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1.
J Chem Inf Model ; 64(12): 4739-4758, 2024 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-38863138

RESUMEN

Despite recent success in the computational approaches of cyclic peptide design, current studies face challenges in modeling noncanonical amino acids and nonstandard cyclizations due to limited data. To address this challenge, we developed an integrated framework for the tailored design of stapled peptides (SPs) targeting the bromodomain of CREBBP (CREBBP-BrD). We introduce a powerful combination of anchored stapling and hierarchical molecular dynamics to design and optimize SPs by employing the MultiScale integrative conformational dynamics assessment (MSICDA) strategy, which involves an initial virtual screening of over 1.5 million SPs, followed by comprehensive simulations amounting to 154.54 µs across 5418 of instances. The MSICDA method provides a detailed and holistic stability view of peptide-protein interactions, systematically isolated optimized peptides and identified two leading candidates, DA#430 and DA#99409, characterized by their enhanced stability, optimized binding, and high affinity toward the CREBBP-BrD. In cell-free assays, DA#430 and DA#99409 exhibited 2- to 12-fold greater potency than inhibitor SGC-CBP30. Cell studies revealed higher peptide selectivity for cancerous versus normal cells over small molecules. DA#430 combined with (+)-JQ-1 showed promising synergistic effects. Our approach enables the identification of peptides with optimized binding, high affinity, and enhanced stability, leading to more precise and effective cyclic peptide design, thereby establishing MSICDA as a generalizable and transformative tool for uncovering novel targeted drug development in various therapeutic areas.


Asunto(s)
Proteína de Unión a CREB , Simulación de Dinámica Molecular , Proteína de Unión a CREB/química , Proteína de Unión a CREB/metabolismo , Proteína de Unión a CREB/antagonistas & inhibidores , Humanos , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/metabolismo , Dominios Proteicos , Conformación Proteica , Péptidos/química , Péptidos/metabolismo , Péptidos/farmacología , Línea Celular Tumoral , Unión Proteica
2.
BMC Infect Dis ; 24(1): 695, 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38997656

RESUMEN

BACKGROUND: Sepsis is a life-threatening organ dysfunction, which seriously threatens human health. The clinical and experimental results have confirmed that Traditional Chinese medicine (TCM), such as Scutellariae Radix, has anti-inflammatory effects. This provides a new idea for the treatment of sepsis. This study systematically analyzed the mechanism of Scutellariae Radix treatment in sepsis based on network pharmacology, RNA sequencing and molecular docking. METHODS: Gene expression analysis was performed using Bulk RNA sequencing on sepsis patients and healthy volunteers. After quality control of the results, the differentially expressed genes (DEGs) were analyzed. The active ingredients and targets of Scutellariae Radix were identified using The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Gene Ontology (GO) and Protein-Protein Interaction (PPI) analysis were performed for disease-drug intersection targets. With the help of GEO database, Survival analysis and Meta-analysis was performed on the cross-targets to evaluate the prognostic value and screen the core targets. Subsequently, single-cell RNA sequencing was used to determine where the core targets are located within the cell. Finally, in this study, molecular docking experiments were performed to further clarify the interrelationship between the active components of Scutellariae Radix and the corresponding targets. RESULTS: There were 72 active ingredients of Scutellariae Radix, and 50 common targets of drug and disease. GO and PPI analysis showed that the intersection targets were mainly involved in response to chemical stress, response to oxygen levels, response to drug, regulation of immune system process. Survival analysis showed that PRKCD, EGLN1 and CFLAR were positively correlated with sepsis prognosis. Meta-analysis found that the three genes were highly expressed in sepsis survivor, while lowly in non-survivor. PRKCD was mostly found in Macrophages, while EGLN1 and CFLAR were widely expressed in immune cells. The active ingredient Apigenin regulates CFLAR expression, Baicalein regulates EGLN1 expression, and Wogonin regulates PRKCD expression. Molecular docking studies confrmed that the three active components of astragalus have good binding activities with their corresponding targets. CONCLUSIONS: Apigenin, Baicalein and Wogonin, important active components of Scutellaria Radix, produce anti-sepsis effects by regulating the expression of their targets CFLAR, EGLN1 and PRKCD.


