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Mitochondrial adaptations dynamically reprogram cellular bioenergetics and metabolism and confer key properties for human cancers. However, the selective regulation of these mitochondrial responses remains largely elusive. Here, inspired by a genetic screening in acute myeloid leukemia (AML), we identify RAS effector RREB1 as a translational regulator and uncover a unique translation control system for nuclear-encoded mitochondrial proteins in human cancers. RREB1 deletion reduces mitochondrial activities and succinate metabolism, thereby damaging leukemia stem cell (LSC) function and AML development. Replenishing complex II subunit SDHD rectifies these deficiencies. Notably, inhibition of complex II re-sensitizes AML cells to venetoclax treatment. Mechanistically, a short RREB1 variant binds to a conserved motif in the 3' UTRs and cooperates with elongation factor eEF1A1 to enhance protein translation of nuclear-encoded mitochondrial mRNAs. Overall, our findings reveal a unique translation control mechanism for mitochondrial adaptations in AML pathogenesis and provide a potential strategy for targeting this vulnerability of LSCs.
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Aiming at the problem of the poor performance of an Mn-MOF-74-derived Mn3O4 catalyst in low-temperature carbon monoxide (CO) oxidation, copper (Cu) and cerium (Ce) elements were used to modify the Mn3O4 catalyst to improve its performance in low-temperature CO oxidation. According to the results of catalytic performance testing, the CO oxidation activity of the Cu0.3Mn2.7O4 catalyst was significantly improved compared with that of the pristine Mn3O4 catalyst, when a CO conversion rate of 90% was achieved at 118 °C. According to X-ray photoelectron spectroscopy and Brunauer-Emmett-Teller analyses, the (Mn2+ + Mn3+)/(Mn2+ + Mn3+ + Mn4+) ratio and the Oads/Ototal ratio increased after Cu doping, indicating promoted oxygen vacancy generation. In addition, the increased specific surface area was beneficial for the adsorption of reactant molecules and the exposure of active sites. According to H2-temperature-programmed reduction characterization, Cu doping significantly enhanced the performance of the Cu0.3Mn2.7O4 catalyst during low-temperature redox. Finally, these factors synergistically promoted the degradation of CO over the Cu0.3Mn2.7O4 catalyst. In addition, operando diffuse reflectance Fourier transform infrared spectroscopy results suggested the presence of more terminal-type oxygen, which is essential for the catalytic oxidation of CO on the surface of the Cu0.3Mn2.7O4 catalyst. Moreover, the Cu0.3Mn2.7O4 catalyst also showed excellent resistance to carbonate, and remarkable stability.
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During lutein extraction, isomerization from all-trans to cis form reduced stability and antioxidant capacity. Alkaline electrolyzed water (AEW), with its reduced-state and small molecular clusters, effectively extracted bioactive substances and inhibited oxidation. Thus, an AEW-assisted ultrasonic extraction method was used to extract lutein from daylily. Compared to ultrasonic extraction alone, AEW treatment increased the lutein yield by 60 %. Structural analysis confirmed the preservation of all-trans lutein by AEW. Assess AEW extraction's impact on lutein's bioactivity by examining its protection against blue light cell damage. The results showed that that lutein extracted using AEW exhibited enhanced antioxidant capacity, significantly boosting the viability of ARPE-19 cells and the activity of intracellular antioxidant enzymes, thereby mitigating oxidative stress damage to the retina caused by blue light exposure. This study provided an effective method for efficiently extracting bioactive substances and preventing the impact of the extraction process on their structure and function.
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Nuclear Bcl-xL is found to promote cancer metastasis independently of its mitochondria-based anti-apoptotic activity. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates histone H3 trimethyl Lys4 (H3K4me3) modification have yet to be understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds to Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced invasion and metastasis in mouse models. Furthermore, knockout of CtBP2 not only reduces the nuclear portion of Bcl-xL but also suppresses Bcl-xL transcription. The binding between Bcl-xL and CtBP2 is required for their interaction with MLL1, a histone H3K4 methyltransferase. Pharmacologic inhibition of the MLL1 enzymatic activity reverses Bcl-xL-induced H3K4me3 and TGFß mRNA upregulation, as well as invasion. Moreover, the cleavage under targets and release using nuclease (CUT&RUN) assay coupled with next-generation sequencing reveals that H3K4me3 modifications are particularly enriched in the promotor regions of genes encoding TGFß and its signaling pathway members in cancer cells overexpressing Bcl-xL. Altogether, the metastatic function of Bcl-xL is mediated by its interaction with CtBP2 and MLL1 and this study offers new therapeutic strategies to treat Bcl-xL-overexpressing cancer.
