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1.
Food Chem ; 373(Pt A): 131368, 2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-34717088

RESUMO

Thermal processing is the most frequently adopted processing technology for sea cucumbers, which can significantly affect their protein composition. In this paper, three thermal processing methods high pressure steaming (HPS), atmospheric pressure boiling (APB), and atmospheric pressure steaming (APS) were adopted and protein compositions of both body walls and cooking liquors by thermal processing stichopus japonicus were systematically analysis by proteomic strategy. The total proteins loss rates of body walls were 11.6%, 13.0%, and 14.8% for HPS, APS, and APB methods, respectively. However, the main types of protein composition were retained. Similar mechanisms of protein loss may exist even if different thermal processing were applied. The most frequent hydrolysis sites in thermal processing were phenylalanine, leucine, asparagine, and tyrosine at both C and N terminals. This study provides theoretical guidance for optimizing the industry thermal processing of sea cucumbers.

2.
Chemosphere ; : 132945, 2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34798108

RESUMO

Perfluorooctanoic acid (PFOA) is a persistent environmental pollutant and will continually accumulate in blood due to its chemical inertness and strong interaction with serum proteins, especially serum albumin (SA), inducing highly adverse health risks. However, the molecular mechanisms of dynamic interactions between PFOA with serum proteins remain unclear, limiting the development of potential therapeutic strategies. Herein, we developed an integrated structural strategy to systematically profile the molecular details of dynamic interactions among PFOA, SA, and ß-cyclodextrin (ß-CD) by combing native mass spectrometry (nMS), lysine reactivity profiling (LRP), and molecular docking (MD) simulation. The SA site 1, site 2 pockets, and cleft nearby are observed as the primary interaction regions of PFOA. Further, ß-CD can disrupt the PFOA combinations with bovine SA regions around sites Lys20, Lys280, Lys350, and Lys431-Lys439, with an overall reversing efficiency of about 26% at an identical concentration to PFOA. The interactome of PFOA with complex human serum proteins is globally profiled with molecular interaction details, including human serum albumin, apolipoprotein A-I, alpha-2-macroglobulin, and complement C3. Our results reveal molecular insights into the detail of the interaction between PFOA and serum proteins, beneficial to understanding PFOA toxicology.

3.
Anal Bioanal Chem ; 413(30): 7431-7440, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34676431

RESUMO

Human serum albumin (HSA) is one of the most important serum carrier proteins that deliver small-molecule drugs to their specific targets. Clarifying the molecular mechanism of the interaction between natural HSA and drugs in an aqueous solution has been a hot topic in pharmaceutical chemistry, clinical medicine, and biochemistry in recent years, but it is still challenging. In this paper, the details of molecular interactions of HSA with a variety of therapeutic drugs including ibuprofen, indomethacin, phenylbutazone, and warfarin are systematically investigated using a mass spectrometry (MS)-based lysine reactivity profiling (LRP) strategy. The results reaffirm that the major ligand binding sites (including Sites I and II) of HSA are located in subdomains IIA and IIIA, while several potential drug-binding areas at subdomain IIIB and α helix IIB-IIIA are newly characterized. The MS-LRP strategy may have important application prospects in pharmacodynamics, pharmacokinetics, and safety evaluation of small-molecule drugs.

4.
Chem Commun (Camb) ; 57(90): 11972-11975, 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34708840

RESUMO

Although halogen atoms can greatly improve the stability, selectivity, and bioactivity of proteins, direct halogenation of proteins or peptides by chemical strategy has been never achieved. Herein, we describe the developments of direct photochemical bromination and iodization of unprotected proteins and peptides in the direct irradiation device and the single-pulsed irradiation capillary reactor with biocompatible aqueous halides Br- and I-, respectively. These novel photochemical modifications are triggered by 193 nm laser photoexcitation of commonly photo-inert halide ions to form active radical species. High protein modification efficiency (>90%) can be achieved under just 10 ns ultra-short irradiation of a single pulse of laser shot while the compact native protein structure could be largely retained. The specifically modified residues are Tyr, His, Trp for bromination and Tyr, His for iodization. The photochemical halogenation sites and rates are highly selective to protein native structures, providing dynamic insights into protein structure alterations and protein-drug interfaces in human serum protein (HSA)-warfarin interaction. This novel 193 nm photochemical strategy opens new opportunities for the protein structure-function explorations.

