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We aimed to explore the biological function of CPNE7 and determine the impact of CPNE7 on chemotherapy resistance in colorectal cancer (CRC) patients. According to the Gene Expression Profiling Interactive Analysis database and previously published data, CPNE7 was identified as a potential oncogene in CRC. RT-qPCR and Western blotting were performed to verify the expression of CPNE7. Chi-square test was used to evaluate the associations between CPNE7 and clinical features. Cell proliferation, colony formation, cell migration and invasion, cell cycle and apoptosis were assessed to determine the effects of CPNE7. Transcriptome sequencing was used to identify potential downstream regulatory genes, and gene set enrichment analysis was performed to investigate downstream pathways. The effect of CPNE7 on 5-fluorouracil chemosensitivity was verified by half maximal inhibitory concentration (IC50). Subcutaneous tumorigenesis assay was used to examine the role of CPNE7 in sensitivity of CRC to chemotherapy in vivo. Transmission electron microscopy was used to detect autophagosomes. CPNE7 was highly expressed in CRC tissues, and its expression was correlated with T stage and tumour site. Knockdown of CPNE7 inhibited the proliferation and colony formation of CRC cells and promoted apoptosis. Knockdown of CPNE7 suppressed the expression of ATG9B and enhanced the sensitivity of CRC cells to 5-fluorouracil in vitro and in vivo. Knockdown of CPNE7 reversed the induction of the autophagy pathway by rapamycin and reduced the number of autophagosomes. Depletion of CPNE7 attenuated the malignant proliferation of CRC cells and enhanced the chemosensitivity of CRC cells to 5-fluorouracil.
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Neoplasias Colorretais , Fluoruracila , Humanos , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Carcinogênese/genética , Proliferação de Células/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas de Membrana/genéticaRESUMO
Pathological cardiac hypertrophy is associated with adverse cardiovascular events and can gradually lead to heart failure, arrhythmia, and even sudden death. However, the current development of treatment strategies has been unsatisfactory. Therefore, it is of great significance to find new and effective drugs for the treatment of myocardial hypertrophy. We found that carnosol can inhibit myocardial hypertrophy induced by PE stimulation, and the effect is very significant at 5 µM. Moreover, we demonstrated that 50 mg/kg of carnosol protect against cardiac hypertrophy and fibrosis induced by TAC surgery in mice. Mechanically, we proved that the inhibitory effect of carnosol on cardiac hypertrophy depends on its regulation on the phosphorylation activation of AMPK. In conclusion, our study suggested that carnosol may be a novel drug component for the treatment of pathological cardiac hypertrophy.
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Proteínas Quinases Ativadas por AMP , Abietanos , Cardiomegalia , Camundongos Endogâmicos C57BL , Miócitos Cardíacos , Animais , Abietanos/farmacologia , Abietanos/uso terapêutico , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/prevenção & controle , Proteínas Quinases Ativadas por AMP/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacosRESUMO
OBJECTIVE: To build and merge a diagnostic model called multi-input DenseNet fused with clinical features (MI-DenseCFNet) for discriminating between Staphylococcus aureus pneumonia (SAP) and Aspergillus pneumonia (ASP) and to evaluate the significant correlation of each clinical feature in determining these two types of pneumonia using a random forest dichotomous diagnosis model. This will enhance diagnostic accuracy and efficiency in distinguishing between SAP and ASP. METHODS: In this study, 60 patients with clinically confirmed SAP and ASP, who were admitted to four large tertiary hospitals in Kunming, China, were included. Thoracic high-resolution CT lung windows of all patients were extracted from the picture archiving and communication system, and the corresponding clinical data of each patient were collected. RESULTS: The MI-DenseCFNet diagnosis model demonstrates an internal validation set with an area under the curve (AUC) of 0.92. Its external validation set demonstrates an AUC of 0.83. The model requires only 10.24s to generate a categorical diagnosis and produce results from 20 cases of data. Compared with high-, mid-, and low-ranking radiologists, the model achieves accuracies of 78% vs. 75% vs. 60% vs. 40%. Eleven significant clinical features were screened by the random forest dichotomous diagnosis model. CONCLUSION: The MI-DenseCFNet multimodal diagnosis model can effectively diagnose SAP and ASP, and its diagnostic performance significantly exceeds that of junior radiologists. The 11 important clinical features were screened in the constructed random forest dichotomous diagnostic model, providing a reference for clinicians. CLINICAL RELEVANCE STATEMENT: MI-DenseCFNet could provide diagnostic assistance for primary hospitals that do not have advanced radiologists, enabling patients with suspected infections like Staphylococcus aureus pneumonia or Aspergillus pneumonia to receive a quicker diagnosis and cut down on the abuse of antibiotics. KEY POINTS: ⢠MI-DenseCFNet combines deep learning neural networks with crucial clinical features to discern between Staphylococcus aureus pneumonia and Aspergillus pneumonia. ⢠The comprehensive group had an area under the curve of 0.92, surpassing the proficiency of junior radiologists. ⢠This model can enhance a primary radiologist's diagnostic capacity.
