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1.
Immunology ; 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33934341

RESUMO

The IL-7/IL-7R pathway plays a vital role in the immune system, especially in the inflammatory response. Monocytes/macrophages (osteoclast precursors) have been recently recognized as important participants in the osteoclastogenesis of rheumatoid arthritis (RA) patients. Here, we aimed to investigate the therapeutic potential of IL-7/IL-7R pathway in RA and to determine whether it could restrain osteoclastogenic functions and thereby ameliorate RA. Firstly, collagen-induced arthritis (CIA) mice were administered with IL-7Rα-target antibodies to assess their therapeutic effect on arthritis. We found that blockade of the IL-7/IL-7R pathway protected CIA mice from bone destruction in addition to inducing inflammatory remission, by altering the RANKL/RANK/OPG ratio and consequently decreasing osteoclast formation. To explore the effect and mechanism of this pathway, bone marrow cells were induced to osteoclasts and treated with IL-7, a STAT5 inhibitor, or supernatants from T cells. The results showed that the IL-7/IL-7R pathway played a direct inhibitory role in osteoclast differentiation via STAT5 signalling pathway in a RANKL-induced manner. We applied flow cytometry to analyze the effect of IL-7 on T cell RANKL expression, and found that IL-7/IL-7R pathway had an indirect role in the osteoclast differentiation process by enhancing the RANKL expression on T cells. In conclusion, the IL-7/IL-7R pathway exhibited a dual effect on osteoclastogenesis of CIA mice by interacting with osteoimmunology processes and could be a novel therapeutic target for autoimmune diseases such as RA.

2.
J Med Chem ; 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33929863

RESUMO

We previously reported that P-retigabine (P-RTG), a retigabine (RTG) analogue bearing a propargyl group at the nitrogen atom in the linker of RTG, displayed moderate anticonvulsant efficacy. Recently, our further efforts led to the discovery of HN37 (pynegabine), which demonstrated satisfactory chemical stability upon deleting the ortho liable -NH2 group and installing two adjacent methyl groups to the carbamate motif. HN37 exhibited enhanced activation potency toward neuronal Kv7 channels and high in vivo efficacy in a range of pre-clinical seizure models, including the maximal electroshock test and a 6 Hz model of pharmacoresistant limbic seizures. With its improved chemical stability, strong efficacy, and better safety margin, HN37 has progressed to clinical trial in China for epilepsy treatment.

3.
Nutrients ; 13(4)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808480

RESUMO

Chronic inflammation is a risk factor for colorectal cancer, and inflammatory cytokines secreted from inflammatory cells and active oxygen facilitate tumorigenesis. Intestinal bacteria are thought to regulate tumorigenesis. The longer the breastfeeding period, the lower is the risk of inflammatory bowel disease. Here, we investigated preventive effects of the probiotic Lactobacillus rhamnosus M9 (Probio-M9) on colitis-associated tumorigenesis. An inflammatory colorectal tumor model was established using a 6-week-old male C57BL/6NCrSlc mouse, which was intraperitoneally administered with azoxymethane (AOM: 12 mg/kg body weight). On weeks 2 and 4, 2% dextran sulfate sodium (DSS) was administered to mice for 7 days through drinking water. On weeks 8 and 10, Probio-M9 (2 × 109/day) was orally administered for 7 days. Animals were sacrificed at 20 weeks after AOM administration and immunohistochemical staining and Western blotting was performed. The α-diversity of microflora (Shannon index), principal coordinate analysis, and distribution of intestinal bacterium genera and metabolic pathways were compared. The AOM/DSS group showed weight loss, diarrhea, intestinal shortening, increased number of colon tumors, proliferating tumorigenesis, increased inflammation score, fibrosis, increased CD68+, or CD163+ macrophage cells in the subserosal layer of non-tumor areas. Inflammation and tumorigenesis ameliorated after Probio-M9 treatment. Fecal microbial functions were altered by AOM/DSS treatment. Probio-M9 significantly upregulated the fecal microbial diversity and reversed fecal microbial functions. Thus, Probio-M9 could suppress tumor formation in the large intestine by regulating the intestinal environment and ameliorating inflammation, suggesting its therapeutic potential for treatment of inflammation and colitis-associated tumorigenesis.

