Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31.800
Filtrar
1.
Zhongguo Zhong Yao Za Zhi ; 46(3): 520-525, 2021 Feb.
Artículo en Chino | MEDLINE | ID: mdl-33645015

RESUMEN

Shouhui Tongbian Capsules was used to explore the therapeutic effect and potential mechanism on slow transit constipation model mice induced by loperamide hydrochloride. In the experiment, loperamide hydrochloride-induced ICR mice were used as the model of slow transit constipation. Fifty ICR mice were divided into the blank group, model group and high, medium and low dose groups of Shouhui Tongbian Capsules extract(100, 200 and 400 mg·kg~(-1)). The model group and the administration groups were then modeled using loperamide hydrochloride intragastrically to obtain slow transit constipation. After successful modeling, high, medium and low doses of drugs were given to each drug group by intragastric administration. After 14 days of administration, the first defecation time, 6 h defecation grain number, 6 h defecation wet weight and dry weight, black feces discharged within 6 h and the fecal water content were measured. Intestinal tissues were taken for c-Kit and SCF immunohistochemical sections to detect the expression of c-Kit and SCF in the blank group, model group and high, medium and low dose groups of the medicinal extract of Shouhui Tongbian Capsules. The tissue changes in the intestinal wall of mice were detected by HE staining. At the same time, partial intestinal tissues were taken to test the activity of ATP synthase and isocitrate dehydrogenase in intestinal tissues of mice. RESULTS:: showed that Shouhui Tongbian Capsules effectively improved the symptoms of slow transit constipation in ICR mice and promoted intestinal movement. Shouhui Tongbian Capsules obviously shortened the time of discharging black stool for the first time, improved the intestinal propulsion rate, increased the water content and amount of feces, and improved the constipation symptoms. Mechanism study revealed that Shouhui Tongbian Capsules increased ATP synthase activity and mitochondrial isocitrate dehydrogenase activity in intestinal tissue, and up-regulated c-Kit/SCF signaling pathway to promote interstitial Cajal cells proliferation, intestinal nerve transmission, intestinal motility and transport capacity.


Asunto(s)
Estreñimiento , Tránsito Gastrointestinal , Animales , Cápsulas , Estreñimiento/tratamiento farmacológico , Loperamida , Ratones , Ratones Endogámicos ICR
2.
Zhongguo Zhong Yao Za Zhi ; 46(3): 532-538, 2021 Feb.
Artículo en Chino | MEDLINE | ID: mdl-33645017

RESUMEN

The effect of Shouhui Tongbian Capsules(SHTB) on the endogenous metabolites of colon tissue in mice with slow transit constipation was analyzed by metabolomics methods to explore its mechanism in the treatment of constipation. ICR mice were randomly divided into normal group, model group and SHTB group according to the body weight. The mice were given diphenoxylate to establish the slow transit constipation model. Mouse carbon ink pushing rate, first defecation time and the number of defecation particles in 12 h were observed. The mouse colon tissue was separated and the mucous cells were detected by Periodic acid Schiff and Alcian blue(AB-PAS) staining. Ultra-high-performance liquid chromatography electrospray ionization orbitrap tandem mass spectrometry(UPLC-ESI-Orbitrap-MS/MS) technology was used to characterize the differences in tissue metabolism to screen out the potential different metabolites and possible metabolic pathways in colon tissue. The results indicated that SHTB could significantly shorten the first defecation time and the number of defecations, and increase the number of intestinal peristalsis and mucous cells in the colonic mucosa compared to the model mice. Metabolomics results showed that, compared with the normal group, a total of 17 potential biomarkers, including L-kynurenine, N6,N6,N6-trimethyl-L-lysine, L-formylkynurenine, N6-acetyl-L-lysine, L-phenylalanine, phenylacetaldehyde, xanthoxin, thymidine, glycyl-L-leucine, cystathionine,(R)-1-aminopropan-2-ol, deoxycytidine, gamma-glutamyl-gamma-aminobutyraldehyde, D-galactose, L-arginine, L-proline and pyruvate, were found and identified in colon tissue. Treated with SHTB, these metabolic differences tended to return to normal levels. Therefore, it could be made a conclusion that the therapeutic effect of SHTB on chronic transit constipation may be related to regulating phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, arginine and proline metabolism, cysteine and methionine metabolism, tyrosine metabolism, arginine biosynthesis, pyruvate metabolism, glycolysis, pyrimidine metabolism, tricarboxylic acid cycle and galactose metabolism.


Asunto(s)
Metabolómica , Espectrometría de Masas en Tándem , Animales , Biomarcadores , Cápsulas , Cromatografía Líquida de Alta Presión , Estreñimiento/tratamiento farmacológico , Ratones , Ratones Endogámicos ICR
3.
Nat Commun ; 12(1): 831, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547306

RESUMEN

The regulation of glutamate receptor localization is critical for development and synaptic plasticity in the central nervous system. Conventional biochemical and molecular biological approaches have been widely used to analyze glutamate receptor trafficking, especially for α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate-type glutamate receptors (AMPARs). However, conflicting findings have been reported because of a lack of useful tools for analyzing endogenous AMPARs. Here, we develop a method for the rapid and selective labeling of AMPARs with chemical probes, by combining affinity-based protein labeling and bioorthogonal click chemistry under physiological temperature in culture medium. This method allows us to quantify AMPAR distribution and trafficking, which reveals some unique features of AMPARs, such as a long lifetime and a rapid recycling in neurons. This method is also successfully expanded to selectively label N-methyl-D-aspartate-type glutamate receptors. Thus, bioorthogonal two-step labeling may be a versatile tool for investigating the physiological and pathophysiological roles of glutamate receptors in neurons.


