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1.
Polymers (Basel) ; 15(2)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36679170

RESUMO

The curvature feature makes the irradiance and absorptivity change, resulting in an uneven power density distribution, which affects the quality of composite parts. In this study, a theoretical model-based Super-Gaussian profile beam in the laser irradiation area was established to obtain the heat flux distribution on the curved surface. The effect of curvature on the surface scattering reflection, temperature distribution, and surface morphology were investigated and verified the validity of the theoretical model. Furthermore, the influence of the laser intensity distribution, laser inclination and curvature radius on the power density distribution and distribution uniformity were studied. Research indicated that the power density increases as the distance from the origin increase resulting from the variation of the irradiance and absorptance along the circumference. The flatter the intensity distribution of the laser beam in the height direction, the less uniform the power density distribution. Accordingly, the typical Gaussian profile beam significantly ameliorates the power density distribution. This research provides a novel understanding of using heat sources during laser heating thermoplastic tape placement.

2.
World Allergy Organ J ; 16(1): 100739, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36694622

RESUMO

Background: Allergic rhinitis (AR) is a common allergic airway disorder that is often poorly managed. There is an urgent need to enhance medication adherence in order to improve treatment outcomes in patients with AR. The efficacy of wearable smart watches in improving medication adherence is currently unclear. Objectives: This study aimed to evaluate the efficacy of a novel smart watch in improving medication adherence and symptom control in patients with AR. The reliability of self-reported medication use was also investigated. Methods: This randomized, open-label, parallel controlled, pilot study enrolled adult patients with AR caused by cypress pollen. Patients were randomized in a 1:2 ratio to an intervention group and control group. Smart watches were only distributed to patients in the intervention group. During the cypress pollen season, all patients were required to take oral antihistamines daily and use nasal corticosteroids and antihistamine eye drops as needed. Daily AR symptom scores and medication usage were recorded in both groups. The smart watch was able to identify medication-taking behaviors of patients via artificial intelligence (AI) and relay this information to physicians, who sent short message service reminders to patients who forgot to take oral antihistamines for more than 2 days. Results: During the pollen season, the adherence rate to oral antihistamines in the intervention group (n = 17) was significantly higher than that in the control group (n = 38) (63.3% ± 28.5% versus 43.2% ± 30.2%, P = 0.02). The daily symptom score of the intervention group was lower than that of the control group (2.4 ± 1.1 versus 3.9 ± 1.0, P < 0.001). There was no significant difference in the on-demand medication score between the 2 groups (1.3 ± 0.4 versus 1.5 ± 0.5, P = 0.13). The consistency rate between self-reported nasal corticosteroid usage and the gold standard (ie, human observation of medication usage in the videos recorded by the smart watch) was 20.0% (0%, 53.7%), and the consistency rate between self-reported antihistamine eye drop usage and the gold standard was 24.3% (2.1%, 67.1%). Conclusions: This pilot study showed that the application of smart watches in patients with AR was associated with improved medication adherence and symptom control. Furthermore, the reliability of self-reported medication usage was limited.

3.
Curr Protein Pept Sci ; 23(11): 731-743, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36523114

RESUMO

Birch belongs to the order Fagales and the family Betulaceae. Birch pollen is one of the most important airborne inhaled allergens in the north temperate zone, leading to allergic rhinitis, asthma and pollen-related food allergy. The sensitization rate to birch pollen is about 8-16% in the general population and 7-57% in patients seen at various allergy centers. Seven birch pollen allergens have been recognized by the International Allergen Nomenclature Sub-committee, with Bet v 1 as the sole major allergen. Component-resolved diagnostics can help to discriminate broad cross-reactivity and false-positive diagnoses of pollen allergy caused by specific IgE to pan-allergens such as Bet v 2, 4 or Bet v 7 from true birch allergy represented by the major allergen Bet v 1-specific IgE. Patients with allergic symptoms to birch pollen showed significantly higher serum anti-Bet v 1 IgE concentrations than asymptomatic individuals with birch sensitization. A higher level of IgE to Bet v 1 also predicted oral allergy syndrome after the ingestion of Rosaceae fruits, nuts, or Apiaceae vegetables, which have cross-reactive homologous allergens with birch allergens. Bet v 1 is one of the first allergens developed using recombinant technology. Many forms of genetically modified Bet v 1 hypo-allergens have been developed and have shown benefit in animal models or even clinical trials of allergen immunotherapy.


