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An unusual crystalline porous framework constructed from four types of cages, including all-inorganic Keggin-type polyoxometalate (POM) cages [H3W12O40]5-, organic hexamethylenetetramine (Hmt) cages, nanosized silver-Hmt coordination cages, and giant POM-silver-Hmt cages, was hydrothermally synthesized and structurally characterized. The framework features a highly symmetrical structure with one-dimensional nanoscale channels and holds good thermal/solvent stability, which endow it with proton conduction properties and heterogeneous catalytic activity for pyrazole. This paper not only contributes to broadening the structural diversity of cage-based crystalline porous framework materials but also sheds new light on the design of new functional framework materials.
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PURPOSE: With the rising prevalence of myopia, especially among the young, orthokeratology (Ortho-K) stands out as a promising approach, not only to reduce myopia but also to control the progression of axial length (AL). This study examined how the intersection area between the pupil and defocus ring influenced retinal defocus and axial growth after Ortho-K. METHODS: A case-control study was conducted with 100 participants (100 eyes). Both AL and the refraction difference value (RDV), that is, the peripheral refractive error measured with respect to the central value after wearing Ortho-K lenses, were determined. Subjects were categorised into two groups based on the size of the intersection area after 3 months of lens wear: Group A (<4.58 mm2 ) and Group B (≥4.58 mm2 ). RESULTS: Group B demonstrated significantly lower changes in AL and RDV at 30-40° and 40-53° compared with Group A after 3 months of lens wear (all p < 0.05). After 6 months of lens wear, Group B showed significantly lower changes in AL and RDV in the 40-53° region compared with Group A (all p < 0.05). Correlation analysis revealed that as the intersection area increased, the changes in AL and RDV at 0-53°, 30-40° and 40-53° eccentricity decreased after both 3 and 6 months of lens wear (all p < 0.01). CONCLUSIONS: A larger intersection area between the pupil and defocus ring within a certain time period can cause a greater amount of myopic defocus at 30-53° from the fovea. The results suggest that a larger intersection area might lead to more effective control of axial growth.
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Miopia , Procedimentos Ortoceratológicos , Erros de Refração , Humanos , Pupila , Estudos de Casos e Controles , Retina , Refração Ocular , Comprimento Axial do Olho , Procedimentos Ortoceratológicos/métodosRESUMO
The present study aims to investigate the mechanism of the nature compound gambogenic acid (GNA) on the apoptosis and ferroptosis in colorectal cancer (CRC). The effect of GNA on the proliferation of CRC cell lines were detected by MTT and clonogenic assay. The xenograft tumor model was established, and the inhibition effect of GNA were evaluated by observing the tumor growth. The endoplasmic reticulum (ER) of HCT116 was observed by using the ER tracker. The TargrtScan database was used to predict the miRNA binding sites. The level of miRNA with GNA treatment was explored by real-time quantitative PCR. The effect of ferroptosis were evaluated by detect the expression of reactive oxygen species (ROS), intracellular ferrous iron (Fe2+ ), malondialdehyde (MDA), glutathione (GSH), subunit solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase (GPX)4, transferrin, and ferritin by Western blot. GNA isolated from gamboge can inhibit the growth and proliferation of CRC cell lines in a concentration-dependent manner. GNA activated ER stress by upregulating miR-1291, and miR-1291 targeted the forkhead box protein A2 (FOXA2). GNA also induced ROS production and mediated the Fenton reaction by activating transferrin to increase Fe2+ , thus inducing ferroptosis. In addition, GNA could induce ferroptosis through the depletion of GSH and GPX4. Furthermore, GNA treatment regulated iron metabolism by activating AMPKα/SLC7A11/GPX4 signaling. In conclusion, GNA activated ER stress via miR-1291 and induced ferroptosis in CRC cells and might be a new inducer of ferroptosis, which can expand the efficacy of chemotherapy drugs.
