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1.
Colloids Surf B Biointerfaces ; 215: 112473, 2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35367745

RESUMO

The aim of this study is to develop a dual-functional ingredient with antioxidant activity and emulsification. The emulsion stability of ovalbumin (OVA) was improved by procyanidins (PC). The interactions between OVA and PC were investigated using multi-spectroscopy and molecular docking. Furthermore, the effect of the addition of the OVA-PC mixture on emulsion stability was evaluated as well. The fluorescence results showed that the quenching mechanism of PC to OVA's endogenous fluorescence was static quenching, and the binding ratio of OVA and PC was 1:1. Circular dichroism (CD) and Fourier Transform Infrared Spectrometer (FT-IR) showed that the addition of PC promoted the unfolding of OVA, and transformed the secondary structure of OVA from α-helix to ß-sheet. The main driving force of OVA and PC was hydrogen bonding, according to molecular docking analysis. Among all the samples, the stability of the emulsion of OVA-PC at a ratio of 1:30 exhibited extremely high stability and the smallest particle size. In comparison with individual OVA emulsions, the OVA-PC emulsions had excellent physical stabilities. Meanwhile, the oxidation degree of protein and oil for the OVA-PC emulsions was lower than that of the native OVA emulsion after 8-day storage. Our work provides important insights for understanding the interaction between OVA and expanding the application of OVA-PC.

2.
Microbiol Spectr ; : e0262421, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35467408

RESUMO

The higher resistance rate to ceftazidime-avibactam (CZA) is mainly related to carbapenem resistance, especially New Delhi metallo-ß-lactamase (NDM). The CZA-susceptible Klebsiella pneumoniae (K191663) and the later CZA-resistant isolates (K191724, K191725, K191773) co-producing NDM-4 and OXA-181 were obtained from the same hospitalized patient returning from Vietnam. Our study aims to elucidate the diversity of K. pneumoniae ST16 through comparative analysis of whole-genome sequencing (WGS) data and identify the potential evolution of plasmids by sequencing longitudinal clinical isolates during antibiotic treatment. Firstly, multilocus sequence typing analysis and phylogenic analysis suggested that these strains belong to the two lineages of K. pneumoniae ST16. Surprisingly, the CZA-resistant strains were closely related to K. pneumoniae ST16 described in South Korea, instead of the blaNDM-4- or blaOXA-181-carrying ST16 reported in Vietnam. Secondly, blaNDM-4, blaTEM-1B, and rmtB co-existed on a self-conjugative IncFII(Yp)-like plasmid, which played a significant role in CZA resistance. It could transfer into the recipient Escherichia coli J53 at high frequency, indicating the risk of mobile carbapenemases. In addition, the loss of 12-kbp fragment occurred in blaNDM-4-positive isolate (K191773), which was likely caused by insertion sequence-mediated homologous recombination. Last but not least, as a repressor of acrAB operon system, acrR was truncated by a frameshift mutation in K191663. Thus, our study provided baseline information for monitoring the occurrence and development of bacterial resistance. IMPORTANCE As a leading health care-acquired infection pathogen, Klebsiella pneumoniae is threatening a large number of inpatients due to its diverse antibiotic resistance and virulence factors. Heretofore, with a growing number of reports about the coexistence of several carbapenemases in carbapenem-resistant K. pneumoniae (CRKP), epidemiologic surveillance has been strengthened. Nevertheless, the nosocomial outbreaks by CRKP ST16 are gradually increasing worldwide. Our study provides a deeper insight into the diversification of clinical isolates of CRKP ST16 in China. In addition, the comparison analysis of resistant plasmids may reveal the transmission of carbapenemase-encoding genes. Furthermore, our study also highlights the importance of longitudinal specimen collection and continuous monitoring during the treatment, which play a crucial role in understanding the development of antibiotic resistance and the evolution of resistance plasmids.

