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BACKGROUND: Globally, only 13.8% of patients with hypertension have their blood pressure (BP) controlled. Trials testing interventions to overcome barriers to BP control have produced mixed results. Type of health care professional delivering the intervention may play an important role in intervention success. The goal of this meta-analysis is to determine which health care professionals are most effective at delivering BP reduction interventions. METHODS: We searched Medline and Embase (until December 2023) for randomized controlled trials of interventions targeting barriers to hypertension control reporting who led intervention delivery. One hundred articles worldwide with 116 comparisons and 90â 474 participants with hypertension were included. Trials were grouped by health care professional, and the effects of the intervention on systolic and diastolic BP were combined using random effects models and generalized estimating equations. RESULTS: Pharmacist-led interventions , community health worker-led interventions, and health educator-led interventions resulted in the greatest systolic BP reductions of -7.3 (95% CI, -9.1 to -5.6), -7.1 (95% CI, -10.8 to -3.4), and -5.2 (95% CI, -7.8 to -2.6) mmâ Hg, respectively. Interventions led by multiple health care professionals, nurses, and physicians also resulted in significant systolic BP reductions of -4.2 (95% CI, -6.1 to -2.4), -3.0 (95% CI, -4.2 to -1.9), and -2.4 (95% CI, -3.4 to -1.5) mmâ Hg, respectively. Similarly, the greatest diastolic BP reductions were -3.9 (95% CI, -5.2 to -2.5) mmâ Hg for pharmacist-led and -3.7 (95% CI, -6.6 to -0.8) mmâ Hg for community health worker-led interventions. In pairwise comparisons, pharmacist were significantly more effective than multiple health care professionals, nurses, and physicians at delivering interventions. CONCLUSIONS: Pharmacists and community health workers are most effective at leading BP intervention implementation and should be prioritized in future hypertension control efforts.
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Background: To assess the alterations in gingival thickness and the occurrence gingival recession subsequent to orthodontic-orthognathic treatment of mandibular incisors in skeletal Class III and identify risk factors associated with gingival recession. Methods: In this retrospective cohort study, we enrolled 33 patients exhibiting skeletal Class III malocclusion, totaling 131 mandibular incisors, who were undergoing orthodontic- orthognathic treatment that did not involve extraction of mandibular teeth. The subjects were categorized into surgery group (S; n = 17; ANB = -5.55 ± 3.26; IOFTN = 4.60 ± 0.51, scores ranging: 4.3-5.3) and non-surgery group (NS; n = 16; ANB = -3.00 ± 4.08; IOFTN = 4.63 ± 0.50, scores ranging: 4.3-5.4), based on if they had history of Periodontally Accelerated Osteogenic Orthodontics surgery (S) or not (NS). Patients in S group received orthognathic surgery about 1-1.5 years after Periodontally Accelerated Osteogenic Orthodontics surgery. Alterations in gingival thickness, gingival recession, and keratinized gingival width were compared before and after orthodontic-orthognathic treatment. Logistic regression analysis was used to construct a gingival recession prediction model and draw nomograms. Results: After orthodontic-orthognathic treatment, the gingival thickness and keratinized gingival width in NS group decreased by 0.15 ± 0.21 mm and 0.74 ± 0.91 mm, whereas those in the S group increased by 0.32 ± 0.28 mm and 2.09 ± 1.51 mm (P < 0.05). After orthodontic-orthognathic, the percentage of gingival recession increased by 47.62 % in NS group, which was 14.77 times that of S group (P < 0.05). Multivariate regression analysis indicated that skeletal Class III patients with a gingival thickness below 0.72 mm, an alveolar bone height exceeding 2.36 mm, and an alveolar bone thickness under 0.45 mm might be at elevated risk for developing gingival recession following orthodontic - orthognathic therapy. Conclusions: Drawing on the findings of our investigation, we concluded the risk of gingival recession of mandibular anterior teeth increased after orthodontic-orthognathic treatment in skeletal Class III, whereas Periodontally Accelerated Osteogenic Orthodontics surgery could significantly improve the periodontal phenotype and prevent gingival recession.