Assuntos
Alérgenos , Hipersensibilidade Alimentar , Animais , Humanos , Betula , Antígenos de Plantas/genética , Pólen , Imunoglobulina E , Reações Cruzadas , Proteínas de Plantas/genética
4.
Hum Cell ; 2022 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-36580272

RESUMO

Piezo ion channel is a mechanosensitive protein on the cell membrane, which contains Piezo1 and Piezo2. Piezo channels are activated by mechanical forces, including stretch, matrix stiffness, static pressure, and shear stress. Piezo channels transmit mechanical signals that cause different downstream responses in the differentiation process, including integrin signaling pathway, ERK1/2 MAPK signaling pathway, Notch signaling, and WNT signaling pathway. In the fate of stem cell differentiation, scientists found differences in Piezo channel expression and found that Piezo channel expression is related to developmental diseases. Here, we briefly review the structure and function of Piezo channels and the relationship between Piezo and mechanical signals, discussing the current understanding of the role of Piezo channels in stem cell fate and associated molecules and developmental diseases. Ultimately, we believe this review will help identify the association between Piezo channels and stem cell fate.

5.
Chin Med J (Engl) ; 135(21): 2563-2569, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36583919

RESUMO

BACKGROUND: Dermatophagoides pteronyssinus is a common allergen causing allergic diseases in China. The aim of this study was to evaluate the efficacy and safety of D. pteronyssinus extracts produced by Peking Union Medical College Hospital (PUMCH) for the skin prick test (SPT) in the diagnosis of D. pteronyssinus allergy. METHODS: A total of 910 subjects with allergic diseases were prescribed D. pteronyssinus SPT and specific sIgE (sIgE) test among the Outpatients of Department of Allergy, PUMCH from August 10, 2015 to August 30, 2017. Receiver operating characteristic curve (ROC) analysis was performed according to the results of D. pteronyssinus-sIgE detection. The accuracy of D. pteronyssinus extracts used for SPT in the diagnosis of D. pteronyssinus allergy was evaluated under different cutoff values. Adverse events after SPT were recorded to evaluate safety. RESULTS: There were 796 and 618 subjects in the full analysis set (FAS) and the per protocol set (PPS), respectively. The areas under the curve of FAS and PPS were 0.871 and 0.873, respectively. According to the ROC of PPS, the optimal and 95% specificity diagnostic cutoff values of D. pteronyssinus SPT mean wheal diameter were 3.25 and 3.75 mm, respectively. No adverse events occurred. CONCLUSION: The extracts of D. pteronyssinus for SPT were simple, highly accurate, and safe and should be considered for recommendation in the clinical diagnosis of D. pteronyssinus allergy.


Assuntos
Dermatophagoides pteronyssinus , Hipersensibilidade , Animais , Humanos , Antígenos de Dermatophagoides , Alérgenos , Testes Cutâneos/métodos
6.
Front Immunol ; 13: 1026121, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36569909

RESUMO

Background: Allergic rhinitis (AR) and asthma are closely related, and AR is regarded as an important risk factor for the onset of asthma. However, the pathogenesis of the development of asthma from AR is still undefined. Objective: The aim of this study was to investigate the mechanisms underlying the development of asthma from AR by comparing the transcriptome features of patients with AR with and without asthma. Methods: Patients with AR with or without asthma caused by weed pollen who presented to the Allergy Clinic of Peking Union Medical College Hospital were recruited for this study. Peripheral blood samples of all the patients were collected during the weed pollen season (September) when the patients had allergic symptoms and outside the pollen season (November) when the patients had no symptoms. Transcriptomic analysis was conducted, and the differentially expressed genes (DEGs) and enriched immune pathways between the patients with AR with asthma (AR-asthma group) and those without asthma (AR group) were identified. In addition, the expression levels of some pivotal differentially expressed RNAs were quantified using quantitative polymerase chain reaction (PCR). Results: During the weed pollen season, the immune-related Gene Ontology (GO) terms with P value < 0.05, enriched by the upregulated genes in the AR-asthma group compared to the AR group included antifungal humoral response, neutrophil-mediated killing of bacterium, antibacterial humoral response, antimicrobial humoral immune response mediated by antimicrobial peptides, and regulation of the T cell receptor signaling pathway. The immune-related GO terms with P values <0.05 enriched by downregulated genes were positive regulation of natural killer cell-mediated cytotoxicity, microglial cell activation, natural killer cell activation, and leukocyte-mediated cytotoxicity. The GO term of antimicrobial humoral immune response mediated by antimicrobial peptides was upregulated both during and outside the pollen season, and the upregulated expression of three DEGs (LTF, PF4, and ELANE) included in this term was verified through quantitative PCR. Conclusions: The activation of the antimicrobial immune response mediated by neutrophils and the depression of cytotoxicity mediated by natural killer cells may play roles in the progression from AR to asthma.


