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AIMS: To systematically evaluate the predictive efficacy of clinical frailty scale (CFS) for postoperative mortality older surgical patients, and to evaluate the prevalence of frailty in the included studies. DESIGN: A systematic review and meta-analysis of observational studies was conducted, utilizing the MOOSE guidelines for the evaluation of both. Quality assessment of the articles was also performed. DATA SOURCES: The protocol was registered (CRD42023423552). Relevant English and Chinese language studies published until October 20th, 2023 were retrieved from PubMed, Web of Science, Embase, Medline, CINAHL,Cochrane, WAN FANG DATA, VIP Information, CNKI, and SinoMed databases. REVIEW METHODS: Study were included in which frailty was measured by the CFS and postoperative mortality was reported for older surgery patients. A meta-analysis to predict postoperative mortality and frailty prevalence was performed using STATA 17.0 software. RESULTS: Sixteen cohort studies were included (5,864 participants) from 1,513 records. All studies' Newcastle-Ottawa Scale (NOS) scores were above 6 points. It was found that the prevalence of surgical frailty in the older was 0.36(CI 0.20-0.52). Patients assessed as frail by the CFS were associated with higher all-cause mortality (OR:4.01; CI 2.59-6.23). Subgroup analysis shows that frailty was associated with1-month mortality (OR:3.85; CI 1.11-13.45) and 1-year mortality (OR:4.43; CI 2.18-8.99). CONCLUSIONS: The prevalence of frailty is high in older surgical patients, and CFS can effectively predict the mortality of older surgical patients with frailty.
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Aesthetic education, conveyed through public art courses, serves as a vital form of humanistic literacy education. It represents an effective approach to fostering innovative and creative thinking among college students. In order to effectively analyze the aesthetic education work of 46 universities, an aesthetic education index evaluation system is constructed, involving indicators including faculty strength, curriculum setting, teaching management, artistic practice, and teaching support. The secondary indicators corresponding to the five indicators are statistically analyzed, and a comprehensive evaluation analysis of the current development status of aesthetic education in 46 universities in Anhui Province is conducted by combining theoretical analysis with empirical analysis. Based on principal component analysis, an integrated evaluation model for the development of aesthetic education in universities in Anhui Province is further constructed. The model designed quantifies the influence weight of each aesthetic education index on the development of aesthetic education in Anhui Province, and forges a theoretical basis for determining the precursors of rapid development of aesthetic education in Anhui Province. Additionally, a novel approach is introduced to gauge the progression of aesthetic education within universities in Anhui Province, considering the dispersion of aesthetic education index data across the province. The comprehensive evaluation model for the development of aesthetic education in Anhui Province exhibits an overall declining trend. Hence, it is suggested to utilize the maximum value of the first derivative of the comprehensive evaluation model as an indicator of the imminent rapid development of aesthetic education in Anhui Province. On this basis, the probability equation of sustainable development of aesthetic education in Anhui Province is defined. Overall, the research results lay a theoretical foundation for the development of aesthetic education in Anhui Province.
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Estética , Análise de Componente Principal , Humanos , Universidades , Currículo , China , Estudantes/psicologia , Modelos EducacionaisRESUMO
Diabetic nephropathy (DN) is one of the most common complications of diabetes. Our previous study showed that CD38 knockout (CD38KO) mice had protective effects on many diseases. However, the roles and mechanisms of CD38 in DN remain unknown. Here, DN mice were generated by HFD feeding plus streptozotocin (STZ) injection in male CD38KO and CD38flox mice. Mesangial cells (SV40 MES 13 cells) were used to mimic the injury of DN with palmitic acid (PA) treatment in vitro. Our results showed that CD38 expression was significantly increased in kidney of diabetic CD38flox mice and SV40 MES 13 cells treated with PA. CD38KO mice were significantly resistant to diabetes-induced renal injury. Moreover, CD38 deficiency markedly decreased HFD/STZ-induced lipid accumulation, fibrosis and oxidative stress in kidney tissue. In contrast, overexpression of CD38 aggravated PA-induced lipid accumulation and oxidative stress. CD38 deficiency increased expression of SIRT3, while overexpression of CD38 decreased its expression. More importantly, 3-TYP, an inhibitor of SIRT3, significantly enhanced PA-induced lipid accumulation and oxidative stress in CD38 overexpressing cell lines. In conclusion, our results demonstrated that CD38 deficiency prevented DN by inhibiting lipid accumulation and oxidative stress through activation of the SIRT3 pathway.