4.
Int J Nanomedicine ; 16: 2271-2282, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33776432

RESUMO

Background: Contrast-enhanced magnetic resonance imaging (MRI) is a powerful diagnostic tool for many diseases. In many situations, the contrasts are repeatedly administrated in order to monitor and assess the disease progression. Objective: To investigate and compare the biological effects of γ-Fe2O3 nanoparticle (NP) and gadolinium dimeglumine (Gd-DTPA) with high and multiple doses on the kidney of healthy mice. Methods: Polydextrose sorbitol carboxymethyl ether coated γ-Fe2O3 NP with hydrodynamic size of 68.2 nm and clinically applied Gd-DTPA were employed on healthy mice with the repeatedly intravenous administration of high doses. The cell viability of human umbilical vein endothelial cells (HUVEC) in high doses of these two contrast agents were measured using the xCELLigence Real-Time Cell Analysis (RTCA) S16 Instrument. The biological effects of γ-Fe2O3 NP and Gd-DTPA on the kidney were obtained using a biochemical automatic analyzer and multiple proinflammatory factor kit on the serum. Histopathological and immunohistochemistry analysis were taken on kidney tissues. Results: It showed that the proinflammatory responses elicited by the γ-Fe2O3 NPs were weaker than that by Gd-DTPA, evidenced by the relatively much lower level of IL-1ß, IL-6, IL-18, TNF-α, C-reactive protein (CRP) and Ferritin. At the same time, the γ-Fe2O3 NPs did not have the biochemical index elevated, while the Gd-DTPA did. Conclusion: The γ-Fe2O3 NPs induced weaker proinflammatory effects in reference to the Gd-DTPA, indicating better renal safety. Therefore, it is suggested that γ-Fe2O3 NPs should be safer and optional choice when repeated contrast-enhanced MRI is necessary.


Assuntos
Meios de Contraste/química , Compostos Férricos/química , Gadolínio DTPA/química , Inflamação/patologia , Rim/fisiopatologia , Nanopartículas/química , Animais , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Proliferação de Células , Sobrevivência Celular , Ferritinas/sangue , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Rim/patologia , Imagem por Ressonância Magnética , Masculino , Camundongos , Espectrometria por Raios X , Fator de Crescimento Transformador beta/metabolismo
5.
J Med Chem ; 64(7): 3911-3939, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33755451

RESUMO

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections.

6.
Biomed Chromatogr ; : e5117, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33742483

RESUMO

A high-performance liquid chromatographic method with a modified QuEChERS extraction for the determination of polycyclic aromatic hydrocarbons (PAHs) in blood serum was developed to investigate the internal exposure level and the carcinogentic toxicity contribution rate of PAHs for pregnant women in Nantong, China. Venous blood (n = 48) was collected in the local hospital and the internal exposure level of 16 PAHs and the contribution rate of carcinogenicity to pregnant women were analyzed. Among all of the detected PAHs, the detection rate of pyrene (77.08%) was the highest, followed by naphthalene (64.58%) and benzo[a]anthracene (BaA, 45.83%). The carcinogenicity contribution rate of BaA (37.37%) was the highest, followed by fluorene (32.96%) and acenaphthylene (22.01%). The results showed that many kinds of carcinogenic PAHs can be detected in the serum of pregnant women in Nantong city, among which BaA should be paid most attention because of its high internal exposure level and carcinogenic risk. Meanwhile, the origins of general PAHs in serum samples were analyzed using the characteristic ratio analysis method. The PAH pollution level of air samples (n = 42) during the collection time of blood samples was also analyzed to compare the possible correlations between the two different results.