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OBJECTIVE: To investigate the effects of luteolin on chronic unpredictable mild stress (CUMS)-induced depressive rats and corticosterone (CORT)-induced depressive primary hippocampal neurons, and to elucidate the mechanism behind the action. METHODS: The antidepressant mechanism of luteolin was studied by using CUMS rat model and primary hippocampal neurons in fetal rats. In vivo, novelty suppressed feeding, open-field and sucrose preference tests as well as Morris water maze were evaluated. The content of brain derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) in serum were detected by enzyme-linked immunosorbent assay. The mechanisms of luteolin were explored based on neurotrophin and hippocampal neurogenesis, and proliferation. Survival of the septo-temporal axis in hippocampus was assayed using the 5-bromo-2-deoxyuridine (BrdU), the expression of BDNF, neurotrophin-3 (NT-3), and nerve growth factor (NGF) in hippocampus dentate gyrus region were measured by Western-blotting. In vitro, BDNF, NT-3, tropomyosin receptor kinase B (TrkB), and phosphorylated cyclic adenosine monophosphate responsive element binding protein (p-CREB) were detected through the high content analysis (HCA) to investigate neurotrophin and apoptosis. RESULTS: Induction of CUMS in rats induced depressive symptoms, while luteolin significantly enhanced sucrose consumption, decreased feeding latency, increased locomotor activity, escape latency, distance of target quadrant and regulated the content of depressive-like biomarkers. Histology analysis revealed that luteolin increased the abundance of new born neurons that had been labeled with BrdU, BrdU + neuronal nuclear antigen, and BrdU + doublecortin in septo-temporal axis of S2 (mid-septal) and T3 (mid-temporal). Moreover, expression of BDNF, NT-3, and NGF increased significantly in the septo-temporal axis of S2 and T3. HCA showed increased expression of BDNF, NT-3, TrkB and p-CREB in primary hippocampal neurons. CONCLUSION: The results provided direct evidence that luteolin has an antidepressant effect and could effectively promote the regeneration of the septotemporal axis nerve and hippocampal neuronutrition, which suggested that the antidepressant effect of luteolin may be related to hippocampal neurogenesis.
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Factor Neurotrófico Derivado del Encéfalo , Hipocampo , Luteolina , Neurogénesis , Neuronas , Ratas Sprague-Dawley , Animales , Luteolina/farmacología , Ratas , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Neurogénesis/efectos de los fármacos , Masculino , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Humanos , Estrés Psicológico/fisiopatología , Estrés Psicológico/tratamiento farmacológico , Femenino , Depresión/tratamiento farmacológico , Depresión/metabolismo , Depresión/fisiopatología , Antidepresivos/farmacología , Neurotrofina 3/metabolismo , Neurotrofina 3/genéticaRESUMEN
Estrogen is an important hormone that plays a role in regulating follicle development and oocyte maturation. Transzonal projections (TZPs) act as communication bridges between follicle somatic cells and oocytes, and their dynamic changes are critical for oocyte development and maturation. However, the roles and mechanisms of estrogen in regulating TZPs during follicular development are not yet understood. We found that the proportion of oocytes spontaneously resuming meiosis increases as the follicle grows, which is accompanied by rising estrogen levels in follicles and decreasing TZPs in cumulus-oocyte complex. To further explore the effect of elevated estrogen levels on TZP assembly, additional estrogen was added to the culture system. The increased estrogen level significantly decreased the mRNA and protein expression levels of TZP assembly-related genes. Subsequent research revealed that TZP regulation by estrogen was mediated by the membrane receptor GPER and downstream ERK1/2 signaling pathway. In summary, our study suggests that estrogen may regulate goat oocyte meiosis arrest by decreasing TZP numbers via estrogen-mediated GPER activation during follicle development.