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Past reviews of cyberbullying preventative interventions have critiqued the field regarding scientific rigor, and a meta-analysis found that randomized controlled trials (RCTs) of such interventions were more effective than non-RCTs. However, no review has examined the risk of bias, dosage, modality, and delivery context of such programs to date. The current study addresses this gap through a systematic review of the literature. Potential articles (N = 4,737) from 4 databases were identified and screened (Academic Search Premier including ERIC, PsychINFO, and the Psychology and Behavioral Collection; PubMed; Web of Science; Compendex); 72 articles were reviewed for eligibility. Final articles included (N = 30) were based on a rigorous search process guided by inclusion and exclusion criteria. The majority of studies were conducted in Europe; two were conducted in the USA, three in Australia, and two in the Middle East. Efforts to reduce risk of bias were evaluated using the Cochrane's Risk of Bias tool. Harvest plots were constructed to qualitatively illustrate the rigor, dosage, modality, and context of the interventions, and meta-analytic random effects models were conducted to examine effect sizes of the interventions on cyberbullying perpetration and victimization. Results suggest that cyberbullying interventions delivered through schools are effective, though expanded follow-up time is suggested, and additional evidence is needed for home settings and digital delivery.
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Bullying , Vítimas de Crime , Cyberbullying , Austrália , Bullying/prevenção & controle , Cyberbullying/prevenção & controle , Humanos , Instituições AcadêmicasRESUMO
OBJECTIVE: Inflammation contributes to skeletal muscle atrophy via protein degradation induced by p38 mitogen-activated protein kinase (MAPK) phosphorylation. Meanwhile, pulsed ultrasound irradiation provides the mechanical stimulation to the target tissue, and has been reported to show anti-inflammatory effects. This study investigated the preventive effects of pulsed ultrasound irradiation on muscle atrophy induced by lipopolysaccharide (LPS) in C2C12 myotubes. METHODS: C2C12 myotubes were used in this research. The pulsed ultrasound (a frequency of 3 MHz, duty cycle of 20%, intensity of 0.5 W/cm2) was irradiated to myotube before LPS administration. RESULTS: The LPS increased phosphorylation of p38 MAPK and decreased the myofibril and myosin heavy chain protein (P < 0.05), followed by atrophy in C2C12 myotubes. The pulsed ultrasound irradiation attenuated p38 MAPK phosphorylation and myotube atrophy induced by LPS (P < 0.05). CONCLUSIONS: Pulsed ultrasound irradiation has the preventive effects on inflammation-induced muscle atrophy through inhibiting phosphorylation of p38 MAPK.
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Fibras Musculares Esqueléticas/enzimologia , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/enzimologia , Atrofia Muscular/patologia , Ondas Ultrassônicas , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Linhagem Celular , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Lipopolissacarídeos , Camundongos , Proteínas Musculares/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/prevenção & controle , Fosforilação , Proteínas Ligases SKP Culina F-Box/metabolismoRESUMO
Extremely cold temperatures are a significant threat to agriculture and transportation in winter in southeastern China. However, due to the shortness of instrumental records and the scarcity of long-term temperature reconstructions, more high-quality temperature reconstructions are still needed to fully examine their spatial-temporal variability over the past several centuries. In this study, we built an earlywood width (EWW) chronology, a latewood width (LWW) chronology, and a tree-ring width (TRW) chronology using tree-ring samples of Pinus taiwanensis Hayata from the western Tianmu Mountains and the Xianyu Mountains in southeastern China. The tree growth-climate relationships were analyzed, and we found the strongest correlation between December and March mean temperature and the EWW chronology. The December-March mean temperature history was then reconstructed over the period of 1871-2016 using a linear regression model, which is the first EWW-based temperature reconstruction in southeastern China. With a higher explained variance (47.0%) than that (31.7%) of a previous reconstruction using a TRW chronology, the quality of the model has largely improved. This reconstruction was also comparable with other nearby records, further demonstrating the reliability of our new model. Furthermore, our reconstruction exhibits a significantly negative relationship with the East Asian winter monsoon index (EAWMI) since the 1920s, which may be attributed to the obviously enhanced EAWMI thereafter.
