro and Gly residues were inserted into the domain responsible for forming the R18 loop, showed markedly high values using artificial substrates. We also showed that the FAE activity of TH2-18 toward corn bran, a natural substrate, was improved by the insertion of the Gly and Pro residues. species are widely distributed bacteria that are predominantly present in soil and function as decomposers in natural environments. They produce various enzymes, such as carbohydrate hydrolases, esterases, and peptidases, which decompose agricultural biomass. In this study, based on the genetic information on two strains, we identified novel feruloyl esterases (FAEs) capable of producing ferulic acid from biomass. These two FAEs shared high similarity in their amino acid sequences but did not resemblance any known FAEs. By comparing chimeric proteins and performing crystal structure analysis, we confirmed that a flexible loop was important for the catalytic activity of FAEs. Furthermore, we determined that the catalytic activity of one FAE was improved drastically by inserting only 2 amino acids into its loop-forming domain. Thus, differences in the amino acid sequence of the loop resulted in different catalytic activities. In conclusion, our findings provide a foundation for the development of novel enzymes for industrial use.
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http://dx.doi.org/10.1128/AEM.02300-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772227PMC
February 2018

[Effects of Low-level Nutrition and Trace Antibiotics on the Fitness Cost of Plasmids Bearing Antibiotic Resistance].

Huan Jing Ke Xue 2016 Aug;37(8):3224-3228

Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China.

The effects of nutrition and antibiotic level on fitness costs of plasmid containing antibiotic resistance in drinking water system were investigated in this study. Three plasmids harboring different antibiotic resistances, i.e. pACYC184, RP4, and PBR322, were selected. It was found that the antibiotic resistance imposed cost on the fitness of all plasmids at different nutrition levels, which was universal. Moreover, the fitness costs were larger at lower nutrition levels. Besides, the fitness costs of plasmid bearing antibiotic resistance were also affected by trace antibiotics. In this study, when exposed to antibiotics (lower than 50% MIC), the fitness costs of plasmid imposed to the bacteria were more apparent than the injury or inhibition effect by antibiotics. The plasmids were unstable. Therefore, it was inferred that the plasmid containing antibiotic resistance imposed large fitness costs on bacteria in drinking water system (with low-level nutrition and ng·L level antibiotic), and it was not stable. Thus, the risk of plasmid bearing antibiotic resistance transmission and spread in drinking water system was low.
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http://dx.doi.org/10.13277/j.hjkx.2016.08.051DOI Listing
August 2016

Molecular insights into the mechanism of thermal stability of actinomycete mannanase.

FEBS Lett 2016 09 23;590(17):2862-9. Epub 2016 Aug 23.

Okayama Prefectural Technology Center for Agriculture, Forestry and Fisheries, Research Institute for Biological Sciences (RIBS), Okayama, Japan.

Streptomyces thermolilacinus mannanase (StMan), which requires Ca(2+) for its enhanced thermal stability and hydrolysis activity, possesses two Ca(2+) -binding sites in loop6 and loop7. We evaluated the function of the Ca(2+) -binding site in loop7 and the hydrogen bond between residues Ser247 in loop6 and Asp279 in loop7. The Ca(2+) -binding in loop7 was involved only in thermal stability. Mutations of Ser247 or Asp279 retained the Ca(2+) -binding ability; however, mutants showed less thermal stability than StMan. Phylogenetic analysis indicated that most glycoside hydrolase family 5 subfamily 8 mannanases could be stabilized by Ca(2+) ; however, the mechanism of StMan thermal stability was found to be quite specific in some actinomycete mannanases.
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http://dx.doi.org/10.1002/1873-3468.12322DOI Listing
September 2016

Novel nanoemulsion based lipid nanosystems for favorable in vitro and in vivo characteristics of curcumin.

Int J Pharm 2016 May 29;504(1-2):80-8. Epub 2016 Mar 29.

Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing 400016, PR China. Electronic address:

The goal of this study was to assess the enhanced elementary characteristics, in vitro release, anti-cancer cytotoxicity, in situ absorption and in vivo bioavailability of a novel nanoemulsion based lipid nanosystems containing curcumin (CNELNs) when administered orally. The CNELNs were first fabricated by loading water-in-oil nanoemulsions into lipid nanosystems using a nanoemulsion-film dispersion-sonication method. The gastro-intestinal absorption, in vitro release and in vivo kinetic property of CNELNs were investigated using an in situ perfusion method, a dialysis method and a concentration-time curve based method, respectively. The inhibitory effects of CNELNs on human lung cancer A549 cell growth were determined using MTT assay. The absorption constants and effective permeabilities of CNELNs in different gastro-intestinal tracts increased 2.29-4.04 times and 4.06-8.27 times that of curcumin (CUR), respectively. The relative bioavailability of CNELNs to free CUR was 733.59%. CNELNs inhibited A549 growth in a dose- and time-dependent manner. CNELNs markedly improved the oral bioavailability of CUR which was probably due to the increased gastro-intestinal absorption. CNELNs had stronger inhibitory effects on the viabilities of A549 cells than that of free CUR. CNELNs might be promising nanosystems for oral delivery of CUR to satisfy clinical requirements.
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http://dx.doi.org/10.1016/j.ijpharm.2016.03.055DOI Listing
May 2016