5.
BMC Psychiatry ; 21(1): 485, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34607584

RESUMO

BACKGROUND: The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are the most commonly used scales to detect mild cognitive impairment (MCI) in population-based epidemiologic studies. However, their comparison on which is best suited to assess cognition is scarce in samples from multiple regions of China. METHODS: We conducted a cross-sectional analysis of 4923 adults aged ≥55 years from the Community-based Cohort Study on Nervous System Diseases. Objective cognition was assessed by Chinese versions of MMSE and MoCA, and total score and subscores of cognitive domains were calculated for each. Education-specific cutoffs of total score were used to diagnose MCI. Demographic and health-related characteristics were collected by questionnaires. Correlation and agreement for MCI between MMSE and MoCA were analyzed; group differences in cognition were evaluated; and multiple logistic regression model was used to clarify risk factors for MCI. RESULTS: The overall MCI prevalence was 28.6% for MMSE and 36.2% for MoCA. MMSE had good correlation with MoCA (Spearman correlation coefficient = 0.8374, p < 0.0001) and moderate agreement for detecting MCI with Kappa value of 0.5973 (p < 0.0001). Ceiling effect for MCI was less frequent using MoCA versus MMSE according to the distribution of total score. Percentage of relative standard deviation, the measure of inter-individual variance, for MoCA (26.9%) was greater than for MMSE (19.0%) overall (p < 0.0001). Increasing age (MMSE: OR = 2.073 for ≥75 years; MoCA: OR = 1.869 for≥75 years), female (OR = 1.280 for MMSE; OR = 1.163 for MoCA), living in county town (OR = 1.386 and 1.862 for MMSE and MoCA, respectively) or village (OR = 2.579 and 2.721 for MMSE and MoCA, respectively), smoking (OR = 1.373 and 1.288 for MMSE and MoCA, respectively), hypertension (MMSE: OR = 1.278; MoCA: OR = 1.208) and depression (MMSE: OR = 1.465; MoCA: OR = 1.350) were independently associated with greater likelihood of MCI compared to corresponding reference group in both scales (all p < 0.05). CONCLUSIONS: MoCA is a better measure of cognitive function due to lack of ceiling effect and with good detection of cognitive heterogeneity. MCI prevalence is higher using MoCA compared to MMSE. Both tools identify concordantly modifiable factors for MCI, which provide important evidence for establishing intervention measures.


Assuntos
Disfunção Cognitiva , Idoso , China/epidemiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Entrevista Psiquiátrica Padronizada , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Testes Neuropsicológicos
6.
Se Pu ; 39(10): 1077-1085, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34505429

