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Plastic waste poses an ecological challenge1-3 and enzymatic degradation offers one, potentially green and scalable, route for polyesters waste recycling4. Poly(ethylene terephthalate) (PET) accounts for 12% of global solid waste5, and a circular carbon economy for PET is theoretically attainable through rapid enzymatic depolymerization followed by repolymerization or conversion/valorization into other products6-10. Application of PET hydrolases, however, has been hampered by their lack of robustness to pH and temperature ranges, slow reaction rates and inability to directly use untreated postconsumer plastics11. Here, we use a structure-based, machine learning algorithm to engineer a robust and active PET hydrolase. Our mutant and scaffold combination (FAST-PETase: functional, active, stable and tolerant PETase) contains five mutations compared to wild-type PETase (N233K/R224Q/S121E from prediction and D186H/R280A from scaffold) and shows superior PET-hydrolytic activity relative to both wild-type and engineered alternatives12 between 30 and 50 °C and a range of pH levels. We demonstrate that untreated, postconsumer-PET from 51 different thermoformed products can all be almost completely degraded by FAST-PETase in 1 week. FAST-PETase can also depolymerize untreated, amorphous portions of a commercial water bottle and an entire thermally pretreated water bottle at 50 ºC. Finally, we demonstrate a closed-loop PET recycling process by using FAST-PETase and resynthesizing PET from the recovered monomers. Collectively, our results demonstrate a viable route for enzymatic plastic recycling at the industrial scale.
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Hidrolasas , Aprendizaje Automático , Tereftalatos Polietilenos , Ingeniería de Proteínas , Hidrolasas/genética , Hidrolasas/metabolismo , Hidrólisis , Plásticos , Tereftalatos Polietilenos/metabolismoRESUMEN
The enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) functions in the shikimate pathway which is responsible for the production of aromatic amino acids and precursors of other essential secondary metabolites in all plant species. EPSPS is also the molecular target of the herbicide glyphosate. While some plant EPSPS variants have been characterized with reduced glyphosate sensitivity and have been used in biotechnology, the glyphosate insensitivity typically comes with a cost to catalytic efficiency. Thus, there exists a need to generate additional EPSPS variants that maintain both high catalytic efficiency and high glyphosate tolerance. Here, we create a synthetic yeast system to rapidly study and evolve heterologous EPSP synthases for these dual traits. Using known EPSPS variants, we first validate that our synthetic yeast system is capable of recapitulating growth characteristics observed in plants grown in varying levels of glyphosate. Next, we demonstrate that variants from mutagenesis libraries with distinct phenotypic traits can be isolated depending on the selection criteria applied. By applying strong dual-trait selection pressure, we identify a notable EPSPS mutant after just a single round of evolution that displays robust glyphosate tolerance (Ki of nearly 1 mM) and improved enzymatic efficiency over the starting point (~2.5 fold). Finally, we show the crystal structure of corn EPSPS and the top resulting mutants and demonstrate that certain mutants have the potential to outperform previously reported glyphosate-resistant EPSPS mutants, such as T102I and P106S (denoted as TIPS), in whole-plant testing. Altogether, this platform helps explore the trade-off between glyphosate resistance and enzymatic efficiency.
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3-Fosfoshikimato 1-Carboxiviniltransferasa , Glicina , Glifosato , Saccharomyces cerevisiae , 3-Fosfoshikimato 1-Carboxiviniltransferasa/genética , 3-Fosfoshikimato 1-Carboxiviniltransferasa/metabolismo , Glicina/análogos & derivados , Glicina/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Herbicidas/farmacología , Herbicidas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Resistencia a los Herbicidas/genéticaRESUMEN
BACKGROUND: Total knee joint replacement (TKR) is an effective method for the treatment of severe knee osteoarthritis. With an increasing number of surgeries, complications such as lower limb edema, pain, and limited mobility have caused a heavy burden. Manual lymphatic drainage (MLD) may be a solution to solve the problem. The study aims to evaluate the efficacy of MLD in reducing knee edema, pain, and improving range of motion (ROM) in patients after TKR. METHODS: A search was conducted in PubMed, Embase, Cochrane Library, Web of Science, CNKI, VIPs, WanFang database, and Google Scholar from inception to June 2023. Only randomized controlled trials (RCTs) that compared the effects of MLD and non-MLD (or another physiotherapy) on improving knee edema, pain, and ROM after TKR were included. Stata 16.0 was used for meta-analysis. GRADE was used to assess the quality of evidence. RESULTS: In total, 7 RCTs with 285 patients were identified. There were no significant differences found in the ROM of knee flexion (standardized mean difference (SMD) = 0.03, 95% confidence interval (CI): -0.22, 0.28, P = 0.812) and the ROM of knee extension (SMD= -0.30, 95%CI: -0.64, 0.04, P = 0.084). No differences were observed in the lower extremity circumference after TKR (SMD= -0.09, 95%CI: -0.27, 0.09, P = 0.324). For postoperative pain, there was no significant advantage between the MLD and non-MLD groups (SMD= -0.33, 95%CI: -0.71, 0.04, P = 0.083). CONCLUSIONS: Based on the current evidence from RCTs, manual lymphatic drainage is not recommended for the rehabilitation of patients following total knee replacement.