Asunto(s)
Neuronas/metabolismo , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Coloración y Etiquetado/métodos , Animales , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Antagonistas de Aminoácidos Excitadores/química , Fluoresceína/química , Colorantes Fluorescentes/química , Expresión Génica , Células HEK293 , Semivida , Hipocampo/citología , Hipocampo/metabolismo , Humanos , Ligandos , Ratones , Ratones Endogámicos ICR , Neuronas/ultraestructura , Cultivo Primario de Células , Transporte de Proteínas , Quinoxalinas/química , Ratas , Ratas Sprague-Dawley , Receptores AMPA/química , Receptores AMPA/genética , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/genética
4.
Biomed Environ Sci ; 34(1): 29-39, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33531105

RESUMEN

Objective: Antimony (Sb) has recently been identified as a novel nerve poison, although the cellular and molecular mechanisms underlying its neurotoxicity remain unclear. This study aimed to assess the effects of the nuclear factor kappa B (NF-κB) signaling pathway on antimony-induced astrocyte activation. Methods: Protein expression levels were detected by Western blotting. Immunofluorescence, cytoplasmic and nuclear fractions separation were used to assess the distribution of p65. The expression of protein in brain tissue sections was detected by immunohistochemistry. The levels of mRNAs were detected by Quantitative real-time polymerase chain reaction (qRT-PCR) and reverse transcription-polymerase chain reaction (RT-PCR). Results: Antimony exposure triggered astrocyte proliferation and increased the expression of two critical protein markers of reactive astrogliosis, inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP), indicating that antimony induced astrocyte activation in vivo and in vitro. Antimony exposure consistently upregulated the expression of inflammatory factors. Moreover, it induced the NF-κB signaling, indicated by increased p65 phosphorylation and translocation to the nucleus. NF-κB inhibition effectively attenuated antimony-induced astrocyte activation. Furthermore, antimony phosphorylated TGF-ß-activated kinase 1 (TAK1), while TAK1 inhibition alleviated antimony-induced p65 phosphorylation and subsequent astrocyte activation. Conclusion: Antimony activated astrocytes by activating the NF-κB signaling pathway.


Asunto(s)
Antimonio/toxicidad , Astrocitos/efectos de los fármacos , FN-kappa B/metabolismo , Animales , Astrocitos/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Quinasas Quinasa Quinasa PAM , Masculino , Ratones Endogámicos ICR , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos
5.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(1): 93-99, 2021 Jan 30.
Artículo en Chino | MEDLINE | ID: mdl-33509759

RESUMEN

OBJECTIVE: To investigate the effect of environmental estrogen bisphenol A (BPA) exposure on apoptosis of mouse ovarian preantral follicular granulosa cells and ovarian development and explore the underlying mechanism. METHODS: Mouse ovarian preantral follicular granulosa cells were isolated from female ICR mice at postnatal day (PND) 10 and cultured in vitro. The cultured cells were treated with 0, 1, 10, 50, 100, 150, 200 and 500 µmol/L BPA, and the changes in cell proliferation, cell cycle, apoptosis and mitochondrial membrane potential were analyzed with CCK-8 method and flow cytometry. The protein expressions of Bcl-2, Bax, p53 and cyclin D1 in the treated cells were determined with Western blotting. Pregnant ICR mice were treated for a week with BPA at the concentration that produced significant effects on the preantral follicular granulosa cells, and the weight changes of the pregnant mice were recorded. The ovarian tissues of the offspring female mice were weighed at PND 10, 17, 21 and 42 followed by histological observation with HE staining and examination of Bcl-2 mRNA expression level with RT-qPCR. RESULTS: Compared with the control cells group, the isolated cells exposed to a low concentration of BPA (50 µmol/L) showed a significantly lowered apoptosis rate, increased mitochondrial membrane potential, and enhanced cellular proliferation (P < 0.05). Exposure to a higher BPA concentration at 200 µmol/L obviously enhanced cell apoptosis by reducing the mitochondrial membrane potential and repressed the cell proliferation (P < 0.05). BPA exposure at 50 µmol/L and 200 µmol/L produced opposite effects on the protein expressions of Bcl-2 (P < 0.01), Bax (P < 0.05) and p53 (P < 0.05) in mouse ovarian preantral follicular granulosa cells. BPA exposure at the doses of 10 and 35 mg/kg caused rapid weight increment of the pregnant mice and changes in ovarian index of the offspring female mice. In the offspring female mice, the changes in Bcl-2 mRNA expression in the ovarian tissue showed a similar pattern to that of ovarian index. Exposure of the pregnant mice to a high BPA concentration at 35 mg/kg resulted in accelerated follicular development into antral follicular stage in PND 21 offspring female mice. CONCLUSIONS: BPA can concentration-dependently regulate the function of ovarian preantral follicular granulosa cells in mice and potentially affects both the pregnant mice and the offspring female mice in light of early ovarian development.