Asunto(s)
Medicamentos Herbarios Chinos , Simulación del Acoplamiento Molecular , Scutellaria baicalensis , Sepsis , Análisis de Secuencia de ARN , Humanos , Sepsis/tratamiento farmacológico , Scutellaria baicalensis/química , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Medicina Tradicional China , Flavanonas/uso terapéutico , Flavanonas/farmacología , Mapas de Interacción de Proteínas , Apigenina/uso terapéutico , Apigenina/farmacología , Perfilación de la Expresión Génica , Ontología de Genes , Farmacología en Red
3.
Nano Lett ; 23(23): 11184-11192, 2023 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-38029280

RESUMEN

Facing the defects and energy barrier at the interface of perovskite solar cells, we propose a chiral molecule engineering strategy to simultaneously heal interfacial defects and regulate interfacial energy band alignment. S-ibuprofen (S-IBU), R-ibuprofen (R-IBU), and racemic ibuprofen (rac-IBU) are used to post-treat perovskite films. rac-IBU molecules possess the strongest anchoring on the surface of perovskites among all chiral molecules, translating into the best defect passivation effect. The hydrophobic isobutyl group and benzene ring could increase the film moisture resistance ability. Due to reduced interfacial defects and interfacial energy barrier, rac-IBU enables efficient devices with a maximum efficiency exceeding 24% based on vacuum flash technology without antisolvents. The encapsulated rac-IBU-modified device could maintain 90% of its initial performance after 1040 h of continuous maximum power point tracking. This work provides a feasible route to minimize interfacial nonradiative recombination losses by controlling spatial conformation via rational chiral molecule engineering.

4.
BMC Immunol ; 24(1): 50, 2023 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-38057716

RESUMEN

PURPOSE: Screening of lysosome-related genes in sepsis patients to provide direction for lysosome-targeted therapy. METHODS: Peripheral blood samples were obtained from 22 patients diagnosed with sepsis and 10 normal controls for the purpose of RNA sequencing and subsequent analysis of differential gene expression. Concurrently, lysosome-related genes were acquired from the Gene Ontology database. The intersecting genes between the differential genes and lysosome-related genes were then subjected to PPI, GO and KEGG analyses. Core genes were identified through survival analysis, and their expression trends in different groups were determined using meta-analysis. Single-cell RNA sequencing was used to clarify the cellular localization of core genes. RESULTS: The intersection of 1328 sepsis-differential genes with 878 lysosome-related genes yielded 76 genes. PPI analysis showed that intersecting genes were mainly involved in Cellular process, Response to stimulus, Immune system process, Signal transduction, Lysosome. GO and KEGG analysis showed that intersecting genes were mainly involved in leukocyte mediated immunity, cell activation involved in immune response, lytic vacuole, lysosome. Survival analysis screened four genes positively correlated with sepsis prognosis, namely GNLY, GZMB, PRF1 and RASGRP1. The meta-analysis revealed that the expression levels of these four genes were significantly higher in the normal control group compared to the sepsis group, which aligns with the findings from RNA sequencing data. Furthermore, single-cell RNA sequencing demonstrated that T cells and NK cells exhibited high expression levels of GNLY, GZMB, PRF1, and RASGRP1. CONCLUSION: GNLY, GZMB, PRF1, and RASGRP1, which are lysosome-related genes, are closely linked to the prognosis of sepsis and could potentially serve as novel research targets for sepsis, offering valuable insights for the development of lysosome-targeted therapy. The clinical trial registration number is ChiCTR1900021261, and the registration date is February 4, 2019.


Asunto(s)
Lisosomas , Sepsis , Humanos , Ontología de Genes , Factores de Intercambio de Guanina Nucleótido , Lisosomas/genética , Sepsis/genética , Análisis de Secuencia de ARN , Pronóstico
5.
Nanotechnology ; 34(50)2023 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-37748477

RESUMEN

Two-dimensional (2D) p-n heterojunctions have attracted great attention due to their outstanding properties in electronic and optoelectronic devices, especially in photodetectors. Various types of heterojunctions have been constituted by mechanical exfoliation and stacking. However, achieving controlled growth of heterojunction structures remains a tremendous challenge. Here, we employed a two-step KI-assisted confined-space chemical vapor deposition method to prepare multilayer WSe2/SnS2p-n heterojunctions. Optical characterization results revealed that the prepared WSe2/SnS2vertical heterostructures have clear interfaces as well as vertical heterostructures. The electrical and optoelectronic properties were investigated by constructing the corresponding heterojunction devices, which exhibited good rectification characteristics and obtained a high detectivity of 7.85 × 1012Jones and a photoresponse of 227.3 A W-1under visible light irradiation, as well as a fast rise/fall time of 166/440µs. These remarkable performances are likely attributed to the ultra-low dark current generated in the depletion region at the junction and the high direct tunneling current during illumination. This work demonstrates the value of multilayer WSe2/SnS2heterojunctions for applications in high-performance photodetectors.