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Clima , Árvores , China , Reprodutibilidade dos Testes , TemperaturaRESUMO
The polycomb group (PcG) proteins are key epigenetic regulators in stem cell maintenance. PcG proteins have been thought to act through one of two polycomb repressive complexes (PRCs), but more recent biochemical analyses have challenged this model in the identification of noncanonical PRC1 (nc-PRC1) complexes characterized by the presence of Rybp or Yaf2 in place of the canonical Chromobox proteins. However, the biological significance of these nc-PRC1s and the potential mechanisms by which they mediate gene repression are largely unknown. Here, we explore the functional consequences of Yaf2 disruption on stem cell regulation. We show that deletion of Yaf2 results in compromised proliferation and abnormal differentiation of mouse embryonic stem cells (mESCs). Genome-wide profiling indicates Yaf2 functions primarily as a transcriptional repressor, particularly impacting genes associated with ectoderm cell fate in a manner distinct from Rybp. We confirm that Yaf2 assembles into a noncanonical PRC complex, with deletion analysis identifying the region encompassing amino acid residues 102-150 as required for this assembly. Furthermore, we identified serine 166 as a Yaf2 phosphorylation site, and we demonstrate that mutation of this site to alanine (S166A) compromises Ring1B-mediated H2A monoubiquitination and in turn its ability to repress target gene expression. We therefore propose that Yaf2 and its phosphorylation status serve as dual regulators to maintain the pluripotent state in mESCs.
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Diferenciação Celular , Histonas/metabolismo , Células-Tronco Embrionárias Murinas/citologia , Proteínas Musculares/fisiologia , Complexo Repressor Polycomb 1/metabolismo , Proteínas Repressoras/fisiologia , Animais , Células Cultivadas , Cromatina/genética , Perfilação da Expressão Gênica , Camundongos , Camundongos Knockout , Células-Tronco Embrionárias Murinas/metabolismo , Fosforilação , Complexo Repressor Polycomb 1/genéticaRESUMO
Environmental remediation by employing visible-light-active semiconductor heterostructures provides effective solutions for handling emerging contaminants by a much greener and lower cost approach compared with other methods. This report demonstrates that the in situ growth of nanosized single-crystal-like defective anatase TiO2-x mesocrystals (DTMCs) on g-C3 N4 nanosheets (NSs) can produce a 3D/2D DTMC/g-C3 N4 NS heterostructure with the two components held together by chemical bonds to form tight interfaces. This nanostructured heterostructure displayed remarkably improved photocatalytic activity toward the removal of the model pollutants Methyl Orange (MO) and CrVI under visible-light irradiation in comparison with the pristine DTMC and g-C3 N4 NS components, which suggests that both the oxidation and reduction abilities of the DTMC/g-C3 N4 NSs were simultaneously enhanced after fabrication. On the basis of the results of a systematic characterization, a reasonable mechanism for the photocatalytic activity based on a direct Z-scheme heterojunction is proposed and further verified by the measurement of . OH. This novel Z-scheme heterojunction endows the heterostructure with improved photogenerated electron/hole pair separation and a strong redox ability for the efficient degradation of wastewater pollutants. This work will be useful for the design and fabrication of direct Z-scheme heterostructured photocatalysts with novel architectures for applications in energy conversion and environmental remediation.
