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RESEARCH QUESTION: Is there a protective effect of the humanin derivative [Gly14]-humanin (HNG) on a D-gal-induced mouse model of primary ovarian insufficiency (POI), and what is the underlying mechanism? DESIGN: D-gal (200 mg/kg/day) was injected subcutaneously for 6 weeks to induce the mouse POI model. Mice treated with HNG were injected intraperitoneally with different concentrations for 6 weeks. Ovarian morphology, function, levels of sex hormones and states of oxidative stress in the ovary and body were evaluated. RESULTS: Compared with the D-gal group, 10 mg/kg HNG improved the abnormal ovarian morphology and oestrous cycle (Pâ¯=â¯0.0036), increased the number of ovarian follicles (Pâ¯=â¯0.0016) and litters (Pâ¯=â¯0.0127), and increased the levels of oestrogen (Pâ¯=â¯0.0043) and AMH (Pâ¯=â¯0.0147). Antioxidant indicators in the ovaries and serum of mice, including total antioxidant capacity (Pâ¯=â¯0.0004 and Pâ¯=â¯0.0032, respectively), catalase (Pâ¯=â¯0.0173 and Pâ¯=â¯0.0103, respectively) and glutathione (both P < 0.0001) were significantly increased. The oxidation indicator malondialdehyde decreased significantly (all P < 0.01). Apoptosis of ovarian granulosa cells was significantly reduced (Pâ¯=â¯0.0140) as was the expression of senescence-related proteins p53, p21 and p16 (all P < 0.01). The level of autophagy in ovarian tissue of mice treated with high increased (significantly increased LC3 protein [P < 0.0001] and significantly reduced p62 protein [Pâ¯=â¯0.0007]). CONCLUSIONS: HNG inhibited D-gal-induced oxidative stress, apoptosis and ovarian damage, promoting ovarian autophagy. HNG may be a potential prophylactic agent against POI.
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Péptidos y Proteínas de Señalización Intracelular , Insuficiencia Ovárica Primaria , Humanos , Femenino , Ratones , Animales , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/prevención & control , Galactosa/efectos adversos , Antioxidantes/farmacologíaRESUMEN
Carabranolides present characteristic NMR resonances for the cyclopropane moiety, which distinctly differ from those of other compounds and were used for an NMR-guided isolation in this study. As a result, 11 undescribed carabranolides (1-11), along with five known ones (12-16), were isolated from the fruits of Carpesium abrotanoides L. Compounds 1-11 are new esters of carabrol at C-4 with different carboxylic acids. Their structures were elucidated by HRESIMS and NMR spectroscopic data analysis. The biological evaluation showed that compounds 2-4, 15, and 16 exhibited significant inhibitory activity against LPS-induced NO release with an IC50 value of 5.6-9.1 µM and dose-dependently decreased iNOS protein expression in RAW264.7 cells.
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Antiinflamatorios , Asteraceae , Frutas , Óxido Nítrico , Animales , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Asteraceae/química , Frutas/química , Lipopolisacáridos/farmacología , Espectroscopía de Resonancia Magnética , Estructura Molecular , Óxido Nítrico/biosíntesis , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Células RAW 264.7 , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacologíaRESUMEN
Wavefront coding (WFC) is an effective technique for extending the depth-of-field of imaging systems, including optical encoding and digital decoding. We applied physical prior information and frequency domain model to the wavefront decoding, proposing a reconstruction method by a generative model. Specifically, we rebuild the baseline inspired by the transformer and propose three modules, including the point spread function (PSF) attention layer, multi-feature fusion block, and frequency domain self-attention block. These models are used for end-to-end learning to extract PSF feature information, fuse it into the image features, and further re-normalize the image feature information, respectively. To verify the validity, in the encoding part, we use the genetic algorithm to design a phase mask in a large field-of-view fluorescence microscope system to generate the encoded images. And the experimental results after wavefront decoding show that our method effectively reduces noise, artifacts, and blur. Therefore, we provide a deep-learning wavefront decoding model, which improves reconstruction image quality while considering the large depth-of-field (DOF) of a large field-of-view system, with good potential in detecting digital polymerase chain reaction (dPCR) and biological images.
