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The objectives of this study were to evaluate the difference of selective attention efficiency between children with low and high socioeconomic status (SES) and the promotional effect of attention network training (an attention network test was used as the training task) on selective attention in children with the low SES. A total of 139 10- to 12-year-old children participated in two experiments (71 in Experiment 1 and 68 in Experiment 2). The results suggest that selective attention and switch ability of children with high SES are better than those of children with low SES. After attention network training, selective attention, switch ability, and working memory of low-SES children improved significantly. The findings provide evidence that attention network training could enhance selective attention in low-SES children and that the beneficial training effect could also transfer to switch ability and working memory. The research may provide a promising method to compensate cognitive delay of low-SES children.
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Estatus Socioeconómico Bajo , Clase Social , Niño , Humanos , Memoria a Corto Plazo , Electroencefalografía , AtenciónRESUMEN
BACKGROUND: Pepsinogen C (PGC) is expressed in chief cells, fundic mucous neck cells, and pyloric gland cells of gastric epithelium and also in breast, prostate, lung, and seminal vesicles. METHODS: We explored the clinicopathological and prognostic significances of PGC mRNA using pathological and bioinformatics analyses. We generated PGC knockout and PGC-cre transgenic mice to observe the effects of PGC deletion and PTEN abrogation in PGC-positive cells on gastric carcinogenesis. Finally, we observed the effects of altered PGC expression on aggressive phenotypes by CCK8, Annexin V staining, wound healing and transwell assays and analyzed the partner proteins of PGC using co-IP (co-immunoprecipitation) and double fluorescence staining. RESULTS: PGC mRNA level was inversely correlated with the T and G stage and a short survival of gastric cancer (p < 0.05). PGC protein expression was negatively linked to lymph node metastasis, dedifferentiation, and low Her-2 expression of gastric cancer (p < 0.05). No difference in body weight or length was evident between wild-type (WT) and PGC knockout (KO) mice (p > 0.05), but PGC KO mice had a shorter survival than WT mice (p < 0.05). No gastric lesions were observed in the mucosa of the granular stomach in PGC KO mice, which displayed lower frequency and severity of gastric lesion than in WT mice after treated with MNU. Transgenic PGC-cre mice showed high cre expression and activity in the lung, stomach, kidney, and breast. Gastric cancer and triple-negative lobular breast adenocarcinoma were found in PGC-cre/PTENf/f mice with two previous pregnancies and breast feeding, but breast cancer was not seen in transgenic mice exposed to either estrogen or progesterone, or those with two previous pregnancies and no breast feeding. PGC suppressed proliferation, migration, invasion, and induced apoptosis, and interacted with CCNT1, CNDP2 and CTSB. CONCLUSION: PGC downregulation was seen in gastric cancer, but PGC deletion resulted in resistance to chemically-induced gastric carcinogenesis. PGC expression suppressed the proliferation and invasion of gastric cancer cells possibly by interacting with CCNT1, CNDP2 and CTSB. Spontaneous triple-negative lobular adenocarcinoma and gastric cancer were seen in PGC-cre/PTENf/f mice, and the breast carcinogenesis was closely linked to pregnancy and breast feeding, but not to single exposure to estrogen or progesterone, or pregnancy. Limiting either pregnancy or breast feeding might help to prevent hereditary breast cancer.