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In view of the problem of poor coupling adaptability and easy rib spalling of coal wall in large mining height comprehensive mining, based on the effective inhibition effect of face guard mechanism on coal wall spalling, the structural characteristics and bearing capacity of different structural forms of the face guard mechanism are compared and analyzed. According to the surrounding rock adaptability of the face guard mechanism, established a numerical analysis model for rigid-flexible coupling of the face guard mechanism under different spalling forms. In order to accurately simulate the stress state of the protective mechanism, a variable stiffness spring damping system is used to replace the hydraulic cylinder. The load-bearing performance and response characteristics of the face guard mechanism under rib spalling coupling conditions were analyzed by applying uniform normal load and impact load to the face guard. The findings indicated that, the integral-type face guard mechanism has a better effect on suppressing rib spalling. When the face guard mechanism bears the static load of the coal wall, the entire response process of the face guard jack can be divided into three stages: initial support, increasing resistance bearing, constant resistance bearing; both the impact load position and the coupling state of the rib spalling will affect the characteristics of force transmission at the face guard mechanism's hinge point, the hinge point between the extensible canopy and the primary face guard is most sensitive to biased load. The research results can provide reference for optimizing the face guard mechanism of large mining height hydraulic support and improving the reliability of coal wall support.
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Background: Studies have shown that gut dysbiosis contributes to the pathophysiology of type 2 diabetes mellitus (T2DM). Identifying specific gut microbiota dysbiosis may provide insight into the pathogenesis of T2DM. Purpose: This study investigated the causal relationship between gut microbiota and T2DM using meta-analysis and Mendelian randomization (MR). Methods: In the first part, we searched for literature on gut microbiota and T2DM, and conducted a meta-analysis. We observed differences in glycosylated hemoglobin and fasting blood glucose levels in both groups. Second, we obtained GWAS data from genome-wide association study database 19 (GWAS). We used two-sample MR analysis to verify the forward and reverse causal associations between gut microbiota and T2DM. Additionally, we selected the European GWAS data from the European Bioinformatics Institute (EBI) as a validation set for external validation of the MR analysis. In the third part, we aimed to clarify which gut microbiota contribute to the degree of causal association between group disorders and T2DM through multivariate MR analysis and Bayesian model averaging (MR-BMA). Results: 1. According to the meta-analysis results, the glycated hemoglobin concentration in the gut probiotic intervention group was significantly lower than in the control group. Following treatment, fasting blood glucose levels in the intervention group were significantly lower than those in the control group. 2. The results of two samples MR analysis revealed that there were causal relationships between six gut microbiota and T2DM. Genus Haemophilus and order Pasteurellaceae were negatively correlated with T2DM. Genus Actinomycetes, class Melanobacteria and genus Lactobacillus were positively correlated. Reverse MR analysis demonstrated that T2DM and gut microbiota did not have any reverse causal relationship. The external validation data set showed a causal relationship between gut microbiota and T2DM. 3. Multivariate MR analysis and MR-BMA results showed that the independent genus Haemophilus collection had the largest PP. Conclusion: Our research results suggest that gut microbiota is closely related to T2DM pathogenesis. The results of further MR research and an analysis of the prediction model indicate that a variety of gut microbiota disorders, including genus Haemophilus, are causally related to the development of T2DM. The findings of this study may provide some insight into the diagnosis and treatment of T2DM. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO.
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Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Diabetes Mellitus Tipo 2/microbiologia , Humanos , Disbiose , Glicemia/análise , Hemoglobinas Glicadas/análise , ProbióticosRESUMO
PURPOSE: Extracellular vesicles (EVs) serve as carriers of intracellular factors with therapeutic effects, including tissue regeneration and attenuation of inflammatory responses. The majority of EVs in vivo are derived from skeletal muscle, which is reported to have anti-inflammatory effects. While high-intensity pulsed ultrasound (US) irradiation has been shown to promote EV secretion from myotubes, the impact of pulse repetition frequency, a US parameter affecting pulse length, on EV release remains unclear. This study aimed to investigate the impact of pulse repetition frequency of US on the release of EVs from myotubes. METHODS: C2C12 myoblasts were used in this study. After differentiation into C2C12 myotubes, US was performed for 5 min at an intensity of 3.0 W/cm2, duty cycle of 20%, acoustic frequency of 1 MHz, and different pulse repetition frequencies (100 Hz, 10 Hz, or 1 Hz). After 12 h, EVs and cells were collected for subsequent analyses. RESULTS: US did not cause a reduction in cell viability across all US groups compared to the control. The concentration of EVs was significantly higher in all US groups compared to the control group. In particular, the highest increase was observed in the 1-Hz group on EV concentration as well as intracellular Ca2+ level. CONCLUSION: This study investigated the effect of three different pulse repetition frequencies of US on the release of EVs from cultured myotubes. It is concluded that a low-pulse repetition frequency of 1 Hz is the most effective for enhancing EV release from cultured myotubes with pulsed ultrasound.