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Preeclampsia (PE) is a specific hypertension-related disease in pregnancies, causing adverse pregnancy outcomes. Endothelial cell dysfunction is a major etiology of PE, of which the regulation could affect disease progression. This study focused on hsa_circ_0088196, evaluating its clinical significance in PE and its effect on endothelial cell injury, aiming to identify a novel biomarker for PE and complete its regulating mechanism in disease development. The study enrolled 165 normal pregnancies and 165 pregnancies with gestational hypertension. The significance of hsa_circ_0088196 in discriminating gestational hypertension, predicting PE, and predicting adverse pregnancy outcomes was evaluated based on its serum expression. The effect and mechanism of hsa_circ_0088196 in HUVEC injury were assessed by CCK8, Transwell, ELISA, and western blotting. Significant downregulation of hsa_circ_0088196 could distinguish gestational hypertension pregnancies and predict the risk of PE. Gestational hypertension pregnancies developed PE showed a lower serum hsa_circ_0088196 level, which also discriminated PE patients, predicted severe conditions and adverse pregnancy outcomes. Overexpressing hsa_circ_0088196 alleviated the enhanced proliferation, migration, inflammation, and angiogenesis by hypoxia/reoxygenation (H/R), which was reversed by miR-145-5p. Silencing miR-145-5p showed similar effects on H/R-induced endothelial cell injury, which was reversed by FLT1. Moreover, FLT1 was positively regulated by hsa_circ_0088196, indicating its involvement in the regulation of HUVEC injury by hsa_circ_0088196. Reduced serum hsa_circ_0088196 served as a biomarker for the diagnosis of gestational hypertension, risk evaluation of PE, and the prediction of adverse pregnancy outcomes. hsa_circ_0088196 suppressed endothelial cell injury induced by H/R through modulating the miR-145-5p/FLT1 axis.
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A photoredox-catalyzed sequential decarboxylative/defluorinative aminoalkylation of CF3-alkenes with N-arylglycines is described. This metal-free and redox-neutral protocol provided efficient access to the monofluoroalkenyl-1,5-diamines in good yields with excellent functional group compatibility. Mechanistic studies revealed that the reaction proceeds via a radical pathway with the gem-difluoroalkenyl amine as an intermediate.
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Aromatization-driven deconstruction and functionalization of spiro dihydroquinazolinones via dual photoredox/nickel catalysis is developed. The aromatization effect was introduced to synergistically drive unstrained cyclic C-C bond cleavage, with the aim of overcoming the ring-size limitation of nitrogen-centered radical induced deconstruction of carbocycles. Herein, we demonstrate the synergistic photoredox/nickel catalyzed deconstructive cross-coupling of spiro dihydroquinazolinones with organic halides. Remarkably, structurally diverse organic halides including aryl, alkenyl, alkynyl, and alkyl bromides were compatible for the coupling. In addition, this protocol is also characterized by its mild and redox-neutral conditions, excellent functional group compatibility, high atom economy, and easy scalability. A telescoped procedure involving condensation and ring-opening/coupling was found to be accessible. This work provides a complementary strategy to the existing radical-mediated C-C bond cleavage of unstrained carbocycles.