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Adenocarcinoma , Neoplasias Gástricas , Masculino , Embarazo , Femenino , Ratones , Animales , Neoplasias Gástricas/patología , Pepsinógeno C/genética , Pepsinógeno C/metabolismo , Progesterona , Carcinogénesis/genética , Carcinogénesis/patología , Mucosa Gástrica/patología , Ratones Transgénicos , Ratones Noqueados , Adenocarcinoma/patología , Estrógenos , ARN Mensajero , TransgenesRESUMEN
Excitability is a pivotal quality in guide dogs because moderately active dogs are more trainable. Excessive activity is associated with behavioral problems and pet surrender. Excitability is a highly heritable trait, yet the relevant genetic factors and markers associated with this condition are poorly characterized. In the present study, we selected six single nucleotide polymorphisms (SNPs) of two genes that are possibly related to excitability in dogs (TH c.264G > A, TH c.1208A > T, TH c.415C > G, TH c.168C > T, TH c.180C > T and MAOB c.199 T > C). We measured the excitability of dogs using seven variables from three behavioral tests: the play test (interest in play, grabbing in throw and tug-of-war), the chase test (following and forward grabbing) and the passive test (moving range and moving time). These behavioral tests are part of the Dog Mentality Assessment developed by Svartberg & Forkman. The activity scores in the guide dog group were higher than in the temperament withdrawal group, and significant differences were detected in the aggregate score (p = 0.02), passive activity score (p = 0.007) and moving range score (p = 0.04). Analysis using the Kruskal-Wallis test and non-parametric Steel-Dwass test to evaluate the relationship between these SNPs and behavioral variable scores revealed that TH c.264G > A was associated with aggregate scores of excitability-related behavioral variables (adj. p = 0.03), object-interaction activity scores (adj. p = 0.03), following scores (adj. p = 0.03) and forward grabbing scores (adj. p = 0.03) in Labrador dogs and MAOB c.199 T > C was associated with moving range scores in these dogs (adj. p = 0.004). However, these results had low power. To explain the behavioral traits, further genetic studies more reliable than candidate gene studies are needed.
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Polimorfismo de Nucleótido Simple , Perros , Animales , FenotipoRESUMEN
Five unknown labdane diterpenoids Stevelins A-E (1-5), three known labdane diterpenoids (6-8) and three labdane norditerpenoids (9-11) were isolated from the Stevia rebaudiana. The structures were determined primarily via NMR spectroscopic data and HR-ESI-MS experiments. X-ray crystallography using CuKα radiation was used to determine the absolute configurations of 1, and the absolute configurations of 2-5 were deduced by electronic circular dichroism (ECD) calculations. The potential anti-atherosclerosis activities of all compounds were evaluated by measuring their inhibitory effects on the macrophage foam cell formation. As a result, most isolated compounds could significantly inhibit oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation, which suggests that these compounds may be promising candidates in the treatment for atherosclerosis.
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Diterpenos , Stevia , Estructura Molecular , Diterpenos/farmacología , Diterpenos/química , Espectroscopía de Resonancia Magnética , Dicroismo CircularRESUMEN
Callicarpnoids A-C (1-3), three new ent-clerodane diterpenoid dimers formed via a [4 + 2] hetero Diels-Alder cycloaddition, appeared as a third example of this type of dimers, were isolated from the stems of Callicarpa arborea Roxb.. Their structures were elucidated by comprehensive spectroscopic analysis, and the absolute configurations were confirmed by single-crystal X-ray diffraction and electronic circular dichroism (ECD) calculations, as well as DP4 + analysis. Cytotoxicity test in two cell lines indicated that compounds 2 and 3 had significant cytotoxic effect against breast cancer cell (MCF-7) and colorectal cancer cell (HCT-116) with IC50 ranging from 5.2 to 7.2 µM, comparable to those of the positive control. Furthermore, the western blot analysis revealed that the protein expression levels of Bax were increased following compounds 2 and 3 treatment, whereas the expression levels of caspase 8, caspase 3, caspase 9 and Bcl2 were decreased in a dose-dependent manner, indicating that compounds 2 and 3 may induce apoptosis via both intrinsic and extrinsic pathways in MCF-7 and HCT-116 cells.