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Células del Cúmulo , Estrógenos , Cabras , Oocitos , Folículo Ovárico , Receptores de Estrógenos , Receptores Acoplados a Proteínas G , Animales , Oocitos/metabolismo , Oocitos/citología , Femenino , Células del Cúmulo/metabolismo , Células del Cúmulo/citología , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores de Estrógenos/metabolismo , Estrógenos/metabolismo , Folículo Ovárico/metabolismo , Folículo Ovárico/crecimiento & desarrollo , Folículo Ovárico/citología , Meiosis/fisiología , Sistema de Señalización de MAP Quinasas/fisiologíaRESUMEN
Cell membrane-camouflaged nanoparticles possess inherent advantages derived from their membrane structure and surface antigens, including prolonged circulation in the bloodstream, specific cell recognition and targeting capabilities, and potential for immunotherapy. Herein, we introduce a cell membrane biomimetic nanodrug platform termed MPB-3BP@CM NPs. Comprising microporous Prussian blue nanoparticles (MPB NPs) serving as both a photothermal sensitizer and carrier for 3-bromopyruvate (3BP), these nanoparticles are cloaked in a genetically programmable cell membrane displaying variants of signal regulatory protein α (SIRPα) with enhanced affinity to CD47. As a result, MPB-3BP@CM NPs inherit the characteristics of the original cell membrane, exhibiting an extended circulation time in the bloodstream and effectively targeting CD47 on the cytomembrane of colorectal cancer (CRC) cells. Notably, blocking CD47 with MPB-3BP@CM NPs enhances the phagocytosis of CRC cells by macrophages. Additionally, 3BP, an inhibitor of hexokinase II (HK2), suppresses glycolysis, leading to a reduction in adenosine triphosphate (ATP) levels and lactate production. Besides, it promotes the polarization of tumor-associated macrophages (TAMs) towards an anti-tumor M1 phenotype. Furthermore, integration with MPB NPs-mediated photothermal therapy (PTT) enhances the therapeutic efficacy against tumors. These advantages make MPB-3BP@CM NPs an attractive platform for the future development of innovative therapeutic approaches for CRC. Concurrently, it introduces a universal approach for engineering disease-tailored cell membranes for tumor therapy.
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Antígeno CD47 , Membrana Celular , Neoplasias Colorrectales , Nanopartículas , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Nanopartículas/química , Humanos , Antígeno CD47/genética , Ratones , Membrana Celular/metabolismo , Membrana Celular/genética , Animales , Piruvatos/química , Piruvatos/farmacología , Hexoquinasa/genética , Línea Celular Tumoral , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , FerrocianurosRESUMEN
The treatment of colorectal cancer is always a major challenge in the field of cancer research. The number of estimated new cases of colorectal cancer worldwide in 2020 is 1 148 515, and the estimated number of deaths is 576 858, revealing that mortality accounted for approximately half of the disease incidence. The development of new drugs and strategies for colorectal cancer treatment is urgently needed. Thermosensitive injectable hydrogel PDLLA-PEG-PDLLA (PLEL) loaded with cabazitaxel (CTX) is used to explore its anti-tumor effect on mice with orthotopic colorectal cancer. CTX/PLEL is characterized by a solution state at room temperature and a hydrogel state at physiologic temperature. The excipients MPEG-PCL and PDLLA-PEG-PDLLA have good biocompatibility and biodegradability. The simple material synthesis and preparation process renders this system cost-effective and more conducive to clinical transformation. An orthotopic colorectal cancer model is established by transplantation subcutaneous tumors onto the cecum of mice. According to the results of experiments in vivo, CTX/PLEL significantly inhibits orthotopic colorectal cancer and liver metastasis in mice. The results indicate that CTX/PLEL nanoparticle preparations have high security and excellent anti-tumor effects, and have great application potential in colorectal cancer therapy.