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Aprendizado Profundo , Tomografia Computadorizada por Raios X , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Diagnóstico Diferencial , Tomografia Computadorizada por Raios X/métodos , Pneumonia Estafilocócica/diagnóstico por imagem , Pneumonia Estafilocócica/microbiologia , Idoso , Aspergilose Pulmonar/diagnóstico por imagem , Staphylococcus aureus/isolamento & purificação , Adulto , Interpretação de Imagem Radiográfica Assistida por Computador/métodosRESUMO
Arnebiae Radix, commonly known as "Zicao," can be easily confused with other compounding species, posing challenges for its clinical use. Here, we developed a comprehensive strategy to systematically characterize the diverse components across Arnebiae Radix and its three confusing species. First, an offline two-dimensional liquid chromatography (2D-LC) system integrating hydrophilic interaction chromatography (HILIC) and reverse phase (RP) separations was established, enabling effective separation and detection of more trace constituents. Second, a polygonal mass defect filtering (MDF) workflow was implemented to screen target ions and generate a precursor ion list (PIL) to guide multistage mass (MSn) data acquisition. Third, a three-step characterization strategy utilizing diagnostic ions and neutral losses was developed for rapid determination of molecular formulas, structure classes, and compound identification. This approach enabled systematic characterization of Arnebiae Radix and its three confusing species, with 437 components characterized including 112 shikonins, 22 shikonfurans, 144 phenolic acids, 131 glycosides, 18 flavonoids, and 10 other compounds. Additionally, 361, 230, 340, and 328 components were identified from RZC, YZC, DZC, and ZZC, respectively, with 142 common components and 30 characteristic components that may serve as potential markers for distinguishing the four species. In summary, this is the first comprehensive characterization and comparison of the phytochemical profiles of Arnebiae Radix and its three confusing species, advancing our understanding of this herbal medicine for quality control.
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Medicamentos de Ervas Chinesas , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Espectrometria de Massa com Cromatografia Líquida , Flavonoides/análise , ÍonsRESUMO
BACKGROUND: Myocardial infarction (MI) is a major disease with high morbidity and mortality worldwide. However, existing treatments are far from satisfactory, making the exploration of potent molecular targets more imperative. The E3 ubiquitin ligase RING finger protein 5 (RNF5) has been previously reported to be involved in several diseases by regulating ubiquitination-mediated protein degradation. Nevertheless, few reports have focused on its function in cardiovascular diseases, including MI. METHODS: In this study, we established RNF5 knockout mice through precise CRISPR-mediated genome editing and utilized left anterior descending coronary artery ligation in 9-11-week-old male C57BL/6 mice. Subsequently, serum biochemical analysis and histopathological examination of heart tissues were performed. Furthermore, we engineered adenoviruses for modulating RNF5 expression and subjected neonatal rat cardiomyocytes to oxygen-glucose deprivation (OGD) to mimic ischemic conditions, demonstrating the impact of RNF5 manipulation on cellular viability. Gene and protein expression analysis provided insights into the molecular mechanisms. Statistical methods were rigorously employed to assess the significance of experimental findings. RESULTS: We found RNF5 was downregulated in infarcted heart tissue of mice and NRCMs subjected to OGD treatment. RNF5 knockout in mice resulted in exacerbated heart dysfunction, more severe inflammatory responses, and increased apoptosis after MI surgery. In vitro, RNF5 knockdown exacerbated the OGD-induced decline in cell activity, increased apoptosis, while RNF5 overexpression had the opposite effect. Mechanistically, it was proven that the kinase cascade initiated by apoptosis signal-regulating kinase 1 (ASK1) activation was closely regulated by RNF5 and mediated RNF5's protective function during MI. CONCLUSIONS: We demonstrated the protective effect of RNF5 on myocardial infarction and its function was dependent on inhibiting the activation of ASK1, which adds a new regulatory component to the myocardial infarction associated network and promises to enable new therapeutic strategy.