6.
Anim Biotechnol ; 34(7): 3008-3015, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36170043

RESUMEN

CNVs (copy number variations) are the novel and common structural variants that could cover entire genes found in plenty of species. CNV may influence economically important traits or disease susceptibility in livestock species. Based on the whole genome resequencing results, we found that there was a CNV region on the LRRFIP1 gene. Then we used qPCR to detect the copy number type distribution in 553 individuals of four sheep breeds and used them for association analysis. The results showed that: (1) In the CKS, the sheep with gain type had a larger heart girth (p = 0.049). (2) For the HS, the CNV could significantly affect rump breadth (p = 0.037) and circumference of the cannon (p = 0.035). And the sheep with median type showed better performance in rump breadth and circumference of cannon. (3) At the STHS, the CNV was significantly correlated with chest width (p = 0.000) with loss type as the most favorable CNV type. Meanwhile, the best was the loss type, and the lowest was the median. (4) This CNV had no significant effect on the LTHS. So, the CNV of LRRFIP1 was related to the growth traits of these three sheep breeds and it may be used as a molecular marker for sheep.


Asunto(s)
Variaciones en el Número de Copia de ADN , Genoma , Animales , Peso Corporal/genética , Variaciones en el Número de Copia de ADN/genética , Fenotipo , Proteínas de Unión al ARN/genética , Análisis de Secuencia de ADN , Ovinos/genética
7.
Environ Geochem Health ; 45(6): 3789-3804, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36580188

RESUMEN

Chlorinated paraffins (CPs) are ubiquitous anthropogenic contaminants that have been found in various environmental media. The objective of this study was to determine concentrations, spatial distribution, possible sources and potential health risk of SCCPs and MCCPs in urban road dust collected from Shanghai, China. The concentrations ranged from 9.74 to 11,400 ng g-1 for ΣSCCPs, 44.1 to 49,900 ng g-1 for ΣMCCPs and 53.9 to 61,400 ng g-1 for total CPs, respectively. MCCPs were the dominant component in all road dust, averagely accounting for 82.8% of total CPs. The concentrations of CPs in dust collected from traffic and commercial areas were significantly higher than those from campus, industrial, park and residential areas (p < 0.01), which could be attributed to tire wear in heavy traffic. All dust samples were divided into two groups by hierarchical cluster analysis for both SCCPs and MCCPs, and the most abundant homologue groups in most samples were C10Cl7-10 and C13Cl7-9 for SCCPs, and C14Cl7-9 and C15Cl8-9 for MCCPs. Correlation analysis showed that all carbon homologues in road dusts were highly correlated each other, suggesting SCCPs and MCCPs in dust maybe came from similar sources. Three sources for CPs in dust samples were apportioned by the PMF model; their relative contributions to the total CPs burden in dust were 25.6% for factor 1 (commercial CP mixture), 13.7% for factor 2 (long-distance transport) and 60.7% for factor 3 (commercial CP mixture). The median estimated daily intakes of total CPs via road dust were 1.78 × 10-5 for children and 3.0 × 10-6 mg kg-1 day-1 for adults, respectively. Quantitative risk assessment using non-cancer hazard index and total margin of exposure of total CPs indicated that total CPs at the present level in road dust pose no significant risk for both children and adults in Shanghai.


Asunto(s)
Polvo , Hidrocarburos Clorados , Adulto , Niño , Humanos , China , Polvo/análisis , Parafina/análisis , Monitoreo del Ambiente , Hidrocarburos Clorados/análisis
8.
Appl Environ Microbiol ; 88(9): e0243621, 2022 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-35416682