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Callicarpa , Diterpenos de Tipo Clerodano , Humanos , Diterpenos de Tipo Clerodano/farmacología , Células MCF-7 , Células HCT116 , Apoptosis , Estructura MolecularRESUMEN
Exploration of lead compounds against Parkinson's disease (PD), a neurodegenerative disease, is of great important. Dioscin, a bioactive natural product, shows various pharmacological effects. However, the activities and mechanisms of dioscin against PD have not been well investigated. In this study, the tests on 6-hydroxydopamine (6-OHDA)-induced PC12 cells and rats were carried out. The results showed that dioscin dramatically improved cell viability, decreased reactive oxygen species (ROS) levels, improved motor behavior and tyrosine hydroxylase(TH) levels and restored the levels of glutathione (GSH) and malondialdehyde (MDA) in rats. Mechanism investigation showed that dioscin not only markedly increased the expression level of dual- specificity phosphatase 6 (DUSP6) by 1.87-fold in cells and 2.56-fold in rats, and decreased phospho-extracellular regulated protein kinases (p-ERK) level by 2.12-fold in cells and 2.34-fold in rats, but also increased the levels of nuclear factor erythroid2-related factor 2 (Nrf2), hemeoxygenase-1 (HO-1), superoxide dismutase (SOD) and decreased the levels of kelch-1ike ECH-associated protein l (Keap1) in vitro and in vivo. Furthermore, DUSP6 siRNA transfection experiment in PC12 cells validated the protective effects of dioscin against PD via regulating DUSP6 to adjust the Keap1/Nrf2 pathway. Our data supported that dioscin has protection against PD in regulating oxidative stress via DUSP6 signal, which should be considered as an efficient candidate for the treatment of PD in the future.
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Diosgenina , Fosfatasa 6 de Especificidad Dual , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Diosgenina/análogos & derivados , Diosgenina/farmacología , Fosfatasa 6 de Especificidad Dual/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo , Oxidopamina/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , RatasRESUMEN
As one classic anticancer drug, clinical application of Doxorubicin (Dox) is limited due to its side effects. In our previous work, we have investigated the drug targets to treat Dox-induced cardiotoxicity, hepatotoxicity and nephrotoxicity. In this paper, the mechanisms and new drug-target associated with Dox-induced hepatotoxicity were explored. The results showed that Dox markedly inhibited cell viability and cellular respiration, induced cell morphologic change and increased ROS level. Moreover, Dox increased ALT and AST levels, caused pathological damage, increased MDA level and decreased SOD level in mice. Mechanism investigation showed that Dox markedly up-regulated the expression level of miR-128-3p, down-regulated Sirt1 expression level and affected the protein levels of Nrf2, Keap1, Sirt3, NQO1 and HO-1 to cause oxidative stress in liver. Furthermore, double-luciferase reporter assay, and co-transfection test showed that miR-128-3p directly targeted Sirt1. In addition, miR-128-3p mimics in AML-12 cells enhanced Dox-induced oxidative damage via inhibiting cellular respiration, increasing ROS level and mitochondrial superoxide formation. The protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1 in miR-128-3p mimic + Dox group were decreased compared with Dox group. Transfection of miR-128-3p inhibitor weakened Dox-induced oxidative damage via increasing cellular respiration, suppressing cellular ROS level and mitochondrial superoxide formation. The protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1 in miR-128-3p inhibitor + Dox group were increased compared with Dox group. In mice, Dox-induced liver damage was deteriorated by miR-128-3p agomir via increasing the levels of ALT, AST, MDA, and down-regulating the protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1. While, miR-128-3p antagomir alleviated liver injury via decreasing the levels of ALT, AST, MDA, and up-regulating the protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1. Our data showed that miRNA-128-3p aggravated Dox-induced liver injury by promoting oxidative stress via targeting Sirt1, which should be considered as one new drug target to treat Dox-induced liver injury.