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Vesículas Extracelulares , Fibras Musculares Esqueléticas , Ondas Ultrassônicas , Fibras Musculares Esqueléticas/efeitos da radiação , Fibras Musculares Esqueléticas/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/efeitos da radiação , Animais , Camundongos , Sobrevivência Celular/efeitos da radiação , Linhagem Celular , Células Cultivadas , Cálcio/metabolismoRESUMO
It is widely recognized that a strong correlation exists between metabolic diseases and chronic kidney disease (CKD). Based on bibliometric statistics, the overall number of Mendelian randomization (MR) analysis in relation to metabolic diseases and CKD has increased since 2005. In recent years, this topic has emerged as a significant area of research interest. In clinical studies, RCTs are often limited due to the intricate causal interplay between metabolic diseases and CKD, which makes it difficult to ascertain the precise etiology of these conditions definitively. In MR studies, genetic variation is incorporated as an instrumental variable (IV). They elucidate the possible causal relationships between associated risk factors and disease risks by including individual innate genetic markers. It is widely believed that MR avoids confounding and can reverse effects to the greatest extent possible. As an increasingly popular technology in the medical field, MR studies have become a popular technology in causal relationships investigation, particularly in epidemiological etiology studies. At present, MR has been widely used for the investigation of medical etiologies, drug development, and decision-making in public health. The article aims to offer insights into the causal relationship between metabolic diseases and CKD, as well as strategies for prevention and treatment, through a summary of MR-related research on these conditions.
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Nowadays, novel and efficient signal amplification strategy in electrochemiluminescence (ECL) platform is urgently needed to enhance the sensitivity of biosensor. In this work, the dual ECL signal enhancement strategy was constructed by the interactions of Pd nanoparticles attached covalent organic frameworks (Pd NPs@COFs) with tris (bipyridine) ruthenium (RuP) and Exonuclease III (Exo.III) cycle reaction. Within this strategy, the COFs composite was generated from the covalent reaction between 2-nitro-1,4-phenylenediamine (NPD) and trialdehyde phloroglucinol (Tp), and then animated by glutamate (Glu) to attach the Pd NPs. Next, the "signal on" ECL biosensor was constructed by the coordination assembly of thiolation capture DNA (cDNA) onto the Pd NPs@COFs modified electrode. After the aptamer recognition of progesterone (P4) with hairpin DNA 1 (HP1), the Exo. III cycle reaction was initiated with HP2 to generate free DNA, which hybridized with cDNA to form double-stranded DNA (dsDNA). For that, the RuP was embedded into the groove of dsDNA and achieved the ultrasensitive detection of P4 with a lower limit of detection (LOD) down to 0.45 pM, as well as the excellent selectivity and stability. This work expands the COFs-based materials application in ECL signal amplification and valuable DNA cyclic reaction in biochemical testing field.