RESUMEN

Microbial dysbiosis in dental plaque contributes to the occurrence of dental caries, to which Streptococcus mutans is a major contributor. Lactobacillus casei can be used as probiotic therapy to treat caries by replacing S. mutans within the dental plaque. However, the effects of probiotic treatment are not always stable. Oxyresveratrol (ORV), a plant-derived polyphenol, displays opposite effects in that it inhibits cariogenic and promotes commensal bacteria. Thus, the objectives of this study are to investigate the effects of ORV on bacterial proportions in S. mutans-L. casei biofilm and to elucidate how ORV weakens the competitiveness of S. mutans. Quantitative real-time PCR confirms a decreased S. mutans-L. casei ratio in dual-species biofilm by action of ORV. The culture supernatant of L. casei after being incubated with ORV (ORVLC) is prepared to explore the joint action of ORV and L. casei. ORVLC displays the strongest anti-biofilm effect against S. mutans when compared with the effects of L. casei supernatant or ORV alone. As a result of this treatment, both exopolysaccharides and bacteria contents in the biofilm are greatly reduced. The biofilm is transformed from water-insoluble glucan-dominant to water-soluble glucan-dominant by ORVLC through the modulation of the glycometabolism-related genes of S. mutans. As for the interactions between ORV and L. casei, ORV promotes L. casei to produce acetic acid, which provides L. casei with a competitive advantage against S. mutans. Taken together, ORV may be very suitable as an adjuvant medicine for probiotic therapy in the control of dental caries. IMPORTANCE The homeostatic imbalance in dental plaque associated with a sharp increase in the number of cariogenic bacteria such as Streptococcus mutans is critical for the occurrence and development of caries. Probiotic therapy can restore ecological balance by replacing cariogenic pathogens with probiotics. The current study innovatively finds that oxyresveratrol, a natural polyphenol, can provide probiotic Lactobacillus casei with competitive dominance in its dual-species biofilm with S. mutans. The joint action of oxyresveratrol and L. casei strongly inhibits the biofilm formation of S. mutans. Additionally, oxyresveratrol promotes L. casei to produce acetic acid, which facilitates L. casei to compete with S. mutans. Through the effects of these two mechanisms, oxyresveratrol leads to a significantly decreased S. mutans-L. casei ratio in their dual-species biofilm. Thus, oxyresveratrol is speculated to be an ideal medicine for the prevention and treatment of caries by regulating oral flora balance.


Asunto(s)
Caries Dental , Placa Dental , Lacticaseibacillus casei , Biopelículas , Glucanos , Humanos , Extractos Vegetales , Polifenoles/farmacología , Estilbenos , Streptococcus mutans/genética , Agua/farmacología
9.
Opt Express ; 30(8): 12722-12731, 2022 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-35472903

RESUMEN

With the rapid development of nanofabrication technology and nonlinear optics, the nonlinear detection by nanostructures is highly appreciated. In this paper, we study the second-harmonic generation by a spherical nonlocal plasmonic nanoparticle wrapped with graphene. We develop a simple method for calculating the electric field at second-harmonic frequency and analyze the influence of the nonlocal response of the metal on the second-harmonic. We find that this nanostructure can probe the material's properties by detecting the radiation intensity of the second-harmonic generation. In addition, the nonlocal response of the plasmonic core can promote the absorption efficiency of second-harmonic generation. Our study may offer a new way for studying the plasmonic quantum effects and nonlinear probing technology and improving the nonlinear conversion efficiency of photonic devices.

10.
J Cell Mol Med ; 25(22): 10454-10465, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34626080

RESUMEN

Emerging evidence indicates extensive oxidative stress is a consequence of obesity which impairs bone formation. Glutathione peroxidase 7 (GPX7) is a conserved endoplasmic reticulum (ER) retention protein, lacking of which causes accumulation of reactive oxygen species (ROS) and promotes adipogenesis. Since the imbalance between osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cell (BMSC) leads to severe bone diseases such as osteoporosis, it is critical to investigate the potential protective role of Gpx7 in osteogenesis. Here, we provide evidence that deficiency of Gpx7 reduces osteogenesis, but increases adipogenesis in both human BMSCs (hBMSCs) and mouse mesenchymal stem cell line. Interestingly, further studies indicate this defect can be alleviated by the ER stress antagonist, but not the ROS inhibitor, unveiling an unexpected finding that, unlike adipogenesis, lacking of Gpx7 inhibits osteogenesis mediating by induced ER stress instead of enhanced ROS. Furthermore, the mTOR signalling pathway is found down-regulation during osteogenic differentiation in Gpx7-deficient condition, which can be rescued by relief of ER stress. Taken together, for the first time we identify a novel function of Gpx7 in BMSCs' osteogenic differentiation and indicate that Gpx7 may protect against osteoporotic deficits in humans through ER stress and mTOR pathway interplay.