Assuntos
Anti-Infecciosos , Asma , Rinite Alérgica Sazonal , Rinite Alérgica , Humanos , Neutrófilos , Rinite Alérgica/genética , Asma/genética , Asma/diagnóstico , Ativação Linfocitária
7.
Biomater Adv ; 143: 213173, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36356468

RESUMO

The application of bone substitutes to reconstruct bone defects is a strategy for repairing alveolar bone loss caused by periodontal disease. Bioactive glasses (BGs) are attractive synthetic bone substitutes owing to their abilities to degrade, form bone-like mineral and stimulate bone regeneration. Our previous studies showed that the incorporation of fluoride into alkali-free bioactive silicate glass promoted osteogenesis to some extent in vitro, while the incorporation of chloride facilitated glass degradation and accelerated the formation of hydroxyapatite. However, whether there is a synergistic effect of incorporating fluoride and chloride on further enhancement of osteogenesis and angiogenesis in vitro and in vivo was not known. Therefore, we synthesized three halide-containing BGs with fluoride only, or chloride only, or mixed fluoride and chloride, investigated their physicochemical properties and osteogenic and angiogenic effects both in vitro and in vivo. The results showed that the addition of both fluoride and chloride in a bioactive silicate glass could combine the structural roles of both, leading to a faster apatite formation than the glass with the presence of fluoride only and a more stable fluorapatite formation than the glass with the presence of chloride only, which formed hydroxyapatite upon immersion. The studied BGs were cytocompatible, as suggested by the cytotoxicity evaluation of hPDLSCs cultivated in the extracted BGs-conditioned culture media. More importantly, these BGs stimulated osteogenic differentiation of hPDLSCs without adding growth factors as indicated by the fact that BGs-conditioned media up-regulated the expression of BMP-2, OPN and VEGF of hPDLSCs and promoted the formation of bone nodules and collagen in vitro. By comparison, the incorporation of fluoride facilitated the expression of osteogenic-related biomarkers and bone nodule formation preferentially, while the incorporation of chloride induced the expression of angiogenic-related biomarkers and collagen formation. The in vivo investigation results demonstrated that the developed halide-containing BGs accelerated the process of bone regeneration, while the glass with mixed fluoride and chloride showed the most significant promotion effect among the three BGs. Therefore, our findings revealed a synergistic effect of incorporating fluoride and chloride into a BG on osteogenesis and angiogenesis in vitro and in vivo and highlighted the potential of fluoride and chloride containing bioactive glasses being bone substitutes for clinical use.


Assuntos
Substitutos Ósseos , Osteogênese , Substitutos Ósseos/química , Fluoretos/farmacologia , Cloretos/farmacologia , Hidroxiapatitas/farmacologia
8.
Front Pharmacol ; 13: 965694, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36339549

RESUMO

Objective: To explore the effect and mechanisms of a traditional Chinese quadri-combination therapy [Bushen, Yiqi, Lixue and Yangtai (BYLY)] in treating recurrent spontaneous abortion (RSA). Methods: A clinical trial was conducted to study the effect of BYLY on RSA. Pharmacological network analysis and UPLC-Q/TOF-mass spectrometry (MS) were applied to investigate the key active component in BYLY and potential targets. Cellular experiments based on former results were performed to examine the mechanism of BYLY in the treatment of RSA. Results: Four hundred and eighty participants enrolled in the clinical trial. The results showed that, compared with the use of BYLY or duphaston alone, a combination of duphaston and BYLY could decrease the early abortion rate in RSA (p < 0.001). Network pharmacological analysis indicated that BYLY contained 132 active components and 146 core targets, and the quercetin maybe the key effective component. In vitro experiments found that pretreatment of quercetin at the correct concentration (2 µM) prevented hypoxia-induced viability and proliferation reduction, and apoptosis and mitochondrial dysfunction. Furthermore, quercetin could modulate mitochondrial fission/fusion balance in trophoblasts, and specifically decrease the expression of Drp1 by regulating miR-34a-5p. Conclusion: BYLY could improve pregnancy outcomes of RSA, based on multi-components and multi-targets. The protective effect of quercetin on trophoblasts, through decreasing Drp1 expression via regulating miR-34a-5p, might be one possible effective mechanism.