RESUMO

After entering human blood circulation, small-molecule drugs interact extensively with various plasma proteins, such as human serum albumin and α1-acid glycoprotein. These interactions profoundly affect the distribution of drugs in vivo and the binding of drugs to targets, thus affecting the efficacy of drugs. In-depth investigation of drug-plasma protein interactions is of great significance for the optimization of drug properties, the development of new drugs, risk assessment, and combination therapy of drugs. Therefore, it is essential to develop highly efficient, sensitive, and accurate methods for elucidating drug-plasma protein interactions. Chromatography is a powerful tool with high throughput, high separation performance, and high sensitivity in the characterization of drug-protein interactions. High-performance affinity chromatography (HPAC) and capillary electrophoresis (CE) have been widely utilized in this field. These methods include the determination of the effects of the posttranslational modification of proteins on binding and the competitive binding of multiple drugs. In addition, various chromatographic methods are used to obtain interaction information such as the binding constant, binding-site number, and dissociation rate constant. In this review, the common strategies and recent advances in HPAC and CE in the study of drug-plasma protein interactions are briefly reviewed. The immobilization methods of proteins, the principles and applications of frontal analysis, zonal elution, ultrafast affinity extraction, peak profiling, and peak decay analysis are discussed for HPAC and affinity capillary electrophoresis (ACE) and capillary electrophoresis frontal analysis (CE-FA) for CE. HPAC relies on the fixation of proteins on the surfaces of chromatographic stationary phases by covalent linking or physical adsorption, followed by obtaining the drug-protein interaction information through a variety of chromatographic methods. In the frontal chromatography analysis, mobile phases with different concentrations of drugs are passed through the HPAC column to obtain different breakthrough times. The process can determine the number of drug binding sites and the binding constant of each site in the affinity protein with high accuracy. The zonal elution method can detect the drug binding sites on proteins using site-specific probes to determine whether there is competition between drugs and probes. The sample consumption and analysis time of the zonal elution method are much less than those in frontal chromatography analysis. The ultrafast affinity extraction method can inject complex samples, such as serum, into affinity columns to determine the free drug components. It can measure the combination and dissociation constants of drug-protein interactions by changing the chromatography flow rate. Peak profiling and peak decay analyses are both effective methods for investigating the dissociation of drugs and proteins. In CE analysis, the drug and protein samples are dissolved in an electrophoresis buffer, and their interactions are measured during electrophoresis with high accuracy and low sample consumption. However, the adsorption of proteins on the capillary wall can compromise CE performance. Common CE methods in drug-protein interaction analysis are ACE and CE-FA. ACE is usually performed by changing the effective mobility of drugs via the addition of different concentrations of proteins. This method has been widely used, and several variant techniques have been developed recently. CE-FA involves the sampling of a drug premixed at a known concentration with a target protein. Compared with other CE methods, CE-FA exhibits the unique advantages of high throughput, automatic online analysis, and the ability to determine high-order drug-protein interactions. Finally, the shortcomings of current chromatography methods are summarized, and the application prospects and development direction of chromatography technology in the field of drug-plasma protein interaction research are discussed.


Assuntos
Proteínas Sanguíneas , Preparações Farmacêuticas , Sítios de Ligação , Proteínas Sanguíneas/metabolismo , Cromatografia de Afinidade , Eletroforese Capilar , Humanos , Ligação Proteica
7.
Front Cell Dev Biol ; 9: 688070, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34386493

RESUMO

Objective: The emergence of multi-drug resistance (MDR) in esophageal carcinoma has severely affected the effect of chemotherapy and shortened the survival of patients. To this end, we intend to develop a biomimetic nano-targeting drug modified by cancer cell membrane, and investigate its therapeutic effect. Methods: The degradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) co-loaded with doxorubicin (DOX) and curcumin (Cur) were prepared by solvent evaporation method. TE10 cell membrane and Distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-PEG) were then coated on the PLGA NPs by membrane extrusion to prepare the PEG-TE10@PLGA@DOX-Cur NPs (PMPNs). Size and zeta potential of the PMPNs were analyzed by lazer particle analyzer, and the morphology of PMPNs was observed by transmission electron microscope. The TE10 cell membrane protein on PMPNs was analyzed by gel electrophoresis. The DOX-resistant esophageal cancer cell model TE10/DOX was established through high-dose induction. The In vitro homologous targeting ability of PMPNs was evaluated by cell uptake assay, and the in vitro anti-tumor effect of PMPNs was assessed through CCK-8, clone formation and flow cytometry. A Balb/c mouse model of TE10/DOX xenograft was constructed to evaluate the anti-tumor effect in vivo and the bio-safety of PMPNs. Results: The prepared cell membrane coated PMPNs had a regular spherical structure with an average diameter of 177 nm. PMPNs could directly target TE10 and TE10/DOX cells or TE10/DOX xenografted tumor and effectively inhibit the growth of DOX-resistant esophageal carcinoma. Besides, the PMPNs was confirmed to have high biosafety. Conclusion: In this study, a targeted biomimetic nano-drug delivery system PMPNs was successfully prepared, which overcome the MDR of esophageal carcinoma by co-delivering DOX and sensitizer curcumin.

