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1.
Cell ; 186(13): 2897-2910.e19, 2023 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-37295417

RESUMEN

Sperm motility is crucial for successful fertilization. Highly decorated doublet microtubules (DMTs) form the sperm tail skeleton, which propels the movement of spermatozoa. Using cryo-electron microscopy (cryo-EM) and artificial intelligence (AI)-based modeling, we determined the structures of mouse and human sperm DMTs and built an atomic model of the 48-nm repeat of the mouse sperm DMT. Our analysis revealed 47 DMT-associated proteins, including 45 microtubule inner proteins (MIPs). We identified 10 sperm-specific MIPs, including seven classes of Tektin5 in the lumen of the A tubule and FAM166 family members that bind the intra-tubulin interfaces. Interestingly, the human sperm DMT lacks some MIPs compared with the mouse sperm DMT. We also discovered variants in 10 distinct MIPs associated with a subtype of asthenozoospermia characterized by impaired sperm motility without evident morphological abnormalities. Our study highlights the conservation and tissue/species specificity of DMTs and expands the genetic spectrum of male infertility.


Asunto(s)
Inteligencia Artificial , Infertilidad Masculina , Masculino , Humanos , Microscopía por Crioelectrón , Motilidad Espermática/genética , Semen , Espermatozoides , Microtúbulos/metabolismo , Cola del Espermatozoide/química , Cola del Espermatozoide/metabolismo , Proteínas de Microtúbulos/química , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo
2.
Cereb Cortex ; 34(8)2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39191665

RESUMEN

Metabolic syndrome exhibits associations with diverse neurological disorders, and its potential influence on the cerebral cortex may be one of the many potential factors contributing to these adverse outcomes. In this study, we aimed to investigate the causal relationship between metabolic syndrome and changes in cerebral cortex structure using Mendelian randomization analysis. Genome-wide association study data for the 5 components of metabolic syndrome were obtained from individuals of European descent in the UK Biobank. Genome-wide association study data for 34 known cortical functional regions were sourced from the ENIGMA Consortium. Data on Alzheimer's disease, major depression, and anxiety disorder were obtained from the IEU Open genome-wide association study database. The causal links between metabolic syndrome elements and cerebral cortex architecture were evaluated using inverse variance weighting, Mendelian randomization-Egger, and weighted median techniques, with inverse variance weighting as the primary method. Inverse variance weighting, Mendelian randomization Egger, weighted median, simple mode, and weighted mode methods were employed to assess the relationships between metabolic syndrome and neurological diseases (Alzheimer's disease, major depression, and anxiety disorder). Outliers, heterogeneity, and pleiotropy were assessed using Cochran's Q test, MR-PRESSO, leave-one-out analysis, and funnel plots. Globally, no causal link was found between metabolic syndrome and overall cortical thickness or surface area. However, regionally, metabolic syndrome may influence the surface area of specific regions, including the caudal anterior cingulate, postcentral, posterior cingulate, rostral anterior cingulate, isthmus cingulate, superior parietal, rostral middle frontal, middle temporal, insula, pars opercularis, cuneus, and inferior temporal. It may also affect the thickness of the medial orbitofrontal, caudal middle frontal, paracentral, superior frontal, superior parietal, and supramarginal regions. These findings were nominally significant and withstood sensitivity analyses, showing no substantial heterogeneity or pleiotropy. Furthermore, we found an association between metabolic syndrome and the risk of Alzheimer's disease, major depression, and anxiety disorder. This study suggests a potential association between metabolic syndrome and changes in cerebral cortex structure, which may underlie certain neurological disorders. Furthermore, we found an association between metabolic syndrome and the risk of Alzheimer's disease, major depression, and anxiety disorder. Early diagnosis of metabolic syndrome holds significance in preventing these neurological disorders.


Asunto(s)
Corteza Cerebral , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Síndrome Metabólico , Humanos , Síndrome Metabólico/genética , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Femenino , Masculino , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Trastorno Depresivo Mayor/genética , Polimorfismo de Nucleótido Simple
3.
Respir Res ; 25(1): 230, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38824593

