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Pancreatic cancer is one of the leading causes of cancer-associated mortality, with a poor treatment approach. Previous study has shown that inducing pyroptosis in pancreatic ductal adenocarcinoma (PDAC) slows the growth of PDACs, implying that pyroptosis inducers are potentially effective for PDAC therapy. Here, we found that Dronedarone hydrochloride (DH), an antiarrhythmic drug, induces pyroptosis in pancreatic cancer cells and inhibits PDAC development in mice. In PANC-1 cells, DH caused cell death in a dosage- and time-dependent manner, with only pyroptosis inhibitors and GSDMD silencing rescuing the cell death, indicating that DH triggered GSDMD-dependent pyroptosis. Further work revealed that DH increased mitochondrial stresses and caused mitochondrial DNA (mtDNA) leakage, activating the cytosolic STING-cGAS and pyroptosis pathways. Finally, we assessed the anti-cancer effects of DH in a pancreatic cancer mouse model and found that DH treatment suppressed pancreatic tumor development in vivo. Collectively, our investigation demonstrates that DH triggers pyroptosis in PDAC and proposes its potential effects on anti-PDAC growth.
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DNA Mitocondrial , Dronedarona , Neoplasias Pancreáticas , Piroptose , Piroptose/efeitos dos fármacos , Animais , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Humanos , Dronedarona/farmacologia , DNA Mitocondrial/metabolismo , DNA Mitocondrial/genética , Camundongos , Linhagem Celular Tumoral , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Camundongos NusRESUMO
In field hydraulic fracturing operation of shale gas development, the high pressure and large displacement liquid-particle two-phase fracturing fluid can be forced to change direction many times through high-pressure double-elbow, and be transported from the outlet pipeline of the fracturing pump to the main pipeline. The high-pressure double-elbow is prone to be affected by erosion wear and Fluid-Structure Interaction (FSI), resulting in perforation and fracture, posing a potential safety threat to field operation. In this study, we conducted the erosion wear experiments on 35CrMo steel used for high-pressure double-elbow in shale-gas fracturing. The erosion rates under different impact angles and flow velocities were obtained, and proposed a novel model of erosion prediction for high-pressure double-elbow. Then the numerical investigation was employed to conduct a comprehensive analysis of erosion wear, structural stress and deformation by the coupling of Computational Fluid Dynamics (CFD) and Finite Element Analysis (FEA). The effects of structural parameters such as connection straight pipe length, pipe inner diameter and fluid turning direction were discussed. The results indicate that with the increase of connection straight pipe length, the flow erosion decreases first then varies little, and the deformation gradually increases. Slight erosion wear but large structural stress and deformation in major inner diameter pipe. And the minimum degree of erosion and flow-induced deformation present with the fluid turning direction of double-elbow as 0°. The study can provide references for the design, installation and detection of high-pressure double-elbow and ensure safety in the process of shale gas fracturing.
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BACKGROUND: Pathological cardiac remodeling is a critical process leading to heart failure, characterized primarily by inflammation and apoptosis. Matairesinol (Mat), a key chemical component of Podocarpus macrophyllus resin, exhibits a wide range of pharmacological activities, including anti-hydatid, antioxidant, antitumor, and anti-inflammatory effects. PURPOSE: This study aims to investigate whether Matairesinol alleviate cardiac hypertrophy and remodeling caused by pressure overload and to elucidate its mechanism of action. METHODS: An in vitro pressure loading model was established using neonatal rat cardiomyocytes treated with angiotensin â ¡, while an in vivo model was created using C57 mice subjected to transverse aortic constriction (TAC). To activate the PI3K/Akt/FoxO1 pathway, Ys-49 was employed. Moreover, small interfering RNA (siRNA) and short hairpin RNA (shRNA) were utilized to silence Prdx1 expression both in vitro and in vivo. Various techniques, including echocardiography, wheat germ agglutinin (WGA) staining, HE