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In brief: Intrauterine adhesion (IUA) is one of the main causes of female infertility. This study reveals that endoplasmic reticulum stress activation upregulates the TGF-ß/SMAD pathway to induce epithelial-mesenchymal transition and promote endometrial fibrosis in an IUA model. Abstract: IUA is a common gynecological disease and is a leading cause of female infertility. Mechanical or infectious damage to the endometrial basal layer can lead to endometrial fibrosis, which is the most common cause of IUA. Endoplasmic reticulum stress (ERS), the transforming growth factor beta signaling pathway (TGF-ß/SMAD) and epithelial-mesenchymal transition (EMT) are important factors promoting endometrial fibrosis. The purpose of this study was to determine the up- and downstream regulatory relationships of the above three in the process of endometrial fibrosis. The rat IUA model was induced by double injury method and prophylactic injection of the ERS inhibitor 4-phenylbutyric acid (4-PBA) was given in vivo. The ERS activator tunicamycin and the TGF-ß/SMAD pathway inhibitor A 83-01 were used in human endometrial epithelial cells (HEECs) in vitro. Masson's trichrome, Sirius red staining, immunohistochemistry, immunofluorescence and Western blot analyses were used to determine ERS, TGF-ß/SMAD pathway, EMT and fibrosis markers in the uterine tissue and HEECs of the different treatment groups. In animal experiments, ERS and the TGF-ß/SMAD pathway had been activated and EMT occurred in an in vivo model of IUA but was suppressed in animals treated with prophylactic 4-PBA. In in vitro experiments, tunicamycin-treated HEECs had increased the activation of ERS, the abundance of TGF-ß/SMAD pathway and fibrosis markers while EMT occurred, but the TGF-ß/SMAD pathway and EMT were significantly inhibited in the tunicamycin+A 83-01 group. Our data suggest that increased ERS can induce EMT and promote endometrial fibrosis through the TGF-ß/SMAD pathway.
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Infertilidad Femenina , Enfermedades Uterinas , Ratas , Femenino , Humanos , Animales , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Tunicamicina/farmacología , Transición Epitelial-Mesenquimal , Fibrosis , Estrés del Retículo EndoplásmicoRESUMEN
The issue of global environmental contamination of microplastics has recently been receiving widespread attention. However, the effects of polystyrene nanoparticles (Nano-PS) on the female reproductive system remain unclear. We investigated the toxicity and explored the potential underlying mechanisms of Nano-PS in both mouse ovarian tissue in vivo and human ovarian granulosa cell lines in vitro. In vivo experiments: Mice were fed different concentrations of Nano-PS for 8 weeks. In vitro experiments: COV434 cells were treated with increasing concentrations of Nano-PS. In the present study, ovarian reserve was found to decrease significantly, while oxidative stress and apoptosis levels increased. Nano-PS increased the proportion of metestrum and diestrus periods, and decreased the proportion of estrous period. The implantation rates and the number of pups per litter decreased. In COV434 cells, Nano-PS reduced cell viability and mitochondrial membrane potential, increased the expression of apoptotic and oxidative stress markers and led to subsequent cell cycle arrest. Specifically, Nano-PS exert their toxic effects on mouse ovarian tissue and COV434 cells by inducing oxidative stress. A potential strategy to overcome this could be to activate the nuclear factor-E2-related factor 2 (Nrf2) signaling pathway to mitigate Nano-PS-induced oxidative stress.