7.
Phytomedicine ; 83: 153479, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33561764

RESUMO

BACKGROUND: The fruit of Terminalia chebula Retz. is one of the most widely used herbal drug in Traditional medicine prescriptions including those for liver diseases. In the screening of bioactive constituents that have potential hepatoprotective activity, chebulinic acid (CA) which is a major chemical constituent of T. chebula fruit showed potent activity. PURPOSE: This work was conducted to investigate the hepatoprotective activity and mechanisms of CA. METHODS: The hepatoprotective effect of CA was examined on hepatotoxic models of cells, zebrafish larvae and mice caused by tert-butyl hydrogen peroxide (t-BHP), acetaminophen (APAP) and CCl4, respectively. RESULTS: Pretreatment with CA could prevent t-BHP-induced damage in L-02 hepatocytes by blocking the production of ROS, reducing LDH levels and enhancing HO-1 and NQO1 expression via MAPK/Nrf2 signaling pathway. In animal experiments, CA significantly protected mice from CCl4-induced liver injury, as demonstrated by reduced ALT, AST and MDA levels, enhanced SOD activity, improved liver histopathological changes, and the activation of the Nrf2/HO-1 signaling pathway. CA metabolized to chebulic acid isomers with DPPH radical scavenging activity. In a transgenic zebrafish line with liver specific expression of DsRed RFP, CA diminished the hepatotoxicity induced by 10 mM APAP. CONCLUSION: Experiments in cell and two animal models demonstrated consistent results and comprehensively expounded the hepatoprotective effects of CA.

8.
AMB Express ; 11(1): 23, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547539

RESUMO

Bacillus velezensis is widely used for agricultural biocontrol, due to its ability to enhance plant growth while suppressing the growth of microbial pathogens. However, there are few reports on its application in fermented feed. Here, a two-stage solid-state fermentation process using Bacillus velezensis followed by Lactobacillus plantarum was developed to degrade antinutritional factors (ANFs) and improve soybean meal (SBM) nutrition for animal feed. The process was evaluated for performance in degrading SBM antinutritional factors, dynamic changes in physicochemical characteristics, microorganisms and metabolites. After two-stage fermentation, degradation rates of glycinin and ß-conglycinin contents reached 78.60% and 72.89%, respectively. The pH of fermented SBM (FSBM) decreased to 4.78 ± 0.04 and lactic acid content reached 183.38 ± 4.86 mmol/kg. NSP-degrading enzymes (Non-starch polysaccharide, NSPases) and protease were detected from the fermented product, which caused the changed microstructure of SBM. Compared to uninoculated SBM, FSBM exhibited increased proportions of crude protein (51.97 ± 0.44% vs. 47.28 ± 0.34%), Ca, total phosphorus (P), and trichloroacetic acid-soluble protein (11.79 ± 0.13% vs. 5.07 ± 0.06%). Additionally, cellulose and hemicellulose proportions declined by 22.10% and 39.15%, respectively. Total amino acid content increased by 5.05%, while the difference of AA content between the 24 h, 48 h and 72 h of fermentation was not significant (P > 0.05). Furthermore, FSBM also showed antibacterial activity against Staphylococcus aureus and Escherichia coli. These results demonstrated that two-stage SBM fermentation process based on Bacillus velezensis 157 and Lactobacillus plantarum BLCC2-0015 is an effective approach to reduce ANFs content and improve the quality of SBM feed.

9.
J Chromatogr Sci ; 59(5): 432-438, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33434918

RESUMO

A bioanalytical method for simultaneous quantification of isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) in plasma was developed and validated using high-performance liquid chromatography with tandem mass spectrometry. After extracted by protein precipitation with acetonitrile, the analytes were separated on a Waters XBridge Amide column by isocratic elution with acetonitrile and 5 mM ammonium acetate solution containing 0.3% formic acid (77:23, v/v) at a flow rate of 0.5 mL/min. The detection was carried out on a triple quadrupole tandem mass spectrometer equipped with an electrospray ionization source in positive mode by monitoring the selected ion transitions at m/z 205.2 â†’ 116.1, m/z 137.9 â†’ 121.2, m/z 124.3 â†’ 78.9 and m/z 213.1 â†’ 122.4 for EMB, INH, PZA and EMB-d8 Internal standard (IS), respectively. The calibration curves were linear over the range of 0.0125-2.00 µg/mL for EMB, 0.0625-10.0 µg/mL for INH and 0.250-40.0 µg/mL for PZA. Neither cross-analytes inter-conversion nor matrix effects were observed. The intra- and inter-assay precision (%RSD) values were within 8.80%, and accuracy (%RE) ranged from -11.13 to 13.49%, indicating that the precision and accuracy were well within the acceptable limits of variation. The method would be helpful for analysis of EMB, INH and PZA in plasma samples from clinical pharmacokinetics and therapeutic drug monitoring.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33512987

