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The spatiotemporal regulation of inflammasome activation remains unclear. To examine the mechanism underlying the assembly and regulation of the inflammasome response, here we perform an immunoprecipitation-mass spectrometry analysis of apoptosis-associated speck-like protein containing a CARD (ASC) and identify NCF4/1/2 as ASC-binding proteins. Reduced NCF4 expression is associated with colorectal cancer development and decreased five-year survival rate in patients with colorectal cancer. NCF4 cooperates with NCF1 and NCF2 to promote NLRP3 and AIM2 inflammasome activation. Mechanistically, NCF4 phosphorylation and puncta distribution switches from the NADPH complex to the perinuclear region, mediating ASC oligomerization, speck formation and inflammasome activation. NCF4 functions as a sensor of ROS levels, to establish a balance between ROS production and inflammasome activation. NCF4 deficiency causes severe colorectal cancer in mice, increases transit-amplifying and precancerous cells, reduces the frequency and activation of CD8+ T and NK cells, and impairs the inflammasome-IL-18-IFN-γ axis during the early phase of colorectal tumorigenesis. Our study implicates NCF4 in determining the spatial positioning of inflammasome assembly and contributing to inflammasome-mediated anti-tumor responses.
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Proteínas Adaptadoras de Sinalização CARD , Neoplasias Colorretais , Vigilância Imunológica , Inflamassomos , Espécies Reativas de Oxigênio , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Inflamassomos/metabolismo , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Espécies Reativas de Oxigênio/metabolismo , Progressão da Doença , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , NADPH Oxidases/metabolismo , NADPH Oxidases/genética , Camundongos Knockout , Interleucina-18/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Feminino , Fosforilação , Linhagem Celular TumoralRESUMO
Decreased levels of ß-hydroxybutyrate (BHB), a lipid metabolic intermediate known to slow the progression of colorectal cancer (CRC), have been observed in the colon mucosa of patients with inflammatory bowel diseases (IBD). In particular, patients with recurrent IBD present an increased risk of developing colitis-associated colorectal cancer (CAC). The role and molecular mechanism of BHB in the inflammatory and carcinogenic process of CAC remains unclear. Here, the anti-tumor effect of BHB was investigated in the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS)-induced CAC model and tumor organoids derivatives. The underlying mechanisms were studied using transcriptome and non-target metabolomic assay and further validated in colon tumor cell lineage CT26 in vitro. The tumor tissues and the nearby non-malignant tissues from colon cancer patients were collected to measure the expression levels of ketogenic enzymes. The exogenous BHB supplement lightened tumor burden and angiogenesis in the CAC model. Notably, transcriptome analysis revealed that BHB effectively decreased the expression of VEGFA in the CAC tumor mucosa. In vitro, BHB directly reduced VEGFA expression in hypoxic-treated CT26 cells by targeting transcriptional factor HIF-1α. Conversely, the deletion of HIF-1α largely reversed the inhibitory effect of BHB on CAC tumorigenesis. Additionally, decreased expression of ketogenesis-related enzymes in tumor tissues were associated with poor survival outcomes in patients with colon cancer. In summary, BHB carries out anti-angiogenic activity in CAC by regulating HIF-1α/VEGFA signaling. These findings emphasize the role of BHB in CAC and may provide novel perspectives for the prevention and treatment of colonic tumors.