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During mammalian oocyte meiosis, spindle migration and asymmetric cytokinesis are unique steps for the successful polar body extrusion. The asymmetry defects of oocytes will lead to the failure of fertilization and embryo implantation. In present study, we reported that an actin nucleating factor Formin-like 2 (FMNL2) played critical roles in the regulation of spindle migration and organelle distribution in mouse and porcine oocytes. Our results showed that FMNL2 mainly localized at the oocyte cortex and periphery of spindle. Depletion of FMNL2 led to the failure of polar body extrusion and large polar bodies in oocytes. Live-cell imaging revealed that the spindle failed to migrate to the oocyte cortex, which caused polar body formation defects, and this might be due to the decreased polymerization of cytoplasmic actin by FMNL2 depletion in the oocytes of both mice and pigs. Furthermore, mass spectrometry analysis indicated that FMNL2 was associated with mitochondria and endoplasmic reticulum (ER)-related proteins, and FMNL2 depletion disrupted the function and distribution of mitochondria and ER, showing with decreased mitochondrial membrane potential and the occurrence of ER stress. Microinjecting Fmnl2-EGFP mRNA into FMNL2-depleted oocytes significantly rescued these defects. Thus, our results indicate that FMNL2 is essential for the actin assembly, which further involves into meiotic spindle migration and ER/mitochondria functions in mammalian oocytes.
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Actinas , Retículo Endoplásmico , Forminas , Meiosis , Mitocondrias , Oocitos , Animales , Femenino , Ratones , Actinas/metabolismo , Retículo Endoplásmico/metabolismo , Forminas/metabolismo , Forminas/genética , Mitocondrias/metabolismo , Oocitos/metabolismo , Huso Acromático/metabolismo , PorcinosRESUMEN
Zearalenone (ZEN) is an extremely hazardous chemical widely existing in cereals, and its high-sensitivity detection possesses significant significance to human health. Here, the cathodic aggregation-induced electrochemiluminescence (AIECL) performance of tetraphenylethylene nanoaggregates (TPE NAs) was modulated by solvent regulation, based on which an electrochemiluminescence (ECL) aptasensor was constructed for sensitive detection of ZEN. The aggregation state and AIECL of TPE NAs were directly and simply controlled by adjusting the type of organic solvent and the fraction of water, which solved the current shortcomings of low strength and weak stability of the cathode ECL signal for TPE. Impressively, in a tetrahydrofuran-water mixed solution (volume ratio, 6:4), the relative ECL efficiency of TPE NAs reached 16.03%, which was 9.2 times that in pure water conditions, and the maximum ECL spectral wavelength was obviously red-shifted to 617 nm. In addition, "H"-shape DNA structure-mediated dual-catalyzed hairpin self-assembly (H-D-CHA) with higher efficiency by the synergistic effect between the two CHA reactions was utilized to construct a sensitive ECL aptasensor for ZEN analysis with a low detection limit of 0.362 fg/mL. In conclusion, solvent regulation was a simple and efficient method for improving the performance of AIECL materials, and the proposed ECL aptasensor had great potential for ZEN monitoring in food safety.
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Técnicas Electroquímicas , Electrodos , Mediciones Luminiscentes , Solventes , Zearalenona , Zearalenona/análisis , Zearalenona/química , Solventes/química , Estilbenos/química , Límite de Detección , Técnicas Biosensibles , Aptámeros de Nucleótidos/químicaRESUMEN
Kinesin family member 3A (KIF3A) is a microtubule-oriented motor protein that belongs to the kinesin-2 family for regulating intracellular transport and microtubule movement. In this study, we characterized the critical roles of KIF3A during mouse oocyte meiosis. We found that KIF3A associated with microtubules during meiosis and depletion of KIF3A resulted in oocyte maturation defects. LC-MS data indicated that KIF3A associated with cell cycle regulation, cytoskeleton, mitochondrial function and intracellular transport-related molecules. Depletion of KIF3A activated the spindle assembly checkpoint, leading to metaphase I arrest of the first meiosis. In addition, KIF3A depletion caused aberrant spindle pole organization based on its association with KIFC1 to regulate expression and polar localization of NuMA and γ-tubulin; and KIF3A knockdown also reduced microtubule stability due to the altered microtubule deacetylation by histone deacetylase 6 (HDAC6). Exogenous Kif3a mRNA supplementation rescued the maturation defects caused by KIF3A depletion. Moreover, KIF3A was also essential for the distribution and function of mitochondria, Golgi apparatus and endoplasmic reticulum in oocytes. Conditional knockout of epithelial splicing regulatory protein 1 (ESRP1) disrupted the expression and localization of KIF3A in oocytes. Overall, our results suggest that KIF3A regulates cell cycle progression, spindle assembly and organelle distribution during mouse oocyte meiosis.