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Técnicas Biossensoriais , Técnicas Eletroquímicas , Exodesoxirribonucleases , Nanopartículas Metálicas , Estruturas Metalorgânicas , Paládio , Progesterona , Nanopartículas Metálicas/química , Estruturas Metalorgânicas/química , Paládio/química , Progesterona/análise , Progesterona/química , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Exodesoxirribonucleases/química , Exodesoxirribonucleases/metabolismo , Limite de Detecção , Medições Luminescentes/métodos , Humanos , DNA/químicaRESUMO
Breast cancer has reached the highest incidence rate worldwide among all malignancies since 2020. Breast imaging plays a significant role in early diagnosis and intervention to improve the outcome of breast cancer patients. In the past decade, deep learning has shown remarkable progress in breast cancer imaging analysis, holding great promise in interpreting the rich information and complex context of breast imaging modalities. Considering the rapid improvement in deep learning technology and the increasing severity of breast cancer, it is critical to summarize past progress and identify future challenges to be addressed. This paper provides an extensive review of deep learning-based breast cancer imaging research, covering studies on mammograms, ultrasound, magnetic resonance imaging, and digital pathology images over the past decade. The major deep learning methods and applications on imaging-based screening, diagnosis, treatment response prediction, and prognosis are elaborated and discussed. Drawn from the findings of this survey, we present a comprehensive discussion of the challenges and potential avenues for future research in deep learning-based breast cancer imaging.
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To increase the anti-digestion ability of extruded rice starch (ERS), the influence of rice glutelin (RG) on digestive and structural characteristics of ERS were investigated. The resistant starch content increased from 4.49 % to 18.08 % as the RG content increased, while the digestion rate and digestion velocity constant were reduced by the incorporation of RG. Morphological observations showed that ERS was adhered and encapsulated by RG, and the specific area of starch granules were decreased after the addition of RG. The results of XRD and FTIR suggested that the long-range and short-range orders of ERS were improved due to the complexation with RG. The thickness of crystalline of ERS was increased while its amorphous region thickness was reduced by the supplementation with RG. The 1H NMR and 13C NMR data revealed that the branching degree and double helix content of ERS was increased by 46.24 % and 52.67 % when RG content reached to 12 %. Additionally, the addition of RG altered the molecular weight and chain length distribution of ERS. The α-amylase activity and glucoamylase activity was inhibited by RG. These results could provide a valuable basis for the application of RG in extruded rice starchy foods with lower glycemic index.
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Oryza , Amido , Amido/química , Oryza/química , Glutens/metabolismo , Digestão , Índice GlicêmicoRESUMO
While previous studies have indicated the involvement of Isthmin 1 (ISM1), a secreted protein, in cancer development, the precise mechanisms have remained elusive. In this study, we unveiled that ISM1 is significantly overexpressed in both the blood and tissue samples of colorectal cancer (CRC) patients, correlating with their poor prognosis. Functional experiments demonstrated that enforced ISM1 expression significantly enhances CRC proliferation, migration, invasion and tumor growth. Notably, our investigation reveals an interaction of ISM1 with epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase (RTK) family of CRC cells. The binding of ISM1 triggered EGFR activation and initiate downstream signaling pathways. Meanwhile, intracellular ISM1 interacted with Y-box binding protein 1 (YBX1), enhancing its transcriptional regulation on EGFR. Furthermore, our research uncovered the regulation of ISM1 expression by the hypoxia-inducible transcription factor HIF-1α in CRC cells. Mechanistically, we identified HIF-1α as a direct regulator of ISM1, binding to a hypoxia response element on its promoter. This novel mechanism illuminated potential therapeutic targets, offering insights into restraining HIF-1α/ISM1/EGFR-driven CRC progression and metastasis.