staining, PSR staining, and Masson trichrome staining, were used to assess cardiac function, cardiomyocyte cross-sectional area, and fibrosis levels in rats. Apoptosis in myocardial tissue and in vitro was detected by TUNEL assay, while reactive oxygen species (ROS) content in tissues and cells was measured using DHE staining. Furthermore, the affinity of Prdx1 with Mat and PI3K was analyzed using computer-simulated molecular docking. Western blotting and RT-PCR were utilized to evaluate Prdx1 levels and proteins related to apoptosis and oxidative stress, as well as the mRNA levels of cardiac hypertrophy and fibrosis-related indicators. RESULTS: Mat significantly alleviated cardiac hypertrophy and fibrosis induced by TAC, preserved cardiac function, and markedly reduced cardiomyocyte apoptosis and oxidative damage. In vitro, mat attenuated ang â ¡ - induced hypertrophy of nrvms and activation of neonatal rat fibroblasts. Notably, activation of the PI3K/Akt/FoxO1 pathway and downregulation of Prdx1 expression were observed in TAC mice; however, these effects were reversed by Mat treatment. Furthermore, Prdx1 knockdown activated the PI3K/Akt/FoxO1 pathway, leading to exacerbation of the disease. Molecular docking indicated that Molecular docking indicated that Mat upregulated Prdx1 expression by binding to it, thereby inhibiting the PI3K/Akt/FoxO1 pathway and protecting the heart by restoring Prdx1 expression levels. CONCLUSION: Matairesinol alleviates pressure overload-induced cardiac remodeling both in vivo and in vitro by upregulating Prdx1 expression and inhibiting the PI3K/Akt/FoxO1 pathway. This study highlights the therapeutic potential of Matairesinol in the treatment of cardiac hypertrophy and remodeling, providing a promising avenue for future research and clinical application.
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Primary liver cancer is a major public health issue in China, with high incidence and mortality rates. Notably, progress has been made in improving the surgical methods and hepatic arterial infusion chemotherapy (HAIC) regimens of liver cancer and the combination of HAIC with immunotherapy is expected to further increase the surgical conversion rate or objective response rate. However, patients with liver cancer often have underlying cirrhosis, which may lead to complications, such as esophageal varices and high-pressure gastric diseases. The present study describes three cases of giant gastric ulcers that occurred during the process of HAIC or combined immunotherapy. Notably, the causal relationship between HAIC and immunotherapy is unclear. In patients with tumors receiving immunotherapy, gastrointestinal adverse reactions are common, and some may develop serious complications, such as gastrointestinal perforation. The present study provides a detailed analysis of this issue and emphasizes the need for further clarification of its mechanisms and effective treatment methods.
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Achieving enzymatic food processing at high substrate concentrations can significantly enhance production efficiency; however, related studies are notably insufficient. This study focused on the enzymatic synthesis of fructooligosaccharides (FOS) at high temperature and high substrate concentration. Results revealed that increased viscosity and limited substrate solubility in high-concentration systems could be alleviated by raising the reaction temperature, provided it aligned with the enzyme's thermostability. Further analysis of enzyme thermostability in real sucrose solutions demonstrates that the enzyme's thermostability was remarkedly improved at higher sucrose concentrations, evidenced by a 10.3 °C increase in melting temperature (Tm) in an 800 g/L sucrose solution. Building upon these findings, we developed a novel method for enzymatic FOS synthesis at elevated temperatures and high sucrose concentrations. Compared to existing commercial methods, the initial transglycosylation rate and volumetric productivity for FOS synthesis increased by 155.9% and 113.5%, respectively, at 65 °C in an 800 g/L sucrose solution. This study underscores the pivotal role of substrate concentration, incubation temperature, and the enzyme's actual status in advancing enzyme-catalyzed processes and demonstrates the potential of enzymatic applications in enhancing food processing technologies, providing innovative strategies for the food industry.