9.
Ann Transl Med ; 10(19): 1056, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36330416

RESUMO

Background: The relationship between gut microbiota and metabolites play an important role in the occurrence and development of type 2 diabetes mellitus (T2DM). However, the interaction between intestinal flora abundance and metabolites is still unclear. The purpose of this study was to investigate the correlation of the interaction network between intestinal flora and fecal metabolites in regulating the occurrence of T2DM. Methods: This a case-control study. T2DM patients with different glucose levels and healthy people were divided into case group and normal controls (NC) group. Fasting plasma and fecal samples were collected from the subjects. Ultra-performance liquid chromatography-tandem mass spectrometry (LC-MS) untargeted fecal metabolomics was used to detect small molecular metabolites within 1,500 Da in two groups. The diversity and richness of intestinal flora were analyzed by the 16SrRNA third-generation full-length sequencing technique and the correlation between intestinal microflora and different metabolites was evaluated. Results: A total of 30 patients with T2DM and 21 NC were included for analysis, glycated hemoglobin (HbAlc) (P<0.001), fasting blood glucose (FBG) (P<0.001), total triglycerides (TG) (P=0.002), and fasting serum insulin (FINS) (P=0.026) were significantly higher in the T2DM group compared with the NC group. The fecal metabolomics profiles of the T2DM group and NC group were significantly different, and 355 different metabolites were identified among the two. Compared with the NC group, the levels of ornithine (P=0.04), L-lysine (P=0.03), glutamate (P=0.01), alpha-linolenic acid (P=0.004), traumatin (P=0.05), and erucic acid (P=0.004) in the T2DM group decreased significantly, while PC[18:3(6Z,9Z,12Z)/24:1(15Z)] (P<0.001) levels increased. Compared with the NC group, the richness of Megamonas and Escherichia increased in T2DM patients, while that of Bacteroidota and Phascolarctobacterium were lower. Pearson correlation analysis revealed associations between gut microbiota and faecal metabolites, and Phascolarctobacterium was positively correlated with alpha-linolenic acid (r=0.72, P<0.001). Conclusions: There may be a mutual regulatory network between intestinal bacteria and fecal metabolites in T2DM. The increased abundance of Phascolarctobacterium may increase alpha-linolenic acid uptake, and alpha-linolenic acid may also increase the abundance of intestinal Phascolarctobacterium in vivo after metabolic transformation. The combination of the two may play an important role in the treatment of diabetes.

10.
Biosci Trends ; 16(5): 346-358, 2022 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-36273897

RESUMO

Female reproductive senescence is heralded by hypothalamus region-specific changes in the transcription of genes such as Kiss1 under estradiol (E2) positive feedback, associated with luteinizing hormone (LH) surge dysfunction and reproductive decline. The current study explored whether the anteroventral periventricular nucleus (AVPV) displayed epigenetic changes mediated by age-related dysregulation of gene expression and whether an epigenetic-based intervention could alleviate an aging-related neuroendocrine disorder. Chromatin immunoprecipitation sequencing (ChIP-seq) and ChIP-qPCR were used to assess the differential acetylation of histone H3 in the AVPV and the expression of genes in hormone-primed middle-aged rats. The association between acetylated histone H3 and Kiss1 expression and the underlying mechanisms of dysregulation were determined using pharmacological inhibitors and molecular experiments in vitro and in vivo. An AVPV gene expression program failed to initiate in middle-aged females displaying typical genome-wide hypoacetylation of histone H3, and this coincided with decreased LH. Hypoacetylation of histone H3 at the 3' intergenic region of Kiss1 in particular was associated with enhanced chromatin looping between the promoter and enhancer. Restoration of physiological histone H3 acetylation by intracerebroventricular injection of trichostatin A (TSA) restored the expression of Kiss1 by modifying chromatin looping and led to the restoration of Kiss1 neuronal activation and Kiss1 synthesis as well as circulating LH. These findings have revealed novel epigenetic-associated changes in gene expression in female reproductive aging. These results also suggest that HDAC enzyme-based treatment is a potential therapeutic approach for insufficient preovulatory LH release in aging females.


Assuntos
Histonas , Kisspeptinas , Feminino , Ratos , Animais , Kisspeptinas/genética , Kisspeptinas/metabolismo , Histonas/metabolismo , Hipotálamo Anterior/metabolismo , Hormônio Luteinizante , Estradiol/farmacologia , Estradiol/metabolismo , Epigênese Genética , Envelhecimento/genética , Expressão Gênica , Cromatina
11.
Biomed Res Int ; 2022: 5432806, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36262972

RESUMO

Background: TP53 mutation is a common mutation gene in uterine corpus endometrial carcinoma (UCEC), and the TP53 signaling pathway plays an essential role in the tumorigenesis, progression, and immune infiltration in UCEC. We aimed to discover TP53 pathway-related lncRNAs in UCEC. Materials and methods. 528 UCEC patients with 587 transcriptional profiles were enrolled in this study. We first investigated the differential status of TP53 signaling pathway between tumor and normal tissues by GSEA analysis, then identified TP53 pathway-related lncRNAs, accordingly establishing a nine TP53 pathway related to the lncRNA signature in the training set and verified this signature in the test set. Besides, the interaction network was constructed; the immune infiltration, drug response to cisplatin and paclitaxel, and mutation atlas were investigated. Finally, we performed a subgroup analysis to check the universality of this signature. Results: A nine TP53 pathway-related lncRNA prognostic signature was constructed and verified superior accuracy in predicting the overall survival of UCEC patients. Besides, high-risk patients showed a poor prognosis, but they were more sensitive to the cisplatin and paclitaxel. Notably, M2 macrophages were higher infiltrated in high-risk patients, and TP53 showed a significantly higher mutation in high-risk patients than low-risk patients. Conclusions: We constructed and verified a nine TP53 pathway-related lncRNA prognostic signature in UCEC, which also contributes to the decision-making of the chemotherapy.