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Proliferação de Células , Neoplasias Colorretais , Progressão da Doença , Receptores ErbB , Regulação Neoplásica da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia , Proteína 1 de Ligação a Y-Box , Humanos , Receptores ErbB/metabolismo , Receptores ErbB/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Proteína 1 de Ligação a Y-Box/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Animais , Movimento Celular , Linhagem Celular Tumoral , Camundongos , Masculino , Transdução de Sinais , Feminino , Camundongos Nus , Células HCT116 , PrognósticoRESUMO
Ischemic stroke, a primary cause of disability and the second leading cause of mortality, has emerged as an urgent public health issue. Growing evidence suggests that the Cyclic GMP-AMP synthase (cGAS)- Stimulator of interferon genes (STING) pathway, a component of innate immunity, is closely associated with microglia activation, neuroinflammation, and regulated cell death in ischemic stroke. However, the mechanisms underlying this pathway remain inadequately understood. This article comprehensively reviews the existing literature on the cGAS-STING pathway and its multifaceted relationship with ischemic stroke. Initially, it examines how various risk factors and pre-disease mechanisms such as metabolic dysfunction and senescence (e.g., hypertension, hyperglycemia, hyperlipidemia) affect the cGAS-STING pathway in relation to ischemic stroke. Subsequently, we explore in depth the potential pathophysiological relationship between this pathway and oxidative stress, endoplasmic reticulum stress, neuroinflammation as well as regulated cell death including ferroptosis and PANoptosis following cerebral ischemia injury. Finally, it suggests that intervention targeting the cGAS-STING pathway may serve as promising therapeutic strategies for addressing neuroinflammation associated with ischemic stroke. Taken together, this review concludes that targeting the microglia cGAS-STING pathway may shed light on the exploration of new therapeutic strategies against ischemic stroke.
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Lesões Encefálicas , AVC Isquêmico , Humanos , Doenças Neuroinflamatórias , Infarto Cerebral , Estresse Oxidativo , NucleotidiltransferasesRESUMO
Gastric cancer (GC) is one of the most common malignancies, and it has become the third most common malignant tumour in the world. Targeting metastasis has also become a key and difficult point in the treatment of GC. Solasodine is an active ingredient isolated from Solanum nigrum L. for the treatment of various cancers, such as breast cancer, pancreatic cancer and lung cancer. In the present study, we investigated the role and mechanism of solasodine in inhibiting GC. In vitro, we found that solasodine not only promoted cell death but also inhibited the migration and invasion of HGC27 and AGS cells. Solasodine regulated epithelial-mesenchymal transition (EMT) and reduced the expression of claudin-2 (CLDN2). Moreover, overexpression of CLDN2 inhibited the prometastatic phenotype and EMT of GC, and solasodine recovered this phenotype. Furthermore, the knockdown of CLDN2 had the opposite effect. We also found that the AMPK activators metformin and AICAR activated phosphorylation of AMPK and downregulated the expression of RhoA and CLDN2, indicating that AMPK was the upstream regulator of CLDN2. Solasodine could also activate AMP-activated protein kinase (AMPK) and inhibit the phosphorylation of STAT3 and the nuclear translocation of NF-κB. Therefore, solasodine may have prevented EMT by modulating the AMPK/STAT3/NF-κB/CLDN2 signalling pathway. In vivo, we established a xenograft model to investigate the phosphorylation of AMPK and the expression of CLDN2 from tumour tissues, and we found that solasodine inhibited tumour growth through AMPK-CLDN2 pathway. To sum up, solasodine prevented EMT by modulating the AMPK/STAT3/NF-κB/CLDN2 signalling pathway, becoming a new solution for inhibiting GC metastasis.