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Ácido 3-Hidroxibutírico , Subunidade alfa do Fator 1 Induzível por Hipóxia , Neovascularização Patológica , Ácido 3-Hidroxibutírico/farmacologia , Ácido 3-Hidroxibutírico/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Animais , Camundongos , Humanos , Neoplasias Associadas a Colite/patologia , Neoplasias Associadas a Colite/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Linhagem Celular Tumoral , Carcinogênese/efeitos dos fármacos , Masculino , Azoximetano/toxicidade , Colite/complicações , Colite/metabolismo , Colite/patologia , Colite/induzido quimicamente , Sulfato de Dextrana , Modelos Animais de Doenças , AngiogêneseRESUMO
Objective: The objective of this study is to elucidate the influence of MCU on the clinical pathological features of GC patients, to investigate the function and mechanism of the mitochondrial calcium uptake transporter MCU in the initiation and progression of GC, and to explore its impact on the metabolic pathways and biosynthesis of mitochondria. The ultimate goal is to identify novel targets and strategies for the clinical management of GC patients. Methods: Tumor and adjacent tissue specimens were obtained from 205 patients with gastric cancer, and immunohistochemical tests were performed to assess the expression of MCU and its correlation with clinical pathological characteristics and prognosis. Data from TCGA, GTEx and GEO databases were retrieved for gastric cancer patients, and bioinformatics analysis was utilized to investigate the association between MCU expression and clinical pathological features. Furthermore, we conducted an in-depth analysis of the role of MCU in GC patients. We investigated the correlation between MCU expression in GC and its impact on mitochondrial function, metabolism, biosynthesis, and immune cells. Additionally, we studied the proteins or molecules that interact with MCU. Results: Our research revealed high expression of MCU in the GC tissues. This high expression was associated with poorer T and N staging, and indicated a worse disease-free survival period. MCU expression was positively correlated with mitochondrial function, mitochondrial metabolism, nucleotide, amino acid, and fatty acid synthesis metabolism, and negatively correlated with nicotinate and nicotinamide metabolism. Furthermore, the MCU also regulates the function of the mitochondrial oxidative respiratory chain. The MCU influences the immune cells of GC patients and regulates ROS generation, cell proliferation, apoptosis, and resistance to platinum-based drugs in gastric cancer cells. Conclusion: High expression of MCU in GC indicates poorer clinical outcomes. The expression of the MCU are affected through impacts the function of mitochondria, energy metabolism, and cellular biosynthesis in gastric cancer cells, thereby influencing the growth and metastasis of gastric cancer cells. Therefore, the mitochondrial changes regulated by MCU could be a new focus for research and treatment of GC.
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ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria baicalensis Georgi (SBG), a widely used traditional Chinese medicine, exhibits anti-inflammatory and antioxidant properties. Wogonin is one of the primary bioactive components of SBG. Acetaminophen (APAP)-induced liver injury (AILI) represents a prevalent form of drug-induced liver damage and is primarily driven by inflammatory responses and oxidative stress. AIM OF STUDY: To investigate the therapeutic effects of Wogonin on AILI and the underlying mechanisms. MATERIALS AND METHODS: C57BL/6 J mice were pre-treated with Wogonin (1, 2.5, and 5 mg/kg bodyweight) for 3 days, followed by treatment with APAP (300 mg/kg bodyweight). The serum and liver tissue samples were collected at 24 h post-APAP treatment. Bone marrow-derived macrophages and RAW264.7 cells were cultured and pre-treated with Wogonin (5, 10, and 20 µM) for 30 min, followed by stimulation with lipopolysaccharide (LPS; 100 ng/mL) for 3 h. To examine the role of the PI3K/AKT signaling pathway in the therapeutic effect of Wogonin on AILI, mice and cells were treated with LY294002 (a PI3K inhibitor) and MK2206 (an AKT inhibitor). RESULTS: Wogonin pre-treatment dose-dependently alleviated AILI in mice. Additionally, Wogonin suppressed oxidative stress and inflammatory responses. Liver transcriptome analysis indicated that Wogonin primarily regulates immune function and cytokines in AILI. Wogonin suppressed inflammatory responses of macrophages by inhibiting the PI3K/AKT signaling pathway. Consistently, Wogonin exerted therapeutic effects on AILI in mice through the PI3K/AKT signaling pathway. CONCLUSIONS: Wogonin alleviated AILI and APAP-induced hepatotoxicity in mice through the PI3K/AKT signaling pathway.