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Apoptose , Modelos Animais de Doenças , MAP Quinase Quinase Quinase 5 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio , Miócitos Cardíacos , Transdução de Sinais , Ubiquitina-Proteína Ligases , Animais , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , MAP Quinase Quinase Quinase 5/metabolismo , MAP Quinase Quinase Quinase 5/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Masculino , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Células Cultivadas , Camundongos , Função Ventricular Esquerda , Hipóxia Celular , RatosRESUMO
Eleven new steroidal alkaloids, along with nine known related compounds, were isolated from the bulbs of Fritillaria sinica. Seven pairs of diastereomers were identified, including six and four 20-deoxy cevanine-type steroidal alkaloid diastereomers with molecular weights of 413 and 415, respectively. Structures were elucidated based on spectroscopic data analysis, chemical derivatization, and single-crystal X-ray diffraction analysis. Compounds 5, 9, 11, 12, 16, and 20 exhibited significant in vitro cytotoxic activity against non-small-cell lung cancer with CC50 values from 6.8 ± 3.9 to 12 ± 5 µM.
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Alcaloides , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Fritillaria , Neoplasias Pulmonares , Humanos , Fritillaria/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estrutura Molecular , Neoplasias Pulmonares/tratamento farmacológico , Alcaloides/química , Esteroides/químicaRESUMO
Enhancing global food security by increasing the productivity of green revolution varieties of cereals risks increasing the collateral environmental damage produced by inorganic nitrogen fertilizers. Improvements in the efficiency of nitrogen use of crops are therefore essential; however, they require an in-depth understanding of the co-regulatory mechanisms that integrate growth, nitrogen assimilation and carbon fixation. Here we show that the balanced opposing activities and physical interactions of the rice GROWTH-REGULATING FACTOR 4 (GRF4) transcription factor and the growth inhibitor DELLA confer homeostatic co-regulation of growth and the metabolism of carbon and nitrogen. GRF4 promotes and integrates nitrogen assimilation, carbon fixation and growth, whereas DELLA inhibits these processes. As a consequence, the accumulation of DELLA that is characteristic of green revolution varieties confers not only yield-enhancing dwarfism, but also reduces the efficiency of nitrogen use. However, the nitrogen-use efficiency of green revolution varieties and grain yield are increased by tipping the GRF4-DELLA balance towards increased GRF4 abundance. Modulation of plant growth and metabolic co-regulation thus enables novel breeding strategies for future sustainable food security and a new green revolution.
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Agricultura/métodos , Produtos Agrícolas/metabolismo , Desenvolvimento Vegetal , Desenvolvimento Sustentável , Compostos de Amônio/metabolismo , Ciclo do Carbono , Nitrogênio/metabolismo , Oryza/crescimento & desenvolvimento , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Triticum/crescimento & desenvolvimento , Triticum/metabolismo , Grãos Integrais/crescimento & desenvolvimento , Grãos Integrais/metabolismoRESUMO
The study of traditional medicine has garnered significant interest, resulting in various research areas including chemical composition analysis, pharmacological research, clinical application, and quality control. The abundance of available data has made databases increasingly essential for researchers to manage the vast amount of information and explore new drugs. In this article we provide a comprehensive overview and summary of 182 databases that are relevant to traditional medicine research, including 73 databases for chemical component analysis, 70 for pharmacology research, and 39 for clinical application and quality control from published literature (2000-2023). The review categorizes the databases by functionality, offering detailed information on websites and capacities to facilitate easier access. Moreover, this article outlines the primary function of each database, supplemented by case studies to aid in database selection. A practical test was conducted on 68 frequently used databases using keywords and functionalities, resulting in the identification of highlighted databases. This review serves as a reference for traditional medicine researchers to choose appropriate databases and also provides insights and considerations for the function and content design of future databases.