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Antibióticos Antineoplásicos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Doxorrubicina/efectos adversos , MicroARNs , Estrés Oxidativo/efectos de los fármacos , Sirtuina 1/metabolismo , Animales , Línea Celular , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Sirtuina 1/genéticaRESUMEN
Inflammatory reaction and cell apoptosis are two important processes in intestinal ischemia/reperfusion (II/R) injury, and exploration of effective lead compounds against II/R injury via regulating inflammation and apoptosis is critical important. In this paper, the results indicated that dioscin significantly increased cell viability, and inhibited inflammation and apoptosis caused by hypoxia-reoxygenation (H/R) injury in IEC-6 cells. in vivo II/R injury, dioscin markedly suppressed inflamma- tion and apoptosis, improved pathological changes, and depressed chiu' score in rats. Mechanistic studies indicated that dioscin notably up-regulated the expression level of MAPK13 through decreasing miR-351-5p level, and thereby decreased the expression levels of p-PKD1, NF-κB, Apaf-1, cleaved Caspase-3 and cleaved Caspase-9. Furthermore, miR-351-5p mimic and inhibitor experiments in IEC-6 cells further proved that dioscin up-regulated MAPK13 expression by decreasing miR-351-5p level to inhibit inflammation and apoptosis. Therefore, dioscin showed protective effect against II/R injury via adjusting miR-351-5/MAPK13-mediated inflammation and apoptosis. Dioscin should be considered as one potent candidate and miR-351-5/ MAPK13 should be one effective drug target for the treatment of II/R injury.
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Antiinflamatorios/uso terapéutico , Diosgenina/análogos & derivados , Sustancias Protectoras/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Línea Celular , Diosgenina/farmacología , Diosgenina/uso terapéutico , Mucosa Intestinal/metabolismo , Masculino , MicroARNs/metabolismo , Proteína Quinasa 13 Activada por Mitógenos/metabolismo , Sustancias Protectoras/farmacología , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismoRESUMEN
Trichinella spiralis (T.spiralis) muscle-larva (ML) excretory-secretory proteins (ESPs) contain antitumour-active substances. ESPs have been shown to inhibit tumour growth. To explore the effects of these proteins on small cell lung cancer cells and the possible mechanisms of their antineoplastic action, H446 SCLC cells were co-cultured with different concentrations of T. spiralis ML ESPs for 12, 24 and 48 h. Our results showed that T. spiralis ML ESPs significantly inhibited H446 cell proliferation, which was dose-and time-dependent. The results of flow cytometry testing indicate a clear apoptosis trend in H446 cells co-cultured with ESPs for 24 h. Reverse transcription polymerase chain reaction and Western blotting results showed increased expression of pro-apoptosis genes Bax, Cyt-C, Apaf-1, caspase-9 and caspase-3, compared with the negative control group, and decreased the expression of anti-apoptosis genes Bcl-2 and Livin. Our results suggest that T. spiralis ML ESPs can induce apoptosis in H446 cells through a mitochondrial pathway, which may be a mechanism of antineoplastic action in T. spiralis ML ESPs.
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Antígenos Helmínticos/fisiología , Apoptosis/fisiología , Proteínas del Helminto/fisiología , Neoplasias Pulmonares/patología , Mitocondrias/patología , Carcinoma Pulmonar de Células Pequeñas/patología , Trichinella spiralis/fisiología , Animales , Antígenos Helmínticos/inmunología , Proliferación Celular , Proteínas del Helminto/inmunología , Larva , Ratones , Músculos/parasitología , ARN Mensajero/metabolismo , Trichinella spiralis/genética , Células Tumorales CultivadasRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Yiqitongmai decoction (YQTMD), a classic TCM, has been widely used in clinical treatment for MI. However, it is still difficult to clarify the potential active compounds and pharmacological mechanisms of it in treating MI. AIM OF THE STUDY: To explore the active ingredients, pharmacological effects, potential targets and mechanisms of YQTMD against MI. MATERIALS AND METHODS: Serum pharmacochemistry by UPLC-MS/MS was applied to analyze the phytochemical components in serum from YQTMD. These components were then used to predict the potential targets using network