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Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Flavanonas , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Acetaminofen/toxicidade , Camundongos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Masculino , Células RAW 264.7 , Fosfatidilinositol 3-Quinases/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Scutellaria baicalensis/químicaRESUMO
Background: This study aimed to investigate the relationship between baseline soluble suppression of tumorigenesis-2 (sST2) concentration and the outcomes of heart failure (HF), atrial fibrillation (AF) or death in patients with coronary heart disease (CHD) with or without renal insufficiency (RI). Methods: Between March 2011 and December 2015, 3454 patients with CHD from the Chinese PLA General Hospital were enrolled in this cohort study. The patients were followed up until October 2021. AF, HF, and death events were recorded. Associations between baseline sST2 concentrations and clinical outcomes were assessed using Kaplan-Meier (K-M) curves, and Cox regression and generalised additive models. Subgroup analysis were carried out between RI and non-RI groups. Results: Among the patients with CHD (61.5 ± 11.8 years; 78.6 % men), 415 (12.02 %) had RI. During a median follow-up of 8.37 years, HF and AF were reported in 216 (6.25 %) and 174 (5.04 %) patients, respectively, and 297 (8.60 %) died. The K-M curves indicated that patients in the higher quartiles of sST2 concentrations were correlated with a poor survival rate of HF, AF, or death (all Ps < 0.001). Generalised additive model (GAM) demonstrated a nonlinear positive association between sST2 concentration and the risk of HF, AF, and death in CHD patients. The cut-off value of sST2 for predicting HF, AF and death were 32.1, 25.4 and 28.6 ng/mL, respectively. CHD patients with sST2 higher than the cut-off value had higher risks of HF (HR: 3.02, 95%CI: 2.24-4.05), AF (HR: 2.86; 95%CI: 2.10-3.90), and death (HR:2.11, 95%CI: 1.67-2.67). Furthermore, in patients with RI (12.02 %, n = 415), the prognostic value of sST2 over the cut-off value for HF and death remained unchanged (HR: 3.21 and 2.35; P < 0.05). In patients with CHD with or without RI, sST2 improved the area under the curve (AUC) of traditional risk models for predicting clinical endpoint events. Conclusions: The biomarker sST2 may be useful for predicting HF, AF, and death in patients with CHD. The predicted value was not affected by renal function.
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BACKGROUND: Mitochondria produce adenosine triphosphate through respiratory activities to power sperm differentiation and motility, and decreased mitochondrial respiratory activity can result in poor sperm motility and asthenospermia. The mitochondrial sheath is a component of the mid-piece of the sperm flagellum, and dysfunction of the sheath can reduce sperm motility and cause male infertility. The membrane occupation and recognition nexus-motif protein 2 (MORN2) is testis enriched in mice, and the MORN motif was reported to play a role in the regulation of bioelectrical signal homeostasis in cardiomyocytes. METHODS: We generated Morn2-/- mice using CRISPR/Cas9 and evaluated the potential functions of MORN2 in spermiogenesis through histological analysis, fertility examination, RT-PCR, CASA, immunofluorescence, TUNEL, electron microscopy analysis, mitochondrial energy metabolism analysis, etc. RESULTS: The Morn2-/- mice were infertile, and their sperm showed severe motility defects. Morn2-/- sperm also had abnormal morphology characterized by bent heads, aberrant mitochondrial sheath formation, lower mitochondrial membrane potential, higher levels of reactive oxygen species, and decreased mitochondrial respiratory activity. CONCLUSIONS: Our study demonstrates that MORN2 is essential for male fertility and indicates that MORN2 functions in mitochondrial sheath formation and regulates mitochondrial respiratory activity.
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Sêmen , Motilidade dos Espermatozoides , Animais , Masculino , Camundongos , Metabolismo Energético , Fertilidade , MitocôndriasRESUMO
Colonoscopy is currently the best method for detecting bowel cancer, but fundamental design and construction have not changed significantly in decades. Conventional colonoscope (CC) is difficult to maneuver and can lead to pain with a risk of damaging the bowel due to its rigidity. We present the MorphGI, a robotic endoscope system that is self-propelling and made of soft material, thus easy to operate and inherently safe to patient. After verifying kinematic control of the distal bending segment, the system was evaluated in: a benchtop colon simulator, using multiple colon configurations; a colon simulator with force sensors; and surgically removed pig colon tissue. In the colon simulator, the MorphGI completed a colonoscopy in an average of 10.84 min. The MorphGI showed an average of 77% and 62% reduction in peak forces compared to a CC in high- and low-stiffness modes, respectively. Self-propulsion was demonstrated in the excised tissue test but not in the live pig test, due to anatomical differences between pig and human colons. This work demonstrates the core features of MorphGI.
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Quickly and accurately completing endoscopic submucosal dissection (ESD) operations within narrow lumens is currently challenging because of the environment's high flexibility, invisible collision, and natural tissue motion. This paper proposes a novel stereo visual servoing control for a dual-segment robotic endoscope (DSRE) for ESD surgery. Departing from conventional monocular-based methods, our DSRE leverages stereoscopic imaging to rapidly extract precise depth data, enabling quicker controller convergence and enhanced surgical accuracy. The system's dual-segment configuration enables agile maneuverability around lesions, while its compliant structure ensures adaptability within the surgical environment. The implemented stereo visual servo controller uses image features for real-time feedback and dynamically updates gain coefficients, facilitating rapid convergence to the target. In visual servoing experiments, the controller demonstrated strong performance across various tasks. Even when subjected to unknown external forces, the controller maintained robust performance in target tracking. The feasibility and effectiveness of the DSRE were further verified through ex vivo experiments. We posit that this novel system holds significant potential for clinical application in ESD surgeries.