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PURPOSE: Tripartite motif-containing protein 13 (TRIM13) directly or indirectly participates in autophagy and apoptosis. However, it remains unclear whether TRIM13 participates in chronic obstructive pulmonary disease (COPD) progression. This study aimed to reveal the molecular mechanisms through which TRIM13 regulates alveolar epithelial cell injury in COPD to provide new molecular targets for COPD treatment. METHODS: The TRIM13 expression levels were determined in clinical COPD patients and a rat emphysema model. A cigarette smoke-induced model of endoplasmic reticulum stress (ERS) and endoplasmic reticulum autophagy (ER-phagy) was developed using A549 cells, and the effects of TRIM13 gene overexpression/knockdown on ERS, ER-phagy, and cell apoptosis were assessed in these cells. RESULTS: TRIM13 expression was significantly decreased in the lung tissues of COPD patients and rats with emphysema. Moreover, the apoptosis level was significantly increased in the lung tissues of rats with emphysema. TRIM13 gene overexpression reduced the expression levels of ERS-related molecules (GRP78, GRP94, XBP-1, and eIF2a) in the COPD model; it also lowered the ER-phagy level, as evidenced by decreased number of autolysosomes observed by transmission electron microscopy, improved endoplasmic reticulum structure, reduced LC3-II/LC3-I and Beclin1 expression levels, and increased expression level of the autophagy inhibitory molecule Bcl-2. TRIM13 gene knockdown, however, led to opposite results. CONCLUSION: TRIM13 expression attenuated alveolar epithelial cell injury in COPD by inhibiting ERS-induced ER-phagy.
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As the most common endocrine cancer, thyroid cancer (TC) has sharply increased globally over the past three decades. The growing incidence of TC might be counted by genetics, radiation, iodine, autoimmune disease, and exposure to environmental endocrine-disrupting chemicals (EDCs). Polybrominated diphenyl ethers (PBDEs), being typical EDCs, have been widely utilized in plastics, electronics, furniture, and textiles as flame retardants since the 1980s, and research has indicated a significant correlation between their exposure and the risk of TC. Even so, PBDEs exposure impact on the metabolic signature for TC remains unexplored. In this study, eight congeners of PBDEs were determined in serum from 111 patents with papillary thyroid cancer (PTC) and 111 healthy participants based on case-control epidemiology using gas chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry (GC-APCI-MS/MS). Based on the tertile distribution of total PBDEs concentrations in 59 participants, metabolomics analysis was further performed by ultra-high performance liquid chromatography coupled to hybrid quadrupole-Orbitrap MS. In the partial correlation analysis, the 29 identified metabolites were correlated with PBDEs exposure (P < 0.05). In addition, PBDEs disrupted the metabolism of glycerophospholipids, sphingolipids, taurine, and hypotaurine, indicating that neurotransmitters, oxidative stress, and inflammation are the vulnerable pathways affected in PTC. Furthermore, (±)-octopamine and 5-hydroxyindole, both of which modulate the actions of neurotransmitters, emerged as potential disturbed metabolite markers for TC following exposure to PBDEs. This study analyzed the impact of PBDEs on PTC in terms of the metabolic changes and further explored possible biomarkers, which helped us have a deep understanding of the possible mechanism of the effects of PBDEs on TC.
