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1.
Chem Commun (Camb) ; 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32167121

RESUMO

Here, a new strategy based on artificial multifunctional allostery (mFA) was explored to regulate the assembly of a DNA nanowire using circulating tumor DNA (ctDNA) as the initiator. Given its unique properties, the mFA-regulated versatile DNA nanowire was applied to engineer a single-step, amplified and dynamic biosensor for the quantitative analysis of ctDNA in serum samples with tunable sensitivity and selectivity.

2.
Metab Brain Dis ; 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152798

RESUMO

Neuroinflammation can cause multiple neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Recent studies have shown that the artemisinin derivative dihydroartemisinin (DHA) can be used as an immunomodulatory, anti-inflammatory and anti-tumor agent. The anti-neuroinflammatory effects of DHA were evaluated in our study, and the underlying mechanisms were explored using the Morris water maze test (MWMT), Open-field test (OFT) and Closed-field test (CFT), Elevated plus maze test (EPMT), Nissl Staining, Immunofluorescence analysis, RT-PCR, and Western Blot. Our results show that DHA significantly inhibits LPS-induced inflammation and attenuates LPS-induced behavioral and memory disorders. 1. Behavioral test results: 1) in the water maze test, the mice in the LPS group showed increased escape latency and length of the movement path on the third day; they also had a decreased number of crossings of the target quadrant after the platform was removed on the 5th day and remained in the target quadrant for less time; 2) in the open- and closed-field experiment, the number of activities and activities in the open-field were significantly reduced; 3) in the elevated cross maze experiment, LPS-treated mice exhibited a significant reduction in the number of times and the time to enter the open arm; the above behavior was reversed after DHA treatment. 2. Nissl staining results: compared with the Control group, the LPS group showed significant damage, and the number of damaged cells in the hippocampal CA1, CA2, CA3 and DG regions was increased; DHA treatment reduced cell damage. 3. RT-PCR results: compared with the Control group, the LPS group showed increased expression of IL-1ß and IL-6 but decreased expression after DHA treatment. 4. GFAP fluorescent staining: compared with the control group, the corresponding reactivity of positive cells in the LPS-induced group was increased in the CA1-CA3 and DG regions of the hippocampus; compared with the LPS-induced mice, cells in the LPS + DHA group showed significantly reduced reactivity (GFAP). 5. Western blot results: compared with the Control group, the LPS group showed increased expression of P-PI3K/PI3K, P-AKT/AKT, IL-6 and TNFα and a decreased expression of P-PI3K/PI3K, IL-6, TNF and P-AKT/AKT after DHA treatment. Our findings provide direct evidence for the potential use of DHA in the treatment of neuroinflammatory diseases.

3.
Behav Brain Res ; 384: 112520, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32006563

RESUMO

Cerebral ischemia/reperfusion (I/R) injury is a leading cause of learning and memory dysfunction. Hydrogen sulfide (H2S) has been shown to confer neuroprotection in various neurodegenerative diseases, including cerebral I/R-induced hippocampal CA1 injury. However, the underlying mechanisms have not been completely understood. In the present study, rats were pretreated with SAM/NaHS (SAM, an H2S agonist, and NaHS, an H2S donor) only or SAM/NaHS combined with CaM (an activator of CaMKII) prior to cerebral ischemia. The Morris water maze test demonstrated that SAM/NaHS could alleviate learning and memory impairment induced by cerebral I/R injury. Cresyl violet staining was used to show the survival of hippocampal CA1 pyramidal neurons. SAM/NaHS significantly increased the number of surviving cells, whereas CaM weakened the protection induced by SAM/NaHS. The immunohistochemistry results indicated that the number of Iba1-positive microglia significantly increased after cerebral I/R. Compared with the I/R group, the number of Iba1-positive microglia in the SAM/NaHS groups significantly decreased. Co-Immunoprecipitation and immunoblotting were conducted to demonstrate that SAM/NaHS suppressed the assembly of CaMKII with the ASK1-MKK3-p38 signal module after cerebral I/R, which decreased the phosphorylation of p38. In contrast, CaM significantly inhibited the effects of SAM/NaHS. Taken together, the results suggested that SAM/NaHS could suppress cerebral I/R injury by downregulating p38 phosphorylation via decreasing the assembly of CaMKII with the ASK1-MKK3-p38 signal module.