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BACKGROUND: Larch is an important timber tree species. The traditional methods of tree genetic breeding have been progressing slowly. It is necessary to carry out gene function analysis and genetically modified breeding research. The NAC transcription factor family is a plant-specific transcription factor family with various biological functions, as shown in recent research. However, there are few studies on the NAC gene among gymnosperm coniferous species. RESULTS: LoNAC3 with complete cds was identified and isolated from the cDNA of Larix olgensis based on transcriptome data. The cDNA length of LoNAC3 is 1185 bp, encoding 394 amino acids, with a conserved NAM domain located at the N-terminus, and subcellular localization in the nucleus. The results of real-time quantitative PCR analysis showed that at different growth stages and in different tissues of L. olgensis, the relative expression level of LoNAC3 was highest in the needles. After drought, salt, alkali stress and hormone treatment, expression was induced to different degrees. The expression level of LoNAC3 was significantly increased under drought and salt conditions. The relative expression level changed under methyl jasmonate (MeJA) and abscisic acid (ABA) treatment. By observing the phenotype of overexpressed LoNAC3 tobacco, it was found that overexpressed tobacco is shorter and blooms earlier than wild-type tobacco. Under abiotic stress, LoNAC3 overexpressed tobacco has lower germination rates and poorer growth status. Transgenic tobacco under stress treatment has a higher malondialdehyde (MDA) content than wild-type tobacco, while peroxidase (POD) activity is lower than wild-type tobacco. CONCLUSIONS: Through the analysis of LoNAC3 sequence and promoter expression, it can be concluded that LoNAC3 is involved in the drought and salt stress response processes of L. olgensis, and is induced by ABA and MeJA expression. Overexpression of LoNAC3 leads to stunted tobacco growth and negatively regulates its tolerance to drought and salt stress through the reactive oxygen species pathway. The preliminary analysis of the expression pattern and function of the LoNAC3 can provide a theoretical basis and high-quality materials for genetic improvement of larch in later stages.
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Larix , Proteínas de Plantas , Fatores de Transcrição , Larix/genética , Larix/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Nicotiana/genética , Regulação da Expressão Gênica de Plantas , Plantas Geneticamente Modificadas/genética , Estresse Fisiológico/genética , Filogenia , Ácido Abscísico/metabolismo , Secas , Genes de Plantas , Acetatos , Ciclopentanos , OxilipinasRESUMO
Traditional fermented foods are known to offer cardiovascular health benefits. However, the potential of fermented Chinese chives (FCC) in reducing coronary heart disease (CHD) remains unclear. This study employed anaerobic fermentation to investigate Lactiplantibacillus plantarum (L. plantarum) P470 from FCC. The results indicated that L. plantarum P470 enhanced hydroxyl radical scavenging and exhibited anti-inflammatory effects on RAW264.7 macrophages in the fecal fermentation supernatant of CHD patients. These effects were attributed to the modulation of gut microbiota and metabolites, including short-chain fatty acids (SCFAs). Specifically, L. plantarum P470 increased the abundance of Bacteroides and Lactobacillus while decreasing Escherichia-Shigella, Enterobacter, Veillonella, Eggerthella, and Helicobacter in CHD patient fecal samples. Furthermore, L. plantarum P470 regulated the biosynthesis of unsaturated fatty acids and linoleic acid metabolism. These findings suggest that L. plantarum P470 from FCC can improve the fecal physiological status in patients with CHD by modulating intestinal microbiota, promoting SCFA production, and regulating lipid metabolism.
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Doença das Coronárias , Ácidos Graxos Voláteis , Fezes , Alimentos Fermentados , Microbioma Gastrointestinal , Lactobacillus plantarum , Humanos , Fezes/microbiologia , Doença das Coronárias/microbiologia , Camundongos , Animais , Alimentos Fermentados/microbiologia , Ácidos Graxos Voláteis/metabolismo , Ácidos Graxos Voláteis/análise , Masculino , Fermentação , Feminino , Pessoa de Meia-Idade , Células RAW 264.7 , Idoso , Probióticos/farmacologiaRESUMO
Acute lung injury (ALI) is the result of damage to the capillary endothelia and the alveolar epithelial cell caused by various direct and indirect factors, leading to significant pulmonary interstitial and alveolar edema and acute hypoxic respiratory insufficiency. A subset of ALI cases progresses to irreversible pulmonary fibrosis, a condition with fatal implications. Zafirlukast is a leukotriene receptor antagonist licensed for asthma prevention and long-term treatment. This study demonstrated a significant improvement in lung tissue pathology and a reduction in inflammatory cell infiltration in models of lipopolysaccharide (LPS)-induced ALI and bleomycin (BLM)-induced lung inflammation following zafirlukast administration, both in vivo and in vitro. Moreover, zafirlukast was found to suppress the inflammatory response of alveolar epithelial cells in vitro and lung inflammation in vivo by reducing the activation of the TLR4/NF-κB/NLRP3 inflammasome pathway. In conclusion, zafirlukast relieved lung injury and the infiltration of inflammatory cells in the lung by regulating the TLR4/NF-κB/NLRP3 pathway.
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Lesão Pulmonar Aguda , Bleomicina , Indóis , Lipopolissacarídeos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fenilcarbamatos , Pneumonia , Sulfonamidas , Receptor 4 Toll-Like , Compostos de Tosil , Animais , Bleomicina/efeitos adversos , Compostos de Tosil/farmacologia , Compostos de Tosil/uso terapêutico , Camundongos , Indóis/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sulfonamidas/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/patologia , Pneumonia/induzido quimicamente , Pneumonia/prevenção & controle , Pneumonia/tratamento farmacológico , Receptor 4 Toll-Like/metabolismo , Modelos Animais de Doenças , Antagonistas de Leucotrienos/farmacologia , Antagonistas de Leucotrienos/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacosRESUMO
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus that is immune/antigen-mediated and often requires targeted treatment. In clinical practice, an oral viscous budesonide suspension prepared by adding sucralose to a budesonide suspension for inhalation (Pulmicort®) is used to treat adult EoE and enhance retention in the esophageal mucosa. Inspired by this off-label drug use, oral viscous budesonide solutions (OVBSs) were developed in this study, and their capacities for adhesion, permeation, and stability were explored. Given the insolubility of budesonide as a BCS II drug, we first evaluated its equilibrium solubility and found that Transcutol® HP was an excellent choice for creating an OVBS at a concentration of 0.2 mg/g. The rheological properties of the OVBSs were evaluated with a rheometer, and shear-thinning, which aids in swallowing, was observed. The addition of hydroxyethyl cellulose (HEC) increased the adhesion strength of the preparation, which was associated with the hydration and thickening mechanism. This result was confirmed in a dynamic gelation study and in vitro elution experiment conducted with porcine esophagus tissue. Furthermore, the permeabilities of the OVBSs in the porcine esophagus were evaluated with a Franz diffusion cell device. More than 80% of the budesonide was released after 24 hours, and the release profile was similar to that of the solution. To explore the storage conditions of OVBSs, critical factors such as pH, content, and impurities were determined. It was found that OVBSs exhibited different behaviors at different pH values and temperatures. Notably, the OVBSs containing 1.7% HEC could be stored for more than 6 months at a temperature of 5°C ± 3°C and a pH of 4.5 without significant degradation. Overall, this study demonstrated that OVBSs have the potential to adhere to the esophageal mucosa, permeate the tissue, and remain stable during storage. Moreover, OVBSs exhibit a distinct advantage over traditional converted inhalation-to-oral budesonide therapies by enabling flexible dose adjustment in clinical applications, thereby potentially minimizing systemic side effects commonly associated with oral glucocorticoid administration.
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Over the past several decades, advancements in the treatment of BRAF-mutant melanoma have led to the development of BRAF inhibitors, BRAF/MEK inhibitor combinations, anti-PD-1 therapy, and anti-CTLA4 therapy. Although these therapies have shown substantial efficacy in clinical trials, their sustained effectiveness is often challenged by the tumor microenvironment, which is a highly heterogeneous and complex milieu of immunosuppressive cells that affect tumor progression. The era of personalized medicine holds substantial promise for the tailoring of treatments to individual genetic profiles. However, tumor heterogeneity and immune evasion mechanisms contribute to the resistance to immunotherapy. Despite these challenges, tumor-infiltrating lymphocyte (TIL) therapy, as exemplified by lifileucel, has demonstrated notable efficacy against BRAF V600-mutant melanoma. Additionally, early response biomarkers, such as COX-2 and MMP2, along with FDG-PET imaging, offer the potential to improve personalized immunotherapy by predicting patient responses and determining the optimal treatment duration. Future efforts should focus on reducing the T-cell harvesting periods and costs associated with TIL therapy to enhance efficiency and accessibility.
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This study investigated the spatial and temporal variations of PM2.5 concentrations in Harbin, China, under the influence of meteorological parameters and gaseous pollutants. The complex relationship between meteorological parameters and pollutants was explored using Pearson correlation analysis and interaction effect analysis. Using the correlation analysis and interaction analysis methods, four mechanical learning models, PCC-Is-CNN, PCC-Is-LSTM, PCC-Is-CNN-LSTM and PCC-Is-BP neural network, were developed for predicting PM2.5 concentration in different time scales by combining the long-term and short-term data with the basic mechanical learning models. The results show that the PCC-Is-CNN-LSTM model has superior prediction performance, especially when integrating short-term and long-term historical data. Meanwhile, applying the model to cities in other climatic zones, the results show that the model performs well in the Dwa climatic zone, while the prediction performance is lower in the CWa climatic zone. This suggests that although the model is well adapted in regions with a similar climate to Harbin, model performance may be limited in areas with complex climatic conditions and diverse pollutant sources. This study emphasizes the importance of considering meteorological and pollutant interactions to improve the accuracy of PM2.5 predictions, providing valuable insights into air quality management in cold regions.
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Rational design and precision fabrication of magnetic-dielectric composites have significant application potential for microwave absorption in the low-frequency range of 2-8 GHz. However, the composition and structure engineering of these composites in regulating their magnetic-dielectric balance to achieve high-performance low-frequency microwave absorption remains challenging. Herein, a self-templating engineering strategy is proposed to fabricate hollow N-doped carbon microspheres anchored with ternary FeCoNi alloys. The high-temperature pyrolysis of FeCoNi alloy precursors creates core-shell FeCoNi alloy-graphitic carbon nano-units that are confined in carbon shells. Moreover, the anchored FeCoNi alloys play a critical role in maintaining hollow structural stability. In conjunction with the additional contribution of multiple heterogeneous interfaces, graphitization, and N doping to the regulation of electromagnetic parameters, hollow FeCoNi@NCMs exhibit a minimum reflection loss (RLmin) of -53.5 dB and an effective absorption bandwidth (EAB) of 2.48 GHz in the low-frequency range of 2-8 GHz. Furthermore, a filler loading of 20 wt% can also be used to achieve a broader EAB of 5.34 GHz with a matching thickness of 1.7 mm. In brief, this work opens up new avenues for the self-templating engineering of magnetic-dielectric composites for low-frequency microwave absorption.
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Pitaya, a desert plant, has an underexplored flowering mechanism due to a lack of functional validation assays. This study reveals that the transition from vegetative to generative growth in pitaya is regulated by significant metabolic shift, underscoring the importance of understanding and address the challenging issue pitaya's phase change. Lateral buds from 6-years-old 'Guanhuahong' pitaya (Hylocereus monacanthus) plants were collected on April 8th, 18th, and 28th 2023, representing early, middle, and late stages of phase transition, respectively. Results showed diminished nitrogen levels concurrent with increased carbon levels and carbon-to-nitrogen (C/N) ratios during pitaya phase transition. Transcriptomic analysis identified batches of differentially expressed genes (DEGs) involved in downregulating nitrogen metabolism and upregulating carbon metabolism. These batches of genes play a central role in the metabolic shifts that predominantly regulate the transition to the generative phase in pitaya. This study unveils the intricate regulatory network involving 6 sugar synthesis and transport, 11 photoperiod (e.g., PHY, CRY, PIF) and 6 vernalization (e.g., VIN3) pathways, alongside 11 structural flowering genes (FCA, FLK, LFY, AGL) out of a vast array of potential candidates in pitaya phase change. These findings provide insights into the metabolic pathways involved in pitaya's phase transition, offering a theoretical framework for managing flowering, guiding breeding strategies to optimize flowering timing and improve crop yields under varied nitrogen conditions.
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Cactaceae , Carbono , Nitrogênio , Nitrogênio/metabolismo , Carbono/metabolismo , Cactaceae/metabolismo , Cactaceae/genética , Cactaceae/fisiologia , Regulação da Expressão Gênica de Plantas , Flores/genética , Flores/crescimento & desenvolvimento , Flores/metabolismo , Perfilação da Expressão Gênica , TranscriptomaRESUMO
Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints.
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Vacinas Anticâncer , Macroglobulinemia de Waldenstrom , Humanos , Masculino , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Pessoa de Meia-Idade , Feminino , Macroglobulinemia de Waldenstrom/imunologia , Macroglobulinemia de Waldenstrom/terapia , Macroglobulinemia de Waldenstrom/genética , Idoso , Microambiente Tumoral/imunologia , Medicina de Precisão/métodos , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico , Antígenos de Neoplasias/imunologia , Linfócitos B/imunologiaRESUMO
BACKGROUND: In China, retail pharmacies are critical sources for obtaining medications and play a vital role in residents' daily access to drugs and treatment of common illnesses. Effectively guiding the placement of these pharmacies in areas of need through government regulation is crucial for enhancing medication access. In this study, we used population and retail pharmacy spatial distribution data from Shanghai to design guidance and supplementary methods for optimizing the spatial layout of retail pharmacies and medical insurance designated pharmacies based on regional characteristics. METHODS: Population distribution, road traffic network, administrative division and retail pharmacy data from Shanghai in 2018 were collected from relevant government departments. ArcGIS 10.3 was used to map the retail pharmacies and population distribution. Based on the spatial distribution of population and the service standards of pharmacies, service circles with insufficient pharmacies were identified, and supplementary methods for retail pharmacies and medical insurance designated pharmacies were developed. RESULTS: In 2018, Shanghai had 3009 retail pharmacies, each serving an average of 6412 residents. The city was divided into 2188 basic pharmaceutical service circles, each within a 15-minute walking distance. The results indicated that there were 1387 service circles without any pharmacies, 151 of which had populations exceeding 5000. Additionally, 356 service circles had pharmacies but lacked medical insurance designated ones. After supplementation, 841 retail pharmacies were planned to be added in residential areas. Compared with before, the coverage area and population served of the pharmacies increased significantly. CONCLUSIONS: This study mapped the spatial distribution of population and retail pharmacies in Shanghai, and designed government guidance and supplementary methods for optimizing the layout of retail pharmacies. The findings offer valuable insights for government agencies in low- and middle-income countries to improve the spatial distribution of retail pharmacies.
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Farmácias , China , Humanos , Farmácias/estatística & dados numéricos , Farmácias/normas , Regulamentação Governamental , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Acessibilidade aos Serviços de Saúde/normas , Análise EspacialRESUMO
Cardiac fibrosis is characterized by the over-proliferation, over-transdifferentiation and over-deposition of extracellular matrix (ECM) of cardiac fibroblasts (CFs). Cardiac sympathetic activation is one of the leading causes of myocardial fibrosis. Meanwhile, cardiac fibrosis is often together with cardiac inflammation, which accelerates fibrosis by mediating inflammatory cytokines secretion. Recently, the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling pathway has been confirmed by its vital role during the progression of cardiac fibrosis. Thus, JAK/STAT3 signaling pathway is thought to be a potential therapeutic target for cardiac fibrosis. Baricitinib (BR), a novel JAK1/2 inhibitor, has been reported excellent effects of anti-fibrosis in multiple fibrotic diseases. However, little is known about whether and how BR ameliorates cardiac fibrosis caused by chronic sympathetic activation. Isoproterenol (ISO), a ß-Adrenergic receptor (ß-AR) nonselective agonist, was used to modulate chronic sympathetic activation in mice. As expected, our results proved that BR ameliorated ISO-induced cardiac dysfunction. Meanwhile, BR attenuated ISO-induced cardiac fibrosis and cardiac inflammation in mice. Moreover, BR also inhibited ISO-induced cardiac fibroblasts activation and macrophages pro-inflammatory secretion. As for mechanism studies, BR reduced ISO-induced cardiac fibroblasts by JAK2/STAT3 and PI3K/Akt signaling, while reduced ISO-induced macrophages pro-inflammatory secretion by JAK1/STAT3 and NF-κB signaling. In summary, BR alleviates cardiac fibrosis and inflammation caused by chronic sympathetic activation. The underlying mechanism involves BR-mediated suppression of JAK1/2/STAT3, PI3K/Akt and NF-κB signaling.
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Azetidinas , Fibroblastos , Fibrose , Camundongos Endogâmicos C57BL , Purinas , Pirazóis , Sulfonamidas , Animais , Fibrose/tratamento farmacológico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Masculino , Fibroblastos/efeitos dos fármacos , Purinas/farmacologia , Purinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Camundongos , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Miocárdio/patologia , Isoproterenol , Células Cultivadas , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , NF-kappa B/metabolismo , Inflamação/tratamento farmacológico , Citocinas/metabolismo , Humanos , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
Grifola frondosa has garnered significant popularity as an edible mushroom attributable to its exceptional taste and nutritional benefits. This study isolated APPLRP, a potent ACE-inhibitory peptide, from the alcohol-soluble fraction of Grifola frondosa. The underlying mechanisms of APPLRP in antihypertension were explored through computational chemistry, cell experiments, and zebrafish model. Results demonstrated that APPLRP was an active competitive ACE inhibitor (IC50 = 29.93 µM) that could bind to the active pocket S2 and S1' of ACE. APPLRP exhibited resistance to pepsin and pancreatin digestion. In vitro experiments revealed that APPLRP significantly attenuated Ang II-induced VSMCs proliferation and migration by down-regulating AT1R expression and inhibiting ERK1/2 and STAT3 phosphorylation. APPLRP intervention significantly ameliorated myocardial fibrosis, as evidenced by reductions in cardiac output, blood flow velocity, and cardiac collagen deposition levels in Ang II-induced hypertensive zebrafish model. Furthermore, APPLRP improved vascular remodeling in hypertensive zebrafish, indicated by increased vessel diameter and decreased vessel wall thickness. Notably, APPLRP treatment resulted in down-regulation of ACE and up-regulation of ACE2 expression in the vessels of hypertensive zebrafish. These findings indicated that APPLRP was a representative component of Grifola frondosa peptides, and its antihypertensive effects were associated with ACE inhibition and the improvement of VSMCs-mediated vascular remodeling.
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Angiotensina II , Inibidores da Enzima Conversora de Angiotensina , Modelos Animais de Doenças , Grifola , Miócitos de Músculo Liso , Peixe-Zebra , Animais , Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Grifola/química , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Peptídeos/farmacologia , Peptídeos/química , Proliferação de Células/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertensão/induzido quimicamente , Remodelação Vascular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Simulação de Acoplamento MolecularRESUMO
BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive tumor with limited effectiveness in its standard chemotherapy treatment. Targeted antiangiogenic therapy and immune checkpoint inhibitors (ICIs) have demonstrated potential as alternative treatments for extensive-stage SCLC (ES-SCLC). However, there is insufficient comparative evidence available to determine the optimal first-line treatment option between ICIs plus chemotherapy and targeted antiangiogenic therapy plus chemotherapy. OBJECTIVE: This study is aimed at analyzing clinical data from ES-SCLC patients treated at the First Affiliated Hospital of Bengbu Medical College between June 2021 and June 2023. The study compared the efficacy and safety of three first-line treatment regimens: standard chemotherapy, antiangiogenic therapy combined with chemotherapy, and immune combination therapy. METHODS: Patients who met the inclusion criteria were divided into three groups: chemotherapy, immune combination therapy, and antiangiogenic therapy combined with chemotherapy. The study collected data on clinical characteristics, treatment regimens, and adverse reactions. The analysis included objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and treatment safety. RESULTS: A total of 101 patients were included in the study, with 49 receiving chemotherapy alone, 19 receiving antiangiogenic therapy, and 33 receiving immune combination therapy. The ORRs were 78.9% for antiangiogenic therapy, 72.7% for immune combination therapy, and 42.9% for chemotherapy alone. The median PFS was 8.0 months for antiangiogenic therapy, 7.8 months for immune combination therapy, and 5.2 months for chemotherapy alone. Both combination therapy groups demonstrated superior efficacy compared to chemotherapy alone. CONCLUSION: Targeted combined chemotherapy and immune combination chemotherapy showed superior efficacy as first-line treatments for ES-SCLC compared to chemotherapy alone, with manageable adverse reactions.
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Protocolos de Quimioterapia Combinada Antineoplásica , Imunoterapia , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/administração & dosagem , Estadiamento de Neoplasias , Adulto , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/efeitos adversos , Resultado do Tratamento , Estudos Retrospectivos , Terapia de Alvo Molecular/métodosRESUMO
BACKGROUND: Ulcerative colitis (UC) is one of the most important risk factors for developing colitis-associated cancer (CAC). Persistent DNA damage increases CAC risk and has been observed in patients with UC. We aimed to identify the regulatory role of RAD50, a DNA double-strand breaks (DSBs) sensor, in UC progression to CAC. METHODS: DSBs and RAD50 expression in IBD and CAC cell and mouse models were assessed. Mice with intestinal epithelial RAD50 deletion (RAD50IEC-KO) were used to examine the role of RAD50 in colitis and CAC. RESULTS: Along with the increased γ-H2AX expression in colitis and CAC models, RAD50 expression reduced in human IBD and CAC as well as in mouse models. Furthermore, RAD50IEC-KO sensitizes mice to dextran sulfate sodium (DSS)-induced acute and chronic experimental colitis. RNA-seq analyses revealed that RAD50 activated the cytokine-cytokine receptor response, which was amplified through the JAK-STAT pathway. RAD50 directly interacts with STAT3 and subsequently inhibits its phosphorylation, which may disrupt the IL-6-JAK1/2-STAT3-IL-6 feed-forward loop. Pharmacological STAT3 inhibition relieves colitis in RAD50IEC-KO mice. Severe DSBs, increased cell proliferation, and extended inflammatory response were identified in RAD50-deficienct cells, which promoted azoxymethane (AOM)-DSS-induced colon tumor development in RAD50IEC-KO mice. CONCLUSION: RAD50 exerts anti-IL-6-related inflammatory effects in colitis and suppresses CAC. Increasing RAD50 level in colon tissues may be promising for treating patients with UC and CAC.
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PURPOSE: To investigate aqueous humor cytokine levels in neovascular age-related macular degeneration (nAMD) patients with subretinal fibrosis and to explore the relationship between cytokine levels and disease severity. METHODS: The aqueous humor samples were collected from 16 eyes with subretinal fibrosis due to nAMD (SRFi group), 33 eyes with nAMD without subretinal fibrosis (nAMD group) and 28 eyes with cataract patients (control group). Clinical samples were analyzed for 5 cytokines,including vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), basic fibroblast growth factor (bFGF), transforming growth factor-α (TGF-α), platelet-derived growth factor-BB (PDGF-BB). RESULTS: Aqueous humor cytokines VEGF and bFGF were significantly higher in nAMD patients than controls (all P < 0.05), and VEGF, bFGF and TGF-α levels were significantly higher in SRFi patients than controls (all P < 0.05). No significant differences in 4 cytokine levels were observed between nAMD and SRFi patients in aqueous humor. We also identified a positive correlation between the aqueous humor levels of IL-6 and VEGF in the SRFi group, while bFGF and TGF-α in the nAMD group. Moreover, VEGF levels were strongly related to BCVA, and bFGF levels were positively related to the maximum thickness of subretinal hyperreflective material (SHRM) in fibrosis due to nAMD. CONCLUSION: VEGF and bFGF levels in aqueous humor were elevated in macular neovascularization with and without subretinal fibrosis. TGF-α levels exclusively differed in neovascular AMD with fibrosis. Cytokines are distributed differently and play a synergistic role in different stages (angiogenesis and fibrogenesis) of nAMD. The bFGF levels could predict the negative prognosis in fibrosis due to nAMD.