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Artroplastia de Reemplazo de Rodilla , Humanos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Artroplastia de Reemplazo de Rodilla/rehabilitación , Drenaje Linfático Manual , Ensayos Clínicos Controlados Aleatorios como Asunto , Edema/terapia , Dolor PostoperatorioRESUMEN
This research study demonstrates an efficient scheme for early detection of cardiorespiratory complications in pandemics by Utilizing Wearable Electrocardiogram (ECG) sensors for pattern generation and Convolution Neural Networks (CNN) for decision analytics. In health-related outbreaks, timely and early diagnosis of such complications is conclusive in reducing mortality rates and alleviating the burden on healthcare facilities. Existing methods rely on clinical assessments, medical history reviews, and hospital-based monitoring, which are valuable but have limitations in terms of accessibility, scalability, and timeliness, particularly during pandemics. The proposed scheme commences by deploying wearable ECG sensors on the patient's body. These sensors collect data by continuously monitoring the cardiac activity and respiratory patterns of the patient. The collected raw data is then transmitted securely in a wireless manner to a centralized server and stored in a database. Subsequently, the stored data is assessed using a preprocessing process which extracts relevant and important features like heart rate variability and respiratory rate. The preprocessed data is then used as input into the CNN model for the classification of normal and abnormal cardiorespiratory patterns. To achieve high accuracy in abnormality detection the CNN model is trained on labeled data with optimized parameters. The performance of the proposed scheme is evaluated and gauged using different scenarios, which shows a robust performance in detecting abnormal cardiorespiratory patterns with a sensitivity of 95% and specificity of 92%. Prominent observations, which highlight the potential for early interventions include subtle changes in heart rate variability and preceding respiratory distress. These findings show the significance of wearable ECG technology in improving pandemic management strategies and informing public health policies, which enhances preparedness and resilience in the face of emerging health threats.
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Diagnóstico Precoz , Electrocardiografía , Redes Neurales de la Computación , Dispositivos Electrónicos Vestibles , Humanos , Electrocardiografía/instrumentación , COVID-19/diagnósticoRESUMEN
Cannabidiol (CBD) is the main active ingredient in the cannabis plant used for treating epilepsy and related diseases. However, how CBD ameliorates epilepsy and its effect on the hippocampus remains unknown. Herein, we evaluated how CBD ameliorates seizure degree in pentylenetetrazol (PTZ) induced epilepsy mice after being exposed to CBD (10 mg/kg p.o). In addition, transcriptome and metabolomic analysis were performed on the hippocampus. Our results suggested that CBD could alleviate PTZ-induced seizure, of which the NPTX2, Gprc5c, Lipg, and Stc2 genes were significantly down-regulated in mice after being exposed to PTZ. Transcriptome analysis showed 97 differently expressed genes (CBD) and the PTZ groups. Metabonomic analysis revealed that compared with the PTZ group, 41 up-regulated and 67 down-regulated metabolites were identified in the hippocampus of epileptic mice exposed to CBD. The correlation analysis for transcriptome and metabolome showed that (±) 15-HETE and carnitine C6:0 were at the core of the network and were involved in the positive or negative regulation of the related genes after being treated with CBD. In conclusion, CBD ameliorates epilepsy by acting on the metabolism, calcium signaling pathway, and tuberculosis pathways in the hippocampus. Our study provided a practical basis for the therapeutic potential of treating epilepsy using CBD.