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Cinesinas , Oocitos , Animales , Ratones , Transporte Biológico , Cinesinas/genética , Meiosis , MetafaseRESUMEN
This study uses real-time monitoring, at microsecond time scales, with a charge-sensing particle detector to investigate the evaporation and fission processes of methanol/micrometer-sized polystyrene beads (PS beads) droplets and bacterial particles droplets generated via electrospray ionization (ESI) under elevated temperatures. By incrementally raising capillary temperatures, the solvent, such as methanol on 0.75 µm PS beads, experiences partial evaporation. Further temperature increase induces fission, and methanol molecules continue to evaporate until PS ions are detected after this range. Similar partial evaporation is observed on 3 µm PS beads. However, the shorter period of the fission temperature range is necessary compared to 0.75 µm PS beads. For the spherical-shaped bacterium, Staphylococcus aureus, the desolvation process shows a similar fission period as compared to 0.75 µm PS beads. Comparably, the rod-shaped bacteria, Escherichia coli EC11303, and E. coli strain W have shorter fission periods than S. aureus. This research provides insights into the evaporation and fission mechanisms of ESI droplets containing different sizes and shapes of micrometer-sized particles, contributing to a better understanding of gaseous macroion formation.
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Escherichia coli , Poliestirenos , Espectrometría de Masa por Ionización de Electrospray , Staphylococcus aureus , Poliestirenos/química , Escherichia coli/química , Tamaño de la Partícula , Temperatura , Volatilización , Metanol/química , MicroesferasRESUMEN
Rabbit hemorrhagic disease (RHD) is an acute fatal disease caused by the rabbit hemorrhagic disease virus (RHDV). Since the first outbreaks of type 2 RHDV (RHDV2) in April 2020 in China, the persistence of this virus in the rabbit population has caused substantial economic losses in rabbit husbandry. Previous failures in preventing RHDV2 prompted us to further investigate the immune mechanisms underlying the virus's pathogenicity, particularly concerning the spleen, a vital component of the mononuclear phagocyte system (MPS). For this, a previous RHDV2 isolate, CHN/SC2020, was utilized to challenge naive adult rabbits. Then, the splenic transcriptome was determined by RNA-Seq. This study showed that the infected adult rabbits had 3148 differentially expressed genes (DEGs), which were associated with disease, signal transduction, cellular processes, and cytokine signaling categories. Of these, 100 upregulated DEGs were involved in inflammatory factors such as IL1α, IL-6, and IL-8. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these DEGs were significantly enriched in the cytokine-cytokine receptor interaction signaling pathway, which may play a vital role in CHN/SC2020 infection. At the same time, proinflammatory cytokines and chemokines were significantly increased in the spleen at the late stages of infection. These findings suggested that RHDV2 (CHN/SC2020) might induce dysregulation of the cytokine network and compromise splenic immunity against viral infection, which expanded our understanding of RHDV2 pathogenicity.