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Background: The anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immunotherapy has been extensively used in patients with non-small cell lung cancer (NSCLC) in which the tumors are negative for oncogenic alterations. However, whether PD-1/PD-L1 blockade therapy could be applicable in patients harboring oncogenic mutations is largely unknown. Methods: In this retrospective study, we analyzed the safety and efficacy of anti-PD-1 inhibitor-based combinational therapy in a NSCLC cohort of 84 patients who harbored oncogenic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), k-Ras, RET, HER2 and BRAF. The patients were followed up till disease progression or death. The adverse effects associated with the treatment were carefully evaluated and timely interrupted. Results: There were 50 patients harboring EGFR mutations, 17 patients with k-Ras mutation, 2 patients with ALK rearrangement, 6 patients with RET rearrangement, 6 patients with HER2 exon20 insertion and 3 patients with BRAF V600E mutation. About 58.8% of the k-Ras mutant patients responded to the combinational treatment. The median progression-free survival (mPFS) of the k-Ras cohort was 14 months, with the 12-month median overall survival (mOS) ratio and the 24-month OS ratio of 86.7% and 75.8%, respectively. Patients with EGFR exon21 L858R mutation or RET rearrangement tended to have a more favorable response, while patients harboring ALK rearrangement, HER2 exon20 insertion and BRAF V600E mutation did not respond well to anti-PD-1 inhibitor-based combinational therapy. The incidence of treatment-related toxicity was 52.3% and the most common immune-related adverse events (irAEs) were PD-1 inhibitors-related hypothyroidism and pneumonitis. The PD-L1 status and lung immune prognostic index (LIPI) could be used as biomarkers dictating therapeutic outcomes of the combinational therapy. Conclusions: The anti-PD-1 inhibitor-based combinational therapy elicited exciting anti-tumor efficacy and prolonged patient survival with manageable adverse effects in NSCLC patients harboring oncogenic alterations. The PD-L1 status and LIPI could be used as a biomarker predicting response to anti-PD-1 inhibitor-based combinational treatment in these patients.
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BACKGROUND: TNF-α processing inhibitor-1 (TAPI-1) is a known metalloproteinase inhibitor with potential anti-inflammatory effects. However, its anti-cancer effects on esophageal squamous cell carcinoma (ESCC) have not been uncovered. AIM: In the present study, the effects of TAPI-1 on ESCC cell viability, migration, invasion, and cisplatin resistance and the underlying molecular mechanisms were investigated in TE-1 and Eca109 cells. METHODS: To this end, TE-1 and Eca109 cells were exposed to TAPI-1 for indicated time intervals. Cell viability was assessed using cell counting kit-8 assay and apoptosis was evaluated using flow cytometry assay. Migration and invasion were assessed using Transwell assays. Gene expressions were analyzed using quantitative reverse transcription polymerase chain reaction. The activation of NF-κB signaling pathway was elucidated via Western blot and chromatin immunoprecipitation assay. RESULTS: We observed that higher doses (10, 20 µM) of TAPI-1 inhibited ESCC cell viability, while a lower dose (5 µM) of TAPI-1 inhibited ESCC cell migration and invasion and enhanced the chemosensitivity of ESCC cells to cisplatin. Moreover, TAPI-1 suppressed the activation of NF-κB signaling and the target genes expression in the stage of transcription initiation. Furthermore, blocking NF-κB signaling in advance could abolish all the effects of TAPI-1 on ESCC cells. CONCLUSION: Overall, these results indicated that TAPI-1 impairs ESCC cell viability, migration, and invasion and facilitates cisplatin-induced apoptosis via suppression of NF-κB signaling pathway. TAPI-1 may serve as a potential adjuvant agent with cisplatin for ESCC therapy.