Assuntos
Carcinoma Endometrioide , Neoplasias do Endométrio , RNA Longo não Codificante , Feminino , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Prognóstico , Cisplatino/metabolismo , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Neoplasias do Endométrio/patologia , Carcinoma Endometrioide/genética , Paclitaxel/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
12.
Life Sci ; 310: 121073, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36244411

RESUMO

AIM: The low-density lipoprotein receptor (LDLR) plays a crucial role in regulating lipid metabolism. However, whether LDLR deficiency affects bone mass and morphology remains controversial. This study aimed to analyze the bone phenotypes of LDLR knockout (LDLR-/-) mice. MAIN METHODS: Eight-week-old LDLR-/- and wild-type (WT) mice were subjected to microcomputed tomography to detect bone phenotypes. Enzyme-linked immunosorbent assay kits were used to detect the serum estrogen levels and matrix metalloproteinase 9 (MMP-9) levels in tissue homogenates. Von Kossa, toluidine blue, tartrate-resistant acid phosphatase (TRAP) staining, and calcein labeling were performed to explore bone turnover parameters. In vitro, osteoclastogenesis was induced in bone marrow cells from LDLR-/- mice and WT mice in the presence or absence of 17ß-estradiol. The microphotographs and number of osteoclasts were validated using TRAP staining. Relative gene expression during osteoclast differentiation and maturation was determined by quantitative real-time polymerase chain reaction. KEY FINDINGS: LDLR deficiency results in reduced bone mineral density of the tibial cancellous bone, indicating bone loss to some extent in LDLR-/- mice. LDLR deficiency significantly increased the number of osteoclasts, but not osteoblasts. In vitro, bone marrow cells from LDLR-/- mice displayed enhanced osteoclastic potential along with increased expression of TRAP, cathepsin K, nuclear factor of activated T-cells 1 (NFATc1), c-fos, and MMP-9 and inhibited dendritic cell-specific transmembrane protein expression. Moreover, 17ß-estradiol treatment can inhibit osteoclastogenesis in vitro. SIGNIFICANCE: Our data demonstrated that LDLR deficiency promoted osteoclastogenesis by upregulating c-fos and NFATc1 expression, reducing cancellous bone mass in LDLR-/- mice.


Assuntos
Reabsorção Óssea , Ligante RANK , Receptores de LDL , Animais , Camundongos , Densidade Óssea , Reabsorção Óssea/metabolismo , Diferenciação Celular , Estradiol/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Osteogênese , Ligante RANK/metabolismo , Microtomografia por Raio-X , Receptores de LDL/genética , Camundongos Knockout
13.
Sci Rep ; 12(1): 14929, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056051

RESUMO

Immune cells play an important role in the development of inflammation in type 1 diabetes mellitus, so we want to explore the changes of CD4+ T cells and macrophages in vivo, which can provide an experimental basis for immunotherapy based on CD4+ T cells and macrophages. The intraperitoneal injection of streptozocin was used to induce a type 1 diabetes mellitus mouse model; the blood glucose, body weight, and the expression of inflammatory factors in the kidney were measured. Immunohistochemistry was applied to determine and analyze the infiltration of CD4+ T cells and macrophages in the spleen, pancreas, and kidney. The subtypes of macrophages in the kidney and CD4+ T cells in the spleen were analyzed by flow cytometry. Our study suggests that CD4+ T cells and macrophages increase, while the inflammatory immune response system is activated in the development of T1DM. CD4+ T cells positively correlated with macrophages in the pancreas and kidney of T1DM. CD4+ T cells turn to pro-inflammatory subtypes in the spleen of T1DM, while macrophages turn to pro-inflammatory subtypes in the kidney of T1DM. Therefore, regulation of CD4+ T cells and macrophages may be a potential target for T1DM and kidney complications.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Animais , Linfócitos T CD4-Positivos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Macrófagos/metabolismo , Camundongos , Linfócitos T
14.
Aging (Albany NY) ; 14(17): 6957-6974, 2022 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-36057261

RESUMO

Fibroblasts (FBs) are the most important functional cells in the process of wound repair, and their functions can be activated by different signals at the pathological site. Although wound repair is associated with microenvironmental stiffness, the effect of matrix stiffness on FBs remains elusive. In this study, TGF-ß1 was used to mimic the fibrotic environment under pathological conditions. We found that the soft substrates made FBs slender compared with tissue culture plastic, and the main altered biological function was the inhibition of proliferation and differentiation ability. Through PPI and WGCNA analysis, 63 hub genes were found, including GADD45A, CDKN3, HIST2H3PS2, ACTB, etc., which may be the main targets of soft substrates affecting the proliferation and differentiation of FBs. Our findings not only provide a more detailed report on the effect of matrix stiffness on the function of human skin FBs, but also may provide new intervention ideas for improving scars and other diseases caused by excessive cell proliferation, with potential clinical application prospects.