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Éteres Difenil Halogenados , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Éteres Difenil Halogenados/sangue , Estudos de Casos e Controles , Feminino , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Adulto , Câncer Papilífero da Tireoide/sangue , Poluentes Ambientais/sangue , Exposição Ambiental , Cromatografia Gasosa-Espectrometria de Massas , IdosoRESUMO
As the best adapted high altitude population, Tibetans feature a relatively high offspring survival rate. Genome-wide studies have identified hundreds of candidate SNPs related to high altitude adaptation of Tibetans, although most of them have unknown functional relevance. To explore the mechanisms behind successful reproduction at high altitudes, we compared the placental transcriptomes of Tibetans, sea level Hans (SLHan), and Han immigrants (ImHan). Among the three populations, placentas from ImHan showed a hyperactive gene expression pattern. Their increased activation demonstrates a hypoxic stress response similar to sea level individuals experiencing hypoxic conditions. Unlike ImHan, Tibetan placentas were characterized by the significant up-regulation of placenta-specific genes, and the activation of autophagy and the tricarboxylic acid (TCA) cycle. Certain conserved hypoxia response functions, including the antioxidant system and angiogenesis, were activated in both ImHan and Tibetans, but mediated by different genes. The coherence of specific transcriptome features linked to possible genetic contribution was observed in Tibetans. Furthermore, we identified a novel Tibetan-specific EPAS1 isoform with a partial deletion at exon six, which may be involved in the adaption to hypoxia through the EPAS1-centred gene network in the placenta. Overall, our results show that the placenta grants successful pregnancies in Tibetans by strengthening the natural functions of the placenta itself. On the other hand, the placenta of ImHan was in an inhabiting time-dependent acclimatization process representing a common hypoxic stress response pattern.
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Altitude , Transcriptoma , Aclimatação/genética , Feminino , Hemoglobinas/genética , Humanos , Hipóxia/metabolismo , Placenta/metabolismo , Gravidez , Reprodução , TibetRESUMO
Animal-derived drugs are an indispensable part of folk medicine worldwide. However, their chemical constituents are poorly approached, which leads to the low level of the quality standard system of animal-derived drugs and further causes a chaotic market. Natural peptides are ubiquitous throughout the organism, especially in animal-derived drugs. Thus, in this study, we used multi-source leeches, including Hirudo nipponica (HN), Whitmania pigra (WP), Whitmania acranulata (WA), and Poecilobdella manillensis (PM), as a model. A strategy integrating proteogenomics and novel pseudotargeted peptidomics was developed to characterize the natural peptide phenotype and screen for signature peptides of four leech species. First, natural peptides were sequenced against an in-house annotated protein database of closely related species constructed from RNA-seq data from the Sequence Read Archive (SRA) website, which is an open-sourced public archive resource. Second, a novel pseudotargeted peptidomics integrating peptide ion pair extraction and retention time transfer was established to achieve high coverage and quantitative accuracy of the natural peptides and to screen for signature peptides for species authentication. In all, 2323 natural peptides were identified from four leech species whose databases were poorly annotated. The strategy was shown to significantly improve peptide identification. In addition, 36 of 167 differential peptides screened by pseudotargeted proteomics were identified, and about one-third of them came from the leucine-rich repeat domain (LRR) proteins, which are widely distributed in organisms. Furthermore, six signature peptides were screened with good specificity and stability, and four of them were validated by synthetic standards. Finally, a dynamic multiple reaction monitoring (dMRM) method based on these signature peptides was established and revealed that one-half of the commercial samples and all of the Tongxinluo capsules were derived from WP. All in all, the strategy developed in this study was effective for natural peptide characterization and signature peptide screening, which could also be applied to other animal-derived drugs, especially for modelless species that are less studied in protein database annotation.