3.
J Agric Food Chem ; 70(16): 5126-5136, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35412315

RESUMO

The comprehensive utilization of food-derived nutraceuticals with different polarities has been extremely restricted by their poor bioavailability and coexistence in a single system. This study aimed to fabricate a self-assembly of amphiphilic nanoparticles (NPs) for the hydrophilic EWDP and hydrophobic curcumin based on the carboxymethyl chitosan (CMCS) shell and γ-cyclodextrin (γ-CD) core. Notably, EWDP could cooperate with CMCS to yield superior colloidal properties with an excellent curcumin aqueous solubility and co-encapsulation capacity (>10%) for the NPs (pH 2.0-7.0). This phenomenon was mainly ascribed to the additional hydrogen-bonding network and hydrophobic interaction introduced by EWDP. Besides, the overall antioxidant activity, bioaccessibility, gastrointestinal stability, and Caco-2 cell absorption properties were significantly improved in the presence of EWDP (>20% increase). Therefore, EWDP could function as both a potential affinity agent and a nutrition enhancer to expand the co-delivery applications for diverse nutraceuticals with promising oral bioavailability enhancement in food and pharmaceutical areas.


Assuntos
Curcumina , Nanopartículas , Disponibilidade Biológica , Células CACO-2 , Curcumina/química , Portadores de Fármacos/química , Humanos , Nanopartículas/química , Tamanho da Partícula , Peptídeos/química , Polissacarídeos
4.
Hepatology ; 2022 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-35108400

RESUMO

BACKGROUND AND AIMS: Metastasis is the primary cause of cancer mortality, and colorectal cancer (CRC) frequently metastasizes to the liver. Our previous studies demonstrated the critical role of KIAA1199 in tumor invasion and metastasis in CRC. In the present study, we described an immune regulatory effect of KIAA1199 that creates a permissive environment for metastasis. APPROACH AND RESULTS: Flow cytometry was used to examine the effects of KIAA1199 on the infiltration of tumor immune cells. Neutrophils and T cells were isolated, stimulated, and/or cultured for in vitro function assays. In the patients with CRC, high expression levels of KIAA1199 were associated with an increased neutrophil infiltration into the liver. This result was further validated in mouse metastasis models. The increased influx of neutrophils contributed to the KIAA1199-driven CRC liver metastasis. Mechanistically, KIAA1199 activated the TGFß signaling pathway by interacting with the TGFBR1/2 to stimulate CXCL1 and CXCL3 production, thereby driving the aggregation of immunosuppressive neutrophils. Genetic blockade or pharmacologic inhibition of KIAA1199 restored tumor immune infiltration, impeded tumor progression, and potentiated response to immune checkpoint blockade (ICB). CONCLUSIONS: These findings indicated that KIAA1199 could facilitate the liver infiltration of immunosuppressive neutrophils via the TGFß-chemokine (C-X-C motif) ligand (CXCL)3/1-CXCR2 axis, which might be clinically targeted for the treatment of hepatic metastasis.

5.
ACS Nano ; 16(2): 2585-2597, 2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-35080858

RESUMO

Extrusion of neutrophil extracellular traps (NETs), a fundamental host innate immune defense against pathogens, has recently been linked to cancer resistance to immunotherapy and distant metastasis. These findings highlight interesting areas of cancer-elicited inflammation and potential therapeutic strategies. Disrupting existing NETs with DNase I has been proved to enhance the therapeutic efficacy of tumor immunotherapy and attenuate metastatic spread. However, systemic biodistribution of DNase I raises safety issues, potentially impairing host defense against infection. Hence, tumor-specific delivery and metastatic niche-targeted effects are attractive options for localized degradation of NETs. We have engineered a nanoplatform with a plasmonic gold blackbody (AuPB) core with broad-spectrum photo activity and a mesoporous polydopamine (mPDA) shell for efficient loading and photoregulated release of DNase I. The on-demand released DNase I triggered by the second near-infrared (NIR-II) light irradiation breaks the "NET-mediated physical barrier", thereby increasing the contact of immune cytotoxic cells with tumor cells in living mice and sensitizing immune checkpoint therapy of primary colorectal cancer (CRC). Moreover, the deposition and light-controlled cargo release from systemically delivered AuPB@mPDA carriers in liver, the most frequent site of CRC metastasis, abolished NET-mediated capture of circulating tumor cells and hence metastatic seeding. Our findings indicate that the localized, light-regulated release of DNase I by photoactive carriers in the NIR-II window represent a translational route for immune-mediated tumor regression and metastasis inhibition.