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Células de la Granulosa , Nanopartículas , Ovario , Poliestirenos , Animales , Femenino , Humanos , Ratones , Células de la Granulosa/efectos de los fármacos , Ovario/efectos de los fármacos , Estrés Oxidativo , Poliestirenos/toxicidad , Nanopartículas/toxicidadRESUMEN
OBJECTIVES: To investigate the level of neuropsychological development in large for gestational age (LGA) infants at the age of 12 months. METHODS: The infants, aged 12 to <13 months, who attended the Outpatient Service of Child Care in the First Affiliated Hospital of Shandong First Medical University from December 2021 to June 2023, were enrolled as subjects. According to the gestational age and birth weight, they were divided into preterm appropriate for gestational age (AGA) group, preterm LGA group, early term AGA group, early term LGA group, full-term AGA group, and full-term LGA group. A modified Poisson regression analysis was used to investigate the association between LGA and neuropsychological development outcome at 12 months of age. RESULTS: After adjustment for confounding factors, compared with the full-term AGA group at the age of 12 months, the full-term LGA group had a significant increase in the risk of language deficit (RR=1.364, 95%CI: 1.063-1.750), the early term LGA group had significant increases in the risk of abnormal gross motor, fine motor, language, and the preterm LGA group had significant increases in the risk of abnormal language, social behavior, and total developmental quotient (P<0.05); also, the early term AGA group had higher risks of developmental delay across all five attributes and in total developmental quotient at the age of 12 months (P<0.05); except for the language attribute, the preterm AGA group had higher risks of developmental delay in the other 4 attributes (P<0.05). CONCLUSIONS: The neuropsychological development of LGA infants with different gestational ages lags behind that of full-term AGA infants at 12 months of age, and follow-up and early intervention of such infants should be taken seriously in clinical practice.
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Bebé Grande para la Edad Gestacional , Recién Nacido Pequeño para la Edad Gestacional , Recién Nacido , Lactante , Niño , Humanos , Peso al Nacer , Edad Gestacional , Salud InfantilRESUMEN
BACKGROUND: Intrauterine adhesion (IUA) is one of the leading causes of infertility and the main clinical challenge is the high recurrence rate. The key to solving this dilemma lies in elucidating the mechanisms of endometrial fibrosis. The aim of our team is to study the mechanism underlying intrauterine adhesion fibrosis and the origin of fibroblasts in the repair of endometrial fibrosis. METHODS: Our experimental study involving an animal model of intrauterine adhesion and detection of fibrosis-related molecules. The levels of molecular factors related to the endothelial-to-mesenchymal transition (EndMT) were examined in a rat model of intrauterine adhesion using immunofluorescence, immunohistochemistry, qPCR and Western blot analyses. Main outcome measures are levels of the endothelial marker CD31 and the mesenchymal markers alpha-smooth muscle actin (α-SMA) and vimentin. RESULTS: Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium. Decreased CD31 levels and increased α-SMA and vimentin levels indicate that EndMT is involved in intrauterine adhesion fibrosis. CONCLUSIONS: Endothelial cells promote the emergence of fibroblasts via the EndMT during the endometrial fibrosis of intrauterine adhesions.
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Endometrio/patología , Transición Epitelial-Mesenquimal/fisiología , Miofibroblastos/patología , Enfermedades Uterinas/etiología , Animales , Modelos Animales de Enfermedad , Femenino , Fibrosis/complicaciones , Humanos , Ratas , Ratas Sprague-Dawley , Adherencias Tisulares/etiología , Enfermedades Uterinas/patologíaRESUMEN
Intrauterine devices containing copper placement will release a large amount of Cu2+ into the uterine fluid, leading to local endometrial damage and inflammation, which is considered to be one of the causes of abnormal uterine bleeding. Studies have shown that the metabolism and function of metal ions are related to the regulation of microRNA. The aims of this study were to investigate changes in endometrial microRNA levels after implantation of an intrauterine device containing copper and to preliminarily explore the signalling pathways involved in abnormal uterine bleeding. The subjects were fertile women, aged 25-35, without major obstetrics and gynaecology diseases. Human endometrial tissues were collected before implantation or removal of the intrauterine device containing copper. High-throughput microRNA sequencing was performed on human endometrial tissues, and real-time quantitative PCR, western blotting and immunohistochemistry were used to detect the expression of relevant genes. MicroRNA sequencing results showed that 72 miRNAs were differentially expressed in the endometrial tissue after the insertion of the intrauterine device containing copper. Implantation of an intrauterine device containing copper implantation can up-regulate the expression of miR-144-3p in endometrial tissue, and therefore, decreases the mRNA and protein expression levels of genes related to endometrial injury and tissue repair, including the MT/NF-κB/MMP damage pathway and the THBS-1/TGF-ß/SMAD3 repair pathway. In this study, the molecular mechanisms of abnormal uterine bleeding due to an intrauterine device containing copper were preliminarily investigated. The information will be beneficial for the clinical treatment of abnormal uterine bleeding caused by intrauterine device.