4.
PLoS One ; 15(2): e0228623, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084152

RESUMO

Hepatopancreatic necrosis disease (HPND) is a newly emerging disease in the Chinese mitten crab, Eriocheir sinensis, which has resulted in large economic losses. However, the underlying cause of this disease remains unclear. To better understand the pathogenesis and pathogenic mechanism of HPND, we compared the transcriptome differences of the hepatopancreas of E. sinensis with and without HPND. The analysis yielded > 30 million reads for each sample of three test (with HPND) and three control groups (without HPND). We observed 978 downregulated genes and 644 upregulated genes. Among the gene ontology categories "biological process," "cellular component," and "molecular function", the subcategories cellular process, single-organism process, biological regulation, metabolic process, cell part, organelle, organelle part, binding, and catalytic were enriched. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that "metabolism of xenobiotics by cytochrome P450," "drug metabolism-cytochrome P450," "chemical carcinogenesis," and "material metabolism" were the "five" most significantly enriched pathways in the hepatopancreas of E. sinensis with HPND. The results revealed that material metabolic abnormalities and drug effects from the external environment might be associated with HPND in the Chinese mitten crab. Considering the wide use of pyrethroids for pond cleaning in Xinghua city, we speculated that pyrethroids might cause HPND in the Chinese mitten crab. Our study provided useful information about the cause and pathogenetic mechanisms of HPND and could help to prevent this disease in production practice.

5.
J Proteome Res ; 19(1): 238-247, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31603327

RESUMO

In recent years, tumor microenvironment (TME) has been recognized as potential targets for tumor treatment and the tumor vascular system is one of such targets. Fusing truncated tissue factor (tTF) with pH low insertion peptides (pHLIP), tTF-pHLIP, can target tumor vessels owing to its acidic TME and cause tumor vessel occlusion by blood clotting and subsequently effectively inhibit tumor growth. To evaluate its bioeffects, we exposed the tTF-pHLIP to normal mice and mice xenograft with B16F10 tumor and analyzed the metabolic profiling of various tissues and biofluids including plasma and urine from mice treated with and without tTF-pHLIP. A combination of nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry and ultra-high-performance liquid chromatography-mass spectrometry was employed in the study. We found that tTF-pHLIP treatment can effectively reduce tumor size and concurrently ameliorate tumor-induced alterations in the TCA cycle metabolism and lipid metabolism. In addition, we found that toxicity of tTF-pHLIP to normal mice is minor and exposure of the tTF-pHLIP induced oxidative stress to the system. Hence, we concluded that tTF-pHLIP is of low toxicity and effective in reducing tumor size as well as rebalancing tumor-induced metabolic derailment.

6.
Sci Total Environ ; 711: 135123, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31818587

RESUMO

The extensive use of roxarsone (ROX) in livestock and poultry husbandry causes the production of arylarsenic-contaminated manure/wastewater. Anaerobic digestion is a conventional technique for livestock manure/wastewater treatment. However, the factors affecting arsenic volatilization are poorly understood in arylarsenic-loaded anaerobic reactors. The main factors such as ROX loading, exposure time of anaerobic granular sludge (AGS) to ROX, and volatile fatty acid (VFA) levels, affecting arsenic volatilization were investigated in this study. The results indicated that ROX loading of 5.70 mg-As·L-1 triggered the maximum volatile arsenic yield of 6.78 ng-As·g-1-VSS·d-1, which was 4.95 times higher compared to the ROX-free assay. The conversion of ROX into inorganic arsenic was an essential step for arsenic volatilization. The 160-day and 270-day exposure of AGS to ROX caused 6-fold and 8-fold increase in volatile arsenic yield, respectively, compared to the 0-day exposure. With the longer-time exposure to ROX, AGS provided more available arsenic for volatilization and its arsenic-volatilizing capacity was significantly enhanced. VFA level was positively associated with arsenic volatilization (r = 0.832-0.950; p < 0.05). The abundance of arsM genes in AGS increased by 34.62-129.05% after the 100-day incubation, and was strongly correlated to arsenic volatilization. Based on these results, possible pathway of arsenic volatilization in ROX-loaded digesters were proposed. The result from this study improves a better understanding of the potential of arsenic volatilization in arylarsenic-contaminated environments.