Asunto(s)
Células de la Granulosa , Folículo Ovárico , Animales , Apoptosis , Compuestos de Bencidrilo , Femenino , Ratones , Ratones Endogámicos ICR , Fenoles , Embarazo
6.
Sci Total Environ ; 764: 144245, 2021 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-33385660

RESUMEN

Neural tube defects (NTDs) have a complex etiology. Few studies have assessed alkaline earth metals exposures and occurrence of NTDs. We examined the association between prenatal exposure to magnesium (Mg), calcium (Ca), strontium (Sr) and barium (Ba) and risk for NTDs in a case-control study, and assessed the teratogenic effects of Ba on mice. Placentas were collected from 408 women with NTD-affected pregnancies and 593 women who delivered healthy infants, and concentrations of these metals were determined as prenatal exposure markers. The single effect of individual exposure and joint effect of coexposure to these metals were evaluated with logistic regression and Bayesian kernel machine regression (BKMR), respectively. Barium chloride (BaCl2) was intragastrically administered to pregnant ICR mice and fetal mice were examined for NTDs. Median concentrations of Mg and Ba were higher in NTD cases than in controls (Pall < 0.001). In logistic regression, higher levels of Ba were associated with 1.6-fold increased risk for NTDs (95% confidence interval: 1.06-2.43). In BKMR, the joint effect of the four-metal mixture on NTD risk increased steadily with the levels of the mixture. A change in Ba concentration from the 25th to 75th percentile displayed a risk effect when the other three metals were fixed at the 25th, 50th or 75th percentile, while such a change in Ca concentration showed a protective effect when the other metals were held at the 25th or 50th percentile. No interactions among metals were found. In the mouse experiment, dams treated with 200 mg/kg BaCl2 showed 16.8% of NTDs in fetal mice, compared to 2.6% in the untreated control group (P < 0.01). Taken together, higher mixture levels of the four alkaline earth metals were associated with increased risk for NTDs, with Ba being the major contributor for the joint effect. Intragastric administration of Ba can induce NTDs in mice.


Asunto(s)
Defectos del Tubo Neural , Efectos Tardíos de la Exposición Prenatal , Animales , Bario/toxicidad , Teorema de Bayes , Estudios de Casos y Controles , Femenino , Ratones , Ratones Endogámicos ICR , Defectos del Tubo Neural/inducido químicamente , Defectos del Tubo Neural/epidemiología , Embarazo
7.
Nat Commun ; 12(1): 487, 2021 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-33473105

RESUMEN

Stress-induced glucocorticoids disturb mitochondrial bioenergetics and dynamics; however, instead of being removed via mitophagy, the damaged mitochondria accumulate. Therefore, we investigate the role of glucocorticoids in mitophagy inhibition and subsequent synaptic defects in hippocampal neurons, SH-SY5Y cells, and ICR mice. First, we observe that glucocorticoids decrease both synaptic density and vesicle recycling due to suppressed mitophagy. Screening data reveal that glucocorticoids downregulate BNIP3-like (BNIP3L)/NIX, resulting in the reduced mitochondrial respiration function and synaptic density. Notably, we find that glucocorticoids direct the glucocorticoid receptor to bind directly to the PGC1α promoter, downregulating its expression and nuclear translocation. PGC1α downregulation selectively decreases NIX-dependent mitophagy. Consistent with these results, NIX enhancer pre-treatment of a corticosterone-exposed mouse elevates mitophagy and synaptic density in hippocampus, improving the outcome of a spatial memory task. In conclusion, glucocorticoids inhibit mitophagy via downregulating NIX and that NIX activation represents a potential target for restoring synapse function.


Asunto(s)
Glucocorticoides/efectos adversos , Proteínas de la Membrana/metabolismo , Proteínas Mitocondriales/metabolismo , Mitofagia/fisiología , Sustancias Protectoras/metabolismo , Sinapsis/metabolismo , Animales , Muerte Celular , Corticosterona/farmacología , Hidrocortisona/farmacología , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos ICR , Mitocondrias/metabolismo , Proteínas Mitocondriales/genética , Mitofagia/efectos de los fármacos , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Proteínas Quinasas/metabolismo
8.
Nat Commun ; 12(1): 493, 2021 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-33479209

RESUMEN

Biofilms contribute to bacterial infection and drug resistance and are a serious threat to global human health. Antibacterial nanomaterials have attracted considerable attention, but the inhibition of biofilms remains a major challenge. Herein, we propose a nanohole-boosted electron transport (NBET) antibiofilm concept. Unlike known antibacterial mechanisms (e.g., reactive oxygen species production and cell membrane damage), nanoholes with atomic vacancies and biofilms serve as electronic donors and receptors, respectively, and thus boost the high electron transport capacity between nanomaterials and biofilms. Electron transport effectively destroys the critical components (proteins, intercellularly adhered polysaccharides and extracellular DNA) of biofilms, and the nanoholes also significantly downregulate the expression of genes related to biofilm formation. The anti-infection capacity is thoroughly verified both in vitro (human cells) and in vivo (rat ocular and mouse intestinal infection models), and the nanohole-enabled nanomaterials are found to be highly biocompatible. Importantly, compared with typical antibiotics, nanomaterials are nonresistant and thereby exhibit high potential for use in various applications. As a proof-of-principle demonstration, these findings hold promise for the use of NBET in treatments for pathogenic bacterial infection and antibiotic drug resistance.