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Carcinoma de Células Escamosas , Dipeptídeos , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Ácidos Hidroxâmicos , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Linhagem Celular Tumoral , Transdução de Sinais , Proliferação de Células , Movimento CelularRESUMO
Injectable hydrogels are currently a topic of great interest in bone tissue engineering, which could fill irregular bone defects in a short time and avoid traditional major surgery. Herein, we developed an injectable gellan gum (GG)-based hydrogel for bone defect repair by blending nano-hydroxyapatite (nHA) and magnesium sulfate (MgSO4). In order to acquire an injectable GG-based hydrogel with superior osteogenesis, nHA were blended into GG solution with an optimized proportion. For the aim of endowing this hydrogel capable of angiogenesis, MgSO4 was also incorporated. Physicochemical evaluation revealed that GG-based hydrogel containing 5% nHA (w/v) and 2.5 mM MgSO4 (GG/5%nHA/MgSO4) had appropriate sol-gel transition time, showed a porosity-like structure, and could release magnesium ions for at least 14 days. Rheological studies showed that the GG/5%nHA/MgSO4 hydrogel had a stable structure and repeatable self-healing properties. In-vitro results determined that GG/5%nHA/MgSO4 hydrogel presented superior ability on stimulating bone marrow mesenchymal stem cells (BMSCs) to differentiate into osteogenic linage and human umbilical vein endothelial cells (HUVECs) to generate vascularization. In-vivo, GG/5%nHA/MgSO4 hydrogel was evaluated via a rat cranial defect model, as shown by better new bone formation and more neovascularization invasion. Therefore, the study demonstrated that the new injectable hydrogel, is a favorable bioactive GG-based hydrogel, and provides potential strategies for robust therapeutic interventions to improve the repair of bone defect.
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Hidrogéis , Osteogênese , Polissacarídeos Bacterianos , Ratos , Humanos , Animais , Hidrogéis/farmacologia , Hidrogéis/química , Angiogênese , Regeneração Óssea , Engenharia Tecidual , Células Endoteliais da Veia Umbilical HumanaRESUMO
BACKGROUND: Excessive hepatic glucose production is a hallmark that contributes to hyperglycemia in type 2 diabetes (T2D). The regulatory network governing this process remains incompletely understood. Here, we demonstrate that TOX3, a high-mobility group family member, acts as a major transcriptional driver for hepatic glucose production. METHODS: Tox3-overexpressed and knockout mice were constructed to explore its metabolic functions. Transcriptomic and chromatin-immunoprecipitation sequencing (ChIP-seq) were used to identify downstream targets of TOX3. Both FoxO1 silencing and inhibitor approaches were used to assess the contribution of FoxO1. TOX3 expression levels were examined in the livers of mice and human subjects. Finally, Tox3 was genetically manipulated in diet-induced obese mice to evaluate its therapeutic potential. RESULTS: Hepatic Tox3 overexpression activates the gluconeogenic program, resulting in hyperglycemia and insulin resistance in mice. Hepatocyte-specific Tox3 knockout suppresses gluconeogenesis and improves insulin sensitivity. Mechanistically, integrated hepatic transcriptomic and ChIP-seq analyses identify FoxO1 as a direct target of TOX3. TOX3 stimulates FoxO1 transcription by directly binding to and activating its promoter, whereas FoxO1 silencing abrogates TOX3-induced dysglycemia in mice. In human subjects, hepatic TOX3 expression shows a significant positive correlation with blood glucose levels under normoglycemic conditions, yet is repressed by high glucose during T2D. Importantly, hepatic Tox3 deficiency markedly protects against and ameliorates the hyperglycemia and glucose intolerance in diet-induced diabetic mice. CONCLUSIONS: Our findings establish TOX3 as a driver for excessive gluconeogenesis through activating hepatic FoxO1 transcription. TOX3 could serve as a promising target for preventing and treating hyperglycemia in T2D.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hiperglicemia , Resistência à Insulina , Animais , Humanos , Camundongos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Gluconeogênese/genética , Glucose/metabolismo , Hiperglicemia/genética , Hiperglicemia/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Anthropogenic activities have significantly increased the influx of carbon dioxide and metals into the marine environment. Combining ocean acidification (OA) and metal pollution may lead to unforeseen biological and ecological consequences. Several studies have shown that OA reduces cadmium (Cd) toxicity in marine diatoms. Although these studies have shed light on the physiological and transcriptomic responses of diatoms exposed to Cd, many aspects of the mechanisms underlying the reduced metal accumulation in diatoms remain unknown. This study aims to address this unresolved question by comparing Cd subcellular distribution, antioxidant enzyme activity, relative expression of metal transporters, surface potential, surface composition, and transmembrane potential in the diatom Phaeodactylum tricornutum grown under ambient and 1200 µatm pCO2 conditions. Our findings reveal that diatoms grown in acidified seawater exhibit higher surface potential and higher plasma membrane depolarization. These changes and the competing effects of increased H+ concentration result in a blunted response of P. tricornutum to the Cd challenge. Consequently, this study offers a new explanation for mitigating Cd toxicity by marine diatoms adapted to OA.