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Cannabidiol , Epilepsia , Ratones , Animales , Cannabidiol/uso terapéutico , Pentilenotetrazol/efectos adversos , Anticonvulsivantes/uso terapéutico , Multiómica , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Convulsiones/inducido químicamenteRESUMEN
Cyclin-dependent kinase 4 (CDK4), which is involved in dynamic regulation of cell cycle, has gained particularly attention for its role in controlling tumor growth.Increasing evidence showed that ß-carboline derivatives have the potential to inhibit CDK4. Herein, on the basis of previous work, we designed and synthesized a series of novel ß-carbolines and evaluated their antitumor activity.Among them, compounds ZDLD13 and ZDLD20, with the most potent anti-proliferative activity and CDK4 enzymatic inhibition activity, were selected for further pharmacological research in vitro and in vivo. The results in vitro showed that ZDLD13 and ZDLD20 exhibited potent anti-HCT116 activityincluding inhibition of colony formation, inhibition of invasion and migration, inducing of apoptosis, and arresting of G1 phase in cell cycle.In vivo,ZDLD13showed significant tumor growth inhibition in HCT116 tumor xenograft model without causing significant weight loss and toxicityconsistent with the acute toxicity test. In addition, silico study showed ZDLD13 and ZDLD20 not only have good biological actions, but also acceptable predicted ADME and physicochemical properties.Taken together, compoundsZDLD13and ZDLD20 could be selected for further modification and preclinical evaluation.
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Antineoplásicos , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carbolinas/farmacología , Carbolinas/uso terapéutico , Línea Celular Tumoral , Proliferación Celular , Quinasa 4 Dependiente de la Ciclina , Humanos , Estructura Molecular , Neoplasias/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Tacrine was the first approved drug by the FDA for the treatment of Alzheimer's disease (AD) but was withdrawn from the market due to its dose-dependent hepatotoxicity. Herein, we describe our efforts toward the discovery of a novel series of tacrine derivatives for cancer therapeutics. Intensive structural modifications of tacrine led to the identification of N-(4-{9-[(3S)-3-aminopyrrolidin-1-yl]-5,6,7,8-tetrahydroacridin-2-yl}pyridin-2-yl)cyclopropanecarboxamide hydrochloride ((S)-45, ZLWT-37) as a potent antiproliferative agent (GI50 = 0.029 µM for HCT116). In addition, ZLWT-37 exhibited lower inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) compared to tacrine. The in vitro studies demonstrated that ZLWT-37 could significantly induce apoptosis and arrest the cell cycle in the G2/M phase in HCT116 cells. The in vivo studies revealed that compound ZLWT-37 showed excellent antitumor efficacy in HCT116 xenograft tumor model and favorable pharmacokinetics profiles (F% = 28.70%) as well as low toxicity in the acute toxicity test with a median lethal dose (LD50) of 380.3 mg/kg. Encouragingly, ZLWT-37 had no obvious hepatotoxicity, nephrotoxicity, and hematologic toxicity. Kinase assay suggested that ZLWT-37 possessed potent cyclin-dependent kinase 9 (CDK9) inhibitory activity (IC50 = 0.002 µM) and good selectivity over CDK2 (IC50 = 0.054 µM). Collectively, these findings indicate that compound ZLWT-37 is a promising anti-cancer agent that deserves further preclinical evaluation.
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Enfermedad de Alzheimer , Antineoplásicos , Enfermedad Hepática Inducida por Sustancias y Drogas , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Butirilcolinesterasa/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Inhibidores de la Colinesterasa/química , Quinasas Ciclina-Dependientes/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Tacrina/químicaRESUMEN
Alcohol dehydrogenases (ADHs) play key roles in the production of various chemical precursors that are essential in pharmaceutical and fine chemical industries. To achieve a practical application of ADHs in industrial processes, tailoring enzyme properties through rational design or directed evolution is often required. Here, we developed a secretion-based dual fluorescence assay (SDFA) for high-throughput screening of ADHs. In SDFA, an ADH of interest is fused to a mutated superfolder green fluorescent protein (MsfGFP), which could result in the secretion of the fusion protein to culture broth. After a simple centrifugation step to remove the cells, the supernatant can be directly used to measure the activity of ADH based on a red fluorescence signal, whose increase is coupled to the formation of NADH (a redox cofactor of ADHs) in the reaction. SDFA allows easy quantification of ADH concentration based on the green fluorescence signal of MsfGFP. This feature is useful in determining specific activity and may improve screening accuracy. Out of five ADHs we have tested with SDFA, four ADHs can be secreted and characterized. We successfully screened a combinatorial library of an ADH from Pichia finlandica and identified a variant with a 197-fold higher kcat /km value toward (S)-2-octanol compared to its wild type.
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Alcohol Deshidrogenasa , Proteínas Fúngicas , Ensayos Analíticos de Alto Rendimiento , Saccharomycetales , Alcohol Deshidrogenasa/análisis , Alcohol Deshidrogenasa/genética , Fluorescencia , Proteínas Fúngicas/análisis , Proteínas Fúngicas/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Saccharomycetales/enzimología , Saccharomycetales/genéticaRESUMEN
Acquired drug-resistant non-small cell lung cancer (NSCLC) has strong proliferation ability and is prone to epithelial-mesenchymal transition (EMT) and subsequent metastasis. Notch pathway mediates cell survival and EMT and is involved in the induction of multidrug resistance (MDR). ZLDI-8 is an inhibitor of Notch activating/cleaving enzyme ADAM-17 we found before. However, the effects of ZLDI-8 on resistant NSCLC was unclear. Here, we demonstrated for the first time that ZLDI-8 could induce apoptosis in lung cancer, especially in chemotherapy-resistant non-small cell lung cancer cells, and also inhibit migration, invasion and EMT phenotype of drug-resistant lung cancer. ZLDI-8 inhibits the Notch signaling pathway, thereby regulating the expression of survival/apoptosis and EMT-related proteins. Moreover, ZLDI-8 suppresses multidrug-resistant lung cancer xenograft growth in vivo and blocks metastasis in a tail vein injection mice model. Therefore, ZLDI-8 is expected to be an effective agent in the treatment of drug-resistant lung cancer.
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Proteína ADAM17/antagonistas & inhibidores , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Células A549 , Animales , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal/efectos de los fármacosRESUMEN
UNLABELLED: Coculturing dark- and photofermentative bacteria is a promising strategy for enhanced hydrogen (H2) production. In this study, next-generation sequencing was used to query the global transcriptomic responses of an artificial coculture of Clostridium cellulovorans 743B and Rhodopseudomonas palustris CGA009. By analyzing differentially regulated gene expression, we showed that, consistent with the physiological observations of enhanced H2 production and cellulose degradation, the nitrogen fixation genes in R. palustris and the cellulosomal genes in C. cellulovorans were upregulated in cocultures. Unexpectedly, genes related to H2 production in C. cellulovorans were downregulated, suggesting that the enhanced H2 yield was contributed mainly by R. palustris A number of genes related to biosynthesis of volatile fatty acids (VFAs) in C. cellulovorans were upregulated, and correspondingly, a gene that mediates organic compound catabolism in R. palustris was also upregulated. Interestingly, a number of genes responsible for chemotaxis in R. palustris were upregulated, which might be elicited by the VFA concentration gradient created by C. cellulovorans In addition, genes responsible for sulfur and thiamine metabolism in C. cellulovorans were downregulated in cocultures, and this could be due to a response to pH changes. A conceptual model illustrating the interactions between the two organisms was constructed based on the transcriptomic results. IMPORTANCE: The findings of this study have important biotechnology applications for biohydrogen production using renewable cellulose, which is an industrially and economically important bioenergy process. Since the molecular characteristics of the interactions of a coculture when cellulose is the substrate are still unclear, this work will be of interest to microbiologists seeking to better understand and optimize hydrogen-producing coculture systems.