RESUMO

In the present work, an amphiphilic and magnetically recyclable graphene oxide (MR-GO) demulsifier was devised and synthesized by graft of magnetic nanoparticles (Fe3O4@SiO2-APTES) and ethylenediamine on the GO surface. The wettability and surface charges of MR-GO under various pH conditions can be regulated via adjusting the contents and species of surface functional groups (such as amino, carboxyl, and hydroxyl). In the demulsificaition test, MR-GO displayed favorable demulsification performance for crude oil-in-water (O/W) emulsion under pH of 2.0-10.0, thusly greatly improving the application scope of common demulsifier. The optimal dosage of MR-GO was 200 mg/L and the demulsification efficiency attained a maximum value of 99.7% for crude O/W emulsion with pH of 6.0. What's more, owing to its magnetic response performance, the MR-GO can be reused and the demulsification efficiency remained above 91.0% after six cycles. Based on the strong interfacial activity, MR-GO can arrive to the crude oil-water interface. With the synergy effects of interfacial adsorption (π-π/n-π) interactions and electrostatic attraction of demulsifier and interfacial films, and the aid of external mechanical forces, the interfacial films stabilized the emulsion were disrupted. Therefore, the oil droplets coated on the water droplets were gathered rapidly to form oily flocs and then migrated to the water surface to accomplish the demulsification of crude O/W emulsion.

11.
Environ Pollut ; 271: 116406, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33412445

RESUMO

As an emerging brominated flame retardant (BFR), tetrabromobisphenol S (TBBPS) has been frequently detected in the environmental media and organisms. Knowledges on the transformation and fate of TBBPS in both environment and engineering systems are essential to its ecological risk assessment. Herein, we reported the photochemical decomposition of TBBPS in aqueous solution upon 254 nm ultraviolet irradiation (UV254). Results show that TBBPS was highly photoreactive, most likely due to the presence of four ortho-bromine substituents. The molar absorption coefficient and quantum yield of TBBPS were found to be pH-dependent, with the monoanionic form being most photoreactive. A series of photoproducts were identified by solid phase extraction (SPE) combined with liquid chromatography-electrospray ionization-triple quadrupole mass spectrometry (LC-ESI(+)-MS/MS. The photolysis of TBBPS likely proceeded through photonucleophilic substitution, photoreductive debromination, and ß-scission reactions. A ketocarbene, possibly derived from the lower lying excited triplet state, was proposed to be involved in the photolysis of TBBPS. Ion chromatography analysis revealed that debromination occurred quickly, and the yield of bromide (Br-) approached 100% after 90 min irradiation. The presence of SRNOM and MRNOM inhibited the photodegradation rate of TBBPS, which is likely due to the light-screening and physical quenching effects of natural organic matter (NOM). Our results reveal that photolysis is an important process for the attenuation of TBBPS in aquatic system; however, naturally occurring species such as NOM can appreciably retard the decay of TBBPS.


Assuntos
Retardadores de Chama , Bifenil Polibromatos , Fotólise , Espectrometria de Massas em Tandem
12.
Int J Pharm ; 594: 120183, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33340596

RESUMO

Lymph node metastases in cancer patients are associated with high aggressiveness, poor prognosis, and short survival time. The chemokine receptor 4 (CXCR4)/stroma derived factor 1α (CXCL12) biological axis plays a critical role in the spread of cancer cells. Designing effective delivery systems that can successfully deliver CXCR4 antagonists to lymph nodes, which are rich in CXCR4-overexpressing cancer cells, for controlling cancer metastasis remain challenging. In this study, we demonstrated that such a challenge may be alleviated by developing nanometer-sized polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelles for the co-delivery of the CXCR4 antagonistic peptide E5 and doxorubicin (M-E5-Dox). This nanomicelle platform enables the preferential accumulation of cargos into lymph nodes and thus can better inhibit cancer metastasis and enhance antitumor efficacy than either free drugs or single drug-loaded micelles in breast cancer-bearing mouse models. Hence, M-E5-Dox is expected to be a potential therapeutic agent that would improve the clinical benefits of breast cancer therapy and treatment of various CXCR4-overexpressing malignancies.