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Cobre/farmacología , Endometrio/efectos de los fármacos , Dispositivos Intrauterinos de Cobre , MicroARNs/genética , Adulto , Estudios de Casos y Controles , Endometrio/metabolismo , Endometrio/patología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , MicroARNs/efectos de los fármacos , Implantación de PrótesisRESUMEN
Thyroid hormones have a profound influence on development, cellular differentiation and metabolism, and are also suspected of playing a role in aggression. We measured territorial aggression, body temperature (Tb) and serum thyroid hormones levels of male striped hamsters (Cricetulus barabensis) acclimated to either cold (5 °C), cool (21 °C) or hot (34 °C) ambient temperatures. The effects of methimazole on territorial aggression, food intake, metabolic rate and serum thyroid hormone levels, were also examined. Territorial aggression was significantly lower in male hamsters acclimated to the hot temperature compared to those acclimated to the cool or cold temperatures. Tb significantly increased during aggressive territorial interactions with intruders but did not significantly differ among the three temperature treatments. Serum T3, T4 and cortisol levels of hamsters acclimated to 34 °C were significantly lower than those acclimated to 21 °C. In addition to significantly reducing territorial aggression, treatment with methimazole also significantly reduced serum T3 and T4 levels, Tb and metabolic rate. These results suggest that exposure to high temperatures reduces the capacity of hamsters to dissipate heat causing them to lower their metabolic rate, which, in turn, causes them to reduce territorial aggression to prevent hyperthermia. The lower metabolic rate mediated by down-regulated thyroid hormones inhibits territorial aggression and could thereby determine the outcome of territorial conflicts.
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Agresión , Calor , Aclimatación , Animales , Cricetinae , Cricetulus , Masculino , TemperaturaRESUMEN
Among the important aspects of climate change, exposure to high temperatures (heat waves) is rapidly emerging as an important issue, in particular for female mammals during lactation. High temperatures adversely impact ability to dissipate heat, which has negative effects on reproductive output. The cumulative effects on growth of F1 offspring after weaning and future reproductive performance of offspring remain uncertain. In this study, the F1 mice that weaned from mothers lactating at 21°C and 32.5°C were housed at 21°C from day 19 till 56 of age; during which food intake and body mass were measured. The F1 adult females that had been weaned at the two temperatures were bred and then both exposed to 32.5°C during lactation. Energy intake, milk output and litter size and mass were determined. The F1 adults weaned at 32.5°C consumed less food and had lower body mass than their counterparts weaned at 21°C. Several visceral organs or reproductive tissues were significantly lower in mass in F1 weaned at 32.5°C than at 21°C. The exposure to 32.5°C significantly decreased energy intake, milk output and litter mass in F1 adult females during lactation. The F1 adult females weaned at 32.5°C produced less milk and raised lighter pups than those previously weaned at 21°C. The data suggest that transient exposure to hot temperature during lactation has long-lasting impacts on the offspring, including stunted growth and decreases in future reproductive performance when adult. This indicates that the offspring of females previously experiencing hot temperatures have a significant fitness disadvantage.
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Exposure to high temperatures (heatwaves) is rapidly emerging as an important issue of climate change, in particular for female mammals during lactation. High temperatures adversely affect the ability to dissipate heat, which has negative effects on reproductive output. The cumulative effects on growth of F1 offspring after weaning, and future reproductive performance of offspring, remain uncertain. In this study, F1 mice weaned from mothers lactating at 21 and 32.5°C were housed at 21°C from day 19 until day 56 of age, during which food intake and body mass were measured. The F1 adult females that were weaned at the two temperatures were bred and then exposed to 32.5°C during lactation. Energy intake and milk output, and litter size and mass, were determined. The F1 adults weaned at 32.5°C consumed less food and had lower body mass than their counterparts weaned at 21°C. Several visceral organs or reproductive tissues were significantly lower in mass in F1 weaned at 32.5°C than at 21°C. The exposure to 32.5°C significantly decreased energy intake, milk output and litter mass in F1 adult females during lactation. The F1 adult females weaned at 32.5°C produced less milk and raised lighter pups than those previously weaned at 21°C. The data suggest that transient exposure to hot temperatures during lactation has long-lasting impacts on offspring, including stunted growth and decreases in future reproductive performance when adult. This indicates that the offspring of females previously experiencing hot temperatures have a significant fitness disadvantage.