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Osteopenia and osteoporosis are among the most common metabolic bone diseases and represent major public health problems, with sufferers having an increased fracture risk. Diabetes is one of the most common diseases contributing to osteopenia and osteoporosis. However, the mechanisms underlying diabetes-induced osteopenia and osteoporosis remain unclear. Bone reconstruction, including bone formation and absorption, is a dynamic process. Large-conductance Ca2+-activated K+ channels (BK channels) regulate the function of bone marrow-derived mesenchymal stem cells, osteoblasts, and osteoclasts. Our previous studies revealed the relationship between BK channels and the function of osteoblasts via various pathways under physiological conditions. In this study, we reported a decrease in the expression of BK channels in mice with diabetes-induced osteopenia. BK deficiency enhanced mitochondrial Ca2+ and activated classical PINK1 (PTEN induced putative kinase 1)-PRKN/Parkin (parkin RBR E3 ubiquitin protein ligase)-dependent mitophagy, whereas the upregulation of BK channels inhibited mitophagy in osteoblasts. Moreover, SLC25A5/ANT2 (solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 5), a critical inner mitochondrial membrane protein participating in PINK1-PRKN-dependent mitophagy, was also regulated by BK channels. Overall, these data identified a novel role of BK channels in regulating mitophagy in osteoblasts, which might be a potential target for diabetes-induced bone diseases.Abbreviations: AGE, advanced glycation end products; Baf A1, bafilomycin A1; BK channels, big-conductance Ca2+-activated K+ channels; BMSCs, bone marrow-derived mesenchymal stem cells; BSA, bovine serum albumin; FBG, fasting blood glucose; IMM, inner mitochondrial membrane; ITPR1, inositol 1,4,5-trisphosphate receptor 1; MAM, mitochondria-associated ER membrane; OMM, outer mitochondrial membrane; PINK1, PTEN induced putative kinase 1; PPID/CyP-D, peptidylprolyl isomerase D (cyclophilin D); PRKN/PARK2, parkin RBR E3 ubiquitin protein ligase; ROS, reactive oxygen species; SLC25A5/ANT2, solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 5; STZ, streptozotocin.
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Epitopes from the Candida cell surface proteins Fba and Met6 are putative vaccine targets for invasive candidiasis. Here, we describe a Candida vaccine approach in which short peptides derived from Fba and Met6 are used in spontaneous nanoliposome antigen particle (SNAP) format. SNAP was enabled by the interaction of cobalt porphyrin phospholipid in liposomes with three histidine residues on the N-terminus of synthetic short peptide immunogens from Fba (F-SNAP), Met6 (M-SNAP), or bivalent Fba and Met6 (FM-SNAP). Liposomes were adjuvanted with synthetic monophosphoryl lipid and QS-21. In mice, immunization with F-SNAP, M-SNAP, or FM-SNAP induced antigen-specific IgG responses and mixed Th1/Th2 immunity. The duplex FM-SNAP vaccine elicited stronger antibody responses against each peptide, even at order-of-magnitude lower peptide dosing than a comparable adjuvanted, conjugate vaccine. Enzyme-linked immunosorbent spot analysis revealed the induction of antigen-specific, cytokine-producing T cells. Compared to F-SNAP or M-SNAP, higher production of TNFα, IL-2, and IFNγ was observed with re-stimulation of splenocytes from bivalent FM-SNAP-immunized mice. When vaccinated BALB/c mice were challenged with Candida auris, analysis of the fungal burden in the kidneys showed that SNAP vaccination protected from disseminated candidiasis. In a lethal fungal exposure model in A/J mice, F-SNAP, M-SNAP, and FM-SNAP vaccination protected mice from candidiasis challenge. Together, these results show that further investigation into the SNAP adjuvant platform is warranted using Fba and Met6 epitopes for a pan-Candida peptide vaccine that provides multifaceted protective immune responses. IMPORTANCE: This study introduces a promising vaccine strategy against invasive candidiasis, a severe fungal infection, by targeting specific peptides on the surface of Candida. Using a novel approach called spontaneous nanoliposome antigen particle (SNAP), we combined peptides from two key Candida proteins, Fba and Met6, into a vaccine. This vaccine induced robust immune responses in mice, including the production of protective antibodies and the activation of immune cells. Importantly, mice vaccinated with SNAP were shielded from disseminated candidiasis in experiments. These findings highlight a potential avenue for developing a broad-spectrum vaccine against Candida infections, which could significantly improve outcomes for patients at risk of these often deadly fungal diseases.