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NF-kappa B , Neoplasias Gástricas , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Claudina-2/metabolismo , Transição Epitelial-Mesenquimal , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/metabolismo , AnimaisRESUMO
Introduction: Macrophages play an important role in the innate immunity. While macrophage inflammation is necessary for biological defense, it must be appropriately controlled. Extracellular vesicles (EVs) are small vesicles released from all types of cells and play a central role in intercellular communication. Skeletal muscle has been suggested to release anti-inflammatory factors, but the effect of myotube-derived EVs on macrophages is unknown. As an anti-inflammatory mechanism of macrophages, the immune responsive gene 1 (IRG1)-itaconate pathway is essential. In this study, we show that skeletal muscle-derived EVs suppress macrophage inflammatory responses, upregulating the IRG1-itaconate pathway. Methods: C2C12 myoblasts were differentiated into myotubes and EVs were extracted by ultracentrifugation. Skeletal myotube-derived EVs were administered to mouse bone marrow-derived macrophages, then lipopolysaccharide (LPS) stimulation was performed and inflammatory cytokine expression was measured by RT-qPCR. Metabolite abundance in macrophages after addition of EVs was measured by CE/MS, and IRG1 expression was measured by RT-PCR. Furthermore, RNA-seq analysis was performed on macrophages after EV treatment. Results: EVs attenuated the expression of LPS-induced pro-inflammatory factors in macrophages. Itaconate abundance and IRG1 expression were significantly increased in the EV-treated group. RNA-seq analysis revealed activation of the PI3K-Akt and JAK-STAT pathways in macrophages after EV treatment. The most abundant miRNA in myotube EVs was miR-206-3p, followed by miR-378a-3p, miR-30d-5p, and miR-21a-5p. Discussion: Skeletal myotube EVs are supposed to increase the production of itaconate via upregulation of IRG1 expression and exhibited an anti-inflammatory effect in macrophages. This anti-inflammatory effect was suggested to involve the PI3K-Akt and JAK-STAT pathways. The miRNA profiles within EVs implied that miR-206-3p, miR-378a-3p, miR-30d-5p, and miR-21a-5p may be responsible for the anti-inflammatory effects of the EVs. In summary, in this study we showed that myotube-derived EVs prevent macrophage inflammatory responses by activating the IRG1-itaconate pathway.
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Vesículas Extracelulares , MicroRNAs , Animais , Camundongos , Lipopolissacarídeos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Macrófagos , MicroRNAs/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Vesículas Extracelulares/metabolismoRESUMO
BACKGROUND & AIMS: Muscle atrophy is one of the most important and frequent problems for critically ill patients. The purpose of this study was to evaluate the effect of lipid mediators on acute muscle atrophy. Skeletal muscle fiber-specific analysis of lipid mediators in endotoxemic rats was therefore performed. METHODS: Male Wistar rats were intraperitoneally injected with lipopolysaccharide (LPS). Slow-twitch soleus muscle and fast-twitch extensor digitorum longus (EDL) muscle were harvested 0, 6, and 24 h after LPS injection. Lipid mediators were profiled using liquid chromatography-tandem mass spectrometry, and free fatty acid (FFA) concentrations were measured using gas chromatography-mass spectrometry. Muscles were weighed and their cross-sectional areas were evaluated. Expression levels of mRNAs encoding inflammatory cytokines, autophagy-related transcription factors, and members of the ubiquitin-proteasome system were measured using real-time PCR. RESULTS: Before LPS injection, the concentrations of all FFAs, including arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, and all measured lipid mediators were higher in soleus muscle than in EDL muscle, especially those of pro-inflammatory prostaglandin E2 (PGE2) and leukotriene B4. LPS injection, increased PGE2 and D2 and decreased FFAs in soleus muscle but did not change in EDL muscle. The concentrations of specialized pro-resolving mediators E-series hydroxy-eicosapentaenoic acid and D-series hydroxy-docosahexaenoic acid were higher in soleus muscle. Muscle cross-sectional area decreased and the expression level of atrogin-1 was upregulated in EDL muscle, but both were unchanged in soleus muscle. After LPS injection, a discrepancy involving an increased PGE2 concentration and decreased muscle atrophy was identified in this acute muscle atrophy model of critical illness. CONCLUSION: Concentrations of FFAs and lipid mediators were higher in soleus muscle than in EDL muscle, and LPS injection rapidly increased concentrations of pro-inflammatory lipid mediators. However, muscle atrophy with upregulation of autophagy-related transcription factors was observed in EDL muscle but not in soleus muscle.