Asunto(s)
Estrés del Retículo Endoplásmico , Glutatión Peroxidasa/genética , Células Madre Mesenquimatosas/metabolismo , Osteogénesis/genética , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Fosfatasa Alcalina/metabolismo , Animales , Apoptosis/genética , Biomarcadores , Ciclo Celular/genética , Diferenciación Celular/genética , Células Cultivadas , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Inmunohistoquímica , Masculino , Células Madre Mesenquimatosas/citología , Ratones , Especies Reactivas de Oxígeno/metabolismo
11.
Stem Cells ; 38(8): 1020-1033, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32346881

RESUMEN

As a profoundly anabolic regulator of bone, Wnt7b is well acknowledged to enhance osteoblast activities. Here, we report that bone marrow mesenchymal stem cells (BMSCs) are another important population responding to Wnt7b. In this study, we systematically investigated the in vivo role of Wnt7b in BMSCs using transgenic mice, high-throughput RNA-seq, immunohistochemistry, RT-qPCR, and in situ hybridization. These methods led us to uncover that Sox11 is induced via Wnt7b in BMSCs. Colony formation assay, flow cytometry, EdU incorporation labeling, RT-qPCR, and Western blot were conducted to detect the self-renewal capacity of BMSCs. Alkaline phosphatase staining, alizarin red staining, and ex vivo BMSCs transplantation were utilized to detect the osteogenic ability of BMSCs. ChIP-qPCR, shRNAs, and immunofluorescence staining were utilized to investigate the underlying mechanisms. Consequently, bone-derived Wnt7b was found to decrease in osteoporosis and elevate in bone fracture healing. During bone fracture healing, Wnt7b was particularly expressed in the mesenchymal cells residing within healing frontiers. RNA-seq data of Wnt7b-overexpressed bones uncovered the significant upregulation of Sox11. Histological results further unveiled that Sox11 is specifically increased in BMSCs. Wnt7b-induced Sox11 was demonstrated to reinforce both self-renewal and osteogenic differentiation of BMSCs. Mechanistically, Wnt7b activates the Ca2+ -dependent Nfatc1 signaling to directly induce Sox11 transcription, which in turn activates the transcriptions of both proliferation-related transcription factors (Ccnb1 and Sox2) and osteogenesis-related factors (Runx2, Sp7) in BMSCs. It is intriguing that this Wnt7b-Sox11 signaling in BMSCs is ß-Catenin-independent. Overall, this study provides brand new insights of Wnt7b in bone formation, namely, Wnt7b can enhance both self-renewal and osteogenic differentiation of BMSCs via inducing Sox11. These findings present a new crosstalk between Wnt and Sox signaling in BMSCs.


Asunto(s)
Células de la Médula Ósea/metabolismo , Células Madre Mesenquimatosas/metabolismo , Osteogénesis/fisiología , Proteínas Proto-Oncogénicas/metabolismo , Factores de Transcripción SOXC/metabolismo , Proteínas Wnt/metabolismo , Animales , Células de la Médula Ósea/citología , Modelos Animales de Enfermedad , Humanos , Masculino , Células Madre Mesenquimatosas/citología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Transducción de Señal
12.
J Med Virol ; 92(6): 683-687, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32162699

RESUMEN

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 has become an important public health issue in the world. More than 118 000 cases were confirmed around the world. The main clinical manifestations were respiratory symptoms and occasional gastrointestinal symptoms. However, there is no unified standard for the diagnosis and treatment of COVID-19. In the retrospective analysis, we report nine cases of COVID-19, describe the history of contact, clinical manifestations, the course of diagnosis and clinical treatment before, during and after treatment.


Asunto(s)
Betacoronavirus/genética , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Interferón alfa-2/uso terapéutico , Neumonía Viral/diagnóstico , Neumonía Viral/tratamiento farmacológico , ARN Viral/genética , Adolescente , Adulto , Betacoronavirus/efectos de los fármacos , Betacoronavirus/aislamiento & purificación , Betacoronavirus/patogenicidad , COVID-19 , Prueba de COVID-19 , China , Técnicas de Laboratorio Clínico/métodos , Trazado de Contacto , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Femenino , Humanos , Lopinavir/uso terapéutico , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Moxifloxacino/uso terapéutico , Orofaringe/virología , Oxígeno/uso terapéutico , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/patología , ARN Viral/aislamiento & purificación , Estudios Retrospectivos , Ritonavir/uso terapéutico , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/virología , Tomografía Computarizada por Rayos X
13.
Stem Cells ; 37(1): 115-127, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30270478