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Anticorpos Antifúngicos , Candidíase , Vacinas Fúngicas , Lipossomos , Camundongos Endogâmicos BALB C , Animais , Camundongos , Vacinas Fúngicas/imunologia , Vacinas Fúngicas/administração & dosagem , Lipossomos/imunologia , Candidíase/prevenção & controle , Candidíase/imunologia , Feminino , Anticorpos Antifúngicos/imunologia , Antígenos de Fungos/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Citocinas/imunologia , Vacinação , Proteínas Fúngicas/imunologia , Proteínas Fúngicas/administração & dosagem , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Adjuvantes Imunológicos/administração & dosagem , Candida albicans/imunologia , Candida/imunologia , Modelos Animais de DoençasRESUMO
Chimeric antigen receptor (CAR) T cell therapy, one of the most promising tumor treatments, combines the targeted recognition of antigen and antibody with the killing effect of T cells. CAR-T has shown a strong therapeutic effect in lymphoid tumors and been applied in clinical practice. However, in the treatment of acute myeloid leukemia (AML), no effective and specific target like CD19 in lymphoid tumors has been found. Therefore, the key research direction is to try multiple probabilities and use optimization strategies to enhance efficacy and reduce toxicity. This review introduces the latest research progress of AML targets in CAR-T therapy in recent years, analyzes the related problems that need to be solved at present, and summarizes the optimization construction strategies mentioned in the research. Hope it can provide reference for related research and clinical application of related product.
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Imunoterapia Adotiva , Leucemia Mieloide Aguda , Receptores de Antígenos Quiméricos , Humanos , Leucemia Mieloide Aguda/terapia , Imunoterapia Adotiva/métodos , Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T , Antígenos CD19/imunologiaRESUMO
PURPOSE: Reproducibility and scale-up production of microspheres through spray drying present significant challenges. In this study, biodegradable microspheres of Triamcinolone Acetonide Acetate (TAA) were prepared using a novel static mixing method by employing poly( lactic-co-glycolic acid) (PLGA) as the sustained-release carrier. METHODS: TAA-loaded microspheres (TAA-MSs) were prepared using a static mixing technique. The PLGA concentration, polyvinyl alcohol concentration (PVA), phase ratio of oil/water, and phase ratio of water/solidification were optimized in terms of the particle size, drug loading (DL), and encapsulation efficiency (EE) of TAA-MSs. The morphology of TAA-MSs was examined using Scanning Electron Microscopy (SEM), while the physicochemical properties were evaluated through X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC), and Fourier Transform Infrared Spectroscopy (FT-IR). The in vitro release of TAA-MSs was compared to that of the pure drug (TAA) using a water-bath vibration method in the medium of pH 7.4 at 37°C. RESULTS: The formulation composition and preparation condition for the preparation of TAA-MSs were optimized as follows: the PLGA concentration was 1%, the phase ratio of oil(dichloromethane) /water (PVA solution) was 1:3, the phase ratio of water (PVA solution)/solidification was 1:2. The optimized TAA-MSs displayed spherical particles with a size range of 30-70 µm, and DL and EE values of 27.09% and 98.67%, respectively. Moreover, the drug-loaded microspheres exhibited a significant, sustained release, with 20% of the drug released over a period of 28 days. The XRD result indicated that the crystalline form of TAA in microspheres had been partly converted into the amorphous form. DSC and FT-IR results revealed that some interactions between TAA and PLGA occurred, indicating that the drug was effectively encapsulated into PLGA microspheres. CONCLUSION: TAA-loaded PLGA microspheres have been successfully prepared via the static mixing technique with enhanced EE and sustained-release manner.