Assuntos
Armadilhas Extracelulares , Células Neoplásicas Circulantes , Animais , Movimento Celular , Armadilhas Extracelulares/metabolismo , Imunoterapia , Camundongos , Neutrófilos/metabolismo , Distribuição Tecidual
6.
Food Funct ; 12(24): 12774-12787, 2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34851341

RESUMO

Active peptides, as an alternative nutrition supplement, have been confirmed to have beneficial efficacy against acute colitis. Herein, egg white peptides (EWPs) were used as a nutritional supplement to relieve dextran sulfate sodium-induced acute colitis symptoms. The potential multi-component synergetic pharmacological intervention mechanism of EWPs was investigated on the basis of in silico pharmacology, bioinformatics analysis, and molecular docking. In vitro experiments demonstrated that the migration rate of HSF cells was enhanced 5.30-fold upon treatment with EWPs relative to the control group. After administration with EWPs, colitis symptoms were alleviated in a dose-dependent manner and the serum amino acid content was significantly enhanced, especially for Ala, Leu, Ser, Thr, and Met. Four peptides identified from EWPs showed a total of 52 acute colitis-related potential targets (Fit score >3.8) with network pharmacology analysis, and the targets participated in 31 signaling pathways (p < 0.001). Among these pathways, PI3K-Akt, VEGF, Ras, TNF, and MAPK signaling pathways may exert essential anti-inflammatory effects and accelerate repairing intestinal mucosa. Molecular docking showed that the majority binding energy of peptides-targets was between -10.35 kcal mol-1 and -18.72 kcal mol-1, and peptides mainly interacted with the core targets (Btk, Gstm1, and Rac1) by hydrogen-bonding interactions. The current study confirmed that EWPs as supplementary nutrition can alleviate acute colitis.


Assuntos
Colite/tratamento farmacológico , Clara de Ovo , Peptídeos/farmacologia , Aminoácidos/sangue , Aminoácidos/efeitos dos fármacos , Animais , Colite/metabolismo , Colo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular/métodos , Peptídeos/metabolismo , Transdução de Sinais
7.
J Am Chem Soc ; 143(49): 20907-20915, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34859675

RESUMO

Hydroformylation is an imperative chemical process traditionally catalyzed by homogeneous catalysts. Designing a heterogeneous catalyst with high activity and selectivity in hydroformylation is challenging but essential to allow the convenient separation and recycling of precious catalysts. Here, we report the development of an outstanding catalyst for efficient heterogeneous hydroformylation, RhZn intermetallic nanoparticles. In the hydroformylation of styrene, it shows three times higher turnover frequency (3090 h-1) compared to the benchmark homogeneous Wilkinson's catalyst (966 h-1), as well as a high chemoselectivity toward aldehyde products. RhZn is active for a variety of olefin substrates and can be recycled without a significant loss of activity. Density functional theory calculations show that the RhZn surfaces reduce the binding strength of reaction intermediates and have lower hydroformylation activation energy barriers compared to pure Rh(111), leading to more favorable reaction energetics on RhZn. The calculations also predict potential catalyst design strategies to achieve high regioselectivity.

8.
Oncogene ; 40(46): 6443-6455, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34608265

RESUMO

Metastasis is the leading cause of colorectal cancer (CRC)-induced death. However, the underlying molecular mechanisms of CRC metastasis are poorly understood. Metabolic reprogramming is an intrinsic feature of cancer, which have complicated effects on cancer metastasis. Here, we find that a novel metastasis-related protein, cell migration-inducing and hyaluronan-binding protein (CEMIP), can act as a novel adaptor protein of O-GlcNAc transferase (OGT) to promote CRC metastasis through glutamine metabolic reprogramming. Mechanistically, CEMIP interacts with OGT and ß-catenin, which leads to elevated O-GlcNAcylation of ß-catenin and enhanced ß-catenin nuclear translocation from cytomembrane. Furthermore, accumulated ß-catenin in nucleus enhances the transcription of CEMIP to reciprocally regulate ß-catenin and contributes to over-expression of glutaminase 1 and glutamine transporters (SLC1A5 and SLC38A2). Combinational inhibition of CEMIP and glutamine metabolism could dramatically attenuate the metastasis of CRC in vivo. Collectively, this study reveals the importance of glutamine metabolic reprogramming in CEMIP-induced CRC metastasis, indicating the great potential of CEMIP and glutamine metabolism for CRC metastasis prevention.