8.
Anal Chem ; 93(30): 10653-10660, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34291915

RESUMO

Monitoring the dynamic alterations of protein structures within an aqueous solution remains enormously challenging. In this study, we describe a size-selective VAILase proteolysis (SVP)-mass spectrometry (MS) strategy to probe the protein structure changes without strict control of the proteolysis kinetics. The unique conformation selectivity of SVP depends on the uniform nano-sized entrance pores of the VAILase hexameric cage as well as the six inherent molecular rulers in the VAILase-substrate recognition and cleavage. The dynamic insights into subtle conformation alterations of both myoglobin unfolding transition and Aurora kinase A-inhibitor binding are successfully captured using the SVP strategy, which matches well with the results in the molecular dynamics simulation. Our work provides a new paradigm of size-selective native proteolysis for exploring the aqueous protein structure-function relationships.


Assuntos
Proteínas , Cinética , Espectrometria de Massas , Conformação Proteica , Proteólise
9.
J Hazard Mater ; 419: 126436, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216967

RESUMO

Nanosized ZnIn2S4 supported on facet-engineered CeO2 nanorods were prepared by solvothermal method to effectively capture gaseous elemental mercury from flue gas. The CeO2/ZnIn2S4 sorbent exhibited excellent mercury removal performance (>90%) in a wide temperature range from 60 to 240 â„ƒ and showed much higher mercury adsorption capacity than pure CeO2 due to the enlarged specific surface area and abundant active oxygen and sulfur sites on the surface. It was found that CeO2/ZnIn2S4 has good resistance to SO2, NO and H2O. At the optimal 120 â„ƒ, the equilibrium Hg0 adsorption capacity of CeO2/ZnIn2S4 can reach 19.172 mg/g, which is superior to the reported series of benchmark materials. X-ray photoelectron spectroscopy and temperature programmed desorption of mercury confirmed that the adsorbed mercury existed on the surface as HgO and HgS, indicating that catalytic oxidation and chemisorption occurred on the surface of the adsorbent. The adsorption energy of Hg0 on the CeO2 (110) and ZnIn2S4 (110) surfaces calculated with density functional theory (DFT), further confirms that the surface activated oxygen and sulfur sites are the most stable adsorption sites. Furthermore, the good regeneration capability of CeO2/ZnIn2S4 makes it more promising for Hg0 capture in practical applications.

10.
J Hazard Mater ; 415: 125692, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34088187

RESUMO

Mercury (Hg0) pollution poses a huge threat to human health and the environment due to its high toxicity, long persistence and bioaccumulation in the environment. Most of the traditional Hg0 adsorbents have a low reaction rate, high operating cost, especially poor resistance to SO2, which limited their practical application. In this work, nanosheet g-C3N4 was used as the support and modified by CuS to capture flue gas mercury. Take advantage of the large specific surface area of g-C3N4 to increase the BET of the composite and decrease the use of CuS. The effects of CuS loading, reaction temperature, and common components in the coal-fired flue gas on the mercury removal performance were studied respectively. The experimental outcomes showed that the 10CuS/g-C3N4 (10CuS/CN) reaches as high as almost 100% Hg0 removal efficiency under the temperature of 40-120 â„ƒ. Meanwhile the common components like SO2, NO, HCl and H2O have no obvious inhibition effects on Hg0 removal efficiency of the 10CuS/CN adsorbent. Sx2- and Cu2+ as the primary bonding sites shows a synergy effect on Hg0 removal. 10CuS/CN is a promising material for Hg0 removal under various flue gas conditions, which is expected to be a substitute for traditional adsorbents.

