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Objective: Gastric intestinal metaplasia (IM) is a precancerous stage associated with gastric cancer. Despite the observed beneficial effects of metformin on IM, its molecular mechanism remains not fully elucidated. This study aims to reveal the effects and potential mechanisms of metformin in treating IM based on both bioinformatics and in vivo investigations. Methods: The seven public databases (GeneCards, DisGeNET, OMIM, SuperPred, Pharm Mapper, Swiss Target Prediction, TargetNet) were used in this work to identify targeted genes related to intestinal metaplasia (IM) and metformin. The shared targeted genes between metformin and IM were further analyzed by network pharmacology, while the interactions in-between were investigated by molecular docking. In parallel, the therapeutic effect of metformin was evaluated in IM mice model, while the core targets and pathways effected by metformin were verified in vivo. Results: We screened out 1,751 IM-related genes and 318 metformin-targeted genes, 99 common genes identified in between were visualized by constructing the protein-protein interaction (PPI) network. The top ten core targeted genes were EGFR, MMP9, HIF1A, HSP90AA1, SIRT1, IL2, MAPK8, STAT1, PIK3CA, and ICAM1. The functional enrichment analysis confirmed that carcinogenesis and HIF-1 signaling pathways were primarily involved in the metformin treatment of IM. Based on molecular docking and dynamics, we found metformin affected the function of its targets by inhibiting receptor binding. Furthermore, metformin administration reduced the progression of IM lesions in Atp4a-/- mice model significantly. Notably, metformin enhanced the expression level of MUC5AC, while inhibited the expression level of CDX2. Our results also showed that metformin modulated the expression of core targets in vivo by reducing the activity of NF-κB and the PI3K/AKT/mTOR/HIF-1α signaling pathway. Conclusion: This study confirms that metformin improves the efficacy of IM treatment by regulating a complex molecular network. Metformin plays a functional role in inhibiting inflammation/apoptosis-related pathways of further IM progression. Our work provides a molecular foundation for understanding metformin and other guanidine medicines in IM treatment.
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BACKGROUND: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that has been found to be associated with dysregulation of gastrointestinal functions and gut microbial homeostasis (the so-called "gut-brain axis"). ASD is often accompanied by poor performances in social interaction and repetitive behaviors. Studies on the gut-brain axis provide novel insights and candidate targets for ASD therapeutics and diagnosis. Based on the ASD mice model, this work aims to reveal the mechanisms behind the interaction of intestinal barrier function and probiotics in ASD mouse models. RESULTS: We found an altered intestinal barrier in both BTBR T+ Itpr3tf/J (BTBR) and valproic acid (VPA) mice, including increased intestinal permeability, decreased expression of intestinal tight junction proteins (claudin1, claudin3, and occludin), and increased levels of IL-6, TNF-α, and IFN-γ. Based on intestinal microbial alternation, C. butyricum can drive reduced expression of histone deacetylases 1 (HDAC1) and enhanced intestinal barrier function, significantly promoting behavioral abnormalities of ASD in BTBR mice. In parallel, we confirmed that C. butyricum was involved in the regulation of intestinal function by the Trek1 channel, indicating that it is a target of C. butyricum/butyric acid to improve intestinal barrier function in ASD mice. CONCLUSIONS: Our finding provides solid evidence for the gut microbiota involved in ASD through the brain-gut axis. In addition, the probiotics C. butyricum hold promise to improve gut health and ameliorate behavioral abnormalities associated with ASD.
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Background: Revealing the role of anoikis resistance plays in CRC is significant for CRC diagnosis and treatment. This study integrated the CRC anoikis-related key genes (CRC-AKGs) and established a novel model for improving the efficiency and accuracy of the prognostic evaluation of CRC. Methods: CRC-ARGs were screened out by performing differential expression and univariate Cox analysis. CRC-AKGs were obtained through the LASSO machine learning algorithm and the LASSO Risk-Score was constructed to build a nomogram clinical prediction model combined with the clinical predictors. In parallel, this work developed a web-based dynamic nomogram to facilitate the generalization and practical application of our model. Results: We identified 10 CRC-AKGs and a risk-related prognostic Risk-Score was calculated. Multivariate COX regression analysis indicated that the Risk-Score, TNM stage, and age were independent risk factors that significantly associated with the CRC prognosis(p < 0.05). A prognostic model was built to predict the outcome with satisfied accuracy (3-year AUC = 0.815) for CRC individuals. The web interactive nomogram (https://yuexiaozhang.shinyapps.io/anoikisCRC/) showed strong generalizability of our model. In parallel, a substantial correlation between tumor microenvironment and Risk-Score was discovered in the present work. Conclusion: This study reveals the potential role of anoikis in CRC and sets new insights into clinical decision-making in colorectal cancer based on both clinical and sequencing data. Also, the interactive tool provides researchers with a user-friendly interface to input relevant clinical variables and obtain personalized risk predictions or prognostic assessments based on our established model.