Assuntos
Neoplasias Colorretais/patologia , Glutamina/metabolismo , Hialuronoglucosaminidase/genética , Hialuronoglucosaminidase/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , beta Catenina/metabolismo , Sistema A de Transporte de Aminoácidos/metabolismo , Sistema ASC de Transporte de Aminoácidos/metabolismo , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Camundongos , Antígenos de Histocompatibilidade Menor/metabolismo , Metástase Neoplásica , Transplante de Neoplasias , Transcrição Genética
9.
J Agric Food Chem ; 69(35): 10350-10357, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34448567

RESUMO

As a membrane protein, the activity of angiotensin I-converting enzyme (ACE) can be modulated via regulation of its localization in the cell membrane with food-derived peptides. This study aimed to explore the effect of egg white peptides on the cell membrane localization and activity of ACE in human umbilical vein endothelial cells. ACE activity was found to be related to lipid rafts by using methyl-ß-cyclodextrin (MßCD). QVPLW and LCAY can inhibit ACE activity by preventing ACE recruitment into lipid rafts, with in situ IC50 values of 238.46 ± 11.35 µM and 31.55 ± 2.64 µM in the control groups, as well as 45.43 ± 6.15 µM and 34.63 ± 1.59 µM in the MßCD groups, respectively. QVPLW and LCAY may alter the cell membrane properties, including the fluidity, potential, and permeability, and eventually promote the transposition of ACE.


Assuntos
Clara de Ovo , Peptidil Dipeptidase A , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Microdomínios da Membrana , Peptídeos/farmacologia
10.
Microb Pathog ; 160: 105162, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34461245

RESUMO

Heteroresistance is a poorly understood mechanism of resistance which refers to a phenomenon where there are different subpopulations of seemingly isogenic bacteria which exhibit a range of susceptibilities to a particular antibiotic. In the current study, we identified a multidrug-resistant, carbapenemase-positive K. pneumoniae strain SWMUF35 which was classified as susceptible to amikacin and resistant to meropenem by clinical diagnostics yet harbored different subpopulations of phenotypically resistant cells, and has the ability to form biofilm. Population analysis profile (PAP) indicated that SWMUF35 showed heteroresistance towards amikacin and meropenem which was considered as co-heteroresistant K. pneumoniae strain. In vitro experiments such as dual PAP, dual Times-killing assays and checkerboard assay showed that antibiotic combination therapy (amikacin combined with meropenem) can effectively combat SWMUF35. Importantly, using an in vivo mouse model of peritonitis, we found that amikacin or meropenem monotherapy was unable to rescue mice infected with SWMUF35. Antibiotic combination therapy could be a rational strategy to use clinically approved antibiotics when monotherapy would fail. Furthermore, our data warn that antibiotic susceptibility testing results may be unreliable due to undetected heteroresistance which can lead to treatment failure and the detection of this phenotype is a prerequisite for a proper choice of antibiotic to support a successful treatment outcome.


Assuntos
Amicacina , Carbapenêmicos , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Modelos Animais de Doenças , Klebsiella pneumoniae , Meropeném/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Falha de Tratamento
11.
Angew Chem Int Ed Engl ; 60(33): 18309-18317, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34114306

RESUMO

Effective control on chemoselectivity in the catalytic hydrogenation of C=O over C=C bonds is uncommon with Pd-based catalysts because of the favored adsorption of C=C bonds on Pd surface. Here we report a unique orthorhombic PdSn intermetallic phase with unprecedented chemoselectivity toward C=O hydrogenation. We observed the formation and metastability of this PdSn phase in situ. During a natural cooling process, the PdSn nanoparticles readily revert to the favored Pd3 Sn2 phase. Instead, using a thermal quenching method, we prepared a pure-phase PdSn nanocatalyst. PdSn shows an >96 % selectivity toward hydrogenating C=O bonds of various α,ß-unsaturated aldehydes, highest in reported Pd-based catalysts. Further study suggests that efficient quenching prevents the reversion from PdSn- to Pd3 Sn2 -structured surface, the key to the desired catalytic performance. Density functional theory calculations and analysis of reaction kinetics provide an explanation for the observed high selectivity.