RESUMEN

Previous research indicates that knocking out absent, small, or homeotic-like (Ash1l) in mice, a histone 3 lysine 4 (H3K4) trimethyltransferase, can result in arthritis with more severe cartilage and bone destruction. Research has documented the essential role of Ash1l in stem cell fate decision such as hematopoietic stem cells and the progenitors of keratinocytes. Following up on those insights, our research seeks to document the function of Ash1l in skeletal formation, specifically whether it controls the fate decision of mesenchymal progenitor cells. Our findings indicate that in osteoporotic bones, Ash1l was significantly decreased, indicating a positive correlation between bone mass and the expression of Ash1l. Silencing of Ash1l that had been markedly upregulated in differentiated C3H10T1/2 (C3) cells hampered osteogenesis and chondrogenesis but promoted adipogenesis. Consistently, overexpression of an Ash1l SET domain-containing fragment 3 rather than Ash1lΔN promoted osteogenic and chondrogenic differentiation of C3 cells and simultaneously inhibited adipogenic differentiation. This indicates that the role of Ash1l in regulating the differentiation of C3 cells is linked to its histone methyltransferase activity. Subcutaneous ex vivo transplantation experiments confirmed the role of Ash1l in the promotion of osteogenesis. Further experiments proved that Ash1l can epigenetically affect the expression of essential osteogenic and chondrogenic transcription factors. It exerts this impact via modifications in the enrichment of H3K4me3 on their promoter regions. Considering the promotional action of Ash1l on bone, it could potentially prompt new therapeutic strategy to promote osteogenesis. Stem Cells 2019;37:115-127.


Asunto(s)
Proteínas de Unión al ADN/genética , Epigénesis Genética/genética , Histona Metiltransferasas/genética , N-Metiltransferasa de Histona-Lisina/genética , Células Madre Mesenquimatosas/metabolismo , Animales , Diferenciación Celular , Proteínas de Unión al ADN/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Ratones , Transfección
14.
Mol Biol Rep ; 47(1): 809-818, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31664596

RESUMEN

Multipotent mesenchymal stromal cells (MMSCs) are promising to treat a variety of traumatic and degenerative diseases. However, in vitro-passage aging induces cell cycle arrest and a series of genetic and biological changes, which greatly limits ex vivo cell number expansion and further clinical application of MMSCs. In most cases, DNA damage and DNA damage response (DDR) act as the main cause and executor of cellular senescence respectively. Mechanistically, DNA damage signals induce cell cycle arrest and DNA damage repair via DDR. If the DNA damage is indelible, MMSCs would entry into a permanent cell cycle arrest. It should be noted that apart from DDR signaling, certain proliferation or metabolism pathways are also occupied in DNA damage related cell cycle arrest. New findings of these aspects will also be summarized in this study. In summary, we aim to provide a comprehensive review of DDR associated cell cycle regulation and other major molecular signaling in the senescence of MMSCs. Above knowledge could contribute to improve the limited capacity of in vitro expansion of MMSCs, and then promote their clinical applications.


Asunto(s)
Ciclo Celular , Senescencia Celular , Daño del ADN , Células Madre Mesenquimatosas , Reparación del ADN , Humanos , Transducción de Señal
15.
Langmuir ; 35(16): 5534-5540, 2019 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-30925838

RESUMEN

Patchy particles are often referred to colloidal particles with physically or chemically patterned surfaces. We investigated the patterning of nanoparticle grafted by polymers, mainly consisting of patchy structures with different numbers of patches ( Npatch) and core-shell structure using the dissipative particle dynamics (DPD) method in good or poor solvents based on the experiment research. Poor solvent, large nanoparticle, proper grafting density and medium polymer length contribute to the formation of patchy structure. We introduce the effective volume fraction as an indicator to distinguish the patchy structure from core-shell structure. The reversible transition between core-shell (in a good solvent) and patchy structure (in a poor solvent) and the dependency relationship between the nanoparticle diameter and grafting density in experiment are verified. Our results pave the way for preparing the colloids with well-defined patches. The anisotropic patchy particles can self-assemble into elaborate superstructures, which are potential blocking materials for drug delivery, sensors, and electronics.