11.
Huan Jing Ke Xue ; 42(5): 2313-2323, 2021 May 08.
Artigo em Chinês | MEDLINE | ID: mdl-33884801

RESUMO

The excessive discharge of phosphate into natural water has caused serious environmental problems. Adsorption is an efficient technology for phosphorus removal from water. In this study, a novel biochar modified by chitosan, ferrous sulfate, and sodium sulfide was synthesized and performed well in phosphorus adsorption. The results of batch experiments showed that the optimum synthesized composite could adsorb 49.32 mg·g-1 of phosphate at 298 K. Meanwhile, the simulation results showed better fitting with the pseudo-second-order model and Langmuir model. The adsorption rate was dominated by three-dimensional diffusion within the inner pores. The adsorption process was defined as physic/chemisorption, while the adsorption mechanism was concluded to be electrostatic adsorption, porous filling, surface chemical precipitation, hydrogen binding, and the ligand effect. This study showed that the composite is effective in phosphorus removal from water, and we anticipate that our research will offer guidelines for adsorbent design and reveal the adsorption mechanism.

12.
Huan Jing Ke Xue ; 42(4): 1913-1922, 2021 Apr 08.
Artigo em Chinês | MEDLINE | ID: mdl-33742826

RESUMO

A significant factor for eutrophication is the excessive discharge of ammonia nitrogen. Unfortunately, traditional methods to remove ammonia nitrogen are ineffective when facing gradually strict rules. Recently, adsorption has gained interest from scholars due to its efficiency and safety in ammonia nitrogen treatment. In this study, a novel biochar, modified with magnetic iron, was synthesized through co-precipitation, which performed well in ammonia nitrogen removal. The maximum adsorption amount at 293 K of the composite that was synthesized at 80℃(MB80) was 17.52 mg·g-1. Meanwhile, the simulation results displayed a good fitting with the pseudo second order model and Langmuir model. Additionally, the adsorption mechanism could be attributed to electrostatic adsorption, porous filling, ion exchange, and hydrogen bonding. Noticeably, MB80 maintained a good performance after 5 cycles, with desirable adsorption amount of 3.18 mg·g-1. This study aimed to provide an efficient method to treat ammonia nitrogen as well as a new way to dispose of municipal sludge.

13.
Anal Chim Acta ; 1155: 338340, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33766312

RESUMO

Further improving the proteomic identification coverage and reliability is still challenging in the mass spectrometry (MS)-based proteomics. Herein, we combine VAILase and trypsin digestion with 193-nm ultraviolet photodissociation (UVPD) and higher-energy collision dissociation (HCD) to improve the performance of bottom-up proteomics. As VAILase exhibits high complementarity to trypsin, the proteome sequence coverage is improved obviously whether with HCD or 193-nm UVPD. The high diversity of fragment ion types produced by UVPD contributes to the improvements of identification reliability for both trypsin- and VAILase-digested peptides with an average XCorr score improvement of 10%.


Assuntos
Proteômica , Espectrometria de Massas em Tandem , Peptídeos , Reprodutibilidade dos Testes , Raios Ultravioleta
14.
BMC Anesthesiol ; 21(1): 63, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648441

RESUMO

BACKGROUND: To investigate the optimal dose of dexmedetomidine to maintain hemodynamic stability, prevent of cough and minimize postoperative pain for patients undergoing laparoscopic cholecystectomy. METHODS: One hundred twenty patients were randomly divided into D1, D2, D3 and NS groups, and dexmedetomidine 0.4, 0.6, 0.8µg/kg and normal saline were administrated respectively. Patients' heart rate, systolic blood pressure and diastolic blood pressure were measured at T1-T7. The incidence of cough was recorded. Other parameters were noted, the time of spontaneous respiratory recovery and extubation, visual analogue scale scores and dosage of tramadol. RESULTS: The heart rate, systolic blood pressure and diastolic blood pressure of D2 and D3 groups has smaller fluctuations at T2-3 and T7 compared with NS and D1 groups (P < 0.05). The incidence of cough was lower in D2 and D3 groups than NS group (P < 0.05). The visual analogue scale scores and tramadol dosage of D2 and D3 groups were lower than NS group (P < 0.05). The time of spontaneous respiratory recovery and extubation in D3 group was longer than that in D1 and D2 groups (P < 0.05). CONCLUSIONS: Intravenous infusion of 0.6µg/kg dexmedetomidine before induction can maintain hemodynamic stability, decrease cough during emergence, relieve postoperative pain of patients undergoing laparoscopic cholecystectomy. TRIAL REGISTRATION: ChiCTR1900024801 , registered at the Chinese Clinical Trial Registry, principal investigator: Qin Ye, date of registration: July 28, 2019.