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Background: The commercial docetaxel (DTX) formulation causes severe side effects due to polysorbate 80 and ethanol. Novel surfactant-free nanoparticle (NP) systems are needed to improve bioavailability and reduce side effects. However, controlling the particle size and stability of NPs and improving the batch-to-batch variation are the major challenges. Methods: DTX-loaded bovine serum albumin nanoparticles (DTX-BSA-NPs) were prepared by a novel thermal-driven self-assembly/microfluidic technology. Single-factor analysis and orthogonal test were conducted to obtain the optimal formulation of DTX-BSA-NPs in terms of particle size, encapsulation efficiency (EE), and drug loading (DL). The effects of oil/water flow rate and pump pressure on the particle size, EE, and DL were investigated to optimize the preparation process of DTX-BSA-NPs. The drug release, physicochemical properties, stability, and pharmacokinetics of NPs were evaluated. Results: The optimized DTX-BSA-NPs were uniform, with a particle size of 118.30 nm, EE of 89.04%, and DL of 8.27%. They showed a sustained release of 70% over 96 hours and an increased stability. There were some interactions between the drug and excipients in DTX-BSA-NPs. The half-life, mean residence time, and area under the curve (AUC) of DTX-BSA-NPs increased, but plasma clearance decreased when compared with DTX. Conclusion: The thermal-driven self-assembly/microfluidic combination method effectively produces BSA-based NPs that improve the bioavailability and stability of DTX, offering a promising alternative to traditional formulations.
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Disponibilidade Biológica , Docetaxel , Estabilidade de Medicamentos , Nanopartículas , Tamanho da Partícula , Soroalbumina Bovina , Docetaxel/farmacocinética , Docetaxel/química , Docetaxel/administração & dosagem , Animais , Soroalbumina Bovina/química , Soroalbumina Bovina/farmacocinética , Soroalbumina Bovina/administração & dosagem , Nanopartículas/química , Taxoides/farmacocinética , Taxoides/química , Taxoides/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Liberação Controlada de Fármacos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Ratos Sprague-Dawley , Masculino , Composição de Medicamentos/métodos , RatosRESUMO
BACKGROUND: Oral traumatic ulcerative lesions (OTUL) are commonly encountered in clinical practice, yet there is limited research on their clinical characteristics and traumatic etiological factors. This retrospective study aimed to analyze the age, gender, clinical characteristics, and traumatic etiological factors in a large cohort of patients with OTUL and provide valuable insights for dental clinicians to optimize patient care and prevention strategies. METHODS: A total of 1543 patients with OTUL were enrolled in this study. Age, gender, medical history, clinical characteristics and traumatic etiological factors were collected and analyzed. Logistic regression analysis was performed to determine the significance of age and gender as factors related to OTUL. RESULTS: The study revealed significant variations in clinical characteristics and traumatic etiological factors among different age groups and between genders. Logistic regression analysis demonstrated that both age and gender were significant factors related to OTUL. CONCLUSION: The clinical characteristics of OTUL and traumatic etiological factors appear to be significantly different according to age and gender. More targeted prevention strategies should be implemented for all age and gender groups.