13.
Lung Cancer ; 152: 39-48, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33341538

RESUMO

OBJECTIVES: Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20 ins) mutations are generally associated with de novo resistance to first- or second-generation EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). However, the real efficacy of osimertinib for this subset remains elusive. We performed this study to investigate the real efficacy of osimertinib for Chinese advanced NSCLC patients harboring EGFR ex20 ins mutations. MATERIALS AND METHODS: We retrospectively collected data of metastatic NSCLC patients with EGFR ex20 ins mutations who were treated with osimertinib 80 mg or 160 mg once daily in our center from June 2017 to May 2020. Progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were assessed. RESULTS: A total of 62 cases with EGFR ex20 ins mutations were included, and the major insertion variant was D770_N771insSVD and V769_D770insASV (45.1 %). Concurrent TP53 mutation was most commonly observed (59.7 %). Four patients showed partial response, 29 cases with stable disease and 29 showed progressive disease as best response to osimertinib (ORR: 6.5 %, DCR: 53.2 %). The median PFS (mPFS) in total patients was 2.3 (95 %CI, 1.5-3.1) months. Patients harboring A763_Y764insFQEA/D770delinsGY variants showed numerically longer mPFS than those with other variants (4.2 vs. 2.2 months, P =  0.164). Patients who failed to osimertinib and occurred extracranial progression showed similar mPFS to those with intracranial progression (2.3 vs. 1.9 months, P =  0.142). Median PFS was not significantly different between patients who received osimertinib 80mg or 160mg once daily (2.5 vs. 1.3 months, P = 0.161), either with no significance when it used in fist-line setteing or bove (3.0 vs. 2.2 months, P =  0.639). CONCLUSION: The unique insertion variant A763_Y764insFQEA and D770delinsGY might better respond to osimertinib than other ex20 ins subtypes. Osimertinib either 80 mg or 160 mg once daily showed less activity in Chinese NSCLC patients harboring diverse EGFR ex20 ins mutations.

14.
Cell Mol Biol (Noisy-le-grand) ; 66(7): 186-189, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33287940

RESUMO

To investigate the diagnostic value of cell-free DNA (cfDNA) and long fragment DNA in breast cancer patients.Female patients with breast cancer (n = 80) were recruited over one year for this study, and served as an observation group. The control group consisted of 50 normal, healthy females. Plasma levels of cfDNA and long fragment DNA were determined a day before treatment, 7 days after treatment, and on the 20th day of treatment. The levels of cfDNA and long fragment DNA in breast cancer patients before treatment were significantly higher than those of the control group (p<0.05). Patients cfDNA and long fragment DNA levels 7 days after treatment were not significantly different from the corresponding values at 1 day before treatment (p>0.05), but they decreased significantly on the 20th day of treatment, when compared with levels before treatment (p<0.05). Before treatment, the optimal cut-off point for cfDNA in patients' peripheral blood, sensitivity, specificity and accuracy were 12.25ng/mL, 79.12%, 86.15%, and 73.32%, respectively. The area under the ROC curve (AUC) was 0.865 (95% CI = 0.754-0.903). Close monitoring of cfDNA levels in peripheral blood of breast cancer patients in real-time can be used for early diagnosis of the disease.

15.
PLoS One ; 15(12): e0243145, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33270695

RESUMO

Hematopoietic progenitor kinase 1 (HPK1), a hematopoietic cell-specific Ste20-related serine/threonine kinase, is a negative regulator of signal transduction in immune cells, including T cells, B cells, and dendritic cells (DCs). In mice, HPK1 deficiency subverts inhibition of the anti-tumor immune response and is associated with functional augmentation of anti-tumor T cells. We have used a potent, small molecule HPK1 inhibitor, Compound 1, to investigate the effects of pharmacological intervention of HPK1 kinase activity in immune cells. Compound 1 enhanced Th1 cytokine production in T cells and fully reverted immune suppression imposed by the prostaglandin E2 (PGE2) and adenosine pathways in human T cells. Moreover, the combination of Compound 1 with pembrolizumab, a humanized monoclonal antibody against the programmed cell death protein 1 (PD-1), demonstrated a synergistic effect, resulting in enhanced interferon (IFN)-γ production. Collectively, our results suggest that blocking HPK1 kinase activity with small molecule inhibitors alone or in combination with checkpoint blockade may be an attractive approach for the immunotherapy of cancer.