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Periodontitis is a critical risk factor for the occurrence and development of diabetes. Porphyromonas gingivalis may participate in insulin resistance (IR) caused by periodontal inflammation, but the functional role and specific mechanisms of P. gingivalis in IR remain unclear. In the present study, clinical samples were analysed to determine the statistical correlation between P. gingivalis and IR occurrence. Through culturing of hepatocytes, myocytes, and adipocytes, and feeding mice P. gingivalis orally, the functional correlation between P. gingivalis and IR occurrence was further studied both in vitro and in vivo. Clinical data suggested that the amount of P. gingivalis isolated was correlated with the Homeostatic Model Assessment for IR score. In vitro studies suggested that coculture with P. gingivalis decreased glucose uptake and insulin receptor (INSR) protein expression in hepatocytes, myocytes, and adipocytes. Mice fed P. gingivalis tended to undergo IR. P. gingivalis was detectable in the liver, skeletal muscle, and adipose tissue of experimental mice. The distribution sites of gingipain coincided with the downregulation of INSR. Gingipain proteolysed the functional insulin-binding region of INSR. Coculture with P. gingivalis significantly decreased the INSR-insulin binding ability. Knocking out gingipain from P. gingivalis alleviated the negative effects of P. gingivalis on IR in vivo. Taken together, these findings indicate that distantly migrated P. gingivalis may directly proteolytically degrade INSR through gingipain, thereby leading to IR. The results provide a new strategy for preventing diabetes by targeting periodontal pathogens and provide new ideas for exploring novel mechanisms by which periodontal inflammation affects the systemic metabolic state.
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Cisteína Endopeptidases Gingipaínas , Resistência à Insulina , Porphyromonas gingivalis , Receptor de Insulina , Porphyromonas gingivalis/metabolismo , Receptor de Insulina/metabolismo , Animais , Camundongos , Cisteína Endopeptidases Gingipaínas/metabolismo , Humanos , Masculino , Adesinas Bacterianas/metabolismo , Cisteína Endopeptidases/metabolismo , Proteólise , Feminino , Adipócitos/metabolismo , Periodontite/microbiologia , Técnicas de CoculturaRESUMO
OBJECTIVE: To observe the therapeutic effects and underlying mechanism of baicalin against colon cancer. METHODS: The effects of baicalin on the proliferation and growth of colon cancer cells MC38 and CT26. WT were observed and predicted potential molecular targets of baicalin for colon cancer therapy were studied by network pharmacology. Furthermore, molecular docking and drug affinity responsive target stability (DARTS) analysis were performed to confirm the interaction between potential targets and baicalin. Finally, the mechanisms predicted by in silico analyses were experimentally verified in-vitro and in-vivo. RESULTS: Baicalin significantly inhibited proliferation, invasion, migration, and induced apoptosis in MC38 and CT26 cells (all P<0.01). Additionally, baicalin caused cell cycle arrest at the S phase, while the G0/G1 phase was detected in the tiny portion of the cells. Subsequent network pharmacology analysis identified 6 therapeutic targets associated with baicalin, which potentially affect various pathways including 39 biological processes and 99 signaling pathways. In addition, molecular docking and DARTS predicted the potential binding of baicalin with cyclin dependent kinase inhibitor 2A (CDKN2A), protein kinase B (AKT), caspase 3, and mitogen-activated protein kinase (MAPK). In vitro, the expressions of CDKN2A, MAPK, and p-AKT were suppressed by baicalin in MC38 and CT26 cells. In vivo, baicalin significantly reduced the tumor size and weight (all P<0.01) in the colon cancer mouse model via inactivating p-AKT, CDKN2A, cyclin dependent kinase 4, cyclin dependent kinase 2, interleukin-1, tumor necrosis factor α, and activating caspase 3 and mouse double minute 2 homolog signaling (all P<0.05). CONCLUSION: Baicalin suppressed the CDKN2A protein level to prevent colon cancer and could be used as a therapeutic target for colon cancer.