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Diatomáceas , Água do Mar , Cádmio/metabolismo , Concentração de Íons de Hidrogênio , Acidificação dos Oceanos , Metais/metabolismo , Antioxidantes/metabolismo , Dióxido de Carbono/farmacologiaRESUMO
This work presents a novel dual-segment flexible robotic endoscope designed to enhance reachability and dexterity during ESD surgery. The proposed system is capable of executing multi-angle cutting operations at a small angle relative to the lesion surface, allowing for efficient en-bloc resection. Additionally, the system incorporates two calibrated RGB cameras and a depth estimation algorithm to provide detailed 3D information of the tumour, which is used to guide the control framework. A stereo visual servoing controller is also implemented to improve path-following performance during surgery. Experiments results indicate that the proposed system improves motion stability and precision. The root means square error (RMSE) of circle path following is 1.1991mm with a maximum of 1.4751mm. Ex-vivo testing demonstrates its significant potential for use in endoscopic surgery.
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Ressecção Endoscópica de Mucosa , Neoplasias Gástricas , Humanos , Ressecção Endoscópica de Mucosa/métodos , Endoscópios , Endoscopia , Mucosa Gástrica/patologia , Mucosa Gástrica/cirurgiaRESUMO
[This corrects the article DOI: 10.3389/fimmu.2022.1047570.].
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Increased anthropogenic emissions of carbon dioxide (CO2) have resulted in ocean acidification (OA) that is intertwined with enhanced ocean stratification. Diatoms are assumed to suffer from a more nutrient-limited condition in the future ocean. This study aimed to explore how OA affects the diatom dynamics under nutrient-poor conditions and the ability of diatoms to perceive nutrients (nitrogen, phosphorus, silicon, and trace metals) and cadmium (Cd) stimuli and assimilate nitrogen when receiving nutrients or Cd supplementation. Our study observed that diatom population grown under OA condition declined faster than those grown under ambient condition. Ocean acidification greatly lower intracellular Ca2+ concentration in diatom cells. Intracellular Ca2+ burst was involved in phosphorus accumulation but not in nitrogen, silicon, essential metals, and cadmium uptake. Our data demonstrate slower NO3- assimilation rates of diatoms grown in acidified seawater. Our study also indicates that diatoms have a poor perception of phosphorus availability under OA condition.
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Cádmio , Diatomáceas , Cádmio/toxicidade , Concentração de Íons de Hidrogênio , Acidificação dos Oceanos , Água do Mar , Silício , Nitrogênio , Nutrientes , FósforoRESUMO
Tumor-associated p53 mutations induce activities different from wild-type p53, thus causing loss of the protein's tumor inhibition function. The cells carrying p53 mutations have more aggressive characteristics related to invasion, metastasis, proliferation, and cell survival. By comparing the gene expression profiles of mutant p53 (mutp53) and mutp53 silenced cohorts, we found that FOS-related antigen-1 (FRA-1), which is encoded by FOSL1, is a potential effector of mutp53-mediated metastasis. We demonstrate that the expression of FRA-1, a gatekeeper of mesenchymal-epithelial transition, is elevated in the presence of p53 mutations. Mechanistically, mutant p53 cooperates with the transcription factor ELK1 in binding and activating the promoter of FOSL1, thus fostering lung metastasis. This study reveals new insights into how mutant p53 contributes to metastasis in breast cancer.