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PURPOSE: To explore the analgesic characteristics of ultrasound-guided great auricular nerve (GAN) block to further improve pain management. DESIGN: Single-center, prospective, randomized, controlled, and double-blind preliminary clinical trial. METHODS: Thirty-seven patients who underwent middle ear surgery were included in this study: 15 in the GAN block group (the large ear nerve block [NB] group) and 22 in the traditional anesthesia group (control [CON] group). After induction of anesthesia, the NB group was given an ultrasound-guided GAN block (0.25 % Ropivacaine 2 mL), while the CON group was exempt from the GAN block. The patient's basic information, perioperative information, the region, and numeric rating scale of postoperative pain (at 1 hour, 6 hours, 12 hours, and 24 hours), and adverse reactions were recorded. Repeated measurement analysis, t test, and Fisher exact probability method were used for statistical analysis. FINDINGS: Compared with the CON group, the numeric rating scale in the NB group was lower after surgery (1 hour: 1.18 ± 0.35 vs 0.27 ± 0.20, P = .023; 6 hours: 1.82 ± 0.37 vs 1.13 ± 0.39, P = .203; 12 hours: 1.05 ± 0.19 vs 0.20 ± 0.10, P < .001; 24 hours: 0.55 ± 0.17 vs 0.13 ± 0.09, P = .029). In the NB group, the region of pain was merely concentrated in the ear canal. In the CON group, the pain extended to areas outside the ear canal, such as tragus and mastoid (at 12 hours, P = .006). There was no significant difference in the risk of postoperative adverse reactions between the two groups. CONCLUSIONS: Ultrasound-guided GAN block can relieve patients' pain after middle ear surgery, especially in the area outside the ear canal.
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Unlocking the intricacies of protein structures and interactions within the dynamic landscape of subcellular organelles presents a significant challenge. To address this, we introduce SPACX, a method for spatially resolved protein complex profiling via biocompatible chemical cross(x)-linking with subcellular isolation, designed to monitor protein conformation, interactions, and translocation in living cells. By rapidly capturing protein complexes in their native physiological state and efficiently enriching cross-linked peptides, SPACX allows comprehensive analysis of the protein interactome within living cells. Leveraging structure refinement with cross-linking restraints, we identify subcellular-specific conformation heterogeneity of PTEN, revealing dynamic differences in its dual specificity domains between the nucleus and cytoplasm. Furthermore, by discerning conformational disparities, we identify 83 cytoplasm-exclusive and 109 nucleus-exclusive PTEN-interacting proteins, each associated with distinct biological functions. Upon induction of ubiquitin-proteasome system stress, we observe dynamic alterations in PTEN assembly and its interacting partners during translocation. These changes, including the identification of components and interaction sites, are characterized using the SPACX approach. Notably, SPACX enables identification of unique interacting proteins specific to PTEN isoforms, including PTEN and PTEN-Long, through the determination of sequence-specific cross-linking interfaces. These findings underscore the potential of SPACX to elucidate the functional diversity of proteins within distinct subcellular sociology.
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Reagentes de Ligações Cruzadas , PTEN Fosfo-Hidrolase , Conformação Proteica , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/química , Humanos , Reagentes de Ligações Cruzadas/química , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Ligação Proteica , Mapeamento de Interação de ProteínasRESUMO
Androgen receptor (AR) overexpression has been identified in gliomas and its stem cells, suggesting that AR plays an important role in tumor carcinogenesis. The prognostic significance of AR overexpression in gliomas remains unknown. AR mRNA expression in gliomas and relevant clinical data were obtained from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. AR expression levels were compared across gliomas of different histopathologic grades and molecular subtypes. Kaplan-Meier analyses in patients with different AR expression levels were investigated for the potential prognostic values of AR. Compared with normal brain tissue, gliomas show significantly higher AR mRNA expression (p < 0.01). AR mRNA expression was more prominent in higher grade disease and in worse prognostic molecular subtypes (p < 0.01). AR protein is more abundant in glioblastoma than in lower grade gliomas (LGG) (grade 2/3) (p < 0.0001). This is corroborated by a linear association between AR mRNA and protein expression (r = 0.65). In LGG, both higher AR mRNA and protein expression was associated with significantly worse overall survival (OS). Five-year OS for LGG patients with high versus low AR expression were 59.1% and 73.3%, respectively (p < 0.0001). AR expression is not prognostic for OS within glioblastoma patients. Gender was not associated with AR expression or prognosis. Higher AR expression levels are associated with higher grade disease and histopathologic features predicting poorer prognosis in lower grade gliomas. Higher gene expression in LGG patients is correlated with poor prognosis but not in the glioblastoma cohort suggesting saturated expression/functions of AR in glioblastoma.