pharmacology approach and molecular dynamics simulations, and then the protective effect of them on H9c2 cells following hypoxic conditions was assessed. Afterwards, the pharmacological effects of YQTMD on MI in mice were tested by determining electrocardiogram (ECG), echocardiography, cardiac biomarkers, oxidative stress, inflammation and pathophysiological changes. The protein levels involving STAT3 signal were detected using Western blot and immunofluorescence assays. Furthermore, STAT3 inhibitor Sttatic was employed to further elucidate the underlying mechanisms. RESULTS: Totally, 26 compounds derived from YQTMD were identified in mice serum, and 201 genes associated with the compounds were collected. The compounds including safflomin A, ferulic acid, gypenoside XVII, ginsenoside Rg1 and glycyrrhizic acid were identified as the critical compounds of YQTMD to regulate STAT3 pathway. In vitro, compounds combination significantly enhanced the viability of H9c2 cells and reduced ROS level compared to model cells. The in vivo results showed that YQTMD effectively reduced myocardial injury, as evidenced by the decreased serum cardiac injury markers, reduction in the size of myocardial infarct, restoration of abnormal alterations in ECG and decrease in cardiomyocyte apoptosis. Additionally, YQTMD attenuated MI-induced cardiac dysfunction, alleviated pathological changes, reduced MDA levels, and enhanced SOD and GSH levels compared with model mice. Significantly, the levels of IL-6, IL-1ß, and TNF-α were observed to decrease in the YQTMD group. The expression levels of key proteins (p-STAT3, HIF-1α, NOX2, TLR5 and Caspase3) in STAT3 pathway were also regulated by YQTMD. However, the cardioprotective effects of YQTMD on MI were attenuated by STAT3 inhibitor Sttatic. CONCLUSIONS: This study investigated the active ingredients and potential mechanisms of YQTMD for MI treatment based on serum pharmacochemistry and network pharmacology approaches, revealing that YQTMD exerts its therapeutic effects on MI by alleviating oxidative stress, inflammation and apoptosis through adjusting STAT3 signaling pathway.
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Medicamentos Herbarios Chinos , Infarto del Miocardio , Farmacología en Red , Animales , Medicamentos Herbarios Chinos/farmacología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Masculino , Ratones , Línea Celular , Estrés Oxidativo/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Ratas , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Espectrometría de Masas en Tándem , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismoRESUMEN
Inflammatory bowel disease (IBD) is a serious disorder, and exploration of active compounds to treat it is necessary. An acidic polysaccharide named SUSP-4 was purified from Selaginella uncinata (Desv.) Spring, which contained galacturonic acid, galactose, xylose, arabinose, and rhamnose with the main chain structure of â4)-α-d-GalAp-(1â and â6)-ß-d-Galp-(1â and the branched structure of â5)-α-l-Araf-(1â . Animal experiments showed that compared with Model group, SUSP-4 significantly improved body weight status, disease activity index (DAI), colonic shortening, and histopathological damage, and elevated occludin and zonula occludens protein 1 (ZO-1) expression in mice induced by dextran sulfate sodium salt (DSS). 16S ribosomal RNA (rRNA) sequencing indicated that SUSP-4 markedly downregulated the level of Akkermansia and Alistipes. Metabolomics results confirmed that SUSP-4 obviously elevated thiamine levels compared with Model mice by adjusting thiamine metabolism, which was further confirmed by a targeted metabolism study. Fecal transplantation experiments showed that SUSP-4 exerted an anti-IBD effect by altering the intestinal flora in mice. A mechanistic study showed that SUSP-4 markedly inhibited macrophage activation by decreasing the levels of phospho-nuclear factor kappa-B (p-NF-κB) and cyclooxygenase-2 (COX-2) and elevating NF-E2-related factor 2 (Nrf2) levels compared with Model group. In conclusion, SUSP-4 affected thiamine metabolism by regulating Akkermania and inhibited macrophage activation to adjust NF-κB/Nrf2/COX-2-mediated inflammation and oxidative stress against IBD. This is the first time that plant polysaccharides have been shown to affect thiamine metabolism against IBD, showing great potential for in-depth research and development applications.