12.
Food Funct ; 12(13): 5989-6000, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34037039

RESUMO

Food-derived peptides can ameliorate colitis but their pharmaceutical targets and action mechanism of ameliorating colitis remain unclear. Here, we aim to investigate the action mechanism of food-derived peptides ameliorating colitis based on the network pharmacology and bioinformatics analysis. 400 dipeptides were used to screen the core targets based on the PharmMapper and GeneCards database. A total of 49 core targets were screened to construct the predicted target set. The target set was then evaluated using the STRING software to construct the protein-protein and protein-dipeptide network. Furthermore, the DAVID software was used to analyze the GO (gene ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways of the core targets. The results of bioinformatics assays showed that the 49 targets mainly participated in the inflammatory and immunomodulatory signaling pathways, particularly in the inflammatory bowel disease-related signaling pathways IL-6/JAK2/STAT3 and TLR4-NF-κB/MAPK. In addition, molecular docking results confirmed that 25 dipeptides mainly interacted with the core targets (ALB, JAK2, and STAT3) by hydrogen-bonding interactions. This study can provide evidence for the potential efficacy and action pathways of food-derived peptides on colitis.


Assuntos
Colite/tratamento farmacológico , Biologia Computacional , Dipeptídeos/farmacologia , Colite/genética , Dipeptídeos/química , Ontologia Genética , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Simulação de Acoplamento Molecular , Conformação Proteica , Mapas de Interação de Proteínas , Transdução de Sinais/efeitos dos fármacos
13.
J Chem Phys ; 154(9): 094710, 2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33685166

RESUMO

Heterogeneous single-metal-site catalyst or single-atom catalyst research has grown rapidly due to the accessibility of modern characterization techniques that can provide invaluable information at the atomic-scale. Herein, we study the structural evolution of isolated single Pt sites incorporated in a metal-organic framework containing bipyridine functional groups using in situ diffuse reflectance infrared Fourier transform spectroscopy with CO as the probe molecule. The structure and electronic properties of the isolated Pt sites are further corroborated by x-ray photoelectron spectroscopy and aberration-corrected scanning transmission electron microscopy. We find the prerequisite of high temperature He treatment for Pt activation and CO insertion and inquire into the structural transformation of Pt site process by dynamic nuclear polarization-enhanced solid-state nuclear magnetic resonance spectroscopy.

14.
Cancer Immunol Immunother ; 70(7): 1841-1851, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33388997

RESUMO

Previously we reported that administration of IgG could inhibit tumor progression in mouse models. At the same time, we also found that some IgGs have glycosylation modifications on their Fab fragments, which may have different biological functions than non-glycosylated IgG. In this study, we employed mouse tumor models to explore the roles of two different forms of IgG, i.e. Fab-glycosylated and Fab-non-glycosylated IgG, in tumor progression. The two types of IgGs were separated with ConA absorption which could react with glycan on the Fab arm but could not access glycan on the Fc fragment. In addition, we performed cytokine array, ELISA, western blotting, immunocytochemistry and other techniques to investigate the possible mechanisms of the actions of Fab-glycosylated IgG in the models. We found that Fab-glycosylated IgG, unlike Fab-non-glycosylated IgG, did not inhibit tumor growth and metastasis in the model. On the contrary, Fab-glycosylated IgG may bind to antigen-bound IgG molecules and macrophages through the glycosidic chain on the Fab fragment to affect antigen-antibody binding and macrophage polarization, which are likely to help tumor cells to evade the immune surveillance. A new mechanism of immune evasion with Fab-glycosylated IgG playing a significant role was proposed.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Fragmentos Fab das Imunoglobulinas/imunologia , Imunoglobulina G/imunologia , Animais , Feminino , Glicosilação , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Sci Total Environ ; 770: 145321, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-33515886

RESUMO

The conversion of lignocellulosic biomass to bioethanol is a potential approach to alleviate the energy crisis and environmental deterioration. To improve the conversion efficiency of bioethanol from wheat straw (WS), the optimization of subcritical water pretreatment and high solid hydrolysis were investigated in this study. Response surface methodology (RSM) accompanied with glucose concentration after enzymatic hydrolysis as a more reasonable response value was applied for the pretreatment optimization, and the optimum conditions were obtained as 220.51 °C of extraction temperature, 22.01 min of extraction time and 2.50% (w/v) of substrate loading. After pretreatment, the hemicellulose decreased by 18.37%, and the cellulose and lignin increased by 25.92% and 8.81%, respectively, which were consistent with the destroyed microstructure and raised crystallinity. The high efficiency of separate hydrolysis and fermentation (SHF) was verified by five commercial cellulases, and yields of hydrolysis and fermentation were 77.85-89.59% and 93.34-96.18%, respectively. Based on the high solid (15%) hydrolysis and fermentation, the ethanol concentration was significantly improved to 37.00 g/L. Interestingly, 64.47% of lignin was accumulated in the solid residue after enzymatic hydrolysis and it did not affect the efficiency of SHF, which further suggested that subcritical water mainly affected the structure of WS rather than the removal of lignin. Therefore, subcritical water pretreatment combined with high solid hydrolysis is a more effective solution for bioethanol conversion, which is also a promising strategy to utilize all components of lignocellulosic biomass.