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Úlceras Orais , Humanos , Masculino , Feminino , Estudos Retrospectivos , Adulto , Fatores Sexuais , Pessoa de Meia-Idade , Fatores Etários , Úlceras Orais/etiologia , Adolescente , Adulto Jovem , Idoso , Criança , Pré-Escolar , Fatores de Risco , Idoso de 80 Anos ou maisRESUMO
Einstein-Podolsky-Rosen (EPR) steering is commonly shared among multiple observers by utilizing unsharp measurements. Nevertheless, their usage is restricted to local measurements and does not encompass all nonlocal measurement-based cases. In this work, a method for finding beneficial local measurement settings has been expanded to include nonlocal measurement cases. This method is applicable for any bipartite state and offers benefits even in scenarios with a high number of measurement settings. Using the Greenberger-Horne-Zeilinger state as an illustration, we show that employing unsharp nonlocal measurements can activate the phenomenon of steering sharing in contrast to using local measurements. Furthermore, our findings demonstrate that nonlocal measurements with unequal strength possess a greater activation capability compared to those with equal strength. Our activation method generates fresh concepts for conservation and recycling quantum resources.
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Serine/threonine kinase 39 (STK39) has been identified as a key regulator of tumour progression. However, whether STK39 plays a role in acute myeloid leukaemia (AML) remains undetermined. This work explored the expression and functions of STK39 in AML. STK39 was found to be overexpressed in AML and was negatively correlated with overall survival. Functionally, silencing STK39 inhibited cell proliferation, promoted cell differentiation and induced cell cycle arrest and apoptosis. The tumour inhibiting effects of STK39 downregulation were also verified by an in vivo xenograft tumour assay. Mechanistically, STK39 was closely related to the PI3K/AKT and Wnt/ß-catenin signalling cascades in AML. Silencing of STK39 had suppressive effects on the PI3K/AKT and Wnt/ß-catenin signalling cascades. The suppressive effect of STK39 silencing on the Wnt/ß-catenin signalling cascade was significantly reversed when PI3K/AKT was reactivated. When ß-catenin was re-expressed, the tumour-inhibiting effects caused by STK39 silencing were significantly eliminated. Therefore, STK39 plays a crucial role in AML and could be targeted for potential therapeutic purposes in treating AML.
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Proliferação de Células , Leucemia Mieloide Aguda , Fosfatidilinositol 3-Quinases , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas c-akt , Via de Sinalização Wnt , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Feminino , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Camundongos , Apoptose , Pessoa de Meia-Idade , Linhagem Celular Tumoral , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , Adulto , beta Catenina/metabolismo , Idoso , Adulto JovemRESUMO
Purpose: The purpose of this study was to investigate the protective effect of CD38 deletion on retinal ganglion cells (RGCs) in a mouse retinal ischemia/reperfusion (I/R) model and an optic nerve crush (ONC) model, and to elucidate the underlying molecular mechanisms. Methods: Retinal I/R and ONC models were constructed in mice. PCR was used to identify the deletion of CD38 gene in mice, hematoxylin and eosin (H&E) staining was used to evaluate the changes in retinal morphology, and electroretinogram (ERG) was used to evaluate the changes in retinal function. The survival of RGCs and activation of retinal macroglia were evaluated by immunofluorescence staining. The expression of Sirt1, CD38, Ac-p65, Ac-p53, TNF-α, IL-1ß, and Caspase3 proteins in the retina was further evaluated by protein imprinting. Results: In retinal I/R and ONC models, CD38 deficiency reduced the loss of RGCs and activation of macroglia and protected the retinal function. CD38 deficiency increased the concentration of NAD+, reduced the degree of acetylation of NF-κB p65 and p53, and reduced expression of the downstream inflammatory cytokines TNFα, IL-1ß, and apoptotic protein Caspase3 in the retina in the ONC model. Intraperitoneal injection of the Sirt1 inhibitor EX-527 partially counteracted the effects of CD38 deficiency, suggesting that CD38 deficiency acts at least in part through the NAD+/Sirt1 pathway. Conclusions: CD38 plays an important role in the pathogenesis of retinal I/R and ONC injury. CD38 deletion protects RGCs by attenuating inflammatory responses and apoptosis through the NAD+/Sirt1 pathway.