Assuntos
Fibroblastos , Fator de Crescimento Transformador beta1 , Proliferação de Células/genética , Células Cultivadas , Humanos , Plásticos/farmacologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/farmacologia
15.
J Virol ; 96(17): e0090722, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-36000844

RESUMO

The rapid global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused serious health problems, highlighting the urgent need for antiviral drugs. The viral main protease (Mpro) plays an important role in viral replication and thus remains the target of choice for the prevention or treatment of several viral diseases due to high sequence and structural conservation. Prolonged use of viral protease inhibitors can lead to the development of mutants resistant to those inhibitors and to many of the available antiviral drugs. Here, we used feline infectious peritonitis virus (FIPV) as a model to investigate its development of resistance under pressure from the Mpro inhibitor GC376. Passage of wild-type (WT) FIPV in the presence of GC376 selected for a mutation in the nsp12 region where Mpro cleaves the substrate between nsp12 and nsp13. This mutation confers up to 3-fold resistance to GC376 and nirmatrelvir, as determined by EC50 assay. In vitro biochemical and cellular experiments confirmed that FIPV adapts to the stress of GC376 by mutating the nsp12 and nsp13 hydrolysis site to facilitate cleavage by Mpro and release to mediate replication and transcription. Finally, we demonstrate that GC376 cannot treat FIP-resistant mutants that cause FIP in animals. Taken together, these results suggest that Mpro affects the replication of coronaviruses (CoVs) and the drug resistance to GC376 by regulating the amount of RdRp from a distant site. These findings provide further support for the use of an antiviral drug combination as a broad-spectrum therapy to protect against contemporary and emerging CoVs. IMPORTANCE CoVs cause serious human infections, and antiviral drugs are currently approved to treat these infections. The development of protease-targeting therapeutics for CoV infection is hindered by resistance mutations. Therefore, we should pay attention to its resistance to antiviral drugs. Here, we identified possible mutations that lead to relapse after clinical treatment of FIP. One amino acid substitution in the nsp12 polymerase at the Mpro cleavage site provided low-level resistance to GC376 after selection exposure to the GC376 parental nucleoside. Resistance mutations enhanced FIPV viral fitness in vitro and attenuated the therapeutic effect of GC376 in an animal model of FIPV infection. Our research explains the evolutionary characteristics of coronaviruses under antiviral drugs, which is helpful for a more comprehensive understanding of the molecular basis of virus resistance and provides important basic data for the effective prevention and control of CoVs.


Assuntos
Antivirais , Proteases 3C de Coronavírus , Coronavirus Felino , Farmacorresistência Viral , Mutação , Inibidores de Proteases , Animais , Antivirais/farmacologia , Gatos/virologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/genética , Proteases 3C de Coronavírus/metabolismo , Coronavirus Felino/efeitos dos fármacos , Coronavirus Felino/enzimologia , Coronavirus Felino/genética , Farmacorresistência Viral/genética , Inibidores de Proteases/farmacologia
16.
Ann Transl Med ; 10(15): 821, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36035012

RESUMO

Background: Pelvic organ prolapse (POP) is a common degenerative disease among females. We previously reported that advanced glycation end products (AGEs), compounds derived from nonenzymatic glycoxidation reactions, accumulated in the human vaginal wall and impaired the function of fibroblasts in the pathogenesis of POP. This study investigated the apoptosis induced by AGEs in human uterosacral ligament fibroblasts and the underlying mechanism. Methods: Human uterosacral ligament fibroblasts were cultured and identified. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to identify the expression of miR-4429, phosphatase and tensin homolog (PTEN), and caspase-3. Flow cytometric analysis was applied to detect the apoptosis rate of fibroblasts. Dual-luciferase reporter assay was performed to verify the relationship between miR-4429 and PTEN. The overexpression of miR-4429 and the inhibition of PTEN were achieved by cell transfections. Western blot analysis was used to detect the protein levels of PTEN, phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt). Results: The AGEs promoted fibroblast apoptosis both in the POP and the non-POP groups. The expression of PTEN increased in fibroblasts from the POP group or fibroblasts treated with AGEs. It was confirmed that miR-4429 interacted with PTEN messenger RNA (mRNA), and the expression level of miR-4429 was reduced in fibroblasts from the POP group or fibroblasts treated with AGEs. Further, overexpression of miR-4429 alleviated increased PTEN expression and fibroblast apoptosis induced by AGEs. Similarly, inhibition of PTEN expression alleviated increased fibroblast apoptosis induced by AGEs. In addition, the protein expressions of PI3K and phosphorylated Akt were reduced in fibroblasts exposed to AGEs. Conclusions: We proposed that AGEs induced fibroblast apoptosis by regulating the miR-4429/PTEN/PI3K/Akt pathway in POP. Our results revealed a novel mechanism by which AGEs contributed to the molecular pathological alteration in POP.