Asunto(s)
Antibacterianos/administración & dosificación , Biopelículas/efectos de los fármacos , Nanoestructuras/administración & dosificación , Staphylococcus aureus/efectos de los fármacos , Animales , Células CACO-2 , Transporte de Electrón/efectos de los fármacos , Humanos , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Ratas Sprague-Dawley , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/fisiología
9.
Nat Commun ; 12(1): 526, 2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33483514

RESUMEN

Aciduric bacteria that can survive in extremely acidic conditions (pH < 4.0) are challenging to the current antimicrobial approaches, including antibiotics and photodynamic bacteria inactivation (PDI). Here, we communicate a photosensitizer design concept of halogenation of fluorescein for extremely acidic PDI. Upon halogenation, the well-known spirocyclization that controls the absorption of fluorescein shifts to the acidic pH range. Meanwhile, the heavy atom effect of halogens boosts the generation of singlet oxygen. Accordingly, several photosensitizers that could work at even pH < 2.0 were discovered for a broad band of aciduric bacteria families, with half maximal inhibitory concentrations (IC50) lower than 1.1 µM. Since one of the discovered photosensitizers is an FDA-approved food additive (2',4',5',7'-tetraiodofluorescein, TIF), successful bacteria growth inhibition in acidic beverages was demonstrated, with greatly extended shelf life from 2 days to ~15 days. Besides, the in vivo PDI of Candidiasis with TIF under extremely acidic condition was also demonstrated.


Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Fluoresceína/farmacología , Luz , Fármacos Fotosensibilizantes/farmacología , Ácidos/química , Animales , Bacterias/clasificación , Bacterias/efectos de la radiación , Femenino , Fluoresceína/química , Halogenación , Humanos , Concentración de Iones de Hidrógeno , Ratones Endogámicos ICR , Viabilidad Microbiana/efectos de los fármacos , Viabilidad Microbiana/efectos de la radiación , Estructura Molecular , Oxígeno Singlete/química , Oxígeno Singlete/metabolismo
10.
Nat Commun ; 12(1): 560, 2021 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-33495473

RESUMEN

The squamous-columnar junction (SCJ) is a boundary consisting of precisely positioned transitional epithelium between the squamous and columnar epithelium. Transitional epithelium is a hotspot for precancerous lesions, and is therefore clinically important; however, the origins and physiological properties of transitional epithelium have not been fully elucidated. Here, by using mouse genetics, lineage tracing, and organoid culture, we examine the development of the SCJ in the mouse stomach, and thus define the unique features of transitional epithelium. We find that two transcription factors, encoded by Sox2 and Gata4, specify primitive transitional epithelium into squamous and columnar epithelium. The proximal-distal segregation of Sox2 and Gata4 expression establishes the boundary of the unspecified transitional epithelium between committed squamous and columnar epithelium. Mechanistically, Gata4-mediated expression of the morphogen Fgf10 in the distal stomach and Sox2-mediated Fgfr2 expression in the proximal stomach induce the intermediate regional activation of MAPK/ERK, which prevents the differentiation of transitional epithelial cells within the SCJ boundary. Our results have implications for tissue regeneration and tumorigenesis, which are related to the SCJ.


Asunto(s)
Células Epiteliales/metabolismo , Factor de Transcripción GATA4/genética , Regulación de la Expresión Génica , Uniones Intercelulares/genética , Sistema de Señalización de MAP Quinasas/genética , Factores de Transcripción SOXB1/genética , Animales , Células Cultivadas , Femenino , Factor de Transcripción GATA4/metabolismo , Mucosa Gástrica/metabolismo , Queratina-7/genética , Queratina-7/metabolismo , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Noqueados , Ratones Transgénicos , Factores de Transcripción SOXB1/metabolismo
11.
AAPS PharmSciTech ; 22(1): 45, 2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33439366

RESUMEN

This study aimed to develop a self-microemulsifying drug delivery system (SMEDDS) to enhance the solubility, oral bioavailability, and hypolipidemic effects of syringic acid (SA), a bioactive and poorly-soluble polyphenol. Based on the response surface methodology-central composite design (RSM-CCD), an optimum formulation of SA-SMEDDS, consisting of ethyl oleate (oil, 12.30%), Cremophor-EL (surfactant, 66.25%), 1,2-propanediol (cosurfactant, 21.44%), and drug loading (50 mg/g), was obtained. The droplets of SA-SMEDDS were nanosized (16.38 ± 0.12 nm), spherically shaped, and homogeneously distributed (PDI = 0.058 ± 0.013) nanoparticles with high encapsulation efficiency (98.04 ± 1.39%) and stability. In vitro release study demonstrated a prolonged and controlled release of SA from SMEDDS. In vitro cell studies signified that SA-SMEDDS droplets substantially promoted cellular internalization. In comparison with the SA suspension, SA-SMEDDS showed significant prolonged Tmax, t1/2, and MRT after oral administration. Also, SA-SMEDDS exhibited a delayed in vivo elimination, increased bioavailability (2.1-fold), and enhanced liver accumulation. Furthermore, SA-SMEDDS demonstrated significant improvement in alleviating serum lipid profiles and hepatic steatosis in high-fat diet-induced hyperlipidemia in mice. Collectively, SMEDDS demonstrated potential as a nanosystem for the oral delivery of SA with enhanced bioavailability and hypolipidemic effects.