15.
Sci Bull (Beijing) ; 66(7): 720-726, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33520336

RESUMO

Fully inactivating SARS-CoV-2, the virus causing coronavirus disease 2019, is of key importance for interrupting virus transmission but is currently performed by using biologically or environmentally hazardous disinfectants. Herein, we report an eco-friendly and efficient electrochemical strategy for inactivating the SARS-CoV-2 using in-situ formed nickel oxide hydroxide as anode catalyst and sodium carbonate as electrolyte. At a voltage of 5 V, the SARS-CoV-2 viruses can be rapidly inactivated with disinfection efficiency reaching 95% in only 30 s and 99.99% in 5 min. Mass spectrometry analysis and theoretical calculations indicate that the reactive oxygen species generated on the anode can oxidize the peptide chains and induce cleavage of the peptide backbone of the receptor binding domain of the SARS-CoV-2 spike glycoprotein, and thereby disables the virus. This strategy provides a sustainable and highly efficient approach for the disinfection of the SARS-CoV-2 viruliferous aerosols and wastewater.

16.
Cell Res ; 31(3): 345-361, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32859993

RESUMO

RNase III DROSHA is upregulated in multiple cancers and contributes to tumor progression by hitherto unclear mechanisms. Here, we demonstrate that DROSHA interacts with ß-Catenin to transactivate STC1 in an RNA cleavage-independent manner, contributing to breast cancer stem-like cell (BCSC) properties. DROSHA mRNA stability is enhanced by N6-methyladenosine (m6A) modification which is activated by AURKA in BCSCs. AURKA stabilizes METTL14 by inhibiting its ubiquitylation and degradation to promote DROSHA mRNA methylation. Moreover, binding of AURKA to DROSHA transcript further strengthens the binding of the m6A reader IGF2BP2 to stabilize m6A-modified DROSHA. In addition, wild-type DROSHA, but not an m6A methylation-deficient mutant, enhances BCSC stemness maintenance, while inhibition of DROSHA m6A modification attenuates BCSC traits. Our study unveils the AURKA-induced oncogenic m6A modification as a key regulator of DROSHA in breast cancer and identifies a novel DROSHA transcriptional function in promoting the BCSC phenotype.

17.
Technol Cancer Res Treat ; 19: 1533033820973282, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33176591

RESUMO

PURPOSE: Esophageal cancer is one of the most common malignancies worldwide. Ubiquitin-dependent degradation of regulatory proteins reportedly plays a central role in diverse cellular processes. This study investigated the expression levels of ubiquitin in esophageal squamous cell carcinoma tissues and the functions of ubiquitin in the context of esophageal squamous cell carcinoma progression. METHODS: The expression of ubiquitin in esophageal squamous cell carcinoma and normal esophageal samples was determined via immunohistochemistry. Serum ubiquitin levels were determined by enzyme-linked immunosorbent assay. The association between serum ubiquitin level and clinicopathological factors was analyzed. Real-time PCR analysis was employed to measure the mRNA levels of the ubiquitin coding genes ubiquitin B and ubiquitin C. Proliferation assays, colony formation assays, and Transwell-based assays were used to determine the influence of ubiquitin on cell growth and cell invasion. Proteomic analysis was performed to identify the proteins associated with ubiquitin. RESULTS: Ubiquitin expression in esophageal squamous cell carcinoma tissues was markedly higher than that in normal and tumor adjacent tissues. The levels of ubiquitin in esophageal squamous cell carcinoma serum samples were significantly higher than those in healthy controls. Serum ubiquitin levels were correlated with tumor stage and lymph node metastasis. To silence the expression of ubiquitin, we knocked down the ubiquitin coding genes ubiquitin B and ubiquitin C in TE-1 and Eca-109 cells. Silencing ubiquitin resulted in the suppression of cell growth, chemoresistance, colony formation and cell migration in esophageal squamous cell carcinoma cells. Proteomic analysis in esophageal squamous cell carcinoma cells showed that knockdown of ubiquitin coding genes deregulated the expression of 159 proteins (92 were upregulated and 67 were downregulated) involved in multiple pathways. These proteins included ferritin light chain, ferritin heavy chain, cellular retinoic acid-binding protein 2, and DNA replication factor 1. CONCLUSION: Ubiquitin expression is upregulated in esophageal squamous cell carcinoma tissues and serum samples. Serum ubiquitin levels were correlated with tumor stage and lymph node metastasis. Downregulation of ubiquitin suppresses the aggressive phenotypes of esophageal squamous cell carcinoma cells by complex mechanisms; ubiquitin may represent a novel target for the treatment of esophageal squamous cell carcinoma.