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Neoplasias Encefálicas , Glioma , Receptores Androgênicos , Humanos , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Glioma/genética , Glioma/patologia , Glioma/metabolismo , Glioma/mortalidade , Prognóstico , Masculino , Feminino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-Idade , Gradação de Tumores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estimativa de Kaplan-Meier , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , AdultoRESUMO
Expansins are cell wall (CW) proteins that mediate the CW loosening and regulate salt tolerance in a positive or negative way. However, the role of Populus trichocarpa expansin A6 (PtEXPA6) in salt tolerance and the relevance to cell wall loosening is still unclear in poplars. PtEXPA6 gene was transferred into the hybrid species, Populus alba × P. tremula var. glandulosa (84K) and Populus tremula × P. alba INRA '717-1B4' (717-1B4). Under salt stress, the stem growth, gas exchange, chlorophyll fluorescence, activity and transcription of antioxidant enzymes, Na+ content, and Na+ flux of root xylem and petiole vascular bundle were investigated in wild-type and transgenic poplars. The correlation analysis and principal component analysis (PCA) were used to analyze the correlations among the characteristics and principal components. Our results show that the transcription of PtEXPA6 was downregulated upon a prolonged duration of salt stress (48 h) after a transient increase induced by NaCl (100 mM). The PtEXPA6-transgenic poplars of 84K and 717-1B4 showed a greater reduction (42-65%) in stem height and diameter growth after 15 days of NaCl treatment compared with wild-type (WT) poplars (11-41%). The Na+ accumulation in roots, stems, and leaves was 14-83% higher in the transgenic lines than in the WT. The Na+ buildup in the transgenic poplars affects photosynthesis; the activity of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT); and the transcription of PODa2, SOD [Cu-Zn], and CAT1. Transient flux kinetics showed that the Na+ efflux of root xylem and leaf petiole vascular bundle were 1.9-3.5-fold greater in the PtEXPA6-transgenic poplars than in the WT poplars. PtEXPA6 overexpression increased root contractility and extensibility by 33% and 32%, indicating that PtEXPA6 increased the CW loosening in the transgenic poplars of 84K and 717-1B4. Noteworthily, the PtEXPA6-promoted CW loosening was shown to facilitate Na+ efflux of root xylem and petiole vascular bundle in the transgenic poplars. We conclude that the overexpression of PtEXPA6 leads to CW loosening that facilitates the radial translocation of Na+ into the root xylem and the subsequent Na+ translocation from roots to leaves, resulting in an excessive Na+ accumulation and consequently, reducing salt tolerance in transgenic poplars. Therefore, the downregulation of PtEXPA6 in NaCl-treated Populus trichocarpa favors the maintenance of ionic and reactive oxygen species (ROS) homeostasis under long-term salt stress.
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Regulação da Expressão Gênica de Plantas , Proteínas de Plantas , Plantas Geneticamente Modificadas , Populus , Estresse Salino , Sódio , Populus/genética , Populus/metabolismo , Populus/crescimento & desenvolvimento , Populus/efeitos dos fármacos , Sódio/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Xilema/metabolismo , Xilema/genética , Raízes de Plantas/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Tolerância ao Sal/genética , Transporte BiológicoRESUMO
Objective: Timely screening and intervention can prevent the development of the diabetic foot. However, delayed visits to the clinic are common among diabetic foot patients. The study aimed to develop and validate a questionnaire to assess healthcare-seeking behavior among patients with diabetic high-risk foot. Methods: The questionnaire of healthcare-seeking intention for patients with diabetic high-risk foot was developed in two phases: (1) Developing the questionnaire: 1) questionnaire items were formulated after literature review, group discussion and semi-qualitative interview; 2) a two-round modified Delphi method was to examine the content validity and the degree of consistency in questionnaire items; 3) conducting pre-survey to revise the questionnaire items. (2) Assessing the internal reliability and construct validity. Results: The final questionnaire consisted of five main themes and 28 items with a five-point rating. Cronbach's alpha coefficients for the five dimensions were respectively 0.937 (relevant knowledge of diabetic foot), 0.669 (attitudes toward seeking care), 0.896 (social support for seeking care), 0.621 (efficacy in coping with foot symptoms), 0.871 (intention to seek care). The Scale-level Content Validity Index of the five parts was 1.00, 0.80, 1.00, 1.00, and 1.00, respectively. The Kaiser-Meyer-Olkin values for each dimension was greater than 0.7, and the p-value for Bartlett's test of sphericity was less than 0.05. Conclusion: This questionnaire showed good validity, internal consistency, and reliability. It provided a potentially useful instrument to evaluate healthcare-seeking intention among patients with diabetic high-risk foot.