Asunto(s)
Sistemas de Liberación de Medicamentos , Emulsiones/administración & dosificación , Ácido Gálico/análogos & derivados , Hipolipemiantes/administración & dosificación , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular , Liberación de Fármacos , Ácido Gálico/administración & dosificación , Ácido Gálico/farmacología , Humanos , Hipolipemiantes/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Ratas , Ratas Sprague-Dawley , Tensoactivos/química
12.
Nat Commun ; 12(1): 645, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33510150

RESUMEN

Hepatocellular carcinoma (HCC) is the most predominant primary malignancy in the liver. Genotoxic and genetic models have revealed that HCC cells are derived from hepatocytes, but where the critical region for tumor foci emergence is and how this transformation occurs are still unclear. Here, hyperpolyploidization of hepatocytes around the centrilobular (CL) region is demonstrated to be closely linked with the development of HCC cells after diethylnitrosamine treatment. We identify the CL region as a dominant lobule for accumulation of hyperpolyploid hepatocytes and preneoplastic tumor foci formation. We also demonstrate that upregulation of Aurkb plays a critical role in promoting hyperpolyploidization. Increase of AURKB phosphorylation is detected on the midbody during cytokinesis, causing abscission failure and hyperpolyploidization. Pharmacological inhibition of AURKB dramatically reduces nucleus size and tumor foci number surrounding the CL region in diethylnitrosamine-treated liver. Our work reveals an intimate molecular link between pathological hyperpolyploidy of CL hepatocytes and transformation into HCC cells.


Asunto(s)
Carcinoma Hepatocelular/genética , Transformación Celular Neoplásica/genética , Hepatocitos/metabolismo , Neoplasias Hepáticas/genética , Hígado/metabolismo , Poliploidía , Lesiones Precancerosas/genética , Animales , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/metabolismo , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/metabolismo , Células Cultivadas , Dietilnitrosamina/toxicidad , Femenino , Hepatocitos/efectos de los fármacos , Humanos , Hígado/efectos de los fármacos , Hígado/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Microscopía Confocal , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/metabolismo
13.
Ecotoxicol Environ Saf ; 208: 111656, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396170

RESUMEN

Although copper is among the indispensable trace elements in animal physiological processes, it exerts toxicity upon over-exposure. The present study aimed to investigate hepatocyte autophagy induced by CuSO4 and its potential mechanism. A total of 240 ICR mice (four-week-old, 120 males and 120 females) were randomly divided into four groups, in which mice separately received 0, 4, 8, and 16 mg/kg of Cu (Cu2+-CuSO4) for 42 d. The results of increased autophagosomes and autophagy marker LC3B brown cell staining showed that excessive intake of Cu enhanced hepatocyte autophagy. Simultaneously, Cu inhibited the activity of mTOR through suppressing mRNA and protein expressions in mTOR, which in turn up-regulated expression levels of ULK1 and initiated autophagy. Also, over-exposure to Cu increased mRNA and protein expressions of Beclin1, Atg12, Atg5, Atg16L1, Atg7, Atg3, and LC3 and decreased mRNA and protein expressions of p62. These results indicate that excess Cu can enhance hepatocyte autophagy via inhibiting the mTOR signaling pathway and regulating mRNA and protein expressions of factors implicated to autophagy in mice.


Asunto(s)
Autofagia/efectos de los fármacos , Cobre/toxicidad , Hepatocitos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Animales , Autofagosomas/efectos de los fármacos , Autofagosomas/metabolismo , Autofagia/genética , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Masculino , Ratones , Ratones Endogámicos ICR , Serina-Treonina Quinasas TOR/genética
14.
J Ethnopharmacol ; 264: 113381, 2021 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-32946961

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Recently, a new drug combination GRS comprising ginsenoside Rb1 (G-Rb1), ruscogenin (R-Rus) and schisandrin (S-SA) was screened based on ShengMai preparations, which exhibited a prominent cardioprotective effects against myocardial ischemia/reperfusion (MI/R) injury. AIM OF THE STUDY: To investigate their systemic and individual mechanism of each compound in combination GRS. MATERIALS AND METHODS: The mice model of MI/R and hypoxia/reoxygenation (H/R)-induced cardiomyocytes injury were performed to explore the respective characteristics of each compound in GRS against myocardial injury. RESULTS: Each component in the combination GRS attenuated MI/R injury as evidenced by decreased myocardial infarct size, ameliorated histological features, and improved biochemical indicators. Meanwhile, ingredient G, R and S in combination also individually performed a significant decrease of apoptotic index in MI/R mice and H/R-induced cardiomyocytes injury. Mechanistically, component G in GRS could markedly increase the ATP content in cardiomyocytes through activation of AMPKα phosphorylation. Interestingly, the anti-apoptotic actions of G were profoundly attenuated by knockdown of AMPKα, while no alteration was observed on composition R and S. Moreover, component R in GRS significantly reduced the IL-6 and TNF-α mRNA expression, as well as the content of IL-6 via the modulation of NF-κB signaling pathway. Further, component S exhibited the most powerful anti-oxidative capacity in GRS and remarkably decreased the production of MDA and ROS, and potential mechanisms might at least in part through activating the Akt-14-3-3 signaling pathway and inhibiting the phosphorylation of Bad and ERK1/2. CONCLUSIONS: Our results indicated that the respective mechanism of each compound in combination GRS against MI/R injury might closely associated with energy metabolism modulation, suppression of inflammation and oxidative stress.