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Calor , Lactancia , Animales , Peso Corporal , Metabolismo Energético , Femenino , Tamaño de la Camada , Ratones , Embarazo , ReproducciónRESUMEN
The aim of the study was to evaluate the effect of regulation of TLR7 on Mycobacterium tuberculosis (Mtb) survival in macrophages. TLR7 expression in macrophages infected by Mtb was detected by RT-PCR and Western blotting. Regulation of TLR7 was achieved by single strand RNA (ssRNA) or siRNA. The effects of TLR7 on Mtb survival and cell viability were detected by acid fast staining and cell counting kit-8, respectively. Cell ultrastructure was observed via transmission electron microscopy (TEM), and autophagy related protein LC3 was analyzed by Western blotting. TLR7 in Mtb infected macrophages was up-regulated and up-regulation of TLR7 could eliminate intracellular Mtb. Up-regulation of TLR7 could increase viability of Mtb infected cells, while down-regulation of TLR7 induced decrease of cell viability compared with the controls. Autophagosome was significantly increased in the Mtb infected macrophages after up-regulation of TLR7 and LC3-II protein showed obvious increase compared with the controls. Autophagosome could not be detected in macrophages after down-regulation of TLR7, rough endoplasmic reticulum was dilated, and nuclear week gap was widened. Moreover, LC3-II protein was reduced in Mtb infected macrophages based upon the down-regulation of TLR7. Up-regulation of TLR7 could eliminate intracellular Mtb through autophagy. J. Cell. Biochem. 118: 4222-4229, 2017. © 2017 Wiley Periodicals, Inc.
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Autofagia , Macrófagos/metabolismo , Mycobacterium tuberculosis/fisiología , Receptor Toll-Like 7/metabolismo , Animales , Regulación de la Expresión Génica , Macrófagos/fisiología , Macrófagos/ultraestructura , Ratones , Mycobacterium tuberculosis/inmunología , Células RAW 264.7 , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/fisiología , Tuberculosis/inmunologíaRESUMEN
Cigarette smoke (CS), the major cause of chronic obstructive pulmonary disease, contains a variety of oxidative components that were implicated in the regulation of Src homology domain 2-containing protein tyrosine phosphatase 2 (Shp2) activity. However, the contribution of Shp2 enzyme to chronic obstructive pulmonary disease pathogenesis remains unclear. We investigated the role of Shp2 enzyme in blockading CS-induced pulmonary inflammation. Shp2 levels were assessed in vivo and in vitro. Mice (C57BL/6) or pulmonary epithelial cells (NCI-H292) were exposed to CS or cigarette smoke extract (CSE) to induce acute injury and inflammation. Lungs of smoking mice showed increased levels of Shp2, compared with those of controls. Treatment of lung epithelial cells with CSE showed elevated levels of Shp2 associated with the increased release of IL-8. Selective inhibition or knockdown of Shp2 resulted in decreased IL-8 release in response to CSE treatment in pulmonary epithelial cells. In comparison with CS-exposed wild-type mice, selective inhibition or conditional knockout of Shp2 in lung epithelia reduced IL-8 release and pulmonary inflammation in CS-exposed mice. In vitro biochemical data correlate CSE-mediated IL-8 release with Shp2-regulated epidermal growth factor receptor/Grb-2-associated binders/MAPK signaling. Our data suggest an important role for Shp2 in the pathological alteration associated with CS-mediated inflammation. Shp2 may be a potential target for therapeutic intervention for inflammation in CS-induced pulmonary diseases.