17.
Front Immunol ; 13: 940713, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35983055

RESUMO

Objective: To evaluate a novel fully automated immunoturbidimetric assay developed by Qiangsheng Biotechnology Company for the detection of anticyclic citrullinated peptide antibodies (anti-CCP) in serum of patients with rheumatoid arthritis (RA) and compare it to the conventional EUROIMMUN- anti-CCP ELISA. Two other commonly used automated assays, the Elecsys anti-CCP assay, an ECLIA that is run on the Modular Analystics E170 (Cobas Diagnostics, Germany), and an anti-CCP CLIA developed by YHLO that is run on the iFlash 3000 Chemiluminescence Immunoassay Analyzer, were included as reference standards. Methods: A total of 264 serum samples were collected from patients attending the First People's Hospital of Wenling affiliated to Wenzhou Medical University between July 2020 and November 2020. These included 131 serum samples collected from patients with RA, 70 serum samples collected from patients with other autoimmune diseases, and 63 serum samples collected from healthy controls at a physical examination. The clinical performance and sensitivity and specificity of the four anti-CCP assays for the diagnosis of RA were compared using receiver operating characteristic (ROC) curve analysis. Results: The Kappa statistic indicated almost perfect agreement between the EUROIMMUN-anti-CCP ELISA and the Elecsys anti-CCP ECLIA (Cobas) (0.863), the EUROIMMUN-anti-CCP ELISA and the anti-CCP CLIA (YHLO) (0.862), and the Elecsys anti-CCP ECLIA (Cobas) and the anti-CCP CLIA (YHLO) (0.816). On ROC curve analysis, AUC values were 0.955 for the EUROIMMUN-anti-CCP ELISA, 0.948 for the anti-CCP CLIA (YHLO), 0.947 for the Elecsys anti-CCP ECLIA (Cobas) and 0.903 for Qiangsheng, indicating all the assays had a good diagnostic performance for RA. Conclusion: The anti-CCP assays provided similar diagnostic information. The novel fully automated immunoturbidimetric assay for anti-CCP developed by Qiangsheng Biotechnology Company may be especially useful for large scale clinical screening in RA as it has a shorter testing time than the commercially available alternatives.


Assuntos
Anticorpos Anti-Proteína Citrulinada , Artrite Reumatoide , Autoanticorpos , Ensaio de Imunoadsorção Enzimática , Humanos , Peptídeos Cíclicos
18.
Biomed Res Int ; 2022: 7848771, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35941968

RESUMO

More than 40% of lung cancers are lung adenocarcinoma (LUAD) worldwide. However, the prognosis of LUAD is poor for the lack of effective treatment methods. Our study identified PLK1 as a novel prognosis biomarker and treatment target for LUAD. Based on the Cancer Genome Atlas (TCGA) database, differentially expressed genes (DEGs) from 551 LUAD cases were analyzed for the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. To explore the biological pathways and the tumor-infiltrating immune cells (TICs) using gene set variation analysis (GSVA) and the CIBERSORT, as well as to analyze DEGs, a protein-protein interaction (PPI) network and Cox regression analysis were performed. Validation of DEGs was achieved through quantitative real-time PCR (qPCR) and immunoblotting. DEGs associated with the cell cycle were sorted out. Cell cycle scores were positively correlated with age, clinical stages, and metastasis and negatively correlated with overall survival of LUAD patients. PPI and Cox analyses showed that PLK1 could be a prognostic factor for LUAD patients. CIBERSORT analysis revealed a positive correlation between the transcription level of PLK1 and the function of CD8+ and activated memory CD4+ T cells, as well as a negative correlation with activated natural killer cells. Furthermore, PLK1 overexpression increased immune cytotoxicity, as measured by the cytolytic activity score, IFN- score, and IFN- level. There is a strong correlation between PLK1 and key features of TICs, indicating its potential as a promising prognostic biomarker for LUAD.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Prognóstico , Microambiente Tumoral/genética
19.
Acta Biomater ; 152: 255-272, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-36041647