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Accurately controlling trace additives in dielectric barium titanate (BaTiO3) layers is important for optimizing the performance of multilayer ceramic capacitors (MLCCs). However, characterizing the spatial distribution and local concentration of the additives, which strongly influence the MLCC performance, poses a significant challenge. Atom probe tomography (APT) is an ideal technique for obtaining this information, but the extremely low electrical conductivity and piezoelectricity of BaTiO3 render its analysis with existing sample preparation approaches difficult. In this study, we developed a new APT sample preparation method involving W coating and heat treatment to investigate the trace additives in the BaTiO3 layer of MLCCs. This method enables determination of the local concentration and distribution of all trace elements in the BaTiO3 layer, including additives and undesired impurities. The developed method is expected to pave the way for the further optimization and advancement of MLCC technology.
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BACKGROUND: Gastric intestinal metaplasia (GIM) is an essential precancerous lesion. Although the reversal of GIM is challenging, it potentially brings a state-to-art strategy for gastric cancer therapeutics (GC). The lack of the appropriate in vitro model limits studies of GIM pathogenesis, which is the issue this work aims to address for further studies. METHOD: The air-liquid interface (ALI) model was adopted for the long-term culture of GIM cells in the present work. This study conducted Immunofluorescence (IF), quantitative real-time polymerase chain reaction (qRT-PCR), transcriptomic sequencing, and mucoproteomic sequencing (MS) techniques to identify the pathways for differential expressed genes (DEGs) enrichment among different groups, furthermore, to verify novel biomarkers of GIM cells. RESULT: Our study suggests that GIM-ALI model is analog to the innate GIM cells, which thus can be used for mucus collection and drug screening. We found genes MUC17, CDA, TRIM15, TBX3, FLVCR2, ONECUT2, ACY3, NMUR2, and MAL2 were highly expressed in GIM cells, while GLDN, SLC5A5, MAL, and MALAT1 showed down-regulated, which can be used as potential biomarkers for GIM cells. In parallel, these genes that highly expressed in GIM samples were mainly involved in cancer-related pathways, such as the MAPK signal pathway and oxidative phosphorylation signal pathway. CONCLUSION: The ALI model is validated for the first time for the in vitro study of GIM. GIM-ALI model is a novel in vitro model that can mimic the tissue micro-environment in GIM patients and further provide an avenue for studying the characteristics of GIM mucus. Our study identified new markers of GIM as well as pathways associated with GIM, which provides outstanding insight for exploring GIM pathogenesis and potentially other related conditions.
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Metaplasia , Humanos , Ar , Modelos Biológicos , Mucosa Gástrica/patologia , Mucosa Gástrica/metabolismo , Estômago/patologia , Organoides/patologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Regulação Neoplásica da Expressão Gênica , Transcriptoma/genética , Intestinos/patologiaRESUMO
Background: Bilateral ductus arteriosus (BDA) is a relatively rare vascular malformation. According to the double arch theory, BDA is formed when the distal ends of the sixth pairs of primitive arches on the left and right sides have not regressed. We describe a fetus with prenatal echocardiographic findings of BDA and right aortic arch mirror-image branching (RAA-MIB) combined with congenital heart disease. Furthermore, to gain a deeper understanding of the embryological mechanism of BDA, we review the literature on all combinations of BDA present in 40 fetuses/infants. Case summary: A 22-year-old female patient underwent fetal echocardiography at 23 weeks of gestation. Both the two-dimensional (2D) grayscale image and color Doppler flow imaging (CDFI) revealed dextro-transposition of the great arteries combined with a ventricular septal defect and RAA-MIB. The following scan revealed a rare vascular ring, which was identified as BDA extending from the confluent of the left pulmonary artery and right pulmonary artery, completely encircling the trachea to form an "O"-shaped vascular ring before finally converging into the descending aorta. A persistent left superior vena cava was also observed. We subsequently used four-dimensional (4D) color Doppler imaging with the spatiotemporal image correlation (STIC) HD live flow and STIC HD live flow silhouette mode to clearly display ventricular arterial connectivity and the direction of vessel travel. Adjusting the image quality and display angle is very important when applying STIC. The 4D images confirmed our diagnosis. After multidisciplinary counseling and discussion with her family, this female patient decided to terminate the pregnancy. Conclusion: Our review of the literature summarized nine combinations classified into three types of BDA and aortic arch pathology. However, our case differs because it is a novel combination of intracardiac structural abnormalities and vascular rings in a fetus. Prenatal ultrasound diagnosis of BDA is important and requires a combination of 2D grayscale, CDFI, and STIC images to assist in scanning.