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Triple-negative breast cancer (TNBC) poses a serious threat to women's life and health due to its high malignancy, strong invasiveness, and propensity for early recurrence and metastasis. Therefore, there is an urgent need to develop a highly effective and low-toxic TNBC treatment scheme to enhance the anti-cancer efficacy and prolong the survival of patients. In this work, we designed and synthesized a chemodynamic therapy (CDT) agent (HA-Fc-Mal). The chemo/chemodynamic (CT/CDT) nanoparticle (HCM@DOX) based on hyaluronic acid induces ferroptosis and apoptotic for TNBC therapy was constructed via self-assembled of HA-Fc-Mal and doxorubicin (DOX). HCM@DOX orderly realized the TNBC targeting, controlled DOX release, GSH depletion and induce ROS erupt. In vivo and in vitro experiments confirmed that HCM@DOX inhibited the growth of 4 T1 tumors through ferroptosis and apoptosis, and the tumor inhibition rate was as high as 81.87 %. In addition, HCM@DOX significantly inhibited lung metastasis and exhibited excellent biosafety. Overall, our findings offer a new strategy for TNBC therapy using a CT/CDT nanoparticle that induces ferroptosis and apoptosis.
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Ferroptosis , Nanopartículas , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Ácido Hialurónico/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Apoptosis , Línea Celular TumoralRESUMEN
Long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). However, their biological roles and function mechanisms in NAFLD remain largely unknown. In this study, we found that Gm28382 may be a potential pathogenic lncRNA of NAFLD and highly expressed in NAFLD through RNA-seq. Overexpression of Gm28382 significantly enhanced the lipid accumulation in AML12 cells, whereas Gm28382 silencing reduced lipogenesis both in palmitic acid (PA)-induced AML12 cells and high fat diet (HFD)-induced mice. Then, bioinformatics were employed to speculate the potential interacting genes of Gm28382, and found that Gm28382 may regulate ChREBP expression through binding with miR-326-3p. Fluorescence in situ hybridization (FISH), dual luciferase reporter assay, immunofluorescence RNA pull-down and RNA immunoprecipitation (RIP) assays were used to validate the binding and targeting relationship of these genes, and we confirmed that Gm28382 competitively binds to miR-326-3p to increase ChREBP expression as a ceRNA. Mechanistically, overexpression of Gm28382 upregulated the ChREBP-mediated lipid synthesis signaling pathway, but the function was sabotaged by miR-326-3p deletion or ChREBP overexpression. Furthermore, in PA-challenged AML12 cells or HFD-induced mice, silencing of Gm28382 reversed the aberrant ChREBP signaling pathway and lipid accumulation, whereas ChREBP overexpression or liver-specific silencing of miR-326-3p blocked this function of Gm28382. Collectively, these findings reveal a critical role of Gm28382 in the promotion of lipogenesis in NAFLD by regulating the ChREBP signaling pathway through interaction with miR-326-3p, which could serve as a potential therapeutic target for NAFLD treatment.
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MicroARNs , Enfermedad del Hígado Graso no Alcohólico , ARN Largo no Codificante , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Lipogénesis/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Hibridación Fluorescente in Situ , Transducción de Señal/genética , Factores de Transcripción/genética , LípidosRESUMEN
Plumbago zeylanica L., a traditional Chinese medicine, has anti-bacterial and anti-inflammatory effects, and it is critical important to explore the chemical compounds and evaluate their biological actions from the medicinal plant. However, the chemical structure and biological activities of polysaccharides from P. zeylanica. were still poorly understood. In this study, two water-soluble polysaccharides named WPZP-2-1 and WPZP-2-2 were purified from P. zeylanica L. Chemical and spectroscopic tests showed that the main chain of WPZP-2-1 was â4)-α-D-GalpA-(1 â 2)-α-L-Rhap-(1â, and the branch chain was galactose or arabinose. The main chain of WPZP-2-2 was composed of â4)-α-D-GalpA-(1 â 2)-α-L-Rhap-(1â, and the O-2 and O-3 of â4)-α-D-GalpA had a small amount of acetylation. In addition, in vitro test showed that WPZP-2-1 and WPZP-2-2 significantly improved the inflammatory damage of LPS + IFN-γ-induced THP-1 cells via reducing the protein levels of CD14, TLR4 and MyD88, thereby promoting IL-10 expression and inhibiting the mRNA levels of TNF-α and IL-1ß. Those findings indicated that WPZP-2-1 and WPZP-2-2 from the plant should be served as the potential anti-inflammatory agents.