16.
Bioorg Med Chem ; 26(12): 3308-3320, 2018 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-29739714

RESUMEN

We report herein the design and synthesis of a series of structural modified dimethylpyridazine compounds as novel hedgehog signaling pathway inhibitors. The bicyclic phthalazine core and 4-methylamino-piperidine moiety of Taladegib were replaced with dimethylpyridazine and different azacycle building blocks, respectively. The in vitro Gli-luciferase assay results demonstrate that the new scaffold still retained potent inhibitory potency. Piperidin-4-amine moiety was found to be the best linker between pharmacophores dimethylpyridazine and fluorine substituted benzoyl group. Furthermore, the optimization of 1-methyl-1H-pyrazol and 4-fluoro-2-(trifluoromethyl)benzamide by different aliphatic or aromatic rings were also investigated and the SAR were described. Several new derivatives were found to show potent Hh signaling inhibitory activity with nanomolar IC50 values. Among these compounds, compound 11c showed the highest inhibitory potency with an IC50 value of 2.33 nM, which was comparable to the lead compound Taladegib. In vivo efficacy of 11c in a ptch+/-p53-/- mouse medulloblastoma allograft model also indicated encouraging results.


Asunto(s)
Antineoplásicos/síntesis química , Proteínas Hedgehog/metabolismo , Piridazinas/química , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sitios de Unión , Dominio Catalítico , Modelos Animales de Enfermedad , Diseño de Fármacos , Proteínas Hedgehog/antagonistas & inhibidores , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/patología , Ratones , Ratones Noqueados , Ratones Desnudos , Simulación del Acoplamiento Molecular , Piridazinas/metabolismo , Piridazinas/farmacología , Piridazinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Receptor Smoothened/química , Receptor Smoothened/metabolismo , Relación Estructura-Actividad , Trasplante Homólogo , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genética
17.
Langmuir ; 33(14): 3427-3433, 2017 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-28221045

RESUMEN

We investigated the self-assembly of surfactant-like amphiphiles consisting of a hydrophilic head and a hydrophobic tail using the dissipative particle dynamics method. By controlling the interaction parameter between the hydrophilic head and the solvent, the length of the hydrophobic tail, the size of the hydrophilic head, and the polymer concentration, we found seven self-assembled morphologies, including spherelike micelles, pomegranate-like micelles, hierarchical colloidal polymeric (HCP) structures, pomegranate-like columnar structures, branched hybrid structures, disklike micelles, and vesicles. Importantly, the HCP structure widely existing in this system has a regular two-component alternating structure and prospective application in soft-matter nanotechnology. The formation process and the structural properties of the HCP structure are intensively studied. The dimension of the HCP structure is largely controlled by the hydrophobic tail and the polymer concentration.

18.
Sensors (Basel) ; 17(11)2017 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-29112177

RESUMEN

Recognition and matching of litchi fruits are critical steps for litchi harvesting robots to successfully grasp litchi. However, due to the randomness of litchi growth, such as clustered growth with uncertain number of fruits and random occlusion by leaves, branches and other fruits, the recognition and matching of the fruit become a challenge. Therefore, this study firstly defined mature litchi fruit as three clustered categories. Then an approach for recognition and matching of clustered mature litchi fruit was developed based on litchi color images acquired by binocular charge-coupled device (CCD) color cameras. The approach mainly included three steps: (1) calibration of binocular color cameras and litchi image acquisition; (2) segmentation of litchi fruits using four kinds of supervised classifiers, and recognition of the pre-defined categories of clustered litchi fruit using a pixel threshold method; and (3) matching the recognized clustered fruit using a geometric center-based matching method. The experimental results showed that the proposed recognition method could be robust against the influences of varying illumination and occlusion conditions, and precisely recognize clustered litchi fruit. In the tested 432 clustered litchi fruits, the highest and lowest average recognition rates were 94.17% and 92.00% under sunny back-lighting and partial occlusion, and sunny front-lighting and non-occlusion conditions, respectively. From 50 pairs of tested images, the highest and lowest matching success rates were 97.37% and 91.96% under sunny back-lighting and non-occlusion, and sunny front-lighting and partial occlusion conditions, respectively.