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An excitonic insulator (EI) is an intriguing correlated electronic phase of condensed excitons. Ta2NiSe5 is a model material for investigating condensed excitonic states. Herein, femtosecond pump-probe spectroscopy is used to study the coherent phonon dynamics and associated exciton-phonon coupling in single-crystal Ta2NiSe5. The reflectivity time series consists of exponential decay due to hot carriers and damped oscillations due to the Ag phonon vibration. Given the in-plane anisotropic thermal conductivity of Ta2NiSe5, coherent phonon oscillations are stronger with perpendicular polarization to its quasi-one-dimensional chains. The 1-, 2-, and 4-THz vibration modes show coherent amplitude responses in the EI phase of Ta2NiSe5 with increasing temperature, totally different from those of normal coherent phonons (the 3- and 3.7-THz modes). The amplitude modes at higher frequencies decouple with the EI order parameter at lower temperatures, as supported by theoretical analysis with a model Hamiltonian of the exciton-phonon coupling system. Our work provides valuable insights into the character of the EI order parameter and its coupling to multiple coherent amplitude modes.
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BACKGROUND: Ferroptosis, characterized by excessive iron ions and lipid peroxides accumulation, contributes to Nonalcoholic Fatty Liver Disease (NAFLD) development. The role of ADAR1, crucial for lipid metabolism and immune regulation, in ferroptosis-related NAFLD remains unexplored. METHODS: In this study, we analyzed the expression of ADAR1 in NAFLD patients using the GSE66676 database. Subsequently, We investigated the effects of ADAR1 knockdown on mitochondrial membrane potential (MMP), Fe2+ levels, oxidation products, and ferroptosis in NAFLD cells through in vitro and in vivo experiments. Additionally, RNA-seq analysis was performed following ADAR1 depletion in an NAFLD cell model. Overlapping and ferroptosis-related genes were identified using a Venn diagram, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted as well. Furthermore, a protein-protein interaction (PPI) network was constructed to identify hub genes associated with ferroptosis. RESULTS: We found the expression level of ADAR1 was downregulated in NAFLD patients and 22 ferroptosis-associated genes were differentially expressed in a NAFLD cell model upon ADAR1 knockdown. Based on PPI network, we identified NOS2, PTGS2, NOX4, ALB, IL6, and CCL5 as the central genes related to ferroptosis. ADAR1 deletion-related NAFLD was found to be involved in the ferroptosis signaling pathway. NOS2, PTGS2, ALB, and IL6 can serve as potential biomarkers. These findings offer new insights and expanded targets for NAFLD prevention and treatment. CONCLUSION: These findings provide new strategies and potential targets for preventing and treating NAFLD. NOS2, PTGS2, ALB, and IL6 may serve as biomarkers for ADAR1 deletion-related NAFLD, which could help for developing its new diagnostic and therapeutic strategies.
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Adenosina Desaminase , Ferroptose , Hepatopatia Gordurosa não Alcoólica , Proteínas de Ligação a RNA , Ferroptose/genética , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Animais , Camundongos , RNA-Seq , Masculino , Camundongos Endogâmicos C57BL , Mapas de Interação de ProteínasRESUMO
In the realm of human motion recognition systems, the augmentation of 3D human pose data plays a pivotal role in enriching and enhancing the quality of original datasets through the generation of synthetic data. This augmentation is vital for addressing the current research gaps in diversity and complexity, particularly when dealing with rare or complex human movements. Our study introduces a groundbreaking approach employing Generative Adversarial Networks (GANs), coupled with Support Vector Machine (SVM) and DenseNet, further enhanced by robot-assisted technology to improve the precision and efficiency of data collection. The GANs in our model are responsible for generating highly realistic and diverse 3D human motion data, while SVM aids in the effective classification of this data. DenseNet is utilized for the extraction of key features, facilitating a comprehensive and integrated approach that significantly elevates both the data augmentation process and the model's ability to process and analyze complex human movements. The experimental outcomes underscore our model's exceptional performance in motion quality assessment, showcasing a substantial improvement over traditional methods in terms of classification accuracy and data processing efficiency. These results validate the effectiveness of our integrated network model, setting a solid foundation for future advancements in the field. Our research not only introduces innovative methodologies for 3D human pose data enhancement but also provides substantial technical support for practical applications across various domains, including sports science, rehabilitation medicine, and virtual reality. By combining advanced algorithmic strategies with robotic technologies, our work addresses key challenges in data augmentation and motion quality assessment, paving the way for new research and development opportunities in these critical areas.