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In this study, a novel customized corneal cross-linking (CXL) treatment is explored that utilizes microneedles (MNs) for targeted riboflavin (RF) administration prior to the CXL procedure. Unlike the conventional "one-size-fits-all" approach, this protocol offers an option for more precise and efficacious treatment. To simulate a customized corneal crosslinking technique, four distinct microneedle (MN) molds designs, including circular, semi-circular, annular and butterfly shaped, are crafted for loading an optimized RF-hyaluronic acid solution and for the subsequent fabrication of MN arrays with varying morphologies. These MNs can gently puncture the corneal epithelium while preserving the integrity of the underlying stromal layer. Following the application of these microneedles, RF solution is replenished to enhance the RF content within the stroma through the punctures created by the MNs, resulting in exceptional customized corneal cross-linking effects that are comparable to the conventional epi-off CXL protocol. Additionally, it flattened the corneal curvature within the treated zone and facilitated rapid postoperative recovery of corneal tissue. These findings suggest that the integration of customized microneedle RF delivery with corneal crosslinking technology represents a potential novel treatment modality, holding promise for the tailored treatment of corneal pathologies, and offering a more precise and efficient alternative to traditional methods.
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The bromodomain and extraterminal domain (BET) family proteins serve as primary readers of acetylated lysine residues and play crucial roles in cell proliferation and differentiation. Dysregulation of BET proteins has been implicated in tumorigenesis, making them important therapeutic targets. BET-bromodomain (BD) inhibitors and BET-targeting degraders have been developed to inhibit BET proteins. In this study, we found that the BET inhibitor MS645 exhibited superior antiproliferative activity than BET degraders including ARV771, AT1, MZ1 and dBET1 in triple-negative breast cancer (TNBC) cells. Treatment with MS645 led to the dissociation of BETs, MED1 and RNA polymerase II from the E2F1-3 promoter, resulting in the suppression of E2F1-3 transcription and subsequent inhibition of cell growth in TNBC. In contrast, while ARV771 displaced BET proteins from chromatin, it did not significantly alter E2F1-3 expression. Mechanistically, ARV771 induced BRD4 depletion at protein level, which markedly increased EGR1 expression. This elevation of EGR1 subsequently recruited septin 2 and septin 9 to E2F1-3 promoters, enhancing E2F1-3 transcription and promoting cell proliferation rate in vitro and in vivo. Our findings provide valuable insights into differential mechanisms of BET inhibition and highlight potential of developing BET-targeting molecules as therapeutic strategies for TNBC.
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Proliferação de Células , Fator de Transcrição E2F1 , Proteína 1 de Resposta de Crescimento Precoce , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Humanos , Proliferação de Células/efeitos dos fármacos , Animais , Fator de Transcrição E2F1/metabolismo , Fator de Transcrição E2F1/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Linhagem Celular Tumoral , Fatores de Transcrição E2F/metabolismo , Fatores de Transcrição E2F/genética , Antineoplásicos/farmacologia , Transcrição Gênica/efeitos dos fármacos , Camundongos Nus , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/metabolismo , Camundongos , Proteínas que Contêm Bromodomínio , Proteínas de Ciclo Celular , Fator de Transcrição E2F3RESUMO
The utilization of biomass pyrolysis is a crucial approach for sustainable development. This study used the typical biomass of pine (PI), rice husk (RH), and corn straw (ST) as feedstocks to evaluate the pyrolysis mechanisms, features and conversion mechanisms of the phenol tar product. The phenolic gaseous products were more trailing in ST, which mostly concentrated around 320-500 °C. Primary phenol tar is produced from lignin through the homolytic cleavage of ß-O and α-O, and C-C bond breakage, primarily occurring before 550 °C. As the degree of aromatization increases, the oxygenates progressively deoxygenate, and the primary tar demethoxylates to form secondary tar as the temperature increases. The pyrolysis of cellulose produces H radicals, which aid the transformation of lignin into phenol tar. This study can provide a theoretical basis for biomass pyrolysis to select the appropriate process parameters to improve the quality of bio-oil and regulate phenol tar products.