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Infecciones por Caliciviridae , Citocinas , Virus de la Enfermedad Hemorrágica del Conejo , Bazo , Transcriptoma , Animales , Virus de la Enfermedad Hemorrágica del Conejo/genética , Virus de la Enfermedad Hemorrágica del Conejo/inmunología , Bazo/virología , Bazo/inmunología , Conejos , Infecciones por Caliciviridae/virología , Infecciones por Caliciviridae/inmunología , Infecciones por Caliciviridae/genética , Citocinas/metabolismo , Citocinas/genética , Perfilación de la Expresión Génica , Inflamación/virología , Inflamación/genéticaRESUMEN
BACKGROUND: The mortality is significantly higher in patients undergoing maintenance hemodialysis (MHD) than in the general population. It is well-known that vascular access (VA) is critical for MHD patients. But the association between VA satisfaction and all-cause mortality in MHD patients is still not clear. The aim of this study was to explore the relationship between VA satisfaction and all-cause mortality in MHD patients with a 30-month follow-up. METHODS: Two hundred twenty-nine MHD patients in two dialysis centers were enrolled in this observational prospective study. VA satisfaction was assessed using the Short Form Vascular Access Questionnaire (VAQ). Health-related quality of life (HRQoL) score was calculated with Short Form 36 (SF-36) questionnaire. Multiple logistic regression analysis was used to evaluate the influencing factors of all-cause mortality. RESULTS: During the 30-month follow-up period, 35 patients dropped out of the study. Among them, 31 patients died, and 4 patients stopped MHD treatment after renal transplantation. Multivariable analyses showed that the age, VAQ total score, social functioning score and dialysis-related complication score of the VAQ, the total score and MCS of the SF-36 were factors influencing all-cause mortality in MHD patients. The Kaplan-Meier curve further showed that the cumulative survival probability was significantly higher in the MHD patients with VAQ scores <7 at baseline than in patients with VAQ scores ⩾7 (p = 0.031). INCLUSION: The present study showed that VA satisfaction was significantly associated with all-cause mortality in MHD patients. These findings suggest that a holistic approach is required for VA choice.
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The gut microbiota is a crucial component of the intricate microecosystem within the human body that engages in interactions with the host and influences various physiological processes and pathological conditions. In recent years, the association between dysbiosis of the gut microbiota and tumorigenesis has garnered increasing attention, as it is recognized as a hallmark of cancer within the scientific community. However, only a few microorganisms have been identified as potential drivers of tumorigenesis, and enhancing the molecular understanding of this process has substantial scientific importance and clinical relevance for cancer treatment. In this review, we delineate the impact of the gut microbiota on tumorigenesis and treatment in multiple types of cancer while also analyzing the associated molecular mechanisms. Moreover, we discuss the utility of gut microbiota data in cancer diagnosis and patient stratification. We further outline current research on harnessing microorganisms for cancer treatment while also analyzing the prospects and challenges associated with this approach.
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Carcinogénesis , Disbiosis , Microbioma Gastrointestinal , Neoplasias , Humanos , Neoplasias/microbiología , Neoplasias/terapia , Disbiosis/microbiología , AnimalesRESUMEN
Pulmonary fibrosis (PF) is a serious and progressive fibrotic interstitial lung disease that is possibly life-threatening and that is characterized by fibroblast accumulation and collagen deposition. Nintedanib and pirfenidone are currently the only two FDA-approved oral medicines for PF. Some drugs such as antihelminthic drug niclosamide (Ncl) have shown promising therapeutic potentials for PF treatment. Unfortunately, poor aqueous solubility problems obstruct clinical application of these drugs. Herein, we prepared Ncl-encapsulated lipid nanoparticles (Ncl-Lips) for pulmonary fibrosis therapy. A mouse model of pulmonary fibrosis induced by bleomycin (BLM) was generated to assess the effects of Ncl-Lips and the mechanisms of reversing fibrosis in vivo. Moreover, cell models treated with transforming growth factor ß1 (TGFß1) were used to investigate the mechanism through which Ncl-Lips inhibit fibrosis in vitro. These findings demonstrated that Ncl-Lips could alleviate fibrosis, consequently reversing the changes in the levels of the associated marker. Moreover, the results of the tissue distribution experiment showed that Ncl-Lips had aggregated in the lung. Additionally, Ncl-Lips improved the immune microenvironment in pulmonary fibrosis induced by BLM. Furthermore, Ncl-Lips suppressed the TGFß1-induced activation of fibroblasts and epithelial-mesenchymal transition (EMT) in epithelial cells. Based on these results, we demonstrated that Ncl-Lips is an efficient strategy for reversing pulmonary fibrosis via drug-delivery.