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INTRODUCTION: Helicobacter pylori (H. pylori) infection has been associated with gastric carcinogenesis. However, the precise involvement of LRP8, the low-density lipoprotein receptor-related protein 8, in H. pylori pathogenesis and gastric cancer (GC) remains poorly understood. OBJECTIVES: To investigate the potential role of LRP8 in H. pylori infection and gastric carcinogenesis. METHODS: Three-dimensional human-derived gastric organoids (hGO) and gastric cancer organoids (hGCO) were synthesized from the tissues obtained from human donors. In this work, multi-omics combined with in vivo and in vitro studies were conducted to investigate the potential involvement of LRP8 in H. pylori-induced GC. RESULTS: We found that H. pylori infection significantly upregulated the expression of LRP8 in human GC tissues, cells, organoids, and mouse gastric mucous. In particular, LRP8 exhibited a distinct enrichment in cancer stem cells (CSC). Functionally, silencing of LRP8 affected the formation and proliferation of tumor spheroids, while increased expression of LRP8 was associated with increased proliferation and stemness of GC cells and organoids. Mechanistically, LRP8 promotes the binding of E-cadherin to ß-catenin, thereby promoting nuclear translocation and transcriptional activity of ß-catenin. Furthermore, LRP8 interacts with the cytotoxin-associated gene A (CagA) to form the CagA/LRP8/ß-catenin complex. This complex further amplifies H. pylori-induced ß-catenin nuclear translocation, leading to increased transcription of inflammatory factors and CSC markers. Clinical analysis demonstrated that abnormal overexpression of LRP8 is correlated with a poor prognosis and resistance to 5-Fluorouracil in patients with GC. CONCLUSION: Our findings provide valuable information on the molecular intricacies of H. pylori-induced gastric carcinogenesis, offering potential therapeutic targets and prognostic markers for GC.
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The inflammatory response is tightly regulated to eliminate invading pathogens and avoid excessive production of inflammatory mediators and tissue damage. Caspase-8 is a cysteine protease that is involved in programmed cell death. Here we show the TRIF-RIPK1-Caspase-8 is required for LPS-induced CYLD degradation in macrophages. TRIF functions in the upstream of RIPK1. The homotypic interaction motif of TRIF and the death domain of RIPK1 are essential for Caspase-8 activation. Caspase-8 cleaves CYLD and the D235A mutant is resistant to the protease activity of Caspase-8. TRIF and RIPK1 serve as substrates of Capase-8 in vitro. cFLIP interacts with Caspase-8 to modulate its protease activity on CYLD and cell death. Deficiency in TRIF, Caspase-8 or CYLD can lead to a decrease or increase in the expression of genes encoding inflammatory cytokines. Together, the TRIF-Caspase-8 and CYLD play opposite roles in the regulation of TLR4 signalling.