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Biomassa , Lignina , Pirólise , Lignina/química , Alcatrões/química , Fenol/química , Fenóis/química , Zea mays/química , Oryza/química , Pinus/química , TemperaturaRESUMO
BACKGROUND: Hypoxic microenvironment is a common feature of most solid tumors including hepatocellular carcinoma (HCC). Vasculogenic mimicry (VM) formation by tumor cells could provide blood supply to tumor cells under hypoxia. NFE2 like basic leucine zipper (bZIP) transcription factor 2 (Nrf2), a regulator of cellular homeostasis, may promote tumor progression in the hypoxic conditions. However, the role and regulatory mechanisms of Nrf2 in HCC are not fully elucidated. METHODS: Nrf2 and assembly factor for spindle microtubules (ASPM) expression modulations were conducted by lentiviral transfections. Western blot, immunofluorescence, ChIP-qPCR, dual-luciferase reporter gene assay, flow cytometry, RNA sequencing, multiple bioinformatics databases analysis, cell function assays in vitro, mouse model in vivo and human HCC tissues were employed to assess the effect of Nrf2/ASPM axis on HCC progression under hypoxia. RESULTS: Nrf2 and ASPM expression facilitated epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) feature, and VM formation of HCC cells under hypoxia. Furthermore, Nrf2-regulated ASPM expression, via binding directly to the promoter region of ASPM and transcriptionally promoting ASPM expression. ASPM re-expression in Nrf2 knockdown cells or ASPM knockdown in Nrf2 overexpression cells reversed the cellular function caused by Nrf2. Meantime, retinol metabolism pathway was disrupted following abnormal ASPM expression. Nrf2/ASPM axis in murine models accelerated tumor growth and VM, corroborating in vitro findings. All-trans retinoic acid treatment reversed stemness and VM of HCC cells in vitro and in vivo. Clinically, Nrf2 and ASPM expressions were related to poor prognosis of HCC patients. CONCLUSIONS: Nrf2 drives EMT, CSCs characteristics and VM in HCC under hypoxia through the modulation of ASPM. Retinol metabolism pathway was dysregulated in HCC cells with ASPM overexpression. Nrf2/ASPM axis and related pathway provided potential therapeutic target for HCC.
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Carcinoma Hepatocelular , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas , Fator 2 Relacionado a NF-E2 , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Humanos , Animais , Camundongos , Transição Epitelial-Mesenquimal/genética , Linhagem Celular Tumoral , Neovascularização Patológica/metabolismo , Regulação Neoplásica da Expressão Gênica , Microambiente Tumoral , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , MasculinoRESUMO
Hydrogen sulfide (H2S) is a gaseous signaling molecule that influences digestive and nervous system functions. Enteric glial cells (EGCs) are integral to the enteric nervous system and play a role in regulating gastrointestinal motility. This study explored the dual effects of exogenous H2S on EGCs and the influence of apoptosis-related pathways and ion channels in EGCs. We also administered honokiol for further interventional studies. The results revealed that low-concentration H2S increased the mitochondrial membrane potential (MMP) of EGCs, decreased the whole-cell membrane potential, downregulated BAX and caspase-3, upregulated Bcl2 expression, reduced apoptosis, and promoted cell proliferation. The Ca2+ concentration, Cx43 mRNA, and protein expression were also increased. A high concentration of H2S had the opposite effect. In addition, GFAP mRNA expression was upregulated in the test-low group, downregulated in the test-high group, and upregulated in the test-high + Hon group. Honokiol treatment increased MMP, reduced whole-cell membrane potential, inhibited BAX and caspase-3 expression, increased Bcl2 expression, decreased cell apoptosis, and increased cell proliferation. The Ca2+ concentration, Cx43 mRNA, and protein expression were also upregulated. In conclusion, our study showed that exogenous H2S can bidirectionally regulate EGC proliferation and apoptosis by affecting MMP and cell membrane potential via the Bcl2/BAX/caspase-3 pathway and modulate Cx43-mediated Ca2+ responses in EGCs to regulate colonic motility bidirectionally. Honokiol can ameliorate the damage to EGCs induced by high H2S concentrations through the Bcl2/BAX/caspase-3 pathway and improve colon motility by increasing Cx43 expression and Ca2+ concentration.