19.
J Proteomics ; 220: 103760, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32244009

RESUMO

Acute lung injury (ALI) is the most common remote organ complication induced by severe acute pancreatitis (SAP). Almost 60-70% SAP-induced deaths are caused by ALI. Efficient clinical therapeutic strategy for SAP-induced ALI is still lacking. In this study, we demonstrate that Emodin (EMO) can significantly alleviate SAP-induced ALI. We investigate the therapeutic mechanisms of EMO by proteomic analysis, which indicates that EMO protects lung tissue against SAP-ALI by negative regulation of endopeptidase activity and inhibition of collagen-containing extracellular matrix degradation. Protein-protein interaction analysis showed Lamc2, Serpina1 and Serpinb1 play important roles in the above pathways. This study elucidates the possible mechanism and suggests the candidacy of EMO in the clinical treatment of SAP-ALI. SIGNIFICANCE: ALI is a major leading cause of death in SAP. DEX is the standard of care drug for treatment of SAP-ALI, but often associated with inevitable side effects. In the present study, EMO was demonstrated to greatly alleviate the lung injury induced by SAP. Through proteomic analysis, the recovered protein profiles in response to EMO treatment in SAP-ALI rat models was obtained, among which Lamc2, Serpina1 and Serpinb1 were discovered as crucial regulatory proteins in SAP-ALI disease. Our study provides the underlying mechanisms and novel targets of EMO protective effect against SAP-ALI.


Assuntos
Emodina , Pancreatite , Doença Aguda , Animais , Emodina/farmacologia , Pulmão , Neutrófilos , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Peptídeo Hidrolases , Proteômica , Ratos
20.
J Med Chem ; 63(8): 3881-3895, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32223194

RESUMO

Exportin-1 (also named as CRM1) plays a prominent role in autoimmune disorders and has emerged as a potential therapeutic target for colitis. Here we report on the rational structure-based discovery of a small-molecule antagonist of exportin-1, LFS-829, with low-range nanomolar activities. The co-crystallographic structure, surface plasmon resonance binding assay, and cell-based phenotypic nuclear export functional assay validated that exportin-1 is a key target of LFS-829. Moreover, we demonstrated that the C528S mutation or the knockdown on exportin-1 can abolish the cellular activities of LFS-829. Strikingly, oral administration of LFS-829 can significantly reverse the pathological features of colitis model mice. We revealed that LFS-829 can attenuate dual NF-κB signaling and the Nrf2 cytoprotection pathway via targeting exportin-1 in colitis mice. Moreover, LFS-829 has a very low risk of cardiotoxicity and acute toxicity. Therefore, LFS-829 holds great promise for the treatment of colitis and may warrant translation for use in clinical trials.


Assuntos
Colite/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Hidrazinas/administração & dosagem , Carioferinas/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/administração & dosagem , Sequência de Aminoácidos , Animais , Colite/metabolismo , Colite/patologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Hidrazinas/química , Carioferinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares/metabolismo , Triazóis/química
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