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Neumonía/inmunología , Neumonía/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/fisiología , Fumar/efectos adversos , Fumar/patología , Productos de Tabaco/toxicidad , Enfermedad Aguda , Animales , Línea Celular , Modelos Animales de Enfermedad , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/prevención & control , Interleucina-8/metabolismo , Interleucina-8/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neumonía/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 11/deficiencia , Alveolos Pulmonares/inmunología , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/patología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Fumar/metabolismoRESUMEN
For small non-hibernating mammals, a high thermogenic capacity is important to increase activity levels in the cold. It has been previously reported that lactating females decrease their thermogenic activity of brown adipose tissue (BAT), whereas their capacity to cope with extreme cold remains uncertain. In this study we examined food intake, body temperature and locomotor behavior, resting metabolic rate, non-shivering thermogenesis, and cytochrome c oxidase activity, and the rate of state 4 respiration of liver, skeletal muscle, and BAT in striped hamsters (Cricetulus barabensis) at peak lactation and non- breeding hamsters (controls). The lactating hamsters and non- breeding controls were acutely exposed to -15°C, and several markers indicative of thermogenic capacity were examined. In comparison to non-breeding females, lactating hamsters significantly increased food intake and body temperature, but decreased locomotor behavior, and the BAT mass, indicative of decreased BAT thermogenesis at peak lactation. Unexpectedly, lactating hamsters showed similar body temperature, resting metabolic rate, non-shivering thermogenesis with non-breeding females after acute exposure to -15°C. Furthermore, cytochrome c oxidase activity of liver, skeletal muscle and BAT, and serum thyroid hormone concentration, and BAT uncoupling protein 1 expression, in lactating hamsters were similar with that in non-breeding hamsters after acute extreme cold exposure. This suggests that lactating females have the same thermogenic capacity to survive cold temperatures compared to non-breeding animals. This is particularly important for females in the field to cope with cold environments during the period of reproduction. Our findings indicate that the females during lactation, one of the highest energy requirement periods, do not impair their thermogenic capacity in response to acute cold exposure.
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Fake news impacts individuals' behavior and decision-making while also disrupting political processes, perceptions of medical advice, and societal trends. Improving individuals' ability to accurately assess fake news can reduce its harmful effects. However, previous research on media literacy interventions designed for improving fake news credibility assessments has yielded inconsistent results. We systematically collected 33 independent studies and performed a meta-analysis to examine the effects of media literacy interventions on assessing fake news credibility (n = 36,256). The results showed that media literacy interventions significantly improved fake news credibility assessments (Hedges' g = 0.53, 95% confidence interval [0.29-0.78], p < 0.001). Gaming interventions were the most effective intervention form. Conversely, the intervention channel, outcome measurement, and subject characteristics (age, gender, and country development level) did not influence the intervention effects.
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Decepción , Medios de Comunicación de Masas , Humanos , ConfianzaRESUMEN
Olibanum, a golden oleo-gum resin from species in the Boswellia genus (Burseraceae family), is a famous traditional herbal medicine widely used around the world. Previous phytochemical studies mainly focused on the non-polar fractions of olibanum. In this study, nine novel diterpenoids, boswellianols A-I (1-9), and three known compounds were isolated from the polar methanolic fraction of the oleo-gum resin of Boswellia carterii. Their structures were determined through comprehensive spectroscopic analysis as well as experimental and calculated electronic circular dichroism (ECD) data comparison. Compound 1 is a novel diterpenoid possessing an undescribed prenylmaaliane-type skeleton with a 6/6/3 tricyclic system. Compounds 2-4 were unusual prenylaromadendrane-type diterpenoids, and compounds 5-9 were new highly oxidized cembrane-type diterpenoids. Compounds 1 and 5 showed significant transforming growth factor ß (TGF-ß) inhibitory activity via inhibiting the TGF-ß-induced phosphorylation of Smad3 and the expression of fibronectin and N-cadherin (the biomarker of the epithelial-mesenchymal transition) in a dose-dependent manner in LX-2 human hepatic stellate cells, indicating that compounds 1 and 5 should be potential anti-fibrosis agents. These findings give a new insight into the chemical constituents of the polar fraction of olibanum and their inhibitory activities on the TGF-ß/Smad signaling pathway.