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Proteínas Adaptadoras de Transporte Vesicular , Caspase 8 , Enzima Desubiquitinante CYLD , Lipopolissacarídeos , Proteína Serina-Treonina Quinases de Interação com Receptores , Transdução de Sinais , Receptor 4 Toll-Like , Caspase 8/metabolismo , Caspase 8/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Enzima Desubiquitinante CYLD/metabolismo , Enzima Desubiquitinante CYLD/genética , Animais , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Camundongos , Humanos , Regulação da Expressão Gênica , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Knockout , Camundongos Endogâmicos C57BL , Proteína de Domínio de Morte Associada a FasRESUMO
Cytochrome P450 1A2 (CYP1A2) is a known tumor suppressor in hepatocellular carcinoma (HCC), but its expression is repressed in HCC and the underlying mechanism is unclear. In this study, we investigated the epigenetic mechanisms of CYP1A2 repression and potential therapeutic implications. In HCC tumor tissues, the methylation rates of CYP1A2 CpG island (CGI) and DNA methyltransferase (DNMT) 3A protein levels were significantly higher, and there was a clear negative correlation between DNMT3A and CYP1A2 protein expression. Knockdown of DNMT3A by siRNA significantly increased CYP1A2 expression in HCC cells. Additionally, treating HCC cells with decitabine (DAC) resulted in a dose-dependent upregulation of CYP1A2 expression by reducing the methylation level of CYP1A2 CGI. Furthermore, we observed a decreased enrichment of H3K27Ac in the promoter region of CYP1A2 in HCC tissues. Treatment with the trichostatin A (TSA) restored CYP1A2 expression in HCC cells by increasing H3K27Ac levels in the CYP1A2 promoter region. Importantly, combination treatment of sorafenib with DAC or TSA resulted in a leftward shift of the dose-response curve, lower IC50 values, and reduced colony numbers in HCC cells. Our findings suggest that hypermethylation of the CGI at the promoter, mediated by the high expression of DNMT3A, and hypoacetylation of H3K27 in the CYP1A2 promoter region, leads to CYP1A2 repression in HCC. Epigenetic drugs DAC and TSA increase HCC cell sensitivity to sorafenib by restoring CYP1A2 expression. Our study provides new insights into the epigenetic regulation of CYP1A2 in HCC and highlights the potential of epigenetic drugs as a therapeutic approach for HCC. SIGNIFICANCE STATEMENT: This study marks the first exploration of the epigenetic mechanisms underlying cytochrome P450 (CYP) 1A2 suppression in hepatocellular carcinoma (HCC). Our findings reveal that heightened DNA methyltransferase expression induces hypermethylation of the CpG island at the promoter, coupled with diminished H3K27Ac levels, resulting in the repression of CYP1A2 in HCC. The use of epigenetic drugs such as decitabine and trichostatin A emerges as a novel therapeutic avenue, demonstrating their potential to restore CYP1A2 expression and enhance sorafenib sensitivity in HCC cells.
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Carcinoma Hepatocelular , Citocromo P-450 CYP1A2 , Metilação de DNA , Epigênese Genética , Neoplasias Hepáticas , Sorafenibe , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Humanos , Sorafenibe/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Metilação de DNA/efeitos dos fármacos , Linhagem Celular Tumoral , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , DNA Metiltransferase 3A , Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Decitabina/farmacologia , Ilhas de CpG/genética , Ácidos Hidroxâmicos/farmacologia , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/efeitos dos fármacosRESUMO
AIM: While insulin sensitivity plays an important role in maintaining glucose metabolic homeostasis and cognitive function, its impact on postoperative delirium (POD) remains unclear. This study aimed to investigate the association between POD and indicators of insulin sensitivity, including insulin resistance and osteocalcin. METHODS: A total of 120 elderly patients undergoing joint replacement were recruited and divided into delirium and non-delirium groups. Plasma and cerebrospinal fluid (CSF) samples were collected for the analysis of biomarkers, including insulin, uncarboxylated osteocalcin (ucOC), total osteocalcin (tOC), and glucose. Insulin resistance was assessed through the homeostatic model assessment of insulin resistance (HOMA-IR). MAIN RESULTS: Out of the total, 28 patients (23.3%) experienced POD within 5 days after surgery. Patients with delirium exhibited higher levels of preoperative HOMA-IR and ucOC in CSF and plasma, and of tOC in CSF (P = 0.028, P < 0.001, P = 0.005, P = 0.019). After adjusting for variables, including age, Mini-Mental State Examination score, surgical site and preoperative fracture, only preoperative ucOC in CSF and HOMA-IR were significantly linked to the incidence of delirium (OR = 5.940, P = 0.008; OR = 1.208, P = 0.046, respectively), both of which also correlated with the severity of delirium (P = 0.007, P < 0.001). Receiver operating curve analysis indicated that preoperative HOMA-IR and ucOC in CSF might partly predict POD (area under the curve [AUC] = 0.697, 95% confidence interval [CI] = 0.501-0.775, AUC = 0.745, 95% CI = 0.659-0.860). CONCLUSIONS: We observed that preoperative elevated HOMA-IR and ucOC in CSF were associated with the incidence and severity of POD. While these preliminary results need confirmation, they suggest a potential involvement of insulin resistance and osteocalcin in the pathological mechanism of POD. Geriatr Gerontol Int 2024; 24: 421-429.