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ADP-Ribosil Ciclase 1 , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , NAD , Traumatismos do Nervo Óptico , Traumatismo por Reperfusão , Células Ganglionares da Retina , Sirtuína 1 , Animais , Sirtuína 1/metabolismo , Sirtuína 1/genética , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/metabolismo , ADP-Ribosil Ciclase 1/metabolismo , ADP-Ribosil Ciclase 1/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Camundongos , NAD/metabolismo , Traumatismos do Nervo Óptico/metabolismo , Eletrorretinografia , Compressão Nervosa , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Masculino , Transdução de Sinais/fisiologiaRESUMO
AIMS: Ubiquitin specific peptidase 5 (USP5), a member of deubiquitinating enzymes, has garnered significant attention for its crucial role in cancer progression. This study aims to explore the role of USP5 and its potential molecular mechanisms in cholangiocarcinoma (CCA). MAIN METHODS: To explore the effect of USP5 on CCA, gain-of-function and loss-of-function assays were conducted in human CCA cell lines RBE and HCCC9810. The CCK8, colony-forming assay, EDU, flow cytometry, transwell assay and xenografts were used to assess cell proliferation, migration and tumorigenesis. Western blot and immunohistochemistry were performed to measure the expression of related proteins. Immunoprecipitation and immunofluorescence were applied to identify the interaction between USP5 and Y box-binding protein 1 (YBX1). Ubiquitination assays and cycloheximide chase assays were carried out to confirm the effect of USP5 on YBX1. KEY FINDINGS: We found USP5 is highly expressed in CCA tissues, and upregulated USP5 is required for the cancer progression. Knockdown of USP5 inhibited cell proliferation, migration and epithelial-mesenchymal transition (EMT) in vitro, along with suppressed xenograft tumor growth and metastasis in vivo. Mechanistically, USP5 could interact with YBX1 and stabilize YBX1 by deubiquitination in CCA cells. Additionally, silencing of USP5 hindered the phosphorylation of YBX1 at serine 102 and its subsequent translocation to the nucleus. Notably, the effect induced by USP5 overexpression in CCA cells was reversed by YBX1 silencing. SIGNIFICANCE: Our findings reveal that USP5 is required for cell proliferation, migration and EMT in CCA by stabilizing YBX1, suggesting USP5-YBX1 axis as a promising therapeutic target for CCA.
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Neoplasias dos Ductos Biliares , Movimento Celular , Proliferação de Células , Colangiocarcinoma , Progressão da Doença , Transição Epitelial-Mesenquimal , Camundongos Nus , Proteína 1 de Ligação a Y-Box , Humanos , Colangiocarcinoma/patologia , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/genética , Animais , Camundongos , Linhagem Celular Tumoral , Proteína 1 de Ligação a Y-Box/metabolismo , Proteína 1 de Ligação a Y-Box/genética , Ubiquitinação , Camundongos Endogâmicos BALB C , Masculino , Endopeptidases/metabolismo , Endopeptidases/genética , Regulação Neoplásica da Expressão Gênica , FemininoRESUMO
With the development of social economy, the incidence of gout is increasing, which is closely related to people's increasingly rich diet. Eating a diet high in purine, fat, sugar and low-fibre for a long time further aggravates gout by affecting uric acid metabolism. The renal metabolism mechanism of uric acid has been thoroughly studied. To find a new treatment method for gout, increasing studies have recently been conducted on the mechanism of intestinal excretion, metabolism and absorption of uric acid. The most important research is the relationship between intestinal microbiota and the risk of gout. Gut microbiota represent bacteria that reside in a host's gastrointestinal tract. The composition of the gut microbiota is associated with protection against pathogen colonization and disease occurrence. This review focuses on how gut microbiota affects gout through uric acid and discusses the types of bacteria that may be involved in the occurrence and progression of gout. We also describe potential therapy for gout by restoring gut microbiota homeostasis and reducing uric acid levels. We hold the perspective that changing intestinal microbiota may become a vital method for effectively preventing or treating gout.