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Steroidal alkaloids are the main bioactive components of the bulbs of Fritillaria, which have been used as traditional Chinese medicine, known as "Beimu", for the treatment of cough for thousands of years in China. Cough and dyspnea are the most common symptoms observed in patients with pulmonary fibrosis. However, the antifibrotic activity of steroidal alkaloids has not been reported yet. In this study, two previously unreported cevanine-type steroidal alkaloids (1 and 2), four previously undescribed cevanine-type alkaloid glycosides (3-6), and 19 known steroidal alkaloids (7-25) were isolated from the bulbs of Fritillaria unibracteata var. wabuensis. The structures of these compounds were elucidated by comprehensive HRESIMS and NMR spectroscopic data analysis, as well as DP4+ NMR calculations. The biological evaluation showed that compounds 2, 7-10, 14, 15, and 17 downregulated fibrotic markers induced by transforming growth factor-ß (TGF-ß) in MRC-5 cells. Moreover, compounds 14 and 17 dose dependently inhibited TGF-ß-induced epithelial-mesenchymal transition in A549 cells, alleviated TGF-ß-induced migration and proliferation of fibroblasts, and decreased the expression of fibrotic markers, fibronectin, and N-cadherin in TGF-ß-induced MRC-5 cells. The research showed the potential of cevanine-type alkaloids as a class of natural antifibrotic agents.
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Alcaloides , Fritillaria , Humanos , Fritillaria/química , Alcaloides/química , Raíces de Plantas/química , Tos , Esteroides/química , Factor de Crecimiento Transformador beta/análisisRESUMEN
CONTEXT: Ultrathin overlays are preventive maintenance measures; the tensile and shear stresses generated inside a structural layer under vehicle load are greater than those of conventional thickness asphalt pavement. Therefore, asphalt binders must use high-viscosity and elasticity unique cementing materials to ensure stability. To investigate the modification mechanism of styrene-butadiene-styrene (SBS)/ethylene-butyl acrylate-glycidyl methacrylate copolymer (PTW) high-viscosity modified asphalt binder suitable for ultrathin overlays, the compatibility and molecular behavior of SBS/PTW high-viscosity modified asphalt binder were analyzed by the molecular dynamics (MD) method. These research results provide a reference for preparing ultrathin overlay high-performance composite modified asphalt binder. METHODS: SBS molecular models, PTW molecular models, asphalt binder molecular models, SBS/asphalt binder blend systems, and SBS/PTW/asphalt binder blend systems were sequentially constructed using Materials Studio (MS) software. The compatibility of SBS, PTW, and SBS/PTW with asphalt binder and the diffusion coefficients of SBS, PTW, and SBS/PTW in the asphalt binder were investigated separately using the MD method. The mechanical properties and molecular behavior of SBS, PTW, and SBS/PTW blended with asphalt binder were studied. The research results indicate that the compatibility of PTW with asphalt binder is better than that of SBS with asphalt binder. PTW can effectively decrease the solubility parameter of asphalt binder and improve the compatibility between SBS and asphalt binder. PTW effectively improves the diffusion coefficient and interaction energy of SBS in asphalt binder by up to 29% and 83%. In addition, SBS/PTW had a significant positive effect on the mechanical properties of the asphalt binders, increasing the elastic modulus (E), bulk modulus (K), and shear modulus (G) of the asphalt binder by 4.6%, 9.5%, and 3.5%, respectively, compared to SBS. The results indicate that the SBS/PTW modified asphalt binder composite can significantly improve the high-temperature shear resistance of asphalt binder. Meanwhile, SBS and PTW improve the self-aggregation behavior between asphalt binder component molecules. The distance between the center of mass of asphalt binder and resin system molecules is increased. PTW enhances the extensibility of the branched chains of asphalt binder component molecules and improves the interaction between asphalt binder components and the chains. This further enhances the density and stability of the asphalt binder molecular structure system, improving the physical properties of the asphalt binder.