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Proteínas Bacterianas/genética , Celulosa/metabolismo , Clostridium cellulovorans/genética , Clostridium cellulovorans/metabolismo , Hidrógeno/metabolismo , Rhodopseudomonas/genética , Rhodopseudomonas/metabolismo , Transcriptoma , Proteínas Bacterianas/metabolismo , Técnicas de CocultivoRESUMEN
Cellulose and xylan are two major components of lignocellulosic biomass, which represents a potentially important energy source, as it is abundant and can be converted to methane by microbial action. However, it is recalcitrant to hydrolysis, and the establishment of a complete anaerobic digestion system requires a specific repertoire of microbial functions. In this study, we maintained 2-year enrichment cultures of anaerobic digestion sludge amended with cellulose or xylan to investigate whether a cellulose- or xylan-digesting microbial system could be assembled from sludge previously used to treat neither of them. While efficient methane-producing communities developed under mesophilic (35°C) incubation, they did not under thermophilic (55°C) conditions. Illumina amplicon sequencing results of the archaeal and bacterial 16S rRNA genes revealed that the mature cultures were much lower in richness than the inocula and were dominated by single archaeal (genus Methanobacterium) and bacterial (order Clostridiales) groups, although at finer taxonomic levels the bacteria were differentiated by substrates. Methanogenesis was primarily via the hydrogenotrophic pathway under all conditions, although the identity and growth requirements of syntrophic acetate-oxidizing bacteria were unclear. Incubation conditions (substrate and temperature) had a much greater effect than inoculum source in shaping the mature microbial community, although analysis based on unweighted UniFrac distance found that the inoculum still determined the pool from which microbes could be enriched. Overall, this study confirmed that anaerobic digestion sludge treating nonlignocellulosic material is a potential source of microbial cellulose- and xylan-digesting functions given appropriate enrichment conditions.
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Archaea/metabolismo , Bacterias/metabolismo , Biota , Celulosa/metabolismo , Metano/metabolismo , Aguas del Alcantarillado/microbiología , Xilanos/metabolismo , Anaerobiosis , Archaea/clasificación , Archaea/genética , Bacterias/clasificación , Bacterias/genética , ADN de Archaea/química , ADN de Archaea/genética , ADN Bacteriano/química , ADN Bacteriano/genética , ADN Ribosómico/química , ADN Ribosómico/genética , Datos de Secuencia Molecular , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , TemperaturaRESUMEN
This study aimed to separately compare and rank the effect of various living-low and training-high (LLTH) modes on aerobic and anaerobic performances in athletes, focusing on training intensity, modality, and volume, through network meta-analysis. We systematically searched PubMed, Web of Science, Embase, EBSCO, and Cochrane from their inception date to June 30, 2023. Based on the hypoxic training modality and the intensity and duration of work intervals, LLTH was divided into intermittent hypoxic exposure, continuous hypoxic training, repeated sprint training in hypoxia (RSH; work interval: 5-10 s and rest interval: approximately 30 s), interval sprint training in hypoxia (ISH; work interval: 15-30 s), short-duration high-intensity interval training (s-IHT; short work interval: 1-2 min), long-duration high-intensity interval training (l-IHT; long work interval: > 5 min), and continuous and interval training under hypoxia. A meta-analysis was conducted to determine the standardized mean differences (SMDs) among the effects of various hypoxic interventions on aerobic and anaerobic performances. From 2,072 originally identified titles, 56 studies were included in the analysis. The pooled data from 53 studies showed that only l-IHT (SMDs: 0.78 [95% credible interval; CrI, 0.52-1.05]) and RSH (SMDs: 0.30 [95% CrI, 0.10-0.50]) compared with normoxic training effectively improved athletes' aerobic performance. Furthermore, the pooled data from 29 studies revealed that active intermittent hypoxic training compared with normoxic training can effectively improve anaerobic performance, with SMDs ranging from 0.97 (95% CrI, 0.12-1.81) for l-IHT to 0.32 (95% CrI, 0.05-0.59) for RSH. When adopting a program for LLTH, sufficient duration and work intensity intervals are key to achieving optimal improvements in athletes' overall performance, regardless of the potential improvement in aerobic or anaerobic performance. Nevertheless, it is essential to acknowledge that this study incorporated merely one study on the improvement of anaerobic performance by l-IHT, undermining the credibility of the results. Accordingly, more related studies are needed in the future to provide evidence-based support. It seems difficult to achieve beneficial adaptive changes in performance with intermittent passive hypoxic exposure and continuous low-intensity hypoxic training.
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Altitud , Rendimiento Atlético , Acondicionamiento Físico Humano , Carrera , Humanos , Hipoxia , Metaanálisis en Red , Consumo de OxígenoRESUMEN
AIMS: The chemotherapy drugs for NSCLC often face the consequences of treatment failure due to acquired drug resistance. Tumor chemotherapy resistance is often accompanied by angiogenesis. Here, we aimed to investigate the effect and underlying mechanisms of ADAM-17 inhibitor ZLDI-8 we found before on angiogenesis and vasculogenic mimicry(VM) in drug-resistant NSCLC. MAIN METHODS: The tube formation assay was used to evaluate angiogenesis and VM. Migration and invasion were assessed with transwell assays in the co-culture condition. To explore the underlying mechanisms of how ZLDI-8 inhibited tubes formation, ELISA assay and western blot assay were preformed. The effects of ZLDI-8 on angiogenesis in vivo were investigated in Matrigel plug, CAM and Rat aortic ring assays. KEY FINDINGS: In the present study, ZLDI-8 significantly inhibited the tube formation of human umbilical vein endothelial cells (HUVECs) in either normal medium or in tumor supernatants. Furthermore, ZLDI-8 also inhibited VM tubes formation of A549/Taxol cells. In the co-culture assay, the interaction between lung cancer cells and HUVECs promotes increased cell migration and invasion, while ZLDI-8 eliminates this promotion. Moreover, the VEGF secretion were decreased by ZLDI-8 and the expression of Notch1, Dll4, HIF1α and VEGF were inhibited by ZLDI-8. In addition, ZLDI-8 can inhibit blood vessel formation in the Matrigel plug, CAM and Rat aortic ring assays. SIGNIFICANCE: ZLDI-8 inhibits angiogenesis and VM in drug-resistant NSCLC through suppressing Notch1-HIF1α-VEGF signaling pathway. This study lays the foundation for the discovery of drugs that inhibit angiogenesis and VM in drug resistant NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Ratas , Animales , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Células Endoteliales/patología , Factor A de Crecimiento Endotelial Vascular , Línea Celular Tumoral , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Movimiento Celular , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patologíaRESUMEN
Melatonin, a neurohormone secreted by the pineal gland and regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, is synthesized and directly released into the cerebrospinal fluid (CSF) of the third ventricle (3rdv), where it undergoes rapid absorption by surrounding tissues to exert its physiological function. The hippocampus, a vital structure in the limbic system adjacent to the ventricles, plays a pivotal role in emotional response and memory formation. Melatonin MT1 and MT2 receptors are G protein-coupled receptors (GPCRs) that primarily mediate melatonin's receptor-dependent effects. In comparison to the MT1 receptor, the widely expressed MT2 receptor is crucial for mediating melatonin's biological functions within the hippocampus. Specifically, MT2 receptor is implicated in hippocampal synaptic plasticity and memory processes, as well as neurogenesis and axogenesis. Numerous studies have demonstrated the involvement of MT2 receptors in the pathophysiology and pharmacology of Alzheimer's disease, depression, and epilepsy. This review focuses on the anatomical localization of MT2 receptor in the hippocampus, their physiological function in this region, and their signal transduction and pharmacological roles in neurological disorders. Additionally, we conducted a comprehensive review of MT2 receptor ligands used in psychopharmacology and other MT2-selective ligands over recent years. Ultimately, we provide an outlook on future research for selective MT2 receptor drug candidates.
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Enfermedad de Alzheimer , Melatonina , Humanos , Hipocampo/metabolismo , Receptor de Melatonina MT2/metabolismo , Receptor de Melatonina MT1/metabolismoRESUMEN
Objective: This study aimed to compare and rank the effect of hypoxic practices on maximum oxygen consumption (VO2max) in athletes and determine the hypoxic dose-response correlation using network meta-analysis. Methods: The Web of Science, PubMed, EMBASE, and EBSCO databases were systematically search for randomized controlled trials on the effect of hypoxc interventions on the VO2max of athletes published from inception until 21 February 2023. Studies that used live-high train-high (LHTH), live-high train-low (LHTL), live-high, train-high/low (HHL), intermittent hypoxic training (IHT), and intermittent hypoxic exposure (IHE) interventions were primarily included. LHTL was further defined according to the type of hypoxic environment (natural and simulated) and the altitude of the training site (low altitude and sea level). A meta-analysis was conducted to determine the standardized mean difference between the effects of various hypoxic interventions on VO2max and dose-response correlation. Furthermore, the hypoxic dosage of the different interventions were coordinated using the "kilometer hour" model. Results: From 2,072 originally identified titles, 59 studies were finally included in this study. After data pooling, LHTL, LHTH, and IHT outperformed normoxic training in improving the VO2max of athletes. According to the P-scores, LHTL combined with low altitude training was the most effective intervention for improving VO2max (natural: 0.92 and simulated: 0.86) and was better than LHTL combined with sea level training (0.56). A reasonable hypoxic dose range for LHTH (470-1,130 kmh) and HL (500-1,415 kmh) was reported with an inverted U-shaped curve relationship. Conclusion: Different types of hypoxic training compared with normoxic training serve as significant approaches for improving aerobic capacity in athletes. Regardless of the type of hypoxic training and the residential condition, LHTL with low altitude training was the most effective intervention. The characteristics of the dose-effect correlation of LHTH and LHTL may be associated with the negative effects of chronic hypoxia.