Assuntos
Triticum , Água , Biomassa , Fermentação , Hidrólise , Lignina/metabolismo , Triticum/metabolismo
16.
Br J Pharmacol ; 178(6): 1475-1491, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33443775

RESUMO

BACKGROUND AND PURPOSE: Colorectal cancer is the third most common cancer worldwide. HER2 and HER3 are two members of human epidermal receptor family of tyrosine kinase receptors (RTKs) and associated with poor survival in colorectal cancer. They have been observed as important therapeutic targets in various types of cancer. Corosolic acid, a natural pentacyclic triterpene, has been demonstrated to have a significant anti-cancer activity. However, the target of corosolic acid has not yet been explored. This study aimed to reveal the direct targets of corosolic acid underlying its anti-cancer activities. EXPERIMENTAL APPROACH: The targets of corosolic acid were revealed by the phospho-RTK array, bio-layer interferometry, co-immunoprecipitation, and proximity ligation assay. The inhibitory action of corosolic acid on HER2/HER3 heterodimerization and related downstream signalling were investigated in HCT116 and SW480 cells. In addition, the chemo-preventive effects of corosolic acid were validated in both HCT116 xenograft model and AOM/DSS model. KEY RESULTS: Our results demonstrated that corosolic acid could prevent NRG1-induced HER2/HER3 heterodimerization and suppress the phosphorylation of both HER2 and HER3. Furthermore, HER2 and HER3 could regulate the downstream signalling pathways of RalA/RalBP1/CDK1 and PI3K/Akt/PKA, respectively, resulting in the changes in phosphorylation of Drp1 and mitochondrial dynamics. corosolic acid exhibited anti-cancer activity in both HCT116 xenograft model and AOM/DSS model. CONCLUSIONS AND IMPLICATIONS: Collectively, our results demonstrated corosolic acid directly targeted HER2 and HER3 heterodimerization and inhibited mitochondrial fission via regulating RalA/RalBP1/CDK1 and PI3K/Akt/PKA pathways, revealing a novel mechanism underlying the beneficial effects of corosolic acid on colorectal cancer.


Assuntos
Neoplasias Colorretais , Receptor ErbB-3 , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Humanos , Fosfatidilinositol 3-Quinases , Receptor ErbB-2 , Triterpenos
18.
J Immunother Cancer ; 8(2)2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32819973

RESUMO

BACKGROUND: Recent impressive advances in cancer immunotherapy have been largely derived from cellular immunity. The role of humoral immunity in carcinogenesis has been less understood. Based on our previous observations we hypothesize that an immunoglobulin subtype IgG4 plays an essential role in cancer immune evasion. METHODS: The distribution, abundance, actions, properties and possible mechanisms of IgG4 were investigated with human cancer samples and animal tumor models with an extensive array of techniques both in vitro and in vivo. RESULTS: In a cohort of patients with esophageal cancer we found that IgG4-containing B lymphocytes and IgG4 concentration were significantly increased in cancer tissue and IgG4 concentrations increased in serum of patients with cancer. Both were positively related to increased cancer malignancy and poor prognoses, that is, more IgG4 appeared to associate with more aggressive cancer growth. We further found that IgG4, regardless of its antigen specificity, inhibited the classic immune reactions of antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against cancer cells in vitro, and these effects were obtained through its Fc fragment reacting to the Fc fragments of cancer-specific IgG1 that has been bound to cancer antigens. We also found that IgG4 competed with IgG1 in reacting to Fc receptors of immune effector cells. Therefore, locally increased IgG4 in cancer microenvironment should inhibit antibody-mediated anticancer responses and help cancer to evade local immune attack and indirectly promote cancer growth. This hypothesis was verified in three different immune potent mouse models. We found that local application of IgG4 significantly accelerated growth of inoculated breast and colorectal cancers and carcinogen-induced skin papilloma. We also tested the antibody drug for cancer immunotherapy nivolumab, which was IgG4 in nature with a stabilizing S228P mutation, and found that it significantly promoted cancer growth in mice. This may provide an explanation to the newly appeared hyperprogressive disease sometimes associated with cancer immunotherapy. CONCLUSION: There appears to be a previously unrecognized immune evasion mechanism with IgG4 playing an essential role in cancer microenvironment with implications in cancer diagnosis and immunotherapy.