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Sanguessugas , Proteogenômica , Animais , Sanguessugas/química , Sanguessugas/genética , Peptídeos/química , ProteômicaRESUMO
BACKGROUND: Immunosenescence occurs as people age, leading to an increased incidence of age-related diseases. The number of senescent T cells also rises with age. T cell senescence and immune response dysfunction can result in a decline in immune function, especially in anti-tumor immune responses. Metformin has been shown to have various beneficial effects on health, such as lowering blood sugar levels, reducing the risk of cancer development, and slowing down the aging process. However, the immunomodulatory effects of metformin on senescent T cells still need to be investigated. METHODS: PBMCs isolation from different age population (n = 88); Flow Cytometry is applied to determine the phenotypic characterization of senescent T lymphocytes; intracellular staining is applied to determine the function of senescent T cells; Enzyme-Linked Immunosorbent Assay (ELISA) is employed to test the telomerase concentration. The RNA-seq analysis of gene expression associated with T cell senescence. RESULTS: The middle-aged group had the highest proportion of senescent T cells. We found that metformin could decrease the number of CD8 + senescent T cells. Metformin affects the secretion of SASP, inhibiting the secretion of IFN-γ in CD8 + senescent T cells. Furthermore, metformin treatment restrained the production of the proinflammatory cytokine IL-6 in lymphocytes. Metformin had minimal effects on Granzyme B secretion in senescent T cells, but it promoted the production of TNF-α in senescent T cells. Additionally, metformin increased the concentration of telomerase and the frequency of undifferentiated T cells. The results of RNA-seq showed that metformin promoted the expression of genes related to stemness and telomerase activity, while inhibiting the expression of DNA damage-associated genes. CONCLUSION: Our findings reveal that metformin could inhibit T cell senescence in terms of cell number, effector function, telomerase content and gene expression in middle-aged individuals, which may serve as a promising approach for preventing age-related diseases in this population.
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Jujube fruit was well-loved and praised by the broad masses due to its delicious taste, abundant nutritional value, and medicinal properties. Few studies reported the quality evaluation and gut microbiota regulation effect of polysaccharides of jujube fruits from different producing areas. In the present study, multi-level fingerprint profiling, including polysaccharides, oligosaccharides, and monosaccharides, was established for the quality evaluation of polysaccharides from jujube fruits. For polysaccharides, the total content in jujube fruits ranged from 1.31% to 2.22%, and the molecular weight distribution (MWD) ranged from 1.14 × 105 to 1.73 × 106 Da. The MWD fingerprint profiling of polysaccharides from eight producing areas was similar, but the profile of infrared spectroscopy (IR) showed differentiation. The characteristic signals were screened and used to establish a discrimination model for the identification of jujube fruits from different areas, and the accuracy of identification reached 100.00%. For oligosaccharides, the main components were galacturonic acid polymers (DP, 2-4), and the profile of oligosaccharides exhibited high similarity. The monosaccharides, GalA, Glc, and Ara, were the primary monosaccharides. Although the fingerprint of monosaccharides was semblable, the composing proportion of monosaccharides revealed significant differences. In addition, the polysaccharides of jujube fruits could regulate the gut microbiota composition and possess potential therapeutic effects on dysentery and nervous system diseases.
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Microbioma Gastrointestinal , Ziziphus , Frutas/química , Ziziphus/química , Polissacarídeos/química , MonossacarídeosRESUMO
3-tert-Butyl-4-hydroxyanisole (3-BHA), one of the widely used food antioxidants, has been found to act as a potential obesogen by promoting adipogenesis in vitro and inducing white adipose tissue development in vivo. Whether 3-BHA-induced visceral obesity was accompanied by a disruption of hepatic lipid homeostasis in mammals remained unclear. In this study, we evaluated the effect of 3-BHA on the development of nonalcoholic fatty liver disease (NAFLD) in male C57BL/6J mice. After 18 weeks of oral administration of 10 mg/kg 3-BHA, the mice fed with a high-fat diet (HFD) had higher hepatic triglyceride concentrations (0.32 mg/mg protein) and severer steatosis (1.57 for the NAFLD score) than the control ones. The in vivo hepatic lipid deposition disturbed by 3-BHA was transcriptionally regulated by the genes involved in lipid uptake, de novo lipogenesis, fatty acid oxidation, and lipid export. The in vitro studies further confirmed that 24 h of exposure to 50 µM 3-BHA could induce intracellular oleic acid (OA) uptake and triglyceride accumulation (1.5-fold of the OA control) in HepG2 cells. Lipidomic analysis indicated the perturbation of 3-BHA in the levels of 30 lipid species related to sphingolipids, glycerophospholipids, and glycerolipids under HFD conditions. The findings herein first revealed the disruption effect of 3-BHA on hepatic lipid homeostasis, thus exacerbating the development of HFD-induced NAFLD.
