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Chemotherapy-induced diarrhea causes dehydration, debilitation, infection, and even death, but there are currently no Food and Drug Administration (FDA)-approved drugs for treatment of chemotherapy-induced diarrhea. It is generally believed that the timely regulation of intestinal stem cell (ISC) fate may provide a meaningful solution for intestinal injuries. However, the lineage plasticity of ISCs during and after chemotherapy remains poorly understood. Here, we demonstrated that palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, regulated the fate of active or quiescent ISCs, provided multilineage protection from the toxicity of several different chemotherapeutics, and accelerated gastrointestinal epithelium recovery. Consistent with in vivo results, we determined that palbociclib enhanced intestinal organoid and ex vivo tissue survival after chemotherapy. Lineage tracing studies have shown that palbociclib protects active ISCs marked by Lgr5 and Olfm4 during chemotherapy and unexpectedly activates quiescent ISCs marked by Bmi1 to immediately participate in crypt regeneration after chemotherapy. Furthermore, palbociclib does not decrease the efficacy of cytotoxic chemotherapy in tumor grafts. The experimental evidence suggests that the combination of CDK4/6 inhibitors with chemotherapy could reduce damage to the gastrointestinal epithelium in patients. © 2023 The Pathological Society of Great Britain and Ireland.
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Antineoplásicos , Diarreia , Humanos , Diarreia/patologia , Diferenciação Celular , Células-Tronco/patologia , Reino Unido , Mucosa Intestinal/patologia , Quinase 4 Dependente de CiclinaRESUMO
Upon virus invasion of the host, APCs process Ags to short peptides for presentation by MHC class II (MHC-II). The recognition of virus-derived peptides in the context of MHC-II by CD4+ T cells initiates the adaptive immune response for virus clearance. As a survival instinct, viruses have evolved mechanisms to evade Ag processing and presentation. In this study, we discovered that IFN-γ induced endogenous MHC-II expression by a sea perch brain cell line through the STAT1/IFN regulatory factor 1 (IRF1)/CIITA signaling pathway. Furthermore, viral hemorrhagic septicemia virus infection significantly inhibited the IFN-γ-induced expression of IRF1, CIITA, MHC-II-α, and MHC-II-ß genes. By contrast, although STAT1 transcript was upregulated, paradoxically, the STAT1 protein level was attenuated. Moreover, overexpression analysis revealed that viral hemorrhagic septicemia virus N protein blocked the IFN-γ-induced expression of IRF1, CIITA, MHC-II-α, and MHC-II-ß genes, but not the STAT1 gene. We also found out that N protein interacted with STAT1 and enhanced the overall ubiquitination level of proteins, including STAT1 in Lateolabrax japonicus brain cells. Enhanced ubiquitination of STAT1 through K48-linked ubiquitination led to its degradation through the ubiquitin-proteasome pathway, thereby inhibiting the biological function of STAT1. Our study suggests that aquatic viruses target Ag presentation in lower vertebrates for immune evasion as do mammalian viruses.
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Antígenos de Histocompatibilidade Classe II/imunologia , Evasão da Resposta Imune/imunologia , Novirhabdovirus/imunologia , Nucleoproteínas/metabolismo , Percas/imunologia , Fator de Transcrição STAT1/metabolismo , Imunidade Adaptativa/imunologia , Animais , Apresentação de Antígeno/imunