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Mineral extraction is regarded as a pollution-intensive industry and is confronted with multiple environmental sustainability challenges. This issue poses an existential crisis for mineral extraction due to continued global pressure to adopt more sustainable practices in their functioning. Despite its importance, there is a notable gap in the literature regarding how these companies encounter financial challenges, particularly in the context of high-risk, long development cycles, and the unique double externalities associated with green innovation. This research, leveraging panel data from 2016 to 2023, aims to fill this gap by examining whether Chinese mineral extraction companies demonstrate distinct preferences for specific financing sources and by evaluating the role of government in facilitating their green innovation activities. Our findings indicate that such companies utilize a mix of internal and external financing to support their green innovation projects. It is observed that the influence of external finances channels, namely government subsidies, equity financing and debt financing, on green innovation progressively weakens, a conclusion supported by multiple robustness checks. Furthermore, the study highlights the crucial role of government subsidies in motivating publicly listed companies to enhance their green innovation activities through debt and equity financing, thereby contributing to a more equitable and sustainable development paradigm in the Global South.
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BACKGROUND: Anlotinib is a multi-target tyrosine kinase inhibitor that can effectively inhibit tumor cell proliferation after receptor kinase activation caused by KIT gene mutation. METHODS: We tested the inhibitory effect of anlotinib in GIST cell lines with different gene mutations and evaluated the efficacy of anlotinib for patients with metastatic GIST after imatinib failure in a multicenter, single-arm, phase II study. RESULTS: In vitro, V654A mutation encoded by KIT exon 13 was intermediately sensitive to anlotinib. Moreover, anlotinib was able to partly suppress the activation loop mutation D820A from exon 17 while another activation loop mutation N822K, also from exon 17, was resistant to anlotinib. From September 2018 to October 2020, 64 patients from 9 Chinese medical centers were enrolled in this study. Seven patients had partial response and 39 patients had stable disease. The median PFS was 8.0 months. There was no statistical significance comparing with PFS of sunitinib second-line therapy at the same period. The most common adverse events related to anlotinib treatment were hypertension, neutropenia, and fatigue. CONCLUSION: Anlotinib showed moderate antitumor activity in drug-resistant GIST cell lines in vitro, and good PFS and better tolerance in second-line therapy study.
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Antineoplásicos , Tumores do Estroma Gastrointestinal , Humanos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Estudos Prospectivos , Sunitinibe/uso terapêutico , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
PURPOSE: Ferroptosis is a form of regulated cell death that has the potential to be targeted as a cancer therapeutic strategy. But cancer cells have a wide range of sensitivities to ferroptosis, which limits its therapeutic potential. Accumulation of lipid peroxides determines the occurrence of ferroptosis. However, the type of lipid involved in peroxidation and the mechanism of lipid peroxide accumulation are less studied. METHODS: The effects of fatty acids (10 µM) with different carbon chain length and unsaturation on ferroptosis were evaluated by MTT and LDH release assay in cell lines derived from prostate cancer (PC3, 22RV1, DU145 and LNCaP), colorectal cancer (HT-29), cervical cancer (HeLa) and liver cancer (HepG2). Inhibitors of apoptosis, necroptosis, autophagy and ferroptosis were used to determine the type of cell death. Then the regulation of reactive oxygen species (ROS) and lipid peroxidation by docosahexaenoic acid (DHA) was measured by HPLC-MS and flow cytometry. The avtive form of DHA was determined by siRNA mediated gene silencing. The role of lipoxygenases was checked by inhibitors and gene silencing. Finally, the effect of DHA on ferroptosis-mediated tumor killing was verified in xenografts. RESULTS: The sensitivity of ferroptosis was positively correlated with the unsaturation of exogenously added fatty acid. DHA (22:6 n-3) sensitized cancer cells to ferroptosis-inducing reagents (FINs) at the highest level in vitro and in vivo. In this process, DHA increased ROS accumulation, lipid peroxidation and protein oxidation independent of its membrane receptor, GPR120. Inhibition of long chain fatty acid-CoA ligases and lysophosphatidylcholine acyltransferases didn't affect the role of DHA. DHA-involved ferroptosis can be induced in both arachidonate lipoxygenase 5 (ALOX5) negative and positive cells. Down regulation of ALOX5 inhibited ferroptosis, while overexpression of ALOX5 promoted ferroptosis. CONCLUSION: DHA can effectively promote ferroptosis-mediated tumor killing by increasing intracellular lipid peroxidation. Both ALOX5 dependent and independent pathways are involved in DHA-FIN induced ferroptosis. And during this process, free DHA plays an important role.
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Ácidos Docosa-Hexaenoicos , Neoplasias , Masculino , Humanos , Ácidos Docosa-Hexaenoicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Peróxidos Lipídicos , Lipoxigenase/metabolismo , Lipoxigenase/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Lisofosfatidilcolinas/farmacologia , Linhagem Celular Tumoral , Morte Celular , Peroxidação de Lipídeos , Lipoxigenases/metabolismo , Araquidonato Lipoxigenases/metabolismo , Araquidonato Lipoxigenases/farmacologia , Aciltransferases/metabolismo , Aciltransferases/farmacologia , Carbono , Coenzima A/metabolismo , Coenzima A/farmacologiaRESUMO
Alternative polarization of macrophages regulates multiple biological processes. While M1-polarized macrophages generally mediate rapid immune responses, M2-polarized macrophages induce chronic and mild immune responses. In either case, polyunsaturated fatty acid (PUFA)-derived lipid mediators act as both products and regulators of macrophages. Prostaglandin E3 (PGE3 ) is an eicosanoid derived from eicosapentaenoic acid, which is converted by cyclooxygenase, followed by prostaglandin E synthase successively. We found that PGE3 played an anti-inflammatory role by inhibiting LPS and interferon-γ-induced M1 polarization and promoting interleukin-4-mediated M2 polarization (M2a). Further, we found that although PGE3 had no direct effect on the growth of prostate cancer cells in vitro, PGE3 could inhibit prostate cancer in vivo in a nude mouse model of neoplasia. Notably, we found that PGE3 significantly inhibited prostate cancer cell growth in a cancer cell-macrophage co-culture system. Experimental results showed that PGE3 inhibited the polarization of tumour-associated M2 macrophages (TAM), consequently producing indirect anti-tumour activity. Mechanistically, we identified that PGE3 regulated the expression and activation of protein kinase A, which is critical for macrophage polarization. In summary, this study indicates that PGE3 can selectively promote M2a polarization, while inhibiting M1 and TAM polarization, thus exerting an anti-inflammatory effect and anti-tumour effect in prostate cancer.
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Alprostadil/análogos & derivados , Anti-Inflamatórios/farmacologia , Diferenciação Celular , Inflamação/tratamento farmacológico , Ativação de Macrófagos/imunologia , Neoplasias da Próstata/tratamento farmacológico , Alprostadil/farmacologia , Animais , Polaridade Celular , Humanos , Inflamação/imunologia , Inflamação/patologia , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Transdução de SinaisRESUMO
Plastic polarization of macrophage is involved in tumorigenesis. M1-polarized macrophage mediates rapid inflammation, entity clearance and may also cause inflammation-induced mutagenesis. M2-polarized macrophage inhibits rapid inflammation but can promote tumour aggravation. ω-3 long-chain polyunsaturated fatty acid (PUFA)-derived metabolites show a strong anti-inflammatory effect because they can skew macrophage polarization from M1 to M2. However, their role in tumour promotive M2 macrophage is still unknown. Resolvin D1 and D2 (RvD1 and RvD2) are docosahexaenoic acid (DHA)-derived docosanoids converted by 15-lipoxygenase then 5-lipoxygenase successively. We found that although dietary DHA can inhibit prostate cancer in vivo, neither DHA (10 µmol/L) nor RvD (100 nmol/L) can directly inhibit the proliferation of prostate cancer cells in vitro. Unexpectedly, in a cancer cell-macrophage co-culture system, both DHA and RvD significantly inhibited cancer cell proliferation. RvD1 and RvD2 inhibited tumour-associated macrophage (TAM or M2d) polarization. Meanwhile, RvD1 and RvD2 also exhibited anti-inflammatory effects by inhibiting LPS-interferon (IFN)-γ-induced M1 polarization as well as promoting interleukin-4 (IL-4)-mediated M2a polarization. These differential polarization processes were mediated, at least in part, by protein kinase A. These results suggest that regulation of macrophage polarization using RvDs may be a potential therapeutic approach in the management of prostate cancer.
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Antineoplásicos/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Animais , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Humanos , Imuno-Histoquímica , Macrófagos/metabolismo , Camundongos , Camundongos Transgênicos , Transdução de Sinais/efeitos dos fármacos , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismoRESUMO
Gastric cancer (GC) is one of the most malignant tumors that seriously threaten human health. Increased reports have indicated that long noncoding RNAs (lncRNAs) are associated with GC. This study aims to investigate the regulatory role of colon cancer-associated transcript-1 (CCAT1) in GC. The results exhibited the fact that CCAT1 was expressed higher in 57 GC tissue samples than in 57 paired adjacent normal tissue samples. The expression of CCAT1 was also increased in GC cell lines (MKN45, Hs746T, and SGC-7901) compared with the gastric epithelial cell line GES-1. Besides this, decreased cell proliferation with increased cell apoptosis was detected in SGC-7902 cells transfected with CCAT1 short hairpin RNA (shRNA). At the same time, a lower cell invasion ability was measured in SCG-7901 cells transfected with CCAT1 shRNA.In addition, miR-219-1 was predicted and convinced a direct target of CCAT1. The expression of miR-219-1 was decreased in GC tissues and GC cell lines. Further studies demonstrated that the roles of CCAT1 in cell proliferation, apoptosis, and invasion were inhibited by miR-219-1. Finally, in vivo experiment indicated that tumor growth of GC was suppressed through knockdown of CCAT1. In conclusion, these results suggested that CAT1 promotes the tumorigenesis and progression of GC by negatively regulating miR-219-1.
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Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/patologia , Animais , Apoptose , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Sepsis-associated encephalopathy (SAE), a diffuse cerebral dysfunction in the absence of direct CNS infection, is associated with increased rates of mortality and morbidity in patients with sepsis. Increased cytokine production and disruption of the blood-brain barrier (BBB) are implicated in the pathogenesis of SAE. The induction of pro-inflammatory mediators is driven, in part, by activation of NF-κΒ. Lipopolysaccharide (LPS), an endotoxin produced by gram-negative bacteria, potently activates NF-κΒ and its downstream targets, including cyclooxygenase-2 (Cox-2). Cox-2 catalyzes prostaglandin synthesis and in the brain prostaglandin, E2 is capable of inducing endothelial permeability. Depletion of polymerase δ-interacting protein 2 (Poldip2) has previously been reported to attenuate BBB disruption, possibly via regulation of NF-κΒ, in response to ischemic stroke. Here we investigated Poldip2 as a novel regulator of NF-κΒ/cyclooxygenase-2 signaling in an LPS model of SAE. METHODS: Intraperitoneal injections of LPS (18 mg/kg) were used to induce BBB disruption in Poldip2+/+ and Poldip2+/- mice. Changes in cerebral vascular permeability and the effect of meloxicam, a selective Cox-2 inhibitor, were assessed by Evans blue dye extravasation. Cerebral cortices of Poldip2+/+ and Poldip2+/- mice were further evaluated by immunoblotting and ELISA. To investigate the role of endothelial Poldip2, immunofluorescence microscopy and immunoblotting were performed to study the effect of siPoldip2 on LPS-mediated NF-κΒ subunit p65 translocation and Cox-2 induction in rat brain microvascular endothelial cells. Finally, FITC-dextran transwell assay was used to assess the effect of siPoldip2 on LPS-induced endothelial permeability. RESULTS: Heterozygous deletion of Poldip2 conferred protection against LPS-induced BBB permeability. Alterations in Poldip2+/+ BBB integrity were preceded by induction of Poldip2, p65, and Cox-2, which was not observed in Poldip2+/- mice. Consistent with these findings, prostaglandin E2 levels were significantly elevated in Poldip2+/+ cerebral cortices compared to Poldip2+/- cortices. Treatment with meloxicam attenuated LPS-induced BBB permeability in Poldip2+/+ mice, while having no significant effect in Poldip2+/- mice. Moreover, silencing of Poldip2 in vitro blocked LPS-induced p65 nuclear translocation, Cox-2 expression, and endothelial permeability. CONCLUSIONS: These data suggest Poldip2 mediates LPS-induced BBB disruption by regulating NF-κΒ subunit p65 activation and Cox-2 and prostaglandin E2 induction. Consequently, targeted inhibition of Poldip2 may provide clinical benefit in the prevention of sepsis-induced BBB disruption.
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Barreira Hematoencefálica/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Nucleares/metabolismo , Encefalopatia Associada a Sepse/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/genética , NF-kappa B/metabolismo , Proteínas Nucleares/genética , Permeabilidade , Encefalopatia Associada a Sepse/genética , Encefalopatia Associada a Sepse/patologiaRESUMO
Gastric cancer (GC) is one of the most malignant tumors that seriously threaten to human health. Increased reports indicated that long non-coding RNAs (lncRNAs) were associated with GC. This study aims to investigate the regulatory role of colon cancer associated transcript-1 (CCAT1) in GC. The results exhibited that CCAT1 was higher expressed in 57 GC tissue samples than in 57 paired adjacent normal tissue samples. The expression of CCAT1 was also increased in GC cell lines (MKN45, Hs746T and SGC-7901) compared with gastric epithelial cell line GES-1. Besides, decreased cell proliferation with increased cell apoptosis were detected in SGC-7902 cells transfected with CCAT1 shRNA. At the same time, lower cell invasion ability was measured in SCG-7901 cells transfected with CCAT1-shRNA. In addition, miR-219-1 was predicted and convinced a direct target of CCAT1. The expression of miR-219-1 was declined in GC tissues and GC cell lines. Further studies demonstrated that the roles of CCAT1 on cell proliferation, apoptosis and invasion were inhibited by miR-219-1. At last, the in vivo experiment indicated that tumor growth of GC was suppressed through knockdown of CCAT1. In conclusion, these results suggested that CAT1 promotes the tumorigenesis and progression of GC by negative-regulating miR-219-1. This article is protected by copyright. All rights reserved.
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BACKGROUND: The mechanisms underlying glucocorticoid responsiveness are largely unknown. Although redox regulation of the glucocorticoid receptor (GR) has been reported, it has not been studied in asthmatic patients. OBJECTIVE: We characterized systemic cysteine oxidation and its association with inflammatory and clinical features in healthy children and children with difficult-to-treat asthma. We hypothesized that cysteine oxidation would be associated with increased markers of oxidative stress and inflammation, increased features of asthma severity, decreased clinically defined glucocorticoid responsiveness, and impaired GR function. METHODS: PBMCs were collected from healthy children (n = 16) and children with asthma (n = 118) aged 6 to 17 years. Children with difficult-to-treat asthma underwent glucocorticoid responsiveness testing with intramuscular triamcinolone. Cysteine, cystine, and inflammatory chemokines and reactive oxygen species generation were quantified, and expression and activity of the GR were assessed. RESULTS: Cysteine oxidation was present in children with difficult-to-treat asthma and accompanied by increased reactive oxygen species generation and increased CCL3 and CXCL1 mRNA expression. Children with the greatest extent of cysteine oxidation had more features of asthma severity, including poorer symptom control, greater medication use, and less glucocorticoid responsiveness despite inhaled glucocorticoid therapy. Cysteine oxidation also modified the GR protein by decreasing available sulfhydryl groups and decreasing nuclear GR expression and activity. CONCLUSIONS: A highly oxidized cysteine redox state promotes a posttranslational modification of the GR that might inhibit its function. Given that cysteine oxidation is prevalent in children with difficult-to-treat asthma, the cysteine redox state might represent a potential therapeutic target for restoration of glucocorticoid responsiveness in this population.
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Asma/tratamento farmacológico , Glucocorticoides/uso terapêutico , Leucócitos Mononucleares/imunologia , Processamento de Proteína Pós-Traducional , Receptores de Glucocorticoides/imunologia , Triancinolona/uso terapêutico , Administração por Inalação , Adolescente , Asma/genética , Asma/imunologia , Asma/patologia , Quimiocina CCL3/genética , Quimiocina CCL3/imunologia , Quimiocina CXCL1/genética , Quimiocina CXCL1/imunologia , Criança , Cisteína/química , Cisteína/imunologia , Cistina/química , Cistina/imunologia , Monitoramento de Medicamentos , Feminino , Expressão Gênica , Humanos , Injeções Intramusculares , Leucócitos Mononucleares/química , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/patologia , Masculino , Oxirredução , Estresse Oxidativo , Cultura Primária de Células , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/genéticaRESUMO
Pramlintide is an artificially designed protein which has the same function as amylin in human body. This protein is extremely difficult to synthesize through prokaryotic expression method because of its two essential active sites, intrachain disulfide bond and C-terminal amide group. Since α-amidating monooxygenase is widely distributed in human and animal, it is possible to use pramlintide precursor with an additional C-terminal glycine (PAG), which is the potential substrate of α-amidating monooxygenase, for in vivo applications. The recombinant PAG was expressed in Escherichia coli using the small ubiquitin-related modifier (SUMO) as the molecular chaperone, and the optimal fusion expression level reached to 36.3% of the total supernatant protein. Under optimal conditions in a 10-L fermentor, the recombinant PAG was obtained with a purity of greater than 95%, and the average expression level was reached to 20 mg/L. The authenticity and the intrachain disulfide bridge of PAG were confirmed by Western blotting and matrix-assisted laser desorption/ionization coupled to time-of-flight mass spectrometry (MALDI-TOF MS) as well as N-terminal sequencing of protein. Based on an L6 myoblast cell model in vitro and an animal model of gastric emptying in vivo, the results of activity revealed that PAG showed a lower biological activity in vitro but has almost the same activity as the chemically synthesized pramlintide in vivo.
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Escherichia coli/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Animais , Linhagem Celular , Esvaziamento Gástrico/efeitos dos fármacos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Masculino , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/genéticaRESUMO
To investigate the local micro-/nanoscale region in a large scale sample, an image reconstruction method for nanometer computed tomography (nano-CT) was proposed in this paper. In the algorithm, wavelets were used to localize the filtered-backprojection (FBP) algorithm because of its space-frequency localization property. After the implementation of the algorithm, two simulation local reconstruction experiments were performed to confirm its effectiveness. Three evaluation criteria were used in the experiments to judge the quality of the reconstructed images. The experimental results showed that the algorithm proposed in this paper performed best because (1) the quality of its results had improved 20%-30% compared to the results of FBP and 10%-30% compared to the results of another wavelet algorithm; (2) the new algorithm was stable under different circumstances. Besides, an actual reconstruction experiment was performed using real projection data that had been collected in a CT experiment. Two-dimensional (2D) and three-dimensional (3D) images of the sample were reconstructed. The microstructure of the sample could be clearly observed in the reconstructed images. Since much attention has been directed towards the nano-CT technique to investigate the microstructure of materials, this new wavelet-based local tomography algorithm could be considered as a meaningful effort.
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Algoritmos , Diagnóstico por Imagem/métodos , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional , Tomografia Computadorizada por Raios XRESUMO
Background: Cerebral microbleeds (CMBs) are an important risk factor for stroke recurrence and prognosis. However, there is no consensus on the safety of antiplatelet therapy in patients with ischemic stroke and CMBs. Objective: This study aimed to observe the effects of dual antiplatelet therapy with aspirin and clopidogrel on bleeding conversion in patients with different degrees of CMBs. Materials and Methods: An observational retrospective study was conducted on 160 patients with acute mild ischemic stroke admitted to the Stroke Center, Affiliated Hospital of Beihua University between March 2021 and December 2022. Patients were divided into the CMBs and non-CMB groups. The CMB group was then divided into the low, medium and high-risk groups. In two groups, all patients were administered dual antiplatelet therapy (aspirin 100 mg and clopidogrel 75 mg orally once a day for 21 days according to the Chinese Stroke Guidelines of 2018), and no other anticoagulant or antiplatelet drugs were administered during the treatment period. Head CT, National Institutes of Health Stroke Scale(NIHSS) and modified Rankin Scale (mRS) score were re-checked, and the number of bleeding conversions was calculated at 21 days. Results: Five patients in the CMB group had intracranial hemorrhage (5/116, 4.3%), while no intracranial hemorrhage was observed in the non-CMB group. There were no differences in the conversion rate of cerebral hemorrhage, NIHSS score, or mRS score between two groups after dual antiplatelet therapy (p>0.05). The conversion rate of cerebral hemorrhage in the high-risk group was higher than that in the non-CMB group (p<0.05), but the NIHSS and mRS score showed no difference between the high-risk and non-CMB groups (p>0.05). Conclusion: Dual antiplatelet therapy with aspirin and clopidogrel does not significantly increase the risk of bleeding transformation; however, it improves neurological recovery or long-term prognosis in patients with acute ischemic cerebral stroke complicated by low-risk and middle-risk CMBs.
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Though years of education have been connected to nonalcoholic fatty liver disease (NAFLD), the exact mechanism underlying this linkage is still unknown. To investigate the causal association between years of education and NAFLD, we will use a 2-sample Mendelian randomization (MR) technique. : Genome-wide association studies data on years of education (nâ =â 766,345) and genome-wide association studies data on nonaffiliated mental illness (nâ =â 778,614) were screened for genetic variations as instrumental variables in the Mr-Base database. MR-Egger regression, weighted median, and inverse variance weighted were used in the MR analysis. Years of education (odds ratioâ =â 0.63; 95% confidence interval: 0.47-0.79; Pâ =â 1.28â ×â 10-8) might be protective against the development of NAFLD. Among the sensitivity analyses were the following: the MR-Egger intercept test revealed Pâ >â .05, suggesting that there was no horizontal pleiotropy in the MR analysis and that the inverse variance weighted results were trustworthy; the Cochran Q test revealed Pâ >â .05, suggesting that there was no heterogeneity between the 2 samples; Funnel plot results demonstrated that there was no bias in the link between the measure of variability and the impact size. Leave-1-out analysis results demonstrated that no 1 single nucleotide polymorphism had a significant effect on the study's results, showing that the MR results were stable. This study has investigated the connection between years of education and NAFLD, offering novel suggestions for NAFLD treatment and prevention.
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Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Escolaridade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Lung cancer has one of the highest mortality rates worldwide, with non-small-cell lung cancer (NSCLC) constituting approximately 85% of all cases. Demethylzeylasteral (DEM), extracted from Tripterygium wilfordii Hook F, exhibits notable anti-tumor properties. In this study, we revealed that DEM could effectively induce NSCLC cell apoptosis. Specifically, DEM can dose-dependently suppress the viability and migration of human NSCLC cells. RNA-seq analysis revealed that DEM regulates the P53-signaling pathway, which was further validated by assessing crucial proteins involved in this pathway. Biacore analysis indicated that DEM has high affinity with the P53 protein. The CDX model demonstrated DEM's anti-tumor actions. This work provided evidence that DEM-P53 interaction stabilizes P53 protein and triggers downstream anti-tumor activities. These findings indicate that DEM treatment holds promise as a potential therapeutic approach for NSCLC, which warrants further clinical assessment in patients with NSCLC.
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AIM: A bridging study of INTRIGUE study to assess the efficacy and safety of ripretinib versus sunitinib as second-line treatment in Chinese GIST patients. METHODS: This was a phase 2, multicenter, randomized, open-label study in China. GIST patients previously treated with imatinib were randomized (1:1) to receive ripretinib 150 mg once daily (QD) by continuous dosing in 42-day cycles or sunitinib 50 mg QD in 42-day cycles (four weeks on/two weeks off). Primary endpoint was progression-free survival (PFS) by independent radiological review (IRR). RESULTS: Between 6 December 2020 and 15 September 2021, 108 patients were randomized to receive ripretinib (n = 54) or sunitinib (n = 54) (all-patient [AP] intention-to-treat [ITT] population). Seventy patients had primary KIT exon 11 mutations (ripretinib, n = 35; sunitinib, n = 35; Ex11 ITT population). By data cut-off (20 July 2022), in AP ITT population, PFS by IRR was comparable between ripretinib and sunitinib arms (HR 0·99, 95 % CI 0·57, 1·69; nominal p = 0·92; median PFS [mPFS] 10·3 vs 8·3 months). In Ex11 ITT population, PFS by IRR was longer for ripretinib than sunitinib (HR 0·46, 95 % CI 0·23, 0·92; nominal p = 0·03; mPFS not reached in ripretinib arm and 4·9 months in sunitinib arm). Fewer patients experienced grade 3/4 treatment-related treatment-emergent adverse events with ripretinib (17%) versus sunitinib (56%). CONCLUSIONS: Ripretinib demonstrated similar efficacy and a favorable safety profile versus sunitinib as second-line treatment in Chinese GIST patients. Furthermore, ripretinib provided greater clinically meaningful benefit versus sunitinib in patients with KIT exon 11 mutation.
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Antineoplásicos , Tumores do Estroma Gastrointestinal , Sunitinibe , Humanos , Antineoplásicos/efeitos adversos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/uso terapêutico , Sunitinibe/efeitos adversosRESUMO
The gut-liver axis plays a key role in the development and progression of non-alcoholic fatty liver disease (NAFLD). Due to the complexity and incomplete understanding of the cross-talk between the gut and liver, effective therapeutic targets are largely unknown. Free fatty acid receptors (FFARs) may bridge the cross-talk between the gut and liver. FFAR4 has received considerable attention due to its important role in lipid metabolism. However, the role of FFAR4 in this cross talk in NAFLD remains unclear. In this study, mice with high endogenous n-3 PUFAs but FFAR4 deficiency were generated by crossbreeding Fat-1 and FFAR4 knockout mice. FFAR4 deficiency blocked the protective effects of high endogenous n-3 PUFAs on intestinal barrier dysfunction and hepatic steatosis. In addition, FFAR4 deficiency decreased gut microbiota diversity and enriched Rikenella, Anaerotruncus, and Enterococcus, and reduced Dubosiella, Ruminococcaceae UCG-010, Ruminococcaceae UCG-014, Coriobacteriaceae UCG-002, Faecalibaculum, Ruminococcaceae UCG-009, and Akkermansia. Notably, FFAR4 deficiency co-regulated pantothenic acid and CoA biosynthesis, ß-alanine metabolism, and sphingolipid metabolism pathways in the gut and liver, potentially associated with the aggravation of NAFLD. Together, the beneficial effects of n-3 PUFAs on the gut and liver were mediated by FFAR4, providing insights on the role of FFAR4 in the treatment of NAFLD through the gut-liver axis.
Assuntos
Ácidos Graxos Ômega-3 , Hepatopatia Gordurosa não Alcoólica , Receptores Acoplados a Proteínas G , Animais , Camundongos , Fenômenos Fisiológicos Celulares , Dieta Hiperlipídica , Ácidos Graxos Ômega-3/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Pulmonary fibrosis (PF) is a persistent and refractory illness accompanied by inflammation and fibrosis. Gracillin, a natural steroidal saponin, is one of the components of Dioscorea quinqueloba which has been used in herbal medicines for treating some inflammatory diseases. Therefore, it may be a potential drug candidate for PF management. AIM OF THE STUDY: This study aims to elucidate and verify the anti-pulmonary fibrosis effect of gracillin. METHODS: We established an in vivo model of PF by treatment of mice with bleomycin (BLM) and an in vitro model by treatment of NIH-3T3 cells with TGF-ß1. Pathological changes to the structure of lung tissue, pulmonary function, inflammatory exudation of bronchoalveolar lavage fluid (BALF) and deposition of collagen were detected in vivo, and extracellular matrix (ECM) deposition and migration were evaluated in vitro. The significance of gracillin on STAT3 phosphorylation and nuclear translocation were evaluated by western blotting, immunohistochemistry and immunofluorescence assays. The STAT3 transcriptional activity was quantified with a dual-luciferase reporter assay. Recovery experiments were performed by plasmid-directed overexpression of STAT3. RESULTS: We found that gracillin could improve pulmonary function, reduce lung inflammation and mitigate collagen deposition to ameliorate BLM-induced PF in mice. Gracillin also suppressed TGF-ß1-induced increases in ECM deposition biomarkers, including COL1A1, fibronectin, α-SMA, N-cad and vimentin, and repressed migration in NIH-3T3 cells. Additionally, gracillin suppressed the phosphorylation, nuclear translocation and transcriptional action of STAT3. Furthermore, the decreased ECM deposition and migration upon gracillin treatment were abrogated upon overexpression of STAT3 in NIH-3T3 cells. CONCLUSIONS: Gracillin protects against PF by inhibiting the STAT3 axis, providing a safe and efficacious approach to treating PF.
Assuntos
Fibrose Pulmonar , Fator de Crescimento Transformador beta1 , Camundongos , Animais , Fator de Crescimento Transformador beta1/farmacologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Pulmão , Colágeno , BleomicinaRESUMO
Two COFs (BT-COF1 and BT-COF2) with isomeric configuration were reported. Compared with BT-COF1, BT-COF2 with the narrower bandgap, smaller resistance and more evident charge transfer property exhibits superior catalytic performance in the photooxidation of sulfides.
RESUMO
A benzothiadiazole-involving donor-acceptor (D-A) covalent organic framework (COF), which has high crystallinity and strong light-harvesting capability (ranging from 300 to 800 nm), can serve as a highly effective photocatalyst for window ledge aerobic cross-dehydrogenative coupling (CDC) reactions (such as Mannich and aza-Henry reactions) even at a gram level.
RESUMO
Background Lung injury, a severe adverse outcome of lipopolysaccharide-induced acute respiratory distress syndrome, is attributed to excessive neutrophil recruitment and effector response. Poldip2 (polymerase δ-interacting protein 2) plays a critical role in regulating endothelial permeability and leukocyte recruitment in acute inflammation. Thus, we hypothesized that myeloid Poldip2 is involved in neutrophil recruitment to inflamed lungs. Methods and Results After characterizing myeloid-specific Poldip2 knockout mice, we showed that at 18 hours post-lipopolysaccharide injection, bronchoalveolar lavage from myeloid Poldip2-deficient mice contained fewer inflammatory cells (8 [4-16] versus 29 [12-57]×104/mL in wild-type mice) and a smaller percentage of neutrophils (30% [28%-34%] versus 38% [33%-41%] in wild-type mice), while the main chemoattractants for neutrophils remained unaffected. In vitro, Poldip2-deficient neutrophils responded as well as wild-type neutrophils to inflammatory stimuli with respect to neutrophil extracellular trap formation, reactive oxygen species production, and induction of cytokines. However, neutrophil adherence to a tumor necrosis factor-α stimulated endothelial monolayer was inhibited by Poldip2 depletion (225 [115-272] wild-type [myePoldip2+/+] versus 133 [62-178] myeloid-specific Poldip2 knockout [myePoldip2-/-] neutrophils) as was transmigration (1.7 [1.3-2.1] versus 1.1 [1.0-1.4] relative to baseline transmigration). To determine the underlying mechanism, we examined the surface expression of ß2-integrin, its binding to soluble intercellular adhesion molecule 1, and Pyk2 phosphorylation. Surface expression of ß2-integrins was not affected by Poldip2 deletion, whereas ß2-integrins and Pyk2 were less activated in Poldip2-deficient neutrophils. Conclusions These results suggest that myeloid Poldip2 is involved in ß2-integrin activation during the inflammatory response, which in turn mediates neutrophil-to-endothelium adhesion in lipopolysaccharide-induced acute respiratory distress syndrome.