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Microbioma Gastrointestinal , Gota , Humanos , Ácido Úrico/metabolismo , Gota/metabolismo , Trato Gastrointestinal/metabolismo , Bactérias/metabolismoRESUMO
BACKGROUND: Colorectal cancer has a low 5-year survival rate and high mortality. Human ß-defensin-1 (hBD-1) may play an integral function in the innate immune system, contributing to the recognition and destruction of cancer cells. Long non-coding RNAs (lncRNAs) are involved in the process of cell differentiation and growth. AIM: To investigate the effect of hBD-1 on the mammalian target of rapamycin (mTOR) pathway and autophagy in human colon cancer SW620 cells. METHODS: CCK8 assay was utilized for the detection of cell proliferation and determination of the optimal drug concentration. Colony formation assay was employed to assess the effect of hBD-1 on SW620 cell proliferation. Bioinformatics was used to screen potentially biologically significant lncRNAs related to the mTOR pathway. Additionally, p-mTOR (Ser2448), Beclin1, and LC3II/I expression levels in SW620 cells were assessed through Western blot analysis. RESULTS: hBD-1 inhibited the proliferative ability of SW620 cells, as evidenced by the reduction in the colony formation capacity of SW620 cells upon exposure to hBD-1. hBD-1 decreased the expression of p-mTOR (Ser2448) protein and increased the expression of Beclin1 and LC3II/I protein. Furthermore, bioinformatics analysis identified seven lncRNAs (2 upregulated and 5 downregulated) related to the mTOR pathway. The lncRNA TCONS_00014506 was ultimately selected. Following the inhibition of the lncRNA TCONS_00014506, exposure to hBD-1 inhibited p-mTOR (Ser2448) and promoted Beclin1 and LC3II/I protein expression. CONCLUSION: hBD-1 inhibits the mTOR pathway and promotes autophagy by upregulating the expression of the lncRNA TCONS_00014506 in SW620 cells.
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Abdominal aortic aneurysm (AAA) is a serious vascular disease which is associated with vascular remodeling. CD38 is a main NAD+-consuming enzyme in mammals, and our previous results showed that CD38 plays the important roles in many cardiovascular diseases. However, the role of CD38 in AAA has not been explored. Here, we report that smooth-muscle-cell-specific deletion of CD38 (CD38SKO) significantly reduced the morbidity of AngII-induced AAA in CD38SKOApoe-/- mice, which was accompanied with a increases in the aortic diameter, medial thickness, collagen deposition, and elastin degradation of aortas. In addition, CD38SKO significantly suppressed the AngII-induced decreases in α-SMA, SM22α, and MYH11 expression; the increase in Vimentin expression in VSMCs; and the increase in VCAM-1 expression in smooth muscle cells and macrophage infiltration. Furthermore, we demonstrated that the role of CD38SKO in attenuating AAA was associated with the activation of sirtuin signaling pathways. Therefore, we concluded that CD38 plays a pivotal role in AngII-induced AAA through promoting vascular remodeling, suggesting that CD38 may serve as a potential therapeutic target for the prevention of AAA.
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ADP-Ribosil Ciclase 1 , Angiotensina II , Aneurisma da Aorta Abdominal , Camundongos Knockout , Miócitos de Músculo Liso , Remodelação Vascular , Animais , Masculino , Camundongos , ADP-Ribosil Ciclase 1/metabolismo , ADP-Ribosil Ciclase 1/genética , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Cadeias Pesadas de Miosina/metabolismo , Cadeias Pesadas de Miosina/genética , Transdução de Sinais , Remodelação Vascular/genéticaRESUMO
A photoredox-catalyzed alkylarylation of activated alkenes via a radical C-C bond cleavage/Truce-Smiles rearrangement cascade is developed. The protocol features mild and redox-neutral conditions, broad substrate scope and excellent functional group compatibility, providing a facile and efficient approach to the long-chain distal keto-amides with all-carbon quaternary centers at the alpha position.