Assuntos
Imunoglobulina G/imunologia , Imunoterapia/métodos , Neoplasias/imunologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Microambiente Tumoral
19.
Int J Parasitol ; 50(8): 595-602, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32592810

RESUMO

The atypical protein kinase RIOK-2 is a non-ribosomal factor essential for ribosome maturation in yeast and human cells; however, little is known about its physiological role in pathogens. Our earlier work examined the expression profile of a RIOK-2 gene (Ss-riok-2) in Strongyloides stercoralis - a prevalent nematode parasite of dogs and humans. Herein, we demonstrate that Ss-RIOK-2 encodes a catalytically active kinase, distributed primarily in the cytoplasm of intestinal and hypodermal cells in transgenic larvae. Its expression oscillates as the free-living L1s develop into infective L3s. Overexpression of a catalytically impaired Ss-RIOK-2-D228A mutant delayed the development of transgenic larvae, while ectopic expression of another dominant negative isoform with a mutation in the ATP-binding site (K123A) abrogated the process of egg hatching, which could be rescued by co-expressing a wild-type Ss-RIOK-2 but not by its Ss-RIOK-1 ortholog. Collectively, our findings show a critical and specific role of Ss-RIOK-2 during the development of a pathogenic roundworm, which can be exploited to develop anti-infectives.


Assuntos
Óvulo/fisiologia , Proteínas Quinases , Strongyloides stercoralis , Animais , Animais Geneticamente Modificados , Sítios de Ligação , Cães , Larva/fisiologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Strongyloides stercoralis/enzimologia , Strongyloides stercoralis/genética
20.
Parasit Vectors ; 13(1): 326, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32586367

RESUMO

BACKGROUND: In most multicellular organisms, the transforming growth factor-ß (TGF-ß) signalling pathway is involved in regulating the growth and stem cell differentiation. Previous studies have demonstrated the importance of three key molecules in this pathway in the parasitic nematode Haemonchus contortus, including one TGF-ß type I receptor (Hc-tgfbr1), one TGF-ß type II receptor (Hc-tgfbr2), and one co-Smad (Hc-daf-3), which regulated the developmental transition from the free-living to the parasitic stages of this parasite. However, almost nothing is known about the function of the TGF-ß ligand (Hc-tgh-2) of H. contortus. METHODS: Here, the temporal transcription profiles of Hc-tgh-2 at eight different developmental stages and spatial expression patterns of Hc-TGH-2 in adult female and male worms of H. contortus have been examined by real-time PCR and immunohistochemistry, respectively. In addition, RNA interference (RNAi) by soaking was employed to assess the importance of Hc-tgh-2 in the development from exsheathed third-stage larvae (xL3s) to fourth-stage larvae (L4s) in H. contortus. RESULTS: Hc-tgh-2 was continuously transcribed in all eight developmental stages of H. contortus studied with the highest level in the infective third-stage larvae (iL3) and Hc-TGH-2 was located in the muscle of the body wall, intestine, ovary of adult females and testes of adult males. Silencing Hc-tgh-2 by the specific double-stranded RNA (dsRNA), decreased the transcript level of Hc-tgh-2 and resulted in fewer xL3s developing to L4s in vitro. CONCLUSIONS: These results suggested that the TGF-ß ligand, Hc-TGH-2, could play important roles in the developmental transition from the free-living (L3s) to the parasitic stage (L4s). Furthermore, it may also take part in the processes such as digestion, absorption, host immune response and reproductive development in H. contortus adults.


Assuntos
Haemonchus , Receptor do Fator de Crescimento Transformador beta Tipo II , Animais , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Perfilação da Expressão Gênica , Haemonchus/embriologia , Haemonchus/genética , Haemonchus/metabolismo , Proteínas de Helminto/genética , Proteínas de Helminto/metabolismo , Estágios do Ciclo de Vida/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
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