RESUMO

Fibroblasts can be directly reprogrammed via a combination of small molecules to generate induced neurons (iNs), bypassing intermediate stages. This method holds great promise for regenerative medicine; however, it remains inefficient. Recently, studies have suggested that physical cues may improve the direct reprogramming of fibroblasts into neurons, but the underlying mechanisms remain to be further explored, and the physical factors reported to date do not exhibit the full properties of the extracellular matrix (ECM). Previous in vitro studies mainly used rigid polystyrene dishes, while one of the characteristics of the native in-vivo environment of neurons is the soft nature of brain ECM. The reported stiffness of brain tissue is very soft ranging between 100 Pa and 3 kPa, and the effect of substrate stiffness on direct neuronal reprogramming has not been explored. Here, we show for the first time that soft substrates substantially improved the production efficiency and quality of iNs, without needing to co-culture with glial cells during reprogramming, producing more glutamatergic neurons with electrophysiological functions in a shorter time. Transcriptome sequencing indicated that soft substrates might promote glutamatergic neuron reprogramming through integrins, actin cytoskeleton, Hippo signalling pathway, and regulation of mesenchymal-to-epithelial transition, and competing endogenous RNA network analysis provided new targets for neuronal reprogramming. We demonstrated that soft substrates may promote neuronal reprogramming by inhibiting microRNA-615-3p-targeting integrin subunit beta 4. Our findings can aid the development of regenerative therapies and help improve our understanding of neuronal reprogramming. STATEMENT OF SIGNIFICANCE: First, we have shown that low stiffness promotes direct reprogramming on the basis of small molecule combinations. To the best of our knowledge, this is the first report on this type of method, which may greatly promote the progress of neural reprogramming. Second, we found that microRNA (miR)-615-3p may interact with integrin subunit beta 4 (ITGB4), and the soft substrates may promote neural reprogramming by inhibiting miR-615-3p targeting ITGB4. We are the first to report on this mechanism. Our findings will provide more functional neurons for subsequent basic and clinical research in neurological regenerative medicine, and will help to improve the overall understanding of neural reprogramming. This work also provides new ideas for the design of medical biomaterials for nerve regeneration.


Assuntos
MicroRNAs , Poliestirenos , Materiais Biocompatíveis/farmacologia , Fibroblastos , Integrinas/metabolismo , MicroRNAs/farmacologia , Neurônios/metabolismo , Poliestirenos/farmacologia
20.
Zhongguo Dang Dai Er Ke Za Zhi ; 24(8): 928-935, 2022 Aug 15.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-36036133

RESUMO

OBJECTIVES: To study the mechanism of retinoic acid receptor α (RARα) signal change to regulate neurexin 1 (NRXN1) in the visual cortex and participate in the autistic-like behavior in rats with vitamin A deficiency (VAD). METHODS: The models of vitamin A normal (VAN) and VAD pregnant rats were established, and some VAD maternal and offspring rats were given vitamin A supplement (VAS) in the early postnatal period. Behavioral tests were performed on 20 offspring rats in each group at the age of 6 weeks. The three-chamber test and the open-field test were used to observe social behavior and repetitive stereotyped behavior. High-performance liquid chromatography was used to measure the serum level of retinol in the offspring rats in each group. Electrophysiological experiments were used to measure the long-term potentiation (LTP) level of the visual cortex in the offspring rats. Quantitative real-time PCR and Western blot were used to measure the expression levels of RARα, NRXN1, and N-methyl-D-aspartate receptor 1 (NMDAR1). Chromatin co-immunoprecipitation was used to measure the enrichment of RARα transcription factor in the promoter region of the NRXN1 gene. RESULTS: The offspring rats in the VAD group had autistic-like behaviors such as impaired social interactions and repetitive stereotypical behaviors, and VAS started immediately after birth improved most of the behavioral deficits in offspring rats. The offspring rats in the VAD group had a significantly lower serum level of retinol than those in the VAN and VAS groups (P<0.05). Compared with the offspring rats in the VAN and VAS groups, the offspring rats in the VAD group had significant reductions in the mRNA and protein expression levels of NMDAR1, RARα, and NRXN1 and the LTP level of the visual cortex (P<0.05). The offspring rats in the VAD group had a significant reduction in the enrichment of RARα transcription factor in the promoter region of the NRXN1 gene in the visual cortex compared with those in the VAN and VAS groups (P<0.05). CONCLUSIONS: RARα affects the synaptic plasticity of the visual cortex in VAD rats by regulating NRXN1, thereby participating in the formation of autistic-like behaviors in VAD rats.


Assuntos
Transtorno Autístico , Córtex Visual , Deficiência de Vitamina A , Animais , Feminino , Gravidez , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato , Receptor alfa de Ácido Retinoico , Vitamina A
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