16.
Transl Oncol ; 14(1): 100942, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33221686

RESUMO

Patients with early-stage non-small cell lung cancer (NSCLC), even stage IA, are at substantial risk of relapse and death. We explored the distinct features of molecular alterations and immune-related gene expression in Formalin-fixed paraffin-embedded (FFPE) samples from 25 relapsed patients compared with 25 non-relapsed patients through using whole-exome sequencing and an immune oncology panel RNA sequencing platform. Results showed that the chemokine, cytolytic activity and tumour-associated antigen gene signatures exhibited significantly higher expression in non-relapsed tumours from stage IA lung adenocarcinoma (LUAD) than that in relapsed tumours. Besides, Kaplan-Meier survival analysis revealed that the gene signatures of chemokines and tumour-associated antigens were significantly associated with the patients' disease-free survival (DFS), indicating their prognostic value in early-stage LUAD. Cytolytic activity displayed a similar trend but failed to reach statistical significance. These findings revealed a weakened immune phenotype in relapsed tumours and provide valuable information for improving the treatment management of these high-risk patients. Due to the overall small patient number in this study, these differences should be further validated in a larger cohort.

17.
J Dairy Sci ; 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33189295

RESUMO

Mammalian lignans are phytoestrogens with important bioactivities, and their concentrations in livestock milk may influence the health of consumers. This research aimed to establish a method to quantify multiple mammalian lignans in the biofluids of dairy sheep using ultra-HPLC-triple quadropole mass spectrometry with multiple-reaction monitoring. Secoisolariciresinol, 2-[(4-hydroxy-3-methoxyphenyl)methyl]-3-[(3-hydroxyphenyl)methyl]-1,4-butanediol, enterodiol (ED), enterolactone (EL), ED-sulfate (ED-S), and EL-sulfate (EL-S) were purified from the urine of flaxseed cake-fed dairy sheep. The structures of these lignans were identified by a combination of mass and nuclear magnetic resonance spectra. These purified lignans were used as standards to optimize their quantification conditions in urine, milk, and plasma of dairy sheep. On this basis, the lignan metabolites in biofluids were quantified. To improve analysis sensitivity, plasma and milk were pretreated with acetonitrile containing 1% formic acid and passed through a HybridSPE-PL 55261-U column (Supelco, Bellefonte, PA). The limit of quantification of the lignans ranged from 1.43 to 18.3 ng/mL in plasma, and from 1.01 to 18.7 ng/mL in milk. The linearity of the calibration curves ranged from their limit of quantification to at least 217 ng/mL in plasma, and 217 ng/mL in milk. Regression coefficient of the calibration curves were above 0.99 for secoisolariciresinol, 2-[(4-hydroxy-3-methoxyphenyl)methyl]-3-[(3-hydroxyphenyl)methyl]-1,4-butanediol, ED, EL, ED-S, and EL-S, indicating satisfactory relationships between the peak areas and concentrations in the quantification range. The relative concentrations of ED-glucuronide and EL-glucuronide (EL-G) in different biofluids were compared based on their chromatogram peak areas. The sheep plasma contained all forms of mammalian lignans (i.e., ED, EL, ED-S, EL-S, ED-glucuronide, and EL-G.); the urine contained ED, EL, ED-S, and EL-S; and the milk contained ED, EL, ED-S, EL-S, and EL-G. Milk-to-plasma concentration ratios of the mammalian lignans indicated that the free forms were more permeable than the sulfated conjugates. Mammalian lignans found in sheep plasma and milk may provide health benefits to the sheep and sheep-product consumers. The analytical method established in this work could be used to quantify mammalian lignans in livestock products.

18.
Nanoscale ; 12(45): 23084-23091, 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33180082

RESUMO

Numerous types of diseases cause serious anemia, which is characterized by a significantly decreased number of circulating red blood cells. The key reason is retarded terminal erythroid differentiation, which is largely involved in the downregulation of intracellular reactive oxygen species (ROS) and insufficient iron uptake. Prussian blue nanoparticles (PBNPs) have been demonstrated to be capable of scavenging ROS via multienzyme-like activity and contain the iron element. The aim of this study was to figure out whether PBNPs can induce terminal erythroid differentiation in myeloid leukemia cells K562 and to investigate the underlying mechanisms. Our results showed that PBNPs were taken up by K562 cells, which reduced the intracellular ROS level in the cells, upregulated the late erythroid surface marker GYPA (CD235a) and downregulated the early erythroid surface marker TFRC (CD71), clearly indicating the occurrence of terminal erythroid differentiation. In addition, the cells became smaller in size after incubation with PBNPs, providing strong side evidence that the cells had undergone terminal differentiation. Mechanistic studies indicated that PBNP-induced terminal differentiation was associated with the upregulation of the nuclear transcriptional factor NFE2 and downregulation of GATA1, both of which are closely related to the variation of intracellular ROS levels. In conclusion, PBNPs demonstrated a novel function by effectively inducing terminal erythroid differentiation in myeloid leukemia cells, which is of great significance in improving the blood profiles of anemia patients.

19.
BMC Cancer ; 20(1): 1051, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131491

RESUMO

BACKGROUND: A higher vitamin D intake improves the prognosis of early stage breast cancer (BC) patients. We hypothesized that vitamin D intake should refer to vitamin D receptor (VDR) expression. In order to prove this hypothesis, we first intend to evaluate the correlation between VDR expression and prognosis of BC patients using meta-analysis. METHODS: Literatures from PubMed, Embase, and the Cochrane Library (last update by May 20, 2020) were retrieved to find studies assessing the prognostic role of VDR in BC. The hazard ratios (HRs) for patients' survival were extracted for pooled analyses. Subgroup analysis, sensitivity analysis and meta-regression were performed to explore the sources of heterogeneity. RESULTS: Seven articles containing eight studies with 2503 patients were enrolled. The results from the pooled analyses showed that the VDR expression generally had no relationship with BC patients' overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), and progression-free survival (PFS) (P > 0.05). Because only the number of studies exploring the relationship between VDR expression and OS is greater than five and there is heterogeneity, we explored the sources of heterogeneity of these studies. Subgroup analyses showed that the VDR expression in the nucleus had no relationship with OS, but high total VDR expression in the nucleus and cytoplasm was related to a better OS (pooled HR = 0.41; 95% CI = 0.18-0.95; P = 0.038). In addition, in subgroup of studies using cut-off values other than 'immunoreactive score (IRS)>5' and 'IRS > 25', high VDR expression was associated with a better OS (pooled HR = 0.47; 95% CI = 0.30-0.74; P = 0.001). Sensitivity analysis showed that the result pattern was not obviously affected by any single study. Meta-regression showed that the source of heterogeneity was not country (P = 0.657), pathological type (P = 0.614), molecular type (P = 0.423), staining location (P = 0.481), or cut-off value (P = 0.509). CONCLUSIONS: The protein expression level of VDR in entire BC cells evaluated by immunohistochemistry is related to the OS of BC patients. It is expected that a more individualized vitamin D intake and a more accurate prognosis assessment can be recommended for BC patients based on the VDR expression. Of course, more preclinical and clinical studies are needed.

20.
Eur J Nutr ; 2020 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-33225399

RESUMO

PURPOSE: Irritable bowel syndrome (IBS) is a functional bowel disorder. This study aimed to assess the effect of a probiotic product (containing Lactobacillus casei Zhang, Lactobacillus plantarum P-8, and Bifdobacterium animalis subsp. lactis V9) as an adjunct to a routine regimen in IBS management. METHODS: Forty-five patients with IBS were randomized into the probiotic (n = 24) and control (n = 21) groups, receiving the routine regimen with or without probiotics for 28 days, respectively. Serum and fecal samples were collected and analyzed. RESULTS: The IBS-symptom severity score (P < 0.01), serum levels of IL-6 (P < 0.01) and TNF-α (P < 0.001) were significantly lower in the probiotic group than the control group at day 28. The probiotic adjunctive treatment resulted in significant decreases in some bacterial genera that worsen IBS, such as Bacteroides (P < 0.01), Escherichia (P < 0.05), and Citrobacter (P < 0.05), significant decreases were also observed in some beneficial genera in the control group, including Bifidobacterium (P < 0.05), Eubacterium (P < 0.05), Dorea (P < 0.01), and Butyricicoccus (P < 0.05). Furthermore, significant correlations were found between some monitored parameters and compositional changes in the fecal microbiota, suggesting that the clinical improvement of IBS was likely associated with gut microbiota modulation. The enterotype analysis revealed that the initial fecal microbiota composition could influence clinical outcomes. CONCLUSIONS: The adjunctive use of probiotics with a routine regimen showed additional clinical effectiveness compared to the routine regimen alone in managing IBS. A pretreatment gut microbiome analysis might help tailor a personalized probiotic regimen to optimize treatment effects.

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