7.
ACS Appl Mater Interfaces ; 12(3): 3354-3362, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31872756

RESUMO

The overprescription and improper use of antibiotics have contributed to the evolution of bacterial resistance, making it urgent to develop alternative therapies and agents with better efficacy as well as less toxicity to combat bacterial infections and keep new resistance from developing. In this work, a novel light-activable nano-antibiotic platform (TC-PCM@GNC-PND) was constructed by the incorporation of gold nanocages (GNC) and two thermosensitive gatekeepers, phase-change materials (PCM) and thermosensitive polymer poly(N-isopropylacrylamide-co-diethylaminoethyl methacrylate) (PND), to realize precisely the synergy of photothermal and antimicrobial drugs. GNC exhibits an excellent photothermal effect owing to its strong absorbance in the near-infrared (NIR) region, and hollow interiors make it a favorable vehicle for loading various antibiotics such as tetracycline (TC). The release of the encapsulated drugs could be precisely controlled by NIR light through the dual thermosensitive interaction of liquid-solid transition of PCM and coil-granule transition of PND, improving efficacy and alleviating side effects with on-demand drug release. The thermosensitive hydrogel was formed in situ upon application with body temperature, enhancing retention of the antimicrobial agent in local infectious sites. Highly effective ablation of bacteria is achieved both in vitro and in periodontitis models with little toxicity owing to the synergy of photothermal effects and chemotherapeutic drug release induced by NIR. This study could provide guidance for the design of antibacterial materials and shed substantial light on synergistic treatment.

8.
Curr Eye Res ; 45(1): 31-37, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31354053

RESUMO

Purpose: To evaluate the short-term influence of uncomplicated phacoemulsification on fundus structure and vasculature change.Methods: A total of 51 eyes from 51 patients with mild-to-moderate cataracts were included. Retinal vessel density, perfusion density, and layer thickness in both macular and peripapillary areas were scanned by OCT at baseline and at 1 day, 1 week, and 1 month after cataract surgery. Cumulative dissipated energy (CDE), U/S total time (USTT) and total aspiration time (TAT) were recorded as parameters of surgical injury to analyze the surgical influence on fundus change.Results: There was a significant increase up in retinal vasculature parameters in both macular and optic nerve area after the surgery. The retinal layer thickness had pronounced increase from 1 week after the surgery (all p < .05, repeated-measures analysis of variance). Retinal nerve fiber layer (RNFL) thickness and ganglion cell layer (GCL) thickness increased more rapidly than other layers. There was a positive correlation between CDE and vasculature changes from 1 week to 1 month (Vessel density in macular to CDE: standardized ß = 0.448, p = .005; Perfusion density in peripapillary area to CDE: standardized ß = 0.382, p = .015).Conclusions: Retinal vasculature and layer thickness increased in short-term follow-up after cataract surgery. Whether these changes would persist over a longer period needs to be verified.

9.
J Exp Clin Cancer Res ; 38(1): 461, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31706322

RESUMO

BACKGROUND: Tumor cell repopulation after radiotherapy is a major cause for the tumor radioresistance and recurrence. This study aims to investigate the underlying mechanism of tumor repopulation after radiotherapy, with focus on whether and how necroptosis takes part in this process. METHODS: Necroptosis after irradiation were examined in vitro and in vivo. And the growth-promoting effect of necroptotic cells was investigated by chemical inhibitors or shRNA against necroptosis associated proteins and genes in in vitro and in vivo tumor repopulation models. Downstream relevance factors of necroptosis were identified by western blot and chemiluminescent immunoassays. Finally, the immunohistochemistry staining of identified necroptosis association growth stimulation factor was conducted in human colorectal tumor specimens to verify the relationship with clinical outcome. RESULTS: Radiation-induced necroptosis depended on activation of RIP1/RIP3/MLKL pathway, and the evidence in vitro and in vivo demonstrated that the inhibition of necroptosis attenuated growth-stimulating effects of irradiated tumor cells on living tumor reporter cells. The JNK/IL-8 were identified as downstream molecules of pMLKL during necroptosis, and inhibition of JNK, IL-8 or IL-8 receptor significantly reduced tumor repopulation after radiotherapy. Moreover, the high expression of IL-8 was associated with poor clinical prognosis in colorectal cancer patients. CONCLUSIONS: Necroptosis associated tumor repopulation after radiotherapy depended on activation of RIP1/RIP3/MLKL/JNK/IL-8 pathway. This novel pathway provided new insight into understanding the mechanism of tumor radioresistance and repopulation, and MLKL/JNK/IL-8 could be developed as promising targets for blocking tumor repopulation to enhance the efficacy of colorectal cancer radiotherapy.

10.
Korean J Parasitol ; 57(5): 489-497, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31715689

RESUMO

Cystic echinococcosis (CE), a zoonotic disease caused by Echinococcus granulosus at the larval stage, predominantly develops in the liver and lungs of intermediate hosts and eventually results in organ malfunction or even death. The interaction between E. granulosus and human body is incompletely understood. Exosomes are nanosized particles ubiquitously present in human body fluids. Exosomes carry biomolecules that facilitate communication between cells. To the best of our knowledge, the role of exosomes in patients with CE is not reported. Here, we isolated exosomes from the sera of patients with CE (CE-exo) and healthy donors and subjected them to liquid chromatography-tandem mass spectrometry analysis. Proteomic analysis identified 49 proteins specifically expressed in CE-exo, including 4 proteins of parasitic origin. The most valuable parasitic proteins included tubulin alpha-1C chain and histone H4. And 8 proteins were differentially regulated in CE-exo (fold change>1.5), as analyzed with bioinformatic methods such as annotation and functional enrichment analyses. These findings may improve our understanding about the interaction between E. granulosus and human body, and may contribute to the diagnosis and prevention of CE.

11.
Sci Rep ; 9(1): 12989, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506451

RESUMO

Chronic hepatitis B Virus (HBV) infection has high morbidity, high pathogenicity and unclear pathogenesis. To elucidate the relationship between HBV replication and host phospholipid metabolites, we measured 10 classes of phospholipids in serum of HBV infected patients and cells using ultra performance liquid chromatograph-triple quadruple mass spectrometry. We found that the levels of phosphatidylcholine (PC), phosphatidylethanolamine, and lyso-phosphatidic acid were increased in HBsAg (+) serum of infected patients compared with HBsAg (-), while phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, and sphingomyelin were decreased, which were confirmed in an HBV infected HepG2.2.15 cell line. We further evaluated the enzyme levels of PC pathways and found that PCYT1A and LPP1 for PC synthesis were up-regulated after HBV infection. Moreover, HBV replication was inhibited when PCYT1A and LPP1 were inhibited. These results indicated that the PC synthesis in HBV infected host are regulated by PCYT1A and LPP1, which suggests that PCYT1A, LPP1 could be new potential targets for HBV treatment.

12.
Phys Chem Chem Phys ; 21(38): 21262-21266, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31538166

RESUMO

Binary skutterudite-type IrP3 possesses a unique structural configuration that exhibits unusual electronic, thermoelectric, and dynamical properties and can be applied in thermoelectric generators; IrP3 has unique square (P4) rings stacked with a relatively loose arrangement and thus has been expected to exhibit fascinating evolution in the bonding patterns and electronic properties under high pressure. Herein, we systematically investigated the global energetically stable structures of IrP3 under ambient- and high-pressure conditions using the swarm intelligence-based structure searching technique in combination with first-principles calculations. Our theoretical prediction shows that the skutterudite-type structure with the Im3[combining macron] symmetry is most stable under ambient conditions. An orthorhombic structure with the Pmma space group was predicted to be energetically superior to the Im3[combining macron] phase above 47.60 GPa. The abrupt volume collapse at the corresponding phase boundaries even reached 14.67%, stemming from the abrupt collapse of large voids in the Im3[combining macron] phase. To explore the possibility of the occurrence of pressure-induced metallization and superconducting states under compressive conditions, the electronic band structures were investigated. Our results showed that the Im3[combining macron] phase was a narrow-gap semiconductor with the band gap of 1.04 eV, whereas the high-pressure Pmma IrP3 was a metallic phase with the superconducting transition temperature of 2.40 K. The current results are beneficial for the further understanding of other skutterudite-type compounds under high pressure.

13.
J Am Soc Cytopathol ; 8(5): 250-257, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31543224

RESUMO

INTRODUCTION: Cervical cancer rates in China remain high, with only limited opportunistic screening in urban centers and large mostly unscreened rural areas. Cervical cytology practices in China have been changing over the last decade with introduction of The Bethesda System reporting terminology, liquid-based cytology (LBC), and programs for cervical cytology screening of underserved rural populations. An effort was undertaken for the first time to collect nationwide data on cervical cytology laboratory practices in China, a possible first step toward increased standardization and potential development of nationwide cytology quality benchmarks. MATERIALS AND METHODS: Data on cervical cytology practices from 1572 laboratories operating in 26 nationwide Provisional Level Administrative Divisions was collected in an online survey approved through the Obstetrics and Gynecology Hospital of Fudan University in Shanghai. RESULTS: Over 90% of cervical cytology laboratories in China now solely use Bethesda System reporting terminology. LBC is now the most commonly utilized form of cervical cytology, with lower-cost Chinese-manufactured LBC formulations used in almost 70% of laboratories. Nationwide, significantly higher abnormal cytology rates were reported with LBC than with the conventional Papanicolaou smear (CPS); however, the CPS remains a useful low-cost alternative as China strives to extend cervical screening to large underserved rural areas. CONCLUSIONS: Abnormal cytology rates were not significantly different when different levels of hospitals were compared. The survey identified nationwide opportunities for cytology quality improvement, including low rates of reporting of unsatisfactory cases and low rates for atypical glandular cells.

14.
Clin Implant Dent Relat Res ; 21(5): 977-986, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31373150

RESUMO

BACKGROUND: In the past few decades, very little research has been carried out to modify implant surfaces to improve osteointegration through the regulation of immune cells. PURPOSE: The aim of this study is to investigate whether the poly(dopamine) (pDA)-assisted immobilization of IL4 on titanium surfaces could modulate the inflammatory profile of macrophages in vitro and search for the possibility of enhancing implant integration in this way. MATERIAL AND METHODS: The surface composition, topography, and roughness of SLA, SLA-pDA, and SLA-pDA-IL4 discs were examined by scanning electron microscope (SEM) and energy dispersive spectrometer (EDS). Then the releasing profile of the SLA-pDA-IL4 implants was recorded for 1 week and the bioactivity of released IL4 was investigated by ELISA. Then macrophage polarization was investigated via three methods including: (a) surface marker via immunofluorescence; (b) mRNA levels of M1 and M2 polarization markers via real-time PCR, and (c) cytokine release via ELISA. RESULTS: SEM and EDS revealed that pDA and IL4 were coated successfully on SLA surfaces. The ELISA results showed that IL4 remained its bioactivity on SLA surface and were immobilized on the SLA surface. The immobilization of IL4 through pDA has no significant influence on the attachment, morphology, and proliferation of macrophages, while it increased the M2/M1 proportion in human macrophages revealed by immunofluorescence. The real-time PCR and ELISA results demonstrated that SLA-pDA-IL4 surface reduced the pro-inflammatory profile compared with SLA-pDA and SLA surfaces. CONCLUSIONS: The SLA-pDA-IL4 surfaces described here is able to activate adherent macrophages into M2 phenotype and reduce the release of pro-inflammatory cytokines. Immobilization of IL4 via pDA is convenient and effective, thus providing an applicable way to control macrophage behavior upon implant insertion and is anticipated to accelerating further bone integration.


Assuntos
Implantes Dentários , Indóis/metabolismo , Interleucina-4/metabolismo , Polímeros/metabolismo , Titânio , Dopamina , Humanos , Macrófagos , Propriedades de Superfície
15.
Int J Mol Med ; 44(3): 995-1005, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31257461

RESUMO

Peroxisomal disorders are genetically heterogeneous metabolic disorders associated with a deficit of very long chain fatty acid ß­oxidation that commonly manifest as early­onset neurodegeneration. Brain microvascular endothelial dysfunction with increased permeability to monocytes has been described in X­linked adrenoleukodystrophy, one of the most common peroxisomal disorders caused by mutations of the ATP binding cassette subfamily D member 1 (ABCD1) gene. The present study demonstrated that dysregulation of sirtuin 1 (SIRT1) in human brain microvascular endothelial cells (HBMECs) mediates changes in adhesion molecules and tight­junction protein expression, as well as increased adhesion to monocytes associated with peroxisomal dysfunction due to ABCD1 or hydroxysteroid 17­ß dehydrogenase 4 silencing. Furthermore, enhancement of the function of SIRT1 by resveratrol attenuated this molecular and functional dysregulation of HBMECs via modulation of the nuclear factor­κB and Krüppel­like factor 4 signaling pathways.


Assuntos
Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Transtornos Peroxissômicos/etiologia , Transtornos Peroxissômicos/metabolismo , Sirtuína 1/metabolismo , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Adesão Celular , Comunicação Celular , Células Cultivadas , Expressão Gênica , Inativação Gênica , Humanos , Fatores de Transcrição Kruppel-Like/genética , Monócitos/metabolismo , Proteína Multifuncional do Peroxissomo-2/genética , Junções Íntimas/metabolismo
16.
J Med Chem ; 62(16): 7473-7488, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31335138

RESUMO

Alterations of fibroblast growth factor receptors (FGFRs) play key roles in numerous cancer progression and development, which makes FGFRs attractive targets in the cancer therapy. In the present study, based on a newly devised FGFR target-specific scoring function, a novel FGFR inhibitor hit was identified through virtual screening. Hit-to-lead optimization was then performed by integrating molecular docking and site-of-metabolism predictions with an array of in vitro evaluations and X-ray cocrystal structure determination, leading to a covalent FGFR inhibitor 15, which showed a highly selective and potent FGFR inhibition profile. Pharmacokinetic assessment, protein kinase profiling, and hERG inhibition evaluation were also conducted, and they confirmed the value of 15 as a lead for further investigation. Overall, this study exemplifies the importance of the integrative use of computational methods and experimental techniques in drug discovery.

17.
Nat Commun ; 10(1): 2829, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249296

RESUMO

Extracellular vesicles (EVs) are involved in the regulation of cell physiological activity and the reconstruction of extracellular environment. Matrix vesicles (MVs) are a type of EVs released by bone-related functional cells, and they participate in the regulation of cell mineralization. Here, we report bioinspired MVs embedded with black phosphorus (BP) and functionalized with cell-specific aptamer (denoted as Apt-bioinspired MVs) for stimulating biomineralization. The aptamer can direct bioinspired MVs to targeted cells, and the increasing concentration of inorganic phosphate originating from BP can facilitate cell biomineralization. The photothermal effect of the Apt-bioinspired MVs can also promote the biomineralization process by stimulating the upregulated expression of heat shock proteins and alkaline phosphatase. In addition, the Apt-bioinspired MVs display outstanding bone regeneration performance. Our strategy provides a method for designing bionic tools to study the mechanisms of biological processes and advance the development of medical engineering.


Assuntos
Vesículas Extracelulares/metabolismo , Fósforo/metabolismo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Aptâmeros de Nucleotídeos/genética , Aptâmeros de Nucleotídeos/metabolismo , Biomineralização , Osso e Ossos/química , Osso e Ossos/citologia , Osso e Ossos/metabolismo , Vesículas Extracelulares/química , Feminino , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/química , Osteoblastos/metabolismo , Fosfatos/metabolismo , Fósforo/química , Ratos
18.
PLoS Biol ; 17(6): e3000292, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31181061