Asunto(s)
Ciclooctanos/administración & dosificación , Medicamentos Herbarios Chinos/administración & dosificación , Ginsenósidos/administración & dosificación , Lignanos/administración & dosificación , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Compuestos Policíclicos/administración & dosificación , Espirostanos/administración & dosificación , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Ciclooctanos/aislamiento & purificación , Combinación de Medicamentos , Medicamentos Herbarios Chinos/aislamiento & purificación , Ginsenósidos/aislamiento & purificación , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Lignanos/aislamiento & purificación , Masculino , Ratones , Ratones Endogámicos ICR , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Compuestos Policíclicos/aislamiento & purificación , Ratas , Espirostanos/aislamiento & purificación , Resultado del Tratamiento
15.
Phytomedicine ; 80: 153381, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33086170

RESUMEN

BACKGROUND: Hyperactivation of B cells by activators has been demonstrated to play a central role in the pathogenesis of Sjögren's syndrome (SS). In this study, we found that artesunate (ART) can attenuate BAFF-induced B cell hyperactivation and SS-like symptoms in NOD/Ltj mice. PURPOSE: To determine the efficacy of ART in attenuating SS-like symptoms in vivo and explore the underlying mechanism in vitro. STUDY DESIGN: ART was intragastrically injected into SS-like NOD/Ltj mice. The cytokine hsBAFF was used to activate Raji and Daudi B cells to mimic B cell hyperactivation in vitro. METHODS: The efficacy of ART in inhibiting SS progression was studied in NOD/Ltj mice. Salivary flow rate, the number of lymphocytic infiltration foci, the level of autoantibodies and the extent of B cell infiltration were measured in the indicated groups. CCK-8 assays, flow cytometry-based EdU staining and Annexin V/PI staining were also used to detect the effect of ART on the survival and proliferation mechanism in BAFF-induced Raji and Daudi cells. Further studies determined that TRAF6 degradation is a potential mechanism by which ART determines B cell fate. RESULTS: Treatment with ART inhibited lymphocytic foci formation, B cell infiltration and autoantibody secretion in SS-like NOD/Ltj mice. In vitro assay results indicated that ART effectively inhibited BAFF-induced viability, survival and proliferation of neoplastic B cells. Mechanistically, ART targeted BAFF-activated NFκB by regulating the proteasome-mediated degradation of TRAF6 in Raji and Daudi cells. CONCLUSION: ART ameliorated murine SS-like symptoms and regulated TRAF6-NFκB signaling, thus determining survival and proliferation of B cells.


Asunto(s)
Artesunato/farmacología , Factor Activador de Células B/farmacología , Linfocitos B/efectos de los fármacos , Factores Inmunológicos/farmacología , Síndrome de Sjögren/inmunología , Animales , Autoanticuerpos/metabolismo , Autoinmunidad/efectos de los fármacos , Factor Activador de Células B/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos B/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Linfocitos/efectos de los fármacos , Ratones Endogámicos ICR , Ratones Endogámicos NOD , FN-kappa B/metabolismo , Glándulas Salivales/efectos de los fármacos , Glándulas Salivales/metabolismo , Transducción de Señal/efectos de los fármacos , Síndrome de Sjögren/tratamiento farmacológico , Síndrome de Sjögren/patología
16.
Phytomedicine ; 80: 153397, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33130475

RESUMEN

BACKGROUND: The fruit of Zanthoxylum piperitum (ZP) is an herbal medicine as well as a spice agent in Asia to treat carminative, stomachic, anthelmintic and degenerative diseases. Z. piperitum was reported to have anti-oxidant, anti-inflammatory, anti-osteoarthritic and osteosarcoma proliferation-control effects. PURPOSE AND STUDY DESIGN: This study was conducted to determine the anti-osteoporotic effects and mechanisms of action of ZP. METHODS: Female ICR mice underwent ovariectomies (OVX) and were orally administered ZP at 1, 10 and 100 mg/kg for 6 weeks. The femoral and tibial bones were assessed by dual-energy X-ray absorptiometry and histology to analyze the bone mineral density (BMD) and the number of osteoclasts. Raw 264.7 cells were stimulated by 100 ng/ml receptor activator of nuclear factor-κB ligand (RANKL) for 7 days in the presence of ZP. RANKL-induced signaling molecules were analyzed in osteoclasts. RESULTS: The levels of femoral and tibial BMD were significantly increased by ZP administration. Serum biomarkers such as osteocalcin, calcium, alkaline phosphatase and bone-specific alkaline phosphatase concentrations were markedly recovered to normal levels in ZP-treated osteoporotic mice. In addition, the number of osteoclasts in the head, trochanter and body of the femur was obviously decreased in the ZP treatment groups. Moreover, ZP treated-cells showed a reduction in the number of TRAP-positive multinuclear cells in RANKL-stimulated Raw 264.7 cells. ZP decreased the RANKL-activated NFATc1 and c-fos, transcription factors of osteoclast formation. The nuclear translocation of NF-κB and phosphorylation of ERK42/44 were inhibited by the ZP treatment in RANKL-induced osteoclasts. CONCLUSION: Collectively, ZP exerts its inhibitory effect against bone resorption by regulating RANKL-mediated c-fos/NFATc1/NF-κB in osteoclast. ZP may prove to be a therapeutic agent for osteoporosis.