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Neoplasias da Mama , Neoplasias Pulmonares , Humanos , Feminino , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Neoplasias da Mama/genética , Mutação , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteínas Elk-1 do Domínio ets/genética , Proteínas Elk-1 do Domínio ets/metabolismoRESUMO
Before use as medicines, most traditional Chinese medicine (TCM) plants are processed and decocted. During processing, there may be some changes in pesticide residues in TCM. In recent years, reports have studied the changes of pesticides during the processes of boiling, drying and peeling of TCM materials but have rarely involved special processing methods for TCM, such as ethanol extraction and volatile oil extraction. The changes of carbendazim, carbofuran, pyridaben and tebuconazole residues in common processing methods for P. cablin products were systemically assessed in this study. After each processing step, the pesticides were quantitated by UPLC-MS/MS. The results showed amount decreases in various pesticides to different extents after each processing procedure. Processing factor (PF) values for the four pesticides after decoction, 75% ethanol extraction and volatile oil extraction were 0.02~0.75, 0.40~0.98 and 0~0.02, respectively, which indicated that residual pesticide concentrations may depend on the processing technique. A risk assessment according to the hazard quotient with PF values showed that residual pesticide amounts in P. cablin were substantially lower than levels potentially posing a health risk. Overall, these findings provide insights into the safety assessment of P. cablin.
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Óleos Voláteis , Resíduos de Praguicidas , Praguicidas , Pogostemon , Cromatografia Líquida , Espectrometria de Massas em Tandem , Resíduos de Praguicidas/análise , Óleos Voláteis/químicaRESUMO
BACKGROUND: Stroke represents the second leading cause of death and the primary cause of long-term disability in humans. The transplantation of mesenchymal stem cells (MSC) reportedly improves functional outcomes in animal models of cerebral ischemia. Here, we evaluate the neuroprotective potential of extracellular vesicles secreted from human-induced pluripotent stem cell-derived mesenchymal stem cells (hiPS-MSC-EV) using preclinical cell-based and animal-based models of ischemic strokes. METHODS: hiPS-MSC-EV were isolated using an ultrafiltration method. HT22 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury for 2 h, followed by treatment with hiPS-MSC-EV (100 µg/mL). Male C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) followed by an intravenous injection of hiPS-MSC-EV (100 µg) at three distinct time points. RESULTS: Our experimental approach revealed hiPS-MSC-EV promoted HT22 cell proliferation, reduced apoptosis, and altered cellular morphology following OGD/R. In addition, hiPS-MSC-EV reduced the volume of infarcts, improved spontaneous movement abilities, and enhanced angiogenesis by expressing the VEGF and CXCR4 proteins in the infarcted hemisphere of the MCAO-treated mouse model. CONCLUSION: Our findings provide evidence of the potential neuroprotective effects of hiPS-MSC-derived extracellular vesicles (hiPS-MSC-EVs) in both in vitro and in vivo mouse models of ischemic stroke. These results suggest that hiPS-MSC-EVs may play a role in neurorestoration and offer insights into potential cell-free strategies for addressing cerebral ischemia.
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BACKGROUND: Growth differentiation factor 15 (GDF-15) has been explored as a potential biomarker for various inflammatory diseases and cardiovascular events. This study aimed to assess the predictive role of GDF-15 levels in cardiovascular events and all-cause mortality, considering traditional risk factors and other biomarkers. METHODS: A prospective study was conducted and 3699 patients with stable coronary artery disease (CAD) were enrolled into the research. Baseline GDF-15 levels were measured. Median follow-up was 3.1 years during the study. We analyzed clinical variables and several biomarkers. Multivariable Cox regression analysis was performed to evaluate prognostic performance of GDF-15 levels in predicting myocardial infarction (MI), heart failure, stroke, cardiovascular death, and non-cardiovascular death. RESULTS: Baseline GDF-15 levels for 3699 patients were grouped by quartile (≤ 1153, 1153-1888, 1888-3043, > 3043 ng/L). Higher GDF-15 levels were associated with older age, male gender, history of hypertension, and elevated levels of N-terminal pro B-type natriuretic peptide (NT-pro BNP), soluble suppression of tumorigenesis-2 (sST2), and creatine (each with P < 0.001). Adjusting for established risk factors and biomarkers in Cox proportional hazards models, a 1 standard deviation (SD) increase in GDF-15 was associated with elevated risk of clinical events [hazard ratio (HR) = 2.18, 95% confidence interval (CI): (1.52-3.11)], including: MI [HR = 2.83 95% CI: (1.03-7.74)], heart failure [HR = 2.71 95% CI: (1.18-6.23)], cardiovascular and non-cardiovascular death [HR = 2.48, 95% CI (1.49-4.11)] during the median follow up of 3.1 years. CONCLUSIONS: Higher levels of GDF-15 consistently provides prognostic information for cardiovascular events and all cause death, independent of clinical risk factors and other biomarkers. GDF-15 could be considered as a valuable addition to future risk prediction model in secondary prevention for predicting clinical events in patient with stable CAD.