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Dieta Hiperlipídica , Hepatopatia Gordurosa não Alcoólica , Animais , Hidroxianisol Butilado , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Mamíferos , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Triglicerídeos/metabolismo , Triglicerídeos/farmacologiaRESUMO
Giving the fact that the disorders of multiple receptor tyrosine kinases (RTKs) are characteristics of various cancers, we assumed that developing novel multi-target drugs might have an advantage in treating the complex cancers. Taking the multi-target c-Met inhibitor Foretinib as the leading compound, we discovered a novel series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety with the help of molecular docking. Among them, the most promising compound 33 showed a prominent activity against Hela (IC50 = 0.21 µM), A549 (IC50 = 0.39 µM), and MCF-7 (IC50 = 0.33 µM), which were 3.28-4.82 times more active than that of Foretinib. Additionally, compound 33 dose dependently induced apoptosis by arresting A549 cells at G1 phase. Enzymatic assays and docking analyses were further confirmed that compound 33 was a multi-target inhibitor with the strong potencies against c-Met (IC50 = 11.77 nM), MEK1 (IC50 = 10.71 nM), and Flt-3 (IC50 = 22.36 nM). In the A549 cells mediated xenograft mouse model, compound 33 inhibited the tumor growth (TGI = 64%) without obvious toxicity, establishing compound 33 as a promising candidate for cancer therapy.
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Amidas/química , Antineoplásicos , Naftiridinas/química , Quinolinas/síntese química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met , Quinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The incidence rates of thyroid tumors and nodular goiter show an upward trend worldwide. There are limited reports on the risk of perchlorate and iodine on thyroid tumors, but evidence from population studies is scarce, and their impact on thyroid function is still uncertain. Therefore, the objective of this study was to investigate the association of perchlorate and iodine with the risk of nodular goiter (NG), papillary thyroid microcarcinoma (PTMC), and papillary thyroid carcinoma (PTC) and to assess the correlation between perchlorate and iodine with thyroid function indicators. METHODS: A case-control population consisting of 184 pairs of thyroid tumors and nodular goiter matched by gender and age (±2 years) was recruited in this study. Serum and urine samples were collected from each participant. Thyroid function indicators in serum were tested by automatic chemical immunofluorescence, and perchlorate and iodine levels in urine were determined by ultra-high performance liquid chromatography tandem-mass spectrometry and inductively coupled plasma-mass spectrometry, respectively. Conditional logistic regressions and multiple linear regressions were used to analyze the associations. RESULTS: Urinary perchlorate concentration was significantly higher in total cases, NG and PTC than in the corresponding controls (P < 0.05). Perchlorate was positively associated with PTC (OR = 1.058, 95% CI: 1.009, 1.110) in a non-linear dose-response relationship, but there was no association between perchlorate and NG or PTMC. Iodine was not associated with the risk of thyroid tumors and NG and did not correlate with the thyroid function indicators. Furthermore, perchlorate showed a positive correlation with thyroid stimulating hormone (TSH) at iodine adequate levels (P < 0.05), and a negative correlation with free triiodothyronine (FT3) and a positive correlation with thyroglobulin antibody (TgAb) at iodine more than adequate or excess levels (P < 0.05). CONCLUSIONS: Perchlorate can increase the risk of PTC in a non-linear dose-response relationship and disturb the thyroid hormone homeostasis and thyroid autoantibody levels.