RESUMEN

BACKGROUND: Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as collagen deposition and structural disturbance, are typical pathological features of airway remodeling. Thus, identifying key mediators that derived from airway epithelium and capable of modulating ECM may provide valuable insights for targeted therapy of asthma. METHODS: The datasets from Gene Expression Omnibus database were analyzed to screen differentially expressed genes in airway epithelium of asthma. We collected bronchoscopic biopsies and serum samples from asthmatic and healthy subjects to assess lysyl oxidase like 2 (LOXL2) expression. RNA sequencing and various experiments were performed to determine the influences of LOXL2 knockdown in ovalbumin (OVA)-induced mouse models. The roles and mechanisms of LOXL2 in bronchial epithelial cells were explored using LOXL2 small interfering RNA, overexpression plasmid and AKT inhibitor. RESULTS: Both bioinformatics analysis and further experiments revealed that LOXL2 is highly expressed in airway epithelium of asthmatics. In vivo, LOXL2 knockdown significantly inhibited OVA-induced ECM deposition and epithelial-mesenchymal transition (EMT) in mice. In vitro, the transfection experiments on 16HBE cells demonstrated that LOXL2 overexpression increases the expression of N-cadherin and fibronectin and reduces the expression of E-cadherin. Conversely, after silencing LOXL2, the expression of E-cadherin is up-regulated. In addition, the remodeling and EMT process that induced by transforming growth factor-ß1 could be enhanced and weakened after LOXL2 overexpression and silencing in 16HBE cells. Combining the RNA sequencing of mouse lung tissues and experiments in vitro, LOXL2 was involved in the regulation of AKT signaling pathway. Moreover, the treatment with AKT inhibitor in vitro partially alleviated the consequences associated with LOXL2 overexpression. CONCLUSIONS: Taken together, the results demonstrated that epithelial LOXL2 plays a role in asthmatic airway remodeling partly via the AKT signaling pathway and highlighted the potential of LOXL2 as a therapeutic target for airway remodeling in asthma.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Aminoácido Oxidorreductasas , Asma , Ovalbúmina , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Aminoácido Oxidorreductasas/metabolismo , Aminoácido Oxidorreductasas/genética , Aminoácido Oxidorreductasas/biosíntesis , Ovalbúmina/toxicidad , Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratones , Humanos , Asma/patología , Asma/metabolismo , Asma/enzimología , Asma/genética , Transducción de Señal/fisiología , Femenino , Ratones Endogámicos BALB C , Masculino , Transición Epitelial-Mesenquimal/fisiología
4.
Respir Res ; 25(1): 271, 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-38987753

RESUMEN

BACKGROUND: Airway epithelial cell (AEC) necroptosis contributes to airway allergic inflammation and asthma exacerbation. Targeting the tumor necrosis factor-like ligand 1 A (TL1A)/death receptor 3 (DR3) axis has a therapeutic effect on asthmatic airway inflammation. The role of TL1A in mediating necroptosis of AECs challenged with ovalbumin (OVA) and its contribution to airway inflammation remains unclear. METHODS: We evaluated the expression of the receptor-interacting serine/threonine-protein kinase 3(RIPK3) and the mixed lineage kinase domain-like protein (MLKL) in human serum and lung, and histologically verified the level of MLKL phosphorylation in lung tissue from asthmatics and OVA-induced mice. Next, using MLKL knockout mice and the RIPK3 inhibitor GSK872, we investigated the effects of TL1A on airway inflammation and airway barrier function through the activation of necroptosis in experimental asthma. RESULTS: High expression of necroptosis marker proteins was observed in the serum of asthmatics, and necroptosis was activated in the airway epithelium of both asthmatics and OVA-induced mice. Blocking necroptosis through MLKL knockout or RIPK3 inhibition effectively attenuated parabronchial inflammation, mucus hypersecretion, and airway collagen fiber accumulation, while also suppressing type 2 inflammatory factors secretion. In addition, TL1A/ DR3 was shown to act as a death trigger for necroptosis in the absence of caspases by silencing or overexpressing TL1A in HBE cells. Furthermore, the recombinant TL1A protein was found to induce necroptosis in vivo, and knockout of MLKL partially reversed the pathological changes induced by TL1A. The necroptosis induced by TL1A disrupted the airway barrier function by decreasing the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin, possibly through the activation of the NF-κB signaling pathway. CONCLUSIONS: TL1A-induced airway epithelial necroptosis plays a significant role in promoting airway inflammation and barrier dysfunction in asthma. Inhibition of the TL1A-induced necroptosis pathway could be a promising therapeutic strategy.