RESUMO

Despite the broad-spectrum antimicrobial activities of silver, its internal usage is restricted, owing to the toxicity. Strategies to enhance its efficacy are highly desirable but rely heavily on the understanding of its molecular mechanism of action. However, up to now, no direct silver-targeting proteins have been mined at a proteome-wide scale, which hinders systemic studies on the biological pathways interrupted by silver. Herein, we build up a unique system, namely liquid chromatography gel electrophoresis inductively coupled plasma mass spectrometry (LC-GE-ICP-MS), allowing 34 proteins directly bound by silver ions to be identified in Escherichia coli. By using integrated omic approaches, including metalloproteomics, metabolomics, bioinformatics, and systemic biology, we delineated the first dynamic antimicrobial actions of silver (Ag+) in E. coli, i.e., it primarily damages multiple enzymes in glycolysis and tricarboxylic acid (TCA) cycle, leading to the stalling of the oxidative branch of the TCA cycle and an adaptive metabolic divergence to the reductive glyoxylate pathway. It then further damages the adaptive glyoxylate pathway and suppresses the cellular oxidative stress responses, causing systemic damages and death of the bacterium. To harness these novel findings, we coadministrated metabolites involved in the Krebs cycles with Ag+ and found that they can significantly potentiate the efficacy of silver both in vitro and in an animal model. Our study reveals the comprehensive and dynamic mechanisms of Ag+ toxicity in E. coli cells and offers a novel and general approach for deciphering molecular mechanisms of metallodrugs in various pathogens and cells to facilitate the development of new therapeutics.


Assuntos
Biologia Computacional/métodos , Escherichia coli/metabolismo , Prata/metabolismo , Prata/uso terapêutico , Antibacterianos/farmacologia , Anti-Infecciosos , Bactérias , Cromatografia Líquida/métodos , Proteínas de Escherichia coli/metabolismo , Espectrometria de Massas/métodos , Metabolômica , Proteômica
19.
J Proteome Res ; 18(9): 3317-3327, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31241341

RESUMO

Fusarium head blight (FHB) mainly resulting from Fusarium graminearum (Fg) Schwabe is a notorious wheat disease causing huge losses in wheat production globally. Fg also produces mycotoxins, which are harmful to human and domestic animals. In our previous study, we obtained two Fg mutants, TPS1- and TPS2-, respectively, with a single deletion of trehalose 6-phosphate synthase (TPS1) and trehalose 6-phosphate phosphatase (TPS2) compared with the wild type (WT). Both mutants were unable to synthesize trehalose and produced fewer mycotoxins. To understand the other biochemical changes induced by TPS gene deletion in Fg, we comprehensively analyzed the metabolomic differences between TPS- mutants and the WT using NMR together with gas chromatography-flame ionization detection/mass spectrometry. The expression of some relevant genes was also quantified. The results showed that TPS1- and TPS2- mutants shared some common metabolic feature such as decreased levels for trehalose, Val, Thr, Lys, Asp, His, Trp, malonate, citrate, uridine, guanosine, inosine, AMP, C10:0, and C16:1 compared with the WT. Both mutants also shared some common expressional patterns for most of the relevant genes. This suggests that apart from the reduced trehalose biosynthesis, both TPS1 and TPS2 have roles in inhibiting glycolysis and the tricarboxylic acid cycle but promoting the phosphopentose pathway and nucleotide synthesis; the depletion of either TPS gene reduces the acetyl-CoA-mediated mycotoxin biosynthesis. TPS2- mutants produced more fatty acids than TPS1- mutants, suggesting different roles for TPS1 and TPS2, with TPS2- mutants having impaired trehalose biosynthesis and trehalose 6-phosphate accumulation. This may offer opportunities for developing new fungicides targeting trehalose biosynthesis in Fg for FHB control and mycotoxin reduction in the FHB-affected cereals.

20.
Front Pharmacol ; 10: 329, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057397

RESUMO

The dry roots of Polygonum multiflorum (PM), involving both the raw and processed materials, are widely used as the traditional Chinese medicine for treating various diseases in China. Hepatotoxicity has been occasionally reported in patients who consume PM. Unfortunately, no definite criteria are currently available regarding the processing technology of PM for reduction the toxicity. In this work, we aimed to investigate the variations of PM metabolite profiles induced by different processing technologies by UHPLC/Q-Orbitrap-MS and multivariate statistical analysis, and to discover the potential toxic compounds by correlating the cytotoxicity of L02 cell with the contents of metabolites in raw and processed PM samples. We could identify two potential toxic compounds, emodin-8-O-glucoside and torachrysone-O-hexose, which could be selected as the toxic markers to evaluate different processing methods. The results indicated all processed PM samples could decrease the cytotoxicity on L02 cell. The best processing technology for PM process was to steam PM in black soybean decoction (BD-PM) for 24 h.

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