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Apoptose , Compostos de Bifenilo , Sinalização do Cálcio , Proliferação de Células , Conexina 43 , Sulfeto de Hidrogênio , Lignanas , Neuroglia , Ratos Sprague-Dawley , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Lignanas/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Ratos , Conexina 43/metabolismo , Conexina 43/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Cálcio/metabolismo , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/metabolismo , Células Cultivadas , Compostos Alílicos , FenóisRESUMO
Although the presence of mental health stigma associated with seeking help has been demonstrated in many parts of the world, this work has largely been from an independent perspective (i.e., "I will be perceived as crazy") rather than from an interdependent perspective (i.e., "My family will be viewed negatively"). Interdependent stigma of seeking help (i.e., the extent to which people believe their family would be devalued and shamed if they seek psychological help) may be an important type of stigma that has not been assessed. Based on self-construal theory, the present study sought to develop and evaluate the psychometric properties of an Interdependent Stigma of Seeking Help (ISSH) scale in eight different countries and regions (i.e., Australia, Brazil, Germany, Hong Kong, Taiwan, Türkiye, the UAE, the United States). Findings suggest that the psychometric properties of the eight-item ISSH are adequate for research purposes (a unidimensional scale with full invariance and internal consistency estimates from .84 to .94). The ISSH was moderately related to other measures of stigma and psychological distress. Some differences in the relationship with specific outcomes by country and region were found, and there were notable country differences in the latent mean levels of ISSH, with Hong Kong and Taiwan having the highest means, and Australia, the United States, and Brazil having the lowest levels. Results suggest that the ISSH could be used to help clarify the complex relationships between stigma and other variables of interest and might be useful in developing culturally relevant interventions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Vital signs are important indicators to evaluate the health status of patients. Channel state information (CSI) can sense the displacement of the chest wall caused by cardiorespiratory activity in a non-contact manner. Due to the influence of clutter, DC components, and respiratory harmonics, it is difficult to detect reliable heartbeat signals. To address this problem, this paper proposes a robust and novel method for simultaneously extracting breath and heartbeat signals using software defined radios (SDR). Specifically, we model and analyze the signal and propose singular value decomposition (SVD)-based clutter suppression method to enhance the vital sign signals. The DC is estimated and compensated by the circle fitting method. Then, the heartbeat signal and respiratory signal are obtained by the modified variational modal decomposition (VMD). The experimental results demonstrate that the proposed method can accurately separate the respiratory signal and the heartbeat signal from the filtered signal. The Bland-Altman analysis shows that the proposed system is in good agreement with the medical sensors. In addition, the proposed system can accurately measure the heart rate variability (HRV) within 0.5m. In summary, our system can be used as a preferred contactless alternative to traditional contact medical sensors, which can provide advanced patient-centered healthcare solutions.