Asunto(s)
Asma , Ratones Noqueados , Necroptosis , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Animales , Asma/metabolismo , Asma/patología , Necroptosis/fisiología , Humanos , Ratones , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Masculino , Femenino , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Ratones Endogámicos C57BL , Proteínas Quinasas/metabolismo , Inflamación/metabolismo , Inflamación/patología , Ovalbúmina/toxicidad
5.
Cytopathology ; 35(3): 398-403, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38441189

RESUMEN

The cytomorphology of MPNST in effusion specimens is rarely described. In this paper, the detailed cytopathological and immunohistochemical characteristics of metastatic MPNST has been described in pleural effusion. Patients' medical history and the judicious utilization of ancillary studies contribute to ensure precise cytological diagnoses. The cytomorphology of malignant peripheral nerve sheath tumour (MPNST) in effusion specimens can be diagnostically challenging. The author presents detailed cytopathological and immunohistochemical characteristics of a case of metastatic MPNST in pleural effusion.


Asunto(s)
Neoplasias Primarias Secundarias , Neurofibrosarcoma , Derrame Pleural Maligno , Derrame Pleural , Humanos , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/patología
6.
Ecotoxicol Environ Saf ; 275: 116230, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38552389

RESUMEN

Epidemiological evidence on the health effects of pesticide exposure among greenhouse workers is limited, and the mechanisms are lacking. Building upon our team's previous population study, we selected two pesticides, CPF and EB, with high detection rates, based on the theoretical foundation that the liver serves as a detoxifying organ, we constructed a toxicity model using HepG2 cells to investigate the impact of individual or combined pesticide exposure on the hepatic metabolism profile, attempting to identify targeted biomarkers. Our results showed that CPF and EB could significantly affect the survival rate of HepG2 cells and disrupt their metabolic profile. There were 117 metabolites interfered by CPF exposure, which mainly affected ABC transporter, biosynthesis of amino acids, center carbon metabolism in cancer, fatty acid biosynthesis and other pathways, 95 metabolites interfered by EB exposure, which mainly affected center carbon metabolism in cancer, HIF-1 signaling pathway, valine, leucine and isoleucine biosynthesis, fatty acid biosynthesis and other pathways. The cross analysis and further biological experiments confirmed that CPF and EB pesticide exposure may affect the HIF-1 signaling pathway and valine, leucine and isoleucine biosynthesis in HepG2 cells, providing reliable experimental evidence for the prevention and treatment of liver damage in greenhouse workers.


Asunto(s)
Cloropirifos , Insecticidas , Ivermectina/análogos & derivados , Plaguicidas , Humanos , Cloropirifos/toxicidad , Cloropirifos/metabolismo , Plaguicidas/toxicidad , Células Hep G2 , Leucina , Isoleucina , Carbono , Valina , Ácidos Grasos , Insecticidas/toxicidad , Insecticidas/metabolismo
7.
Zhongguo Zhong Yao Za Zhi ; 49(14): 3868-3877, 2024 Jul.
Artículo en Zh | MEDLINE | ID: mdl-39099360

RESUMEN

The study investigated the effect of Compound Shougong Powder(CSGP) on the biological functions of triple-negative breast cancer(TNBC) cells and whether its mechanism of action was related to the epithelial-mesenchymal transition(EMT) signaling pathway. TNBC cells(MDA-MB-231 and BT-549) were treated with different concentrations of CSGP-containing serum. MTS assay was used to detect the effect of CSGP on the proliferation of TNBC cells. The EdU staining was used to detect the effect of CSGP on the proliferation of TNBC cells. Flow cytometry was used to examine the impact of CSGP on apoptosis of TNBC cells. Wound-healing and Transwell assays were used to evaluate the effects of different concentrations of CSGP on the migration and invasion capabilities of TNBC cells. RNA sequencing technology was utilized to elucidate its mechanism. Subsequently, qRT-PCR was performed to measure the mRNA expression levels of E-cadherin, N-cadherin, Slug, Snail, Vimentin, Twist, Zinc finger E-box-Binding homeobox 1(Zeb1), and Zinc finger E-box-Binding homeobox 2(Zeb2). Western blot was used to assess the protein expression levels of Slug, Vimentin, and E-cadherin. After intervention with CSGP, the proliferation of MDA-MB-231 and BT-549 cells significantly decreased, while the apoptosis rate markedly increased. The expression levels of the epithelial marker protein E-cadherin significantly increased, while the expression levels of the EMT-related transcription factors Slug and Vimentin showed a decrease. In conclusion, CSGP inhibits the EMT, thereby suppressing the malignant progression of TNBC.


Asunto(s)
Apoptosis , Proliferación Celular , Medicamentos Herbarios Chinos , Transición Epitelial-Mesenquimal , Neoplasias de la Mama Triple Negativas , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Medicamentos Herbarios Chinos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Polvos/química , Cadherinas/genética , Cadherinas/metabolismo
8.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 41(2): 360-367, 2024 Apr 25.
Artículo en Zh | MEDLINE | ID: mdl-38686418

RESUMEN

Tumor-treating fields (TTFields) is a novel treatment modality for malignant solid tumors, often employing electric field simulations to analyze the distribution of electric fields on the tumor under different parameters of TTFields. Due to the present difficulties and high costs associated with reproducing or implementing the simulation model construction techniques, this study used readily available open-source software tools to construct a highly accurate, easily implementable finite element simulation model for TTFields. The accuracy of the model is at a level of 1 mm 3. Using this simulation model, the study carried out analyses of different factors, such as tissue electrical parameters and electrode configurations. The results show that factors influncing the distribution of the internal electric field of the tumor include changes in scalp and skull conductivity (with a maximum variation of 21.0% in the treatment field of the tumor), changes in tumor conductivity (with a maximum variation of 157.8% in the treatment field of the tumor), and different electrode positions and combinations (with a maximum variation of 74.2% in the treatment field of the tumor). In summary, the results of this study validate the feasibility and effectiveness of the proposed modeling method, which can provide an important reference for future simulation analyses of TTFields and clinical applications.


Asunto(s)
Simulación por Computador , Análisis de Elementos Finitos , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/radioterapia , Electrodos , Conductividad Eléctrica , Programas Informáticos , Cuero Cabelludo , Cráneo
9.
Angew Chem Int Ed Engl ; : e202412796, 2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-39126151

RESUMEN

Photocatalytic overall splitting of pure water (H2O) without sacrificial reagent to hydrogen (H2) and oxygen (O2) holds a great potential for achieving carbon neutrality. Herein, by anchoring cobalt sulfide (Co9S8) as cocatalyst and cadmium sulfide (CdS) as light absorber to channel wall of a porous polymer microreactor (PP12), continuous violent H2 and O2 bubbling productions from photocatalytic overall splitting of pure H2O without sacrificial reagent is achieved, with H2 and O2 production rates as high as 4.41 and 2.20 mmol h-1 gcat.-1 respectively. These are significantly enhanced than those in the widely used stirred tank-type reactor in which no O2 is produced and H2 production rate is only 0.004 mmol h-1 gcat.-1. Besides improved charge separation and interaction of H2O with photocatalyst in PP12, bonding interaction of Co9S8 with PP12 creates abundant catalytic active sites for simultaneous productions of H2 and O2, thus leading to the significantly enhanced H2 and O2 bubbling productions in PP12. This offers a new strategy to enhance photocatalytic overall splitting of pure H2O without sacrificial reagent.

10.
Angew Chem Int Ed Engl ; 63(18): e202402369, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38446496

RESUMEN

Solar-energy-driven photoreduction of CO2 is promising in alleviating environment burden, but suffers from low efficiency and over-reliance on sacrificial agents. Herein, rhenium (Re) is atomically dispersed in In2O3 to fabricate a 2Re-In2O3 photocatalyst. In sacrificial-agent-free photoreduction of CO2 with H2O, 2Re-In2O3 shows a long-term stable efficiency which is enhanced by 3.5 times than that of pure In2O3 and is also higher than those on Au-In2O3, Ag-In2O3, Cu-In2O3, Ir-In2O3, Ru-In2O3, Rh-In2O3 and Pt-In2O3 photocatalysts. Moreover, carbon-based product of the photoreduction overturns from CO on pure In2O3 to CH3OH on 2Re-In2O3. Re promotes charge separation, H2O dissociation and CO2 activation, thus enhancing photoreduction efficiency of CO2 on 2Re-In2O3. During the photoreduction, CO is a key intermediate. CO prefers to desorption rather than hydrogenation on pure In2O3, as CO binds to pure In2O3 very weakly. Re strengthens the interaction of CO with 2Re-In2O3 by 5.0 times, thus limiting CO desorption but enhancing CO hydrogenation to CH3OH. This could be the origin for photoreduction product overturn from CO on pure In2O3 to CH3OH on 2Re-In2O3. The present work opens a new way to boost sacrificial-agent-free photoreduction of CO2.

11.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(5): 529-534, 2024 May 15.
Artículo en Zh | MEDLINE | ID: mdl-38802916

RESUMEN

Functional gastrointestinal disorders (FGIDs) are common digestive system diseases in children, which can severely affect the growth and development of infants and toddlers. Probiotics therapy, as a relatively safe treatment method, have attracted the attention of researchers. However, their effectiveness in treating FGIDs in infants and toddlers is still unclear. This article reviews the mechanisms of probiotics in treating FGIDs in infants and toddlers, explores the reasons for the inconsistency in various research results, and aims to provide assistance for the clinical treatment of FGIDs in infants and toddlers and future research.


Asunto(s)
Enfermedades Gastrointestinales , Probióticos , Humanos , Probióticos/uso terapéutico , Enfermedades Gastrointestinales/terapia , Lactante , Preescolar
12.
J Proteome Res ; 22(11): 3640-3651, 2023 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-37851947

RESUMEN

Inflammation plays an important role in the development of sepsis-acute respiratory distress syndrome (ARDS). Olink inflammation-related biomarker panels were used to analyze the levels of 92 inflammation-related proteins in plasma with sepsis-ARDS (n = 25) and healthy subjects (n = 25). There were significant differences in 64 inflammatory factors, including TNFRSF11B in sepsis-ARDS, which was significantly higher than that in controls. Functional analysis showed that TNFRSF11B was closely focused on signal transduction, immune response, and inflammatory response. The TNFRSF11B level in sepsis-ARDS plasma, LPS-induced mice, and LPS-stimulated HUVECs significantly increased. The highest plasma concentration of TNFRSF11B in patients with sepsis-ARDS was 10-20 ng/mL, and 10 ng/mL was selected to stimulate HUVECs. Western blot results demonstrated that the levels of syndecan-1, claudin-5, VE-cadherin, occludin, aquaporin-1, and caveolin-1 in TNFRSF11B-stimulated HUVECs decreased, whereas that of connexin-43 increased in TNFRSF11B-stimulated HUVECs. To the best of the authors' knowledge, this study was the first to reveal elevated TNFRSF11B in sepsis-ARDS associated with vascular endothelial dysfunction. In summary, TNFRSF11B may be a new potential predictive and diagnostic biomarker for vascular endothelium damage in sepsis-ARDS.


Asunto(s)
Osteoprotegerina , Síndrome de Dificultad Respiratoria , Sepsis , Enfermedades Vasculares , Animales , Humanos , Ratones , Biomarcadores/sangre , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Osteoprotegerina/sangre , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/complicaciones , Síndrome de Dificultad Respiratoria/diagnóstico , Sepsis/sangre , Sepsis/complicaciones , Sepsis/diagnóstico , Enfermedades Vasculares/sangre , Enfermedades Vasculares/complicaciones , Enfermedades Vasculares/diagnóstico
13.
Respir Res ; 24(1): 182, 2023 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-37434162

RESUMEN

Alveolar epithelial barrier is a potential therapeutic target for acute respiratory distress syndrome (ARDS). However, an effective intervention against alveolar epithelial barrier has not been developed. Here, based on single-cell RNA and mRNA sequencing results, death receptor 3 (DR3) and its only known ligand tumor necrosis factor ligand-associated molecule 1A (TL1A) were significantly reduced in epithelium from an ARDS mice and cell models. The apparent reduction in the TL1A/DR3 axis in lungs from septic-ARDS patients was correlated with the severity of the disease. The examination of knockout (KO) and alveolar epithelium conditional KO (CKO) mice showed that TL1A deficiency exacerbated alveolar inflammation and permeability in lipopolysaccharide (LPS)-induced ARDS. Mechanistically, TL1A deficiency decreased glycocalyx syndecan-1 and tight junction-associated zonula occludens 3 by increasing cathepsin E level for strengthening cell-to-cell permeability. Additionally, DR3 deletion aggravated barrier dysfunction and pulmonary edema in LPS-induced ARDS through the above mechanisms based on the analyses of DR3 CKO mice and DR3 overexpression cells. Therefore, the TL1A/DR3 axis has a potential value as a key therapeutic signaling for the protection of alveolar epithelial barrier.


Asunto(s)
Miembro 25 de Receptores de Factores de Necrosis Tumoral , Síndrome de Dificultad Respiratoria , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Animales , Ratones , Epitelio , Ligandos , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/genética , Factor de Necrosis Tumoral alfa , Miembro 25 de Receptores de Factores de Necrosis Tumoral/genética , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética
14.
Diabet Med ; 40(2): e14968, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36209373

RESUMEN

AIMS: Experiments confirmed that circular RNAs contributed to the pathogenesis of diabetic foot ulcers (DFUs). CircHIPK3 was upregulated in type 2 diabetes mellitus (T2DM), but its role in DFU remained unknown. Our study aimed to investigate the regulatory functions of exosomal circHIPK3 and its potential mechanisms in DFU. METHODS: Exosomal size and distribution, marker proteins, and circHIPK3 levels were evaluated by transmission electron microscope, ExoView R200, western blot, and qRT-PCR. Flow cytometry, MTT, Wound healing assays, and tube formation assays were used to assess the roles of exosomal circHIPK3 in high glucose (HG)-treated human umbilical vein endothelial cells (HUVECs). The relationships between Nrf2/VEGFA/circHIPK3 and miR-20b-5p, and between Nrf2 and VEGFA were determined by luciferase reporter assay and RNA immunoprecipitation. We used cell and mice models to investigate the mechanisms of exosomal circHIPK3 under diabetic conditions. RESULTS: CircHIPK3 was significantly upregulated in exo-circHIPK3 rather than exo-vector. Exo-circHIPK3 remarkably inhibited cell apoptosis but promoted cell proliferation, migration, and tube formation in HG-treated HUVECs. Luciferase reporter and RIP assays showed that miR-20b-5p targeted and inhibited Nrf2 and VEGFA, and circHIPK3 acted as a ceRNA of miR-20b-5p to inhibit the binding to its downstream genes Nrf2 and VEGFA. Mechanistically, circHIPK3 promoted cell proliferation, migration, and angiogenesis via downregulating miR-20b-5p to upregulate Nrf2 and VEGFA. However, the overexpressed miR-20b-5p could abolish the promoting effects of circHIPK3 overexpression on cell proliferation, migration, and tube formation under HG conditions. CONCLUSION: UCMSCs-derived exosomal circHIPK3 protected HG-treated HUVECs via miR-20b-5p/Nrf2/VEGFA axis. The exosomal circHIPK3 might be a therapeutic candidate to treat DFU.


Asunto(s)
Diabetes Mellitus Tipo 2 , MicroARNs , Humanos , Ratones , Animales , MicroARNs/genética , MicroARNs/metabolismo , MicroARNs/farmacología , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/farmacología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Proliferación Celular/genética , Factor A de Crecimiento Endotelial Vascular
15.
BMC Cardiovasc Disord ; 23(1): 370, 2023 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-37488501

RESUMEN

OBJECTIVE: The purpose of this meta-analysis is to evaluate the role of high-intensity statin pretreatment on coronary microvascular dysfunction in patients with coronary heart disease undergoing percutaneous coronary intervention (PCI). METHODS: PubMed, Cochrane, and Embase were searched. This meta-analysis selection included randomized controlled trials (RCTs), involving high-intensity statin pretreatment as active treatment, and measurement of thrombolysis in myocardial infarction (TIMI), myocardial blush grade (MBG) or index of microvascular resistance (IMR) in coronary heart disease (CHD) patients undergoing PCI. I2 test was used to evaluate heterogeneity. Pooled effects of continuous variables were reported as Standard mean difference (SMD) and 95% confidence intervals (CI). Pooled effects of discontinuous variables were reported as risk ratios (RR) and 95% confidence intervals (CI). Random-effect or fix-effect meta-analyses were performed. The Benefit was further examined based on clinical characteristics including diagnosis and statin type by using subgroup analyses. Publication bias was examined by quantitative Egger's test and funnel plot. We performed sensitivity analyses to examine the robustness of pooled effects. RESULTS: Twenty RCTs were enrolled. The data on TIMI < 3 was reported in 18 studies. Comparing with non-high-intensity statin, high-intensity statin pretreatment significantly improved TIMI after PCI (RR = 0.62, 95%CI: 0.50 to 0.78, P < 0.0001). The data on MBG < 2 was reported in 3 studies. The rate of MBG < 2 was not different between groups (RR = 1.29, 95% CI: 0.87 to 1.93, P = 0.21). The data on IMR was reported in 2 studies. High-dose statin pretreatment significantly improved IMR after PCI comparing with non-high-dose statin (SMD = -0.94, 95% CI: -1.47 to -0.42, P = 0.0004). There were no significant between-subgroup differences in subgroups based on statin type and diagnosis. Publication bias was not indicated by using quantitative Egger's test (P = 0.97) and funnel plot. Sensitivity analyses confirmed the robustness of these findings. CONCLUSIONS: Comparing with non-high-intensity statin, high-intensity statin pretreatment significantly improved TIMI and IMR after PCI. In the future, RCTs with high quality and large samples are needed to test these endpoints.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Infarto del Miocardio , Isquemia Miocárdica , Humanos , Miocardio , Oportunidad Relativa
16.
Appl Opt ; 62(19): 5115-5125, 2023 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-37707214