Asunto(s)
Osteoclastos/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Extractos Vegetales/farmacología , Zanthoxylum/química , Animales , Densidad Ósea/efectos de los fármacos , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/metabolismo , Femenino , Ratones , Ratones Endogámicos ICR , FN-kappa B/metabolismo , Factores de Transcripción NFATC/metabolismo , Osteoclastos/metabolismo , Osteoporosis/etiología , Osteoporosis/metabolismo , Ovariectomía/efectos adversos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ligando RANK/metabolismo , Células RAW 264.7
17.
Environ Pollut ; 270: 116297, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33348144

RESUMEN

BACKGROUND: Evidence proved that gestational ozone (O3) exposure can increase the risk of neonatal adverse respiratory outcomes, but offspring asthma is unclear. OBJECTIVE: This study aimed to investigate whether gestational O3 exposure could exacerbate offspring asthma, and to research the differences in effects of O3 exposure at different gestational periods on offspring asthma. METHODS: The pregnant ICR mice were randomly grouped and were administered O3 (air as control) at gestational day (GD) 1-6, 7-12, and 13-18, respectively. The pups aged 2-4 weeks were treated with ovalbumin (OVA) to establish a model of early life asthma. Asthma characteristics such as pulmonary inflammation, goblet cell proliferation, airway remodeling, OVA-specific immunoglobulin (Ig) E secretion and cytokines were examined. RESULTS: OVA sensitization and challenge successfully induced asthma in offspring. Compared with the air control, pulmonary inflammation infiltration, mucous secretion, the concentration of OVA-specific IgE, the level of tumor necrosis factor (TNF)-α, and T helper (Th) 2-skewed response were significantly exacerbated when O3 exposure at GD13-18 following inhaling OVA, while pulmonary inflammatory infiltration, mucus secretion, and Th2-skewed response were not significantly changed when O3 exposure at both GD1-6 and GD7-12. What's more, the above indicators in asthmatic offspring due to O3 exposure at GD13-18 were more severe than at GD1-6 and GD7-12. Interestingly, the signs of asthma only appeared in the offspring after OVA inhalation. When offspring were not treated with OVA, the prenatal O3 exposure alone did not lead to asthmatic reactions in offspring. In addition, O3 exposure at GD13-18 markedly increased the number of neutrophils and macrophages in Bronchoalveolar Lavage Fluid (BALF) of asthmatic offspring, and significantly exacerbated Th2 immune imbalance in asthmatic offspring, but had no effect on Th17 immune imbalance. CONCLUSION: Exposure to O3 during pregnancy aggravated asthma in offspring, in which the third trimester is the most sensitive window.


Asunto(s)
Asma , Animales , Asma/inducido químicamente , Líquido del Lavado Bronquioalveolar , Modelos Animales de Enfermedad , Femenino , Pulmón , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ovalbúmina , Embarazo
18.
Phytomedicine ; 80: 153360, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33038867

RESUMEN

BACKGROUND: Curcumin is a naturally occurring polyphenol found in Curcuma longa with multiple therapeutic properties, such as anti-inflammatory, wound healing and anti-cancer effects. Curcuma longa is also used as a galactagogue to improve milk production during lactation. PURPOSE: To assess curcumin could have therapeutic potential for breastfeeding mothers, we investigated whether and how curcumin influences milk production in lactating mammary epithelial cells (MECs) at the cellular and molecular levels. METHODS: We prepared a lactating MEC culture model that produced milk components and formed less-permeable tight junctions (TJs) to investigate the molecular mechanism of curcumin on milk production, TJs, and inflammation in vitro. RESULTS: Curcumin downregulated milk production in lactation MECs concurrently with inactivation of lactogenesis-relating signaling (STAT5 and glucocorticoid receptor). The maintenance of a less-permeable TJ barrier was also confirmed, although the TJ protein claudin-4 increased. Curcumin inactivated NFκB and STAT3 signaling, which are closely involved in inflammatory responses in weaning and mastitis mammary glands. The expression levels of IL-1ß and TNF-α were also decreased by curcumin treatment. Furthermore, curcumin blocked activation of inflammatory signaling by lipopolysaccharide treatment in MECs, similar to those in MECs that were treated with diclofenac sodium. The drastic phosphorylation of ERK was induced by curcumin treatment in the absence of EGF. U0126, an inhibitor of ERK phosphorylation, attenuated the adverse effects of curcumin on lactating MECs. CONCLUSION: The results of the present study suggests that curcumin downregulates milk production via inactivation of STAT5 and GR signaling with concurrent suppression of inflammatory responses via STAT3 and NFκB signaling in MECs. These findings provide new insights into the role of curcumin as a mild suppressor of milk production without inflammatory damages in breastfeeding mothers.