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Artroplastia de Substituição , Delírio do Despertar , Resistência à Insulina , Humanos , Idoso , Osteocalcina , Incidência , Glucose , Artroplastia de Substituição/efeitos adversosRESUMO
BACKGROUND: Ureteropelvic junction obstruction (UPJO) is a common obstructive disease of the urinary tract. UPJO patients commonly exhibit coexistent renal calculi. The main aim of therapy is to relieve the obstruction and remove the stones at the same time. METHODS: This retrospective study included 110 patients diagnosed with UPJO coexisting with multiple renal calculi at Shanxi Bethune Hospital and the First Hospital of Shanxi Medical University between March 2016 and January 2022. Patients were divided according to the methods used for dealing with UPJO and renal calculi. In Group A, patients underwent traditional open pyeloplasty and pyelolithotomy. In Group B, patients underwent percutaneous nephrolithotomy first and then laparoscopic pyeloplasty. In Group C, patients underwent flexible cystoscopy to remove stones and then laparoscopic pyeloplasty. In Group D, patients underwent flexible vacuum-assisted ureteral access sheath (FV-UAS)assisted flexible ureteroscopy (f-URS) and underwent laparoscopic pyeloplasty. The stones were broken up using a holmium laser. The pyeloplasty success rate, stone clearance rate, operation time, bleeding amount, complication occurrence rate, postsurgical pain, length of stay, and hospitalization cost were compared between the groups. The follow-up period was at least 2 years. RESULTS: The use of f-URS and the FV-UAS, significantly increased the renal stone clearance rate and significantly reduced the complication incidence and operation time in UPJO patients with multiple coexisting renal calculi. CONCLUSIONS: Laparoscopic pyeloplasty combined with f-URS and FV-UAS is safe and effective for treating UPJO in patients complicated by renal caliceal stones. TRIAL REGISTRATION: Retrospectively registered.
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Cálculos Renais , Laparoscopia , Cálculos Ureterais , Obstrução Ureteral , Humanos , Ureteroscopia/efeitos adversos , Estudos Retrospectivos , Pelve Renal/cirurgia , Laparoscopia/métodos , Obstrução Ureteral/cirurgia , Cálculos Renais/cirurgia , Resultado do Tratamento , Cálculos Ureterais/cirurgiaRESUMO
The development of cancer is not just the growth and proliferation of a single transformed cell, but its tumor microenvironment (TME) also coevolves with it, which is primarily involved in tumor initiation, development, metastasis, and therapeutic responses. Recent years, TME has been emerged as a potential target for cancer diagnosis and treatment. However, the clinical efficacy of treatments targeting the TME, especially its specific components, remains insufficient. In parallel, the gut microbiome is an essential TME component that is crucial in cancer immunotherapy. Thus, assessing and constructing frameworks between the gut microbiota and the TME can significantly enhance the exploration of effective treatment strategies for various tumors. In this review the role of the gut microbiota in human cancers, including its function and relationship with various tumors was summarized. In addition, the interaction between the gut microbiota and the TME as well as its potential applications in cancer therapeutics was described. Furthermore, it was summarized that fecal microbiota transplantation, dietary adjustments, and synthetic biology to introduce gut microbiota-based medical technologies for cancer treatment. This review provides a comprehensive summary for uncovering the mechanism underlying the effects of the gut microbiota on the TME and lays a foundation for the development of personalized medicine in further studies.