RESUMEN

Dynamic 3D displacement field measurement is an effective means to characterize the electrical performance stability and structural soundness of microsystems. Combining off-axis lensless Fourier transform multiplexed digital holography and multi-illumination profilometry, a dual-wavelength dual-camera optical setup with a multi-illumination system is developed to simultaneously acquire four phase images with different sensitivity vectors, as well as the object shapes. Meanwhile, the shared reference wave in off-axis lensless Fourier holography gives a convenient way for sensitivity vector modification and phase image registration, which are based on the stereo checkerboard calibration method. The dynamic 3D displacement fields and the strain maps of an energized integrated circuit board reveal that the inhomogeneous thermal expansion may cause some damage to chips, such as pin desoldering and microstructure fracture.

17.
Proc Natl Acad Sci U S A ; 117(12): 6559-6570, 2020 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-32156735

RESUMEN

Secretagogin (SCGN) is a hexa-EF-hand protein that is highly expressed in the pancreas, brain, and gastrointestinal tract. SCGN is known to modulate regulated exocytosis in multiple cell lines and tissues; however, its exact functions and underlying mechanisms remain unclear. Here, we report that SCGN interacts with the plasma membrane SNARE SNAP-25, but not the assembled SNARE complex, in a Ca2+-dependent manner. The crystal structure of SCGN in complex with a SNAP-25 fragment reveals that SNAP-25 adopts a helical structure and binds to EF-hands 5 and 6 of SCGN. SCGN strongly inhibits SNARE-mediated vesicle fusion in vitro by binding to SNAP-25. SCGN promotes the plasma membrane localization of SNAP-25, but not Syntaxin-1a, in SCGN-expressing cells. Finally, SCGN controls neuronal growth and brain development in zebrafish, likely via interacting with SNAP-25 or its close homolog, SNAP-23. Our results thus provide insights into the regulation of SNAREs and suggest that aberrant synapse functions underlie multiple neurological disorders caused by SCGN deficiency.


Asunto(s)
Exocitosis , Secretagoginas/química , Secretagoginas/metabolismo , Animales , Sitios de Unión , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Calcio/metabolismo , Línea Celular , Membrana Celular/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Mutación , Unión Proteica , Conformación Proteica , Secretagoginas/genética , Proteína 25 Asociada a Sinaptosomas/genética , Proteína 25 Asociada a Sinaptosomas/metabolismo , Pez Cebra
18.
Anim Biotechnol ; 34(3): 574-584, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34629027

RESUMEN

DNA methyltransferase 2 (DNMT2) was renamed as tRNA aspartic acid methyltransferase 1 (TRDMT1) by catalyzing the methylation of tRNAAsp anti-codon loop C38. The development of sequencing of nucleic acids and protein detection techniques have prompted the demonstration that TRDMT1 mediated tRNA modification affects protein synthesis efficiency. This process affects the growth and development of animals. The DNA of 224 Qinchuan cattles aged 2-4 years old was collected in this experiment. The genetic variations of TRDMT1 exon and some intron regions were detected by mixed pool sequencing technology. qRT-PCR and Western Blot were used to detect the expression levels of mRNA and protein produced with the combination of different genetic variant loci. Three haplotypes were detected and the distribution ratios were different. Muscle tissue mRNA and protein testing showed that there were differences in mRNA expression levels among different genotypes (P < 0.05) and the protein expression levels between different genotypes show the same trend as mRNA. This study provides potential molecular materials for the improvement of Qinchuan cattle reproductivity and provides theoretical support for studying the effects of livestock TRDMT1 on animal growth and development.