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Background: It is crucial to probe into the biological effect and mechanism of miRNA-485-5p regulating keratin 17 (KRT17) in pancreatic cancer (PC) to understand its pathogenesis and identify potential biological targets. Methods: The bioinformatics means were used to evaluate the clinical significance of KRT17 expression in the Cancer Genome Atlas (TCGA) database. TargetScan database analysis in conjunction with dual luciferase and RNA Immunoprecipitation (RIP) experiments was used to probe the interaction relationship of miRNA-485-5p with KRT17. The expression of miRNA-485-5p and KRT17 in PC tissue and cancer cell lines was detected by Q-PCR paired with western blot assay. The biological function of miRNA-485-5p in regulating KRT17 was investigated in the PC cell line via gene silencing/overexpression technique. A western blot experiment was utilized to investigate the regulatory effect of KRT17 on cell cycle-related proteins and the FAK/Src/ERK signal pathway. Results: The level of KRT17 was increased in PC tissues and this significantly decreased the survival rate of PC patients. TargetScan in combination with dual luciferase and RIP experiments verified the miRNA-485-5p target KRT17. The expression of KRT17 was high in the PC cell line, although the expression of miRNA-485-5p was low. Silencing KRT17 or overexpression of miRNA-485-5p significantly inhibited PC cell viability, proliferation, invasion, and colony formation, while promoting apoptosis. Overexpression of KRT17 drastically reversed the function of miRNA-485-5p. The silenced KRT17 remarkably downregulated the expression of cyclinD1, Cyclin Dependent Kinase 1 (CDK1), CDK2, Phospho-Focal Adhesion Kinase (p-FAK), p-Src, and p-ERK proteins in the PC cells. Conclusion: Generally, an essential signaling cascade of miRNA-485-5p/KRT17/FAK/Src/ERK influences the biological functions of PC cells.
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BACKGROUND: T cell receptor (TCR) signaling and T cell activation are tightly regulated by gatekeepers to maintain immune tolerance and avoid autoimmunity. The TRAIL receptor (TRAIL-R) is a TNF-family death receptor that transduces apoptotic signals to induce cell death. Recent studies have indicated that TRAIL-R regulates T cell-mediated immune responses by directly inhibiting T cell activation without inducing apoptosis; however, the distinct signaling pathway that regulates T cell activation remains unclear. In this study, we screened for intracellular TRAIL-R-binding proteins within T cells to explore the novel signaling pathway transduced by TRAIL-R that directly inhibits T cell activation. METHODS: Whole-transcriptome RNA sequencing was used to identify gene expression signatures associated with TRAIL-R signaling during T cell activation. High-throughput screening with mass spectrometry was used to identify the novel TRAIL-R binding proteins within T cells. Co-immunoprecipitation, lipid raft isolation, and confocal microscopic analyses were conducted to verify the association between TRAIL-R and the identified binding proteins within T cells. RESULTS: TRAIL engagement downregulated gene signatures in TCR signaling pathways and profoundly suppressed phosphorylation of TCR proximal tyrosine kinases without inducing cell death. The tyrosine phosphatase SHP-1 was identified as the major TRAIL-R binding protein within T cells, using high throughput mass spectrometry-based proteomics analysis. Furthermore, Lck was co-immunoprecipitated with the TRAIL-R/SHP-1 complex in the activated T cells. TRAIL engagement profoundly inhibited phosphorylation of Lck (Y394) and suppressed the recruitment of Lck into lipid rafts in the activated T cells, leading to the interruption of proximal TCR signaling and subsequent T cell activation. CONCLUSIONS: TRAIL-R associates with phosphatase SHP-1 and transduces a unique and distinct immune gatekeeper signal to repress TCR signaling and T cell activation via inactivating Lck. Thus, our results define TRAIL-R as a new class of immune checkpoint receptors for restraining T cell activation, and TRAIL-R/SHP-1 axis can serve as a potential therapeutic target for immune-mediated diseases.