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Plantas Medicinales , Plumbaginaceae , Plumbaginaceae/química , Polisacáridos/química , Antiinflamatorios/farmacología , Extractos Vegetales/químicaRESUMEN
Intestinal ischemia reperfusion injury (II/R injury) is a common and intractable pathophysiological process in critical patients, for which exploring new treatments and mechanisms is of great importance to improve treatment outcomes. Apigenin-7-O-Glucoside (AGL) is a sugar derivative of apigenin natural product with various pharmacological activities to protect against intestinal diseases. In this study, we synthesized two amphiphilic molecules, namely DTPA-N10-10 and mPEG-TK-DA, which can scavenge free radicals and reactive oxygen species (ROS). They were successfully encapsulated AGL through self-assembly, resulting in the formation of multi-site ROS scavenging nanoparticles called PDN@AGL. In vitro and in vivo experiments demonstrated that PDN@AGL could protect intestinal tissues by reducing lipid peroxidation, lowering ROS levels and inhibiting ferroptosis during II/R injury. Furthermore, our study revealed, for the first time, that the regulation of the ATF3/SLC7A11 pathway by PDN@AGL may play a crucial role in mitigating II/R injury. In conclusion, our study confirmed the beneficial effects of PDN@AGL in combating II/R injury through the ATF3/SLC7A11-mediated regulation of ferroptosis and oxidative stress. These findings lay the groundwork for the potential application of PDN@AGL in the treatment of II/R injury.
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Factor de Transcripción Activador 3 , Sistema de Transporte de Aminoácidos y+ , Apigenina , Ferroptosis , Intestinos , Nanopartículas , Daño por Reperfusión , Humanos , Apigenina/administración & dosificación , Apigenina/farmacología , Especies Reactivas de Oxígeno , Daño por Reperfusión/tratamiento farmacológico , Intestinos/irrigación sanguíneaRESUMEN
The synergistic effect of apoptosis and cuproptosis, along with the activation of the immune system, presents a promising approach to enhance the efficacy against triple-negative breast cancer (TNBC). Here, two prodrugs are synthesized: a reactive oxygen species (ROS)-responsive prodrug PEG-TK-DOX and a glutathione (GSH)-responsive prodrug PEG-DTPA-SS-CPT. These prodrugs are self-assembled and chelated Cu2+ to prepare nanoparticle PCD@Cu that simultaneously loaded doxorubicin (DOX), camptothecin (CPT), and Cu2+. The elevated levels of ROS and GSH in TNBC cells disrupted the PCD@Cu structure, leading to the release of Cu+, DOX, and CPT and the depletion of GSH. DOX and CPT triggered apoptosis with immunogenic cell death (ICD) in TNBC cells. Simultaneously, PCD@Cu downregulated the expression of copper transporting ATPase 2 (ATP7B), causing a significant accumulation of copper ions in TNBC cells. This further induced the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and downregulation of iron-sulfur (Fe-S) cluster proteins, ultimately leading to cuproptosis and ICD in TNBC. In vitro and in vivo experiments confirmed that PCD@Cu induced apoptosis and cuproptosis in TNBC and activated the immune system, demonstrating strong anti-tumor capabilities. Moreover, PCD@Cu exhibited an excellent biosafety profile. Overall, this study provides a promising strategy for effective TNBC therapy.
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Three new diterpenoids, named nematocynine A-C (1-3), together with twelve known compounds (4-15) were isolated from the aerial part of Euphorbia nematocypha Hand.-Mazz (Hereinafter referred to E. nematocypha). Their structures were elucidated by detailed spectroscopic analysis and comparison with literature data. In addition, all the compounds were tested for their anti-candida albicans activities used alone or in combination with fluconazole against sensitive strain and resistant strain in vitro. Wherein only compound 11 shows weak activity against candida albicans resistant strain (MIC50 = 128.15 µg/mL) when used alone. Compounds 1, 4, 7, 8, 9, 10, 12, 13 and 15 in combination with fluconazole showed potent anti-fungal activities (MIC50 = 15 ± 5 µg/mL, FICI = 0.05 ± 0.04) against the Candida albicans resistant strain SC5314-FR. The synergistic effects were weaker against the Candida albicans resistant strain SC5314-FR when the compounds 2, 3, 5 and 14 were combined with fluconazole (FICI = 0.16 ± 0.06).