Asunto(s)
Curcumina/farmacología , Células Epiteliales/efectos de los fármacos , Glándulas Mamarias Animales/citología , Leche/metabolismo , Animales , Caseínas/metabolismo , Células Cultivadas , Curcumina/efectos adversos , Células Epiteliales/metabolismo , Femenino , Glucocorticoides/metabolismo , Lactancia/efectos de los fármacos , Lactancia/metabolismo , Lipopolisacáridos/toxicidad , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/metabolismo , Mastitis/tratamiento farmacológico , Mastitis/metabolismo , Ratones Endogámicos ICR , FN-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Uniones Estrechas/efectos de los fármacos
19.
Phytomedicine ; 80: 153340, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33130471

RESUMEN

BACKGROUND: Oleanolic acid (OA) is an active compound found in a variety of medicinal herbs and plants. Though OA has been widely attributed with a variety of biological activities, studies focused on its anti-allergic inflammation properties are insufficient. PURPOSE: Given the rapid increase in allergic diseases and the lack of fundamental treatment options, this study aimed to find a safe and effective therapy for allergic disorders. METHODS: We evaluated the inhibitory effect of OA on allergic inflammatory response and the possible mechanisms underlying the effect using phorbol-12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated human mast cell (HMC)-1, and a mouse model of compound 48/80-induced anaphylactic shock. RESULTS: OA suppressed pro-inflammatory cytokine expressions in PMACI-induced HMC-1 cells by inhibiting activation of the Akt, p38 mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and signal transducer and activator of transcription (STAT) 1 signaling pathways. Moreover, OA showed a protective effect against compound 48/80-induced anaphylactic shock through inhibition of histamine release and immunoglobulin E level via regulation of NF-κB and STAT1 activation. CONCLUSION: The results showed that OA suppressed mast cell-mediated allergic response by transcriptional regulation. We suggest that OA has potential effect against allergic inflammatory disorders, including anaphylaxis, and might be a useful therapeutic agent for allergic disease.


Asunto(s)
Anafilaxia/prevención & control , Antialérgicos/farmacología , Mastocitos/efectos de los fármacos , Ácido Oleanólico/farmacología , Anafilaxia/inducido químicamente , Animales , Calcimicina/toxicidad , Línea Celular , Citocinas/metabolismo , Liberación de Histamina/efectos de los fármacos , Humanos , Inflamación/tratamiento farmacológico , Mediadores de Inflamación/metabolismo , Masculino , Mastocitos/metabolismo , Ratones Endogámicos ICR , FN-kappa B/metabolismo , Ésteres del Forbol/toxicidad , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT1/metabolismo , p-Metoxi-N-metilfenetilamina/toxicidad , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
20.
Biomed Pharmacother ; 134: 111151, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33370629

RESUMEN

Different portions (stem GIS and leaf GIL) of Garcinia linii were extracted by ethanol/water and crude extracts were employed to investigate the contents of total phenol and flavonoids, antioxidation activities, and inhibitory activities of α-amylase and α-glucosidase via enzymatic assay and OGTT and OSTT for lowering glucose levels. The data revealed that GlS and GlL contained different levels of flavonoids and total phenol. Furthermore, the results showed the extracts exhibited remarkable antioxidation activities and inhibitory activities of α-amylase and α-glucosidase. In silico docking studies were done using Gold software and the probable molecules retrieved from PubChem were docked with several anti-diabetic relate targets, the results showed several components of G. linii could potentially inhibit diabetic molecules when compared with clinic drugs. The cell glucose uptake data also confirmed that GlL and GlS could retain the active component in the regulation of insulin, AMPK, PPARγ, and DPP4. In vivo, the evidence showed G. linii extracts including syringaldehyde suppressed effect of hyperglycemia on OSTT and OGTT assays. These results suggest that G. linii extract has a potential therapeutic value for the treatment of diabetes in humans.


Asunto(s)
Antioxidantes/farmacología , Glucemia/efectos de los fármacos , Diabetes Mellitus/tratamiento farmacológico , Garcinia , Inhibidores de Glicósido Hidrolasas/farmacología , Extractos Vegetales/farmacología , alfa-Amilasas/antagonistas & inhibidores , Células 3T3 , Adipocitos/efectos de los fármacos , Adipocitos/enzimología , Animales , Antioxidantes/aislamiento & purificación , Biomarcadores/sangre , Glucemia/metabolismo , Diabetes Mellitus/sangre , Diabetes Mellitus/enzimología , Diabetes Mellitus/etiología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Garcinia/química , Inhibidores de Glicósido Hidrolasas/aislamiento & purificación , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Masculino , Ratones , Ratones Endogámicos ICR , Simulación del Acoplamiento Molecular , Obesidad/etiología , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta , Tallos de la Planta , alfa-Amilasas/metabolismo , alfa-Glucosidasas/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...