Asunto(s)
Pesos y Medidas Corporales , Polimorfismo de Nucleótido Simple , Bovinos/genética , Animales , Genotipo , Haplotipos , ARN Mensajero/genética , ARN Mensajero/metabolismo
19.
Ecotoxicol Environ Saf ; 250: 114470, 2023 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-36586163

RESUMEN

Chlorpyrifos (CPF) is associated with depression, cognitive dysfunction, and other neurological disorders. Increasing evidence has suggested that the gut microbiota plays a vital role in regulating the development of depression. However, it is unknown whether gut microbiota is associated with CPF-related depression. This study aimed to explore the effect of CPF on depressive-like behavior in mice and investigated the role of gut microbiota in this behavior. In our study, we selected fifty male C57BL/6 J mice for the model and subjected them to CPF poisoning by gavage for 14 days. The depressive-like behaviors of mice were assessed by the open field test (OFT), sucrose preference test (SPT), and forced swimming test (FST). Furthermore, we selected the high-dose group (CPF10) with obvious changes in depressive-like behaviors for the hippocampus and colon histopathological analysis, examined the changes in the gut microbiota by 16 S rRNA sequencing, screened the different microbiota among groups by linear discriminant analysis effect size (LEfSe), analyzed the correlation between intestinal bacteria and depression-like behavior indicators by Spearman analysis, and evaluated the predictive ability of different bacteria to CPF-induced depressive-like behavior using the receiver operator characteristic (ROC) curve. The results showed that CPF caused depressive-like behaviors with pathological changes in the hippocampus and colon. CPF induced changes in gut microbiota, including 49 differential bacteria. Among the top 10 abundant bacteria, Actinobacteria and Deferribacteres were increased, and Cyanobacteria, Patescibacteria and Verrucomicrobia were decreased at the phylum level. Muribaculum, Ruminococcaceae.UCG.014 and uncultured Bacteroides bacterium were decreased at the genus level. Correlation analysis demonstrated that 18 differentially abundant bacteria were correlated with CPF-induced depression. ROC curves revealed that Deferribacteres, Mucispirillum, Rikenella and GCA900066575 are potential biomarkers for depression caused by CPF. These findings will provide an experimental basis for the neurological health of the pesticide-exposed population.


Asunto(s)
Cloropirifos , Microbioma Gastrointestinal , Plaguicidas , Ratones , Masculino , Animales , Cloropirifos/toxicidad , Ratones Endogámicos C57BL , Depresión/inducido químicamente , Plaguicidas/farmacología , Conducta Animal
20.
Pharm Biol ; 61(1): 165-176, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36604842

RESUMEN

CONTEXT: Luteolin can affect multiple biological functions, such as anti-inflammatory, antioxidant and immune enhancement processes. Luteolin can inhibit inflammation of T2-high asthma, but its role in neutrophilic asthma has been insufficently studied. OBJECTIVE: This study determines the effect of luteolin on IL-36γ secretion-mediated MAPK pathway signalling in neutrophilic asthma. MATERIALS AND METHODS: The asthma model was established by using ovalbumin/lipopolysaccharide (OVA/LPS). Female 6-8-week-old C57BL/6 mice were divided into control, asthma, luteolin (20 mg/kg) and asthma + luteolin (20 mg/kg) groups. To explore the mechanism of anti-inflammatory effects of luteolin in neutrophilic asthma, Beas-2B cells were treated with luteolin (20 µmol/L), LPS (100 ng/mL), recombinant human IL-36γ protein (rhIL-36γ; 100 ng/mL) or IL-36γ siRNA. RESULTS: IL-36γ secretion and MAPK/IL-1ß signalling were significantly increased in the asthma mouse model compared with the control (p < 0.05). However, the levels of IL-36γ secretion and MAPK/IL-1ß signalling were reduced by luteolin (p < 0.05). In addition, luteolin inhibited IL-36γ and MAPK/IL-1ß levels after LPS (100 ng/mL) stimulation of Beas-2B cells (p < 0.05). We found that in Beas-2B cells, luteolin inhibited activation of the MAPK pathway and IL-1ß secretion following stimulation with rhIL-36γ (100 ng/mL; p < 0.05). Finally, IL-1ß and phosphorylated MAPK levels were found to be lower in the IL-36γ siRNA + LPS (100 ng/mL) group than in the nonspecific control (NC) siRNA + LPS group (p < 0.05). DISCUSSION AND CONCLUSIONS: Luteolin alleviated neutrophilic asthma by inhibiting IL-36γ secretion-mediated MAPK pathways. These findings provided a theoretical basis for the application of luteolin in the treatment of neutrophilic asthma.


Asunto(s)
Asma , Interleucina-1 , Luteolina , Animales , Femenino , Humanos , Ratones , Antiinflamatorios/uso terapéutico , Luteolina/farmacología , Ratones Endogámicos C57BL , ARN Interferente Pequeño , Interleucina-1/farmacología
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