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Receptores de Antígenos de Linfocitos T , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF , Humanos , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Células Jurkat , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Transducción de Señal , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/metabolismo , Fosforilación , Activación de Linfocitos , Tirosina/metabolismoRESUMEN
It is well known that low-silica SAPO-34, with an extra porosity (meso- and/or macropores) system, affords excellent catalytic performance in the methanol-to-olefins (MTO) reaction, while the direct synthesis of low-silica SAPO-34 with a hierarchical structure is difficult to achieve, principally because the crystal impurities are usually formed under a low silica content in a gel precursor. Herein, low-silica SAPO-34 nanocrystals were successfully fabricated for the first time by constructing an isomorphous core-shell structure in an epitaxial growth manner. In which, low-silica, ultrasmall nanosquare-shaped SAPO-34 crystals with the same growth orientation along the (100) crystal plane compactly grow on the monocrystal SAPO-34 cores. Crucially, the external surface acid properties of the core SAPO-34 with the Si-rich outer layer are effectively modified by the low-silica SAPO-34 shell. Furthermore, the growth process and Si-substitution mechanism of the shell zeolite were comprehensively investigated. It was found that with the prolonged crystallization time, more and more coordinated Si(4Al) and Si(3Al) structures via two substitution mechanisms (SM2 and SM3) are generated in the nanocrystalline SAPO-34 shell, which endow moderate acidity of the core-shell SAPO-34. Compared to the uncoated SAPO-34, the core-shell SAPO-34 performs a longer lifespan and a higher average selectivity of light olefins (ethylene plus propylene) when applied to the MTO reaction, which is attributed to the positive effects of the luxuriant interstitial pores offering a fast diffusion channel and the moderate acid density depressing the hydrogen transfer reaction of light olefins. This work provides new insights into the fabrication of low-silica SAPO-34 nanocrystals, which are based on the rational design of the isomorphous core-shell zeolite.
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Anticuerpos Monoclonales Humanizados , Dermatitis Atópica , Humanos , Dermatitis Atópica/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Resultado del Tratamiento , Femenino , Niño , Masculino , Adolescente , Adulto , China/epidemiología , Preescolar , Adulto Joven , Persona de Mediana Edad , Pueblo Asiatico , Lactante , Pueblos del Este de AsiaRESUMEN
Bullous pemphigoid (BP) is a subepidermal blistering skin disease with a complex pathogenesis involving various immune cells. However, the transcriptional features of these cells remain poorly defined. In this study, we constructed a comprehensive and single-cell resolution atlas of various immune cells within BP skin lesions through integrative single-cell analysis, flow cytometry, and multiplex immunohistochemistry. We observed prominent expansion and transcriptional changes in mast cells, macrophages, basophils, and neutrophils within BP lesions. Mast cells within the lesions adopted an active state and exhibited an elevated capacity for producing proinflammatory mediators. We observed an imbalance of macrophages/dendritic cells within BP lesions. Two macrophage subpopulations (NLRP3+ and C1q+) with distinct transcriptional profiles were identified and upregulated effector programs. T-peripheral helper-like T helper 2 cells were expanded in skin lesions and peripheral blood of patients with BP and were capable of promoting B-cell responses. In addition, we observed clonally expanded granzyme B-positive CD8+ T cells within BP lesions. Chemokine receptor mapping revealed the potential roles of macrophages and mast cells in recruiting pathogenic immune cells and underlying mechanisms within BP lesions. Thus, this study reveals key immune pathogenic features of BP lesions, thereby providing valuable insights for potential therapeutic interventions in this disease.