Assuntos
Frequência Cardíaca , Processamento de Sinais Assistido por Computador , Software , Humanos , Frequência Cardíaca/fisiologia , Masculino , Adulto , Algoritmos , Monitorização Fisiológica/métodos , Monitorização Fisiológica/instrumentação , Feminino , Respiração , Adulto JovemRESUMO
Background and Aims: Organic anion-transporting polypeptides (OATPs) play a crucial role in the transport of bile acids and bilirubin. In our previous study, interleukin 6 (IL-6) reduced OATP1B3 levels in cholestatic disease. However, it remains unclear whether IL-6 inhibits OATP1B1 expression in cholestatic diseases. This study aimed to investigate whether IL-6 can inhibit OATP1B1 expression and explore the underlying mechanisms. Methods: The effect of stimulator of interferon genes (STING) signaling on inflammatory factors was investigated in a cholestatic mouse model using RT-qPCR and enzyme-linked immunosorbent assay. To assess the impact of inflammatory factors on OATP1B1 expression in hepatocellular carcinoma, we analyzed OATP1B1 expression by RT-qPCR and Western Blot after treating PLC/PRF/5 cells with TNF-α, IL-1ß, and IL-6. To elucidate the mechanism by which IL-6 inhibits OATP1B1 expression, we examined the expression of the OATP1B1 regulator TCF4 in PLC/PRF/5 and HepG2 cells using RT-qPCR and Western Blot. The interaction mechanism between ß-catenin/TCF4 and OATP1B1 was investigated by knocking down ß-catenin/TCF4 through siRNA transfection. Results: The STING inhibitor decreased inflammatory factor levels in the cholestatic mouse model, with IL-6 exhibiting the most potent inhibitory effect on OATP1B1. IL-6 downregulated ß-catenin/TCF4, leading to decreased OATP1B1 expression. Knocking-down ß-catenin/TCF4 counteracted the ß-catenin/TCF4-mediated repression of OATP1B1. Conclusions: STING-mediated IL-6 up-regulation may inhibit OATP1B1, leading to reduced transport of bile acids and bilirubin by OATP1B1. This may contribute to altered pharmacokinetics in patients with diseases associated with increased IL-6 production.
RESUMO
Chromosome instability (CIN) and subsequent aneuploidy are prevalent in various human malignancies, influencing tumor progression such as metastases and relapses. Extensive studies demonstrate the development of chemoresistance in high-CIN tumors, which poses significant therapeutic challenges. Given the association of CIN with poorer prognosis and suppressed immune microenvironment observed in colorectal carcinoma (CRC), here we aimed to discover chemotherapeutic drugs exhibiting increased inhibition against high-CIN CRC cells. By using machine learning methods, we screened out two BCL-XL inhibitors Navitoclax and WEHI-539 as CIN-sensitive reagents in CRC. Subsequent analyses using a CIN-aneuploidy cell model confirmed the vulnerability of high-CIN CRC cells to these drugs. We further revealed the critical role of BCL-XL in the viability of high-CIN CRC cells. In addition, to ease the evaluation of CIN levels in clinic, we developed a three-gene signature as a CIN surrogate to predict prognosis, chemotherapeutic and immune responses in CRC samples. Our results demonstrate the potential value of CIN as a therapeutic target in CRC treatment and the importance of BCL-XL in regulating survival of high-CIN CRC cells, therefore representing a valuable attempt to translate a common trait of heterogeneous tumor cells into an effective therapeutic target.
RESUMO
Acetyl tripeptide-30 citrulline, a commercialized bio-active peptide, is widely used in anti-wrinkle formulations. Volunteer-based tests have demonstrated that topical application of products containing acetyl tripeptide-30 citrulline significantly reduces the visibility of stretch marks. However, there is still a lack of research dedicated to systematically and holistically evaluating its cosmetic properties and elucidating its mechanisms of action. In this study, we assessed the cosmetic potential of acetyl tripeptide-30 citrulline using human immortalized keratinocytes (HaCaT) and mouse embryonic fibroblasts (3T3). Our findings reveal that acetyl tripeptide-30 citrulline exhibits anti-inflammatory and antioxidant activities in skin cells, particularly effective against the inflammatory markers cyclooxygenase-2 (COX2), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6), and the extent of inhibition of reactive oxygen species (ROS) production ranged from 95 % to 340 %. Moreover, acetyl tripeptide-30 citrulline specifically up-regulates Collagen IV and down-regulates matrix metalloproteinase-9 (MMP9), enhances the expression of skin barrier proteins transglutaminase 1 (TGM1) and filaggrin (FLG), thereby demonstrating its reparative capabilities. Additionally, acetyl tripeptide-30 citrulline increases the expression of the water channel protein aquaporin 3 (AQP3), thus improving skin hydration function. These results substantiate the previously proclaimed cosmetic attributes of acetyl tripeptide-30 citrulline and support its efficacy as an anti-aging agent in dermatological applications.