19.
Sensors (Basel) ; 16(12)2016 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-27973409

RESUMEN

The automatic fruit detection and precision picking in unstructured environments was always a difficult and frontline problem in the harvesting robots field. To realize the accurate identification of grape clusters in a vineyard, an approach for the automatic detection of ripe grape by combining the AdaBoost framework and multiple color components was developed by using a simple vision sensor. This approach mainly included three steps: (1) the dataset of classifier training samples was obtained by capturing the images from grape planting scenes using a color digital camera, extracting the effective color components for grape clusters, and then constructing the corresponding linear classification models using the threshold method; (2) based on these linear models and the dataset, a strong classifier was constructed by using the AdaBoost framework; and (3) all the pixels of the captured images were classified by the strong classifier, the noise was eliminated by the region threshold method and morphological filtering, and the grape clusters were finally marked using the enclosing rectangle method. Nine hundred testing samples were used to verify the constructed strong classifier, and the classification accuracy reached up to 96.56%, higher than other linear classification models. Moreover, 200 images captured under three different illuminations in the vineyard were selected as the testing images on which the proposed approach was applied, and the average detection rate was as high as 93.74%. The experimental results show that the approach can partly restrain the influence of the complex background such as the weather condition, leaves and changing illumination.

20.
Inflamm Res ; 64(9): 707-20, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26174156

RESUMEN

BACKGROUND: Interleukin-6 (IL-6) is an important mediator of atherosclerotic disease and is also associated with coronary artery disease (CAD). The growing evidences suggest that polymorphisms in the IL-6 promoter region influence the progression of CAD. This study was performed to update the systematic results of association of IL-6 gene polymorphisms with CAD. METHODS: PubMed, Embase, and China Biology Medicine were searched systematically for English and Chinese articles published up to October 31, 2014. Data were extracted using standardized forms. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of associations. Subgroup analyses were made on ethnicity. RESULTS: A total of 42 studies including 15,145 cases and 21,496 controls were combined in this meta-analysis. IL-6 gene -174G/C polymorphism was associated with an increased risk of CAD (for C allele versus G allele: OR = 1.11, 95 % CI 1.02-1.20; for C/C versus G/G: OR = 1.21, 95 % CI 1.03-1.42; for C/C + C/G versus G/G: OR = 1.14, 95 % CI 1.03-1.27). In the subgroup analyses based on ethnicity, a significant association was found between -174 G/C polymorphism and CAD in Caucasians (for C allele versus G allele: OR = 1.12, 95 % CI 1.03-1.22; for C/C versus G/G: OR = 1.21, 95 % CI 1.02-1.42; for C/C + C/G versus G/G: OR = 1.16, 95 % CI 1.05-1.29). In order to reduce heterogeneity, we removed the outlier studies by a Galbraith plot analysis. As a result, the pooled ORs demonstrated no association of -174G/C polymorphism and CAD (C allele versus G allele: OR = 1.02, 95 % CI 0.97-1.06, p = 0.48; C/C versus G/G: OR = 0.1.03, 95 % CI 0.94-1.13, p = 0.48; C/G + C/C versus G/G: OR = 1.03, 95 % CI 0.96-1.09, p = 0.41; C/C versus C/G + G/G: OR = 1.02, 95 % CI 0.94-1.10, p = 0.70, respectively). The polymorphism of -572 G/C was not associated with CAD significantly (for C allele versus G allele: OR = 0.86, 95 % CI 0.74-1.01; C/C versus G/G: OR = 0.99, 95 % CI 0.43-2.27; C/G + C/C versus G/G: OR = 0.96, 95 % CI 0.80-1.15, respectively). In addition, subgroup analyses showed an association between -572 G/C polymorphism and CAD risk among Chinese (C allele versus G allele: OR = 0.64, 95 % CI 0.48-0.85; C/C versus G/G: OR = 0.38, 95 % CI 0.18-0.81; C/G + C/C versus G/G: OR = 0.47, 95 % CI 0.22-1.00; C/C versus C/G + G/G: OR = 0.58, 95 % CI 0.42-0.81). CONCLUSION: The C allele of -174G/C polymorphism may associate with increased sensibility to CAD among Caucasians in overall analysis. Nevertheless, the effect is interfered by heterogeneity across the included studies. The C allele of -572G/C polymorphism may decrease the risk of CAD in Chinese.


Asunto(s)
Enfermedad de la Arteria Coronaria/genética , Interleucina-6/genética , Predisposición Genética a la Enfermedad , Humanos , Oportunidad Relativa , Polimorfismo de Nucleótido Simple
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