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BACKGROUND & AIMS: Epidemiologic studies have examined the association between dietary fatty acids and type 2 diabetes risk in general populations. Evidence regarding their associations with gestational diabetes mellitus (GDM) risk remains limited. This study aimed to evaluate prepregnancy fatty acids intake in relation to GDM risk. METHODS: 3,725 pregnant women from the Xi'an Birth Cohort Study who were free of previous GDM or pre-existing chronic diseases were included. Dietary intake of total fat and individual fatty acids (including saturated fatty acids [SFA], monounsaturated fatty acids [MUFA], polyunsaturated fatty acids [PUFA], and trans fatty acids) during the year preceding pregnancy was assessed by a validated food-frequency questionnaire before 16 weeks of gestation. GDM was confirmed based on the 75-g oral glucose tolerance test. Log-binomial or modified Poisson regression models were applied to estimate the relative risks (RRs) and 95 % confidence intervals (95%CIs) of GDM for fatty acids intake. Generalized linear regression was adopted for blood glucose levels with fatty acids intake. RESULTS: 644 (17.3 %) incident GDM cases were confirmed in our study. Participants in the highest intake of total fat substituting for carbohydrates had a 33 % reduced risk of GDM than those in the lowest intake (RR:0.67; 95%CI:0.55,0.81). For individual fatty acids, only PUFA intake was associated with a lower risk of GDM, with RR comparing extreme tertiles of 0.61 (95%CI:0.49,0.76). Each 2 % increase in energy from total fat and PUFA replacing carbohydrates decreased the risk of GDM by 6 % (95%CI:3 %,9 %) and 15 % (95%CI:9 %,21 %), respectively. Similar inverse associations with intake of total fat and PUFA were observed for blood glucose levels. Further analyses of SFA substitution showed that replacement of 2 % energy from SFA with PUFA and MUFA was associated with 26 % (RR:0.74; 95%CI:0.62,0.88) and 30 % (RR:0.70; 95%CI:0.50, 0.98) decreased risk of GDM, respectively. CONCLUSIONS: Greater intake of total fat and PUFA before pregnancy was associated with lower risk of GDM when replacing carbohydrates. Substitution SFA with PUFA and MUFA was also inversely associated with GDM risk. These findings support the important role of optimal dietary fatty acids composition in the prevention of GDM.
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Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Humanos , Feminino , Gravidez , Diabetes Gestacional/epidemiologia , Estudos de Coortes , Dieta/efeitos adversos , Estudos Prospectivos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Glicemia , Gorduras na Dieta/efeitos adversos , Ácidos Graxos , Ácidos Graxos Insaturados , Ácidos Graxos MonoinsaturadosRESUMO
ZNF131 is a Zinc finger protein that acts as a transcription factor with oncogenic effects in multiple cancers. In this study, we aimed to explore the alternative splicing profile of ZNF131 in hepatocellular carcinoma (HCC), its regulatory effects on cell-cycle progression, and the downstream effectors. ZNF131 transcriptional profile and HCC survival analysis were conducted using data from the Cancer Genome Atlas (TCGA)-Liver Hepatocellular Cancer (LIHC) dataset. Chromatin immunoprecipitation (ChIP)-qPCR and dual-luciferase reporter assays were utilized to explore transcriptional regulation. CCK-8, colony formation and xenograft tumor models were used to study HCC tumor growth. Results showed that ZNF131 isoform 2 is upregulated in HCC tissues and its upregulation was associated with unfavorable overall survival (OS) and progression-free interval (PFI). Knockdown of endogenous ZNF131 inhibits HCC cell growth and induces G2/M cell-cycle arrest. ZNF131 binds to the SMC4 promoter by interacting with ZBTB33 and the ZBTB33 recognizing motif. ZNF131 transcriptionally activates SMC4 expression in HCC cells. The tumor-suppressive effects of ZNF131 shRNA could be partially reversed by enforced SMC4 overexpression. In summary, this study highlights the ZNF131/ZBTB33/SMC4 axis as a driver of pathological cell cycling and proliferation in HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Animais , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Fatores de Transcrição/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Adenosina Trifosfatases/metabolismo , Proteínas Cromossômicas não Histona/metabolismoRESUMO
Dioctyl phthalate, commonly known as bis(2-ethylhexyl) phthalate (DEHP), is a widely used plasticizer in various industries and has been shown to directly or indirectly impact human health. However, there is a lack of comprehensive studies evaluating the potential health risks associated with DEHP accumulation in different organs across various age groups. This study aimed to assess the effects of low (50 mg/kg·bw) and high (500 mg/kg·bw) doses of DEHP on five different organs in mice at young (4-week-old) and aged (76-week-old) life stages. Our findings revealed that both low and high doses of DEHP exposure led to significant dose-dependent inflammation in the liver, spleen, and kidney. Furthermore, regardless of age, DEHP exposure resulted in elevated activity of alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in the liver, as well as increased levels of creatinine (Cr) and urea in the kidney. Moreover, analysis of the fecal microbiota using 16S rRNA sequencing demonstrated that DEHP exposure disrupted the homeostasis of the gut microbiota, characterized by an increased abundance of pathogenic bacteria such as Desulfovibrio and Muribaculum, and a decreased abundance of beneficial bacteria like Lactobacillus. This study provides compelling evidence that DEHP at different concentrations can induce damage to multiple organs and disrupt gut microbiota composition. These findings lay the groundwork for further investigations into DEHP toxicity in various human organs, contributing to a better understanding of the potential health risks associated with DEHP exposure.