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The traditional Li4SiO4-based CO2 sorbent pellets prepared from mechanical granulation methods usually presented densified microstructures. Hence, wheat straw, an agricultural waste featured with huge production and low cost, was used as porosity creator to improve the microstructures and CO2 capture performance of Li4SiO4 pellets. The results indicated that wheat straw effectively enhanced the cyclic CO2 sorption capacity of the pellets. In particular, 30 wt% wheat straw-templated Li4SiO4 pellets (LA-WS30) exhibited the capacity of ~0.15 g/g that is almost twice as high as that of unmodified pellets. The enriched porosity and improved porous structures resulted from the quick release of burning gases was considered as the main reason for the performance enhancement. In addition, the alkaline (K and Na) salts in wheat straw played a positive role in CO2 sorption of Li4SiO4 pellets due to the reduced diffusion resistance. However, the pore plugging of residual wheat straw ashes after high-temperature treatment decreased the contact areas and, thus, led to the capacity reduction. To conclude, the comprehensive performance of wheat straw-templated Li4SiO4 pellets is the result of the combined effects of porosity creation, alkali doping and pore plugging by ashes.
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Dióxido de Carbono , Triticum , Dióxido de Carbono/química , Agricultura/métodos , Gases , ÁlcalisRESUMEN
Targeting the tumor microenvironment is a promising strategy to prevent metastasis, overcome acquired drug resistance, and improve the therapeutic effect. Hypoxia is one of the characteristics of the tumor microenvironment, which is mainly regulated by hypoxia-inducible factors. Hypoxia-inducible factors (HIFs) including HIF-1α, HIF-2α, and HIF-3α, of which HIF-2α has assumed a more important role in tumor hypoxia environment. It has been demonstrated that HIF-2α plays an important role in tumor diseases, including renal cell carcinoma, breast cancer, non-small cell lung cancer, and gastric cancer, among others. Therefore, targeting HIF-2α has become one of the important strategies for treating cancers. HIF-2α inhibitors can be divided into two categories: specific inhibitors and non-specific inhibitors. The former includes synthetic monomer compounds and traditional Chinese medicine extracts. In this review, we summarized, classified, and discussed current research on the structure, structure-activity relationship (SAR), and pharmacology of HIF-2α inhibitors, which is helpful to the rational design of effective drugs for various types of malignant tumors.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Hipoxia , Microambiente TumoralRESUMEN
BACKGROUND: Epilepsy is a common neurological disorder affecting more than 70 million people worldwide. Despite numerous efforts on new antiepileptic drugs, approximately one-third of epilepsy patients suffer from uncontrolled seizures. It leads to serious psychosocial consequences, cognitive problems, and decreased quality of life. OBJECTIVE: Our previous studies have shown that N. incisum root extract (NRE) can improve cognitive dysfunction in Alzheimer's disease (AD) mice. In addition, our research shows that AD and epilepsy have pathological mechanisms overlapping. Therefore, we tried to investigate whether NRE can ameliorate the seizures of epileptic mice in this study. METHODS: NRE-treated mice group was given an oral administration with 1 g/kg/d for 7 days. On the 8th day, mice were exposed to PTZ (i.p. injection) to induce epilepsy. Then the cognitive tests of mice in the water maze were carried out, and the biochemical indexes and pathological tests were carried out after the mice were sacrificed. RESULTS: SOD level in the NRE group was significantly higher than that in the PTZ group, while MDA, TNF-α, and IL-1ß levels were decreased. The cognitive ability of NRE-treated mice was significantly improved compared with the PTZ group. Immunohistochemistry (IHC) results showed that the activation of microglia and astrocytes in the hippocampus and cortex of NRE mice were inhibited. CONCLUSION: This study suggests that NRE can alleviate epilepsy and improve cognitive function in mice with epilepsy, and its mechanism may be through reducing inflammation and enhancing antioxidant defense.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Epilepsia , Ratones , Animales , Calidad de Vida , Pentilenotetrazol/toxicidad , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Epilepsia/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Anticonvulsivantes/farmacología , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/tratamiento farmacológico , Modelos Animales de EnfermedadRESUMEN