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Bócio Nodular , Iodo , Neoplasias da Glândula Tireoide , Estudos de Casos e Controles , China/epidemiologia , Bócio Nodular/epidemiologia , Humanos , Incidência , Percloratos , Neoplasias da Glândula Tireoide/epidemiologia , TireotropinaRESUMO
INTRODUCTION: Achyranthes bidentata Blume (AB) has been used for a long time and is recorded in the Chinese Pharmacopoeia 2020 edition. It is commonly confused with Achyranthes aspera Linn (AA), Cyathula officinalis Kuan (CO) and Cyathula capitata (Wall.) Moq. (CC), belonging to the Achyranthes and Cyathula genera of the Amaranthaceae family. It is of great significance to recognize and distinguish chemical components of AB, AA, CO and CC. OBJECTIVE: The purpose of this study was to develop an analytical method for in-depth characterization and comparison of saponins in AB, AA, CO and CC. METHODS: The extracts of AB, AA, CO and CC were analyzed by an RP × RP (C18 × Phenyl-Hexyl) 2D LC system, eluted by acidic × ion pair mobile phases and detected by high resolution mass spectrometry. Fragmentation patterns of saponins were elucidated and proposed according to reference compounds or literature reports. RESULTS: As a result, 839 saponins consisting of 81, 415, 99 and 392 components corresponding to AB, AA, CO and CC, respectively, were characterized, including 594 potentially new saponins. Meanwhile, 29 kinds of aglycones were elucidated, among which 25 were new ones. Besides, 14, 91, 37 and 174 characteristic potential quality markers with MS intensities exceeding 10,000 were found in AB, AA, CO and CC, respectively. CONCLUSION: This comprehensive study not only expands our knowledge of the types of saponins in Achyranthes and Cyathula, but also reveals the differences among four kinds of analogous herbs (AB, AA, CO and CC), which facilitates the quality control of these herbal medicines in the future.
Assuntos
Achyranthes , Plantas Medicinais , Saponinas , Achyranthes/química , Espectrometria de Massas , Controle de Qualidade , Saponinas/químicaRESUMO
Fluoride is an essential micronutrient for humans. Nonetheless, when the amount of fluoride ion is greater than required, it will cause skeletal fluorosis and dental fluorosis to threaten human health. In this paper, a series of sodium alginate (SA)-based foam materials are prepared by freeze-drying technique and anchored with the nano-activated alumina (nAl2O3) in the SA to obtain a novel adsorbent of SA-nAl2O3 foam used for fluoride ions removal. The SA-nAl2O3 foam morphology was further explored and confirmed that nAl2O3 existed stably in the SA. The adsorption results showed that the maximal fluoride ion adsorption capacity was 5.09 mg/g with 20 mg/L fluorine solutions at a pH of 3. The adsorption isotherm fitted adequately to the Langmuir isotherm model, which demonstrated that the adsorption process is closer to monolayer adsorption. The adsorption kinetics behavior of SA-nAl2O3 foam was described by a pseudo-second-order model, and the adsorption process occurred by chemisorption. Adsorption thermodynamics analysis emphasized that the adsorption process was spontaneous and endothermic. The main mechanism of the foam is ion exchange. The SA-nAl2O3 foam exhibited excellent regeneration performance and stability after three cycles.
Assuntos
Poluentes Químicos da Água , Purificação da Água , Adsorção , Alginatos , Fluoretos , Flúor , Humanos , Concentração de Íons de Hidrogênio , Cinética , TermodinâmicaRESUMO
Fluorine is one of the essential trace elements for human life activities, but excessive intake of fluoride poses a great risk to people's health. In this paper, a series of mixed matrix membrane (MMM)-based polysulfone for removing fluoride were prepared by phase inversion, and their properties, adsorption capacity, adsorption isotherms, adsorption kinetics of fluoride ions, and mechanism were all investigated. The results confirmed that the MMM contained a large number of hydroxyl and aluminum functional groups due to resin being added. The MMM exhibited the best fluorine ion adsorption capacity of 2.502 mg/g at a pH of 6 with the initial concentration of 6 mg/L. As well, adsorption kinetics of fluorine ion on MMM followed the pseudo-second-order model, while the adsorption behavior of fluorine ion on MMM was well simulated by the Langmuir isotherm model. The adsorption capacity of MMM remained stable after six cycles and the regeneration efficiency was still above 80%, resulting in a long-term stability adequate for fluorine ion removal. Complexation and ion exchange played a key role in the fluorine ion adsorption of MMM. These results indicated the MMM as novel type of absorbent had an excellent capacity for removing fluoride.