Asunto(s)
Diterpenos , Euphorbia , Fluconazol/farmacología , Euphorbia/química , Candida albicans , Diterpenos/farmacología , Antifúngicos/farmacología , Pruebas de Sensibilidad Microbiana , Farmacorresistencia FúngicaRESUMEN
Leaf photosynthetic pigments play a crucial role in evaluating nutritional elements and physiological states. In facility agriculture, it is vital to rapidly and accurately obtain the pigment content and distribution of leaves to ensure precise water and fertilizer management. In our research, we utilized chlorophyll a (Chla), chlorophyll b (Chlb), total chlorophylls (Chls) and total carotenoids (Cars) as indicators to study the variations in the leaf positions of Lycopersicon esculentum Mill. Under 10 nitrogen concentration applications, a total of 2610 leaves (435 samples) were collected using visible-near infrared hyperspectral imaging (VNIR-HSI). In this study, a "coarse-fine" screening strategy was proposed using competitive adaptive reweighted sampling (CARS) and the iteratively retained informative variable (IRIV) algorithm to extract the characteristic wavelengths. Finally, simultaneous and quantitative models were established using partial least squares regression (PLSR). The CARS-IRIV-PLSR was used to create models to achieve a better prediction effect. The coefficient determination (R2), root mean square error (RMSE) and ratio performance deviation (RPD) were predicted to be 0.8240, 1.43 and 2.38 for Chla; 0.8391, 0.53 and 2.49 for Chlb; 0.7899, 2.24 and 2.18 for Chls; and 0.7577, 0.27 and 2.03 for Cars, respectively. The combination of these models with the pseudo-color image allowed for a visual inversion of the content and distribution of the pigment. These findings have important implications for guiding pigment distribution, nutrient diagnosis and fertilization decisions in plant growth management.
RESUMEN
It is necessary to explore potent therapeutic agents via regulating gut microbiota and metabolism to combat Parkinson's disease (PD). Dioscin, a bioactive steroidal saponin, shows various activities. However, its effects and mechanisms against PD are limited. In this study, dioscin dramatically alleviated neuroinflammation and oxidative stress, and restored the disorders of mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 16 S rDNA sequencing assay demonstrated that dioscin reversed MPTP-induced gut dysbiosis to decrease Firmicutes-to-Bacteroidetes ratio and the abundances of Enterococcus, Streptococcus, Bacteroides and Lactobacillus genera, which further inhibited bile salt hydrolase (BSH) activity and blocked bile acid (BA) deconjugation. Fecal microbiome transplantation test showed that the anti-PD effect of dioscin was gut microbiota-dependent. In addition, non-targeted fecal metabolomics assays revealed many differential metabolites in adjusting steroid biosynthesis and primary bile acid biosynthesis. Moreover, targeted bile acid metabolomics assay indicated that dioscin increased the levels of ursodeoxycholic acid, tauroursodeoxycholic acid, taurodeoxycholic acid and ß-muricholic acid in feces and serum. In addition, ursodeoxycholic acid administration markedly improved the protective effects of dioscin against PD in mice. Mechanistic test indicated that dioscin significantly up-regulated the levels of takeda G protein-coupled receptor 5 (TGR5), glucagon-like peptide-1 receptor (GLP-1R), GLP-1, superoxide dismutase (SOD), and down-regulated NADPH oxidases 2 (NOX2) and nuclear factor-kappaB (NF-κB) levels. Our data indicated that dioscin ameliorated PD phenotype by restoring gut dysbiosis and regulating bile acid-mediated oxidative stress and neuroinflammation via targeting GLP-1 signal in MPTP-induced PD mice, suggesting that the compound should be considered as a prebiotic agent to treat PD in the future.