Multidrug resistance (MDR) is considered as a primary hindrance for paclitaxel failure in non-small cell lung cancer (NSCLC) patients, in which P-glycoprotein (P-gp) is overexpressed and the PI3K/Akt signaling pathway is dysregulated. Previously, we designed and synthesized DHW-221, a dual PI3K/mTOR inhibitor, which exerts a remarkable antitumor potency in NSCLC cells, but its effects and underlying mechanisms in resistant NSCLC cells remain unknown. Here, we reported for the first time that DHW-221 had favorable antiproliferative activity and suppressed cell migration and invasion in A549/Taxol cells in vitro and in vivo. Importantly, DHW-221 acted as a P-gp inhibitor via binding to P-gp, which resulted in decreased P-gp expression and function. A mechanistic study revealed that the DHW-221-induced FOXO3a nuclear translocation via Akt inhibition was involved in mitochondrial apoptosis and G0/G1 cell cycle arrest only in A549/Taxol cells and not in A549 cells. Interestingly, we observed that high-concentration DHW-221 reinforced the pro-paraptotic effect via stimulating endoplasmic reticulum (ER) stress and the mitogen-activated protein kinase (MAPK) pathway. Additionally, intragastrically administrated DHW-221 generated superior potency without obvious toxicity via FOXO3a nuclear translocation in an orthotopic A549/Taxol tumor mouse model. In conclusion, these results demonstrated that DHW-221, as a novel P-gp inhibitor, represents a prospective therapeutic candidate to overcome MDR in Taxol-resistant NSCLC treatment.
RESUMEN
BACKGROUND: Cinnamomum cassia (L.) J.Presl (Cinnamon) was known as a kind of hot herb, improved circulation and warmed the body. However, the active components and mechanisms of dispelling cold remain unknown. METHODS: The effects of several Chinses herbs on thermogenesis were evaluated on body temperature and activation of brown adipose tissue. After confirming the effect, the components of cinnamon were identified using HPLC-Q-TOF/MS and screened with databases. The targets of components were obtained with TCMSP, SymMap, Swiss and STITCH databases. Thermogenesis genes were predicted with DisGeNET and GeneCards databases. The protein-protein interaction network was constructed with Cytoscape 3.7.1 software. GO enrichment analysis was accomplished with STRING databases. KEGG pathway analysis was established with Omicshare tools. The top 20 targets for four compounds were obtained according to the number of edges of PPI network. In addition, the network results were verified with experimental research for the effects of extracts and major compounds. RESULTS: Cinnamon extract significantly upregulated the body temperature during cold exposure.121 components were identified in HPLC-Q-TOF/MS. Among them, 60 compounds were included in the databases. 116 targets were obtained for the compounds, and 41 genes were related to thermogenesis. The network results revealed that 27 active ingredients and 39 target genes. Through the KEGG analysis, the top 3 pathways were PPAR signaling pathway, AMPK signaling pathway, thermogenesis pathway. The thermogenic protein PPARγ, UCP1 and PGC1-α was included in the critical targets of four major compounds. The three major compounds increased the lipid consumption and activated the brown adipocyte. They also upregulated the expression of UCP1, PGC1-α and pHSL, especially 2-methoxycinnamaldehyde was confirmed the effect for the first time. Furthermore, cinnamaldehyde and cinnamon extract activated the expression of TRPA1 on DRG cells. CONCLUSION: The mechanisms of cinnamon on cold resistance were investigated with network pharmacology and experiment validation. This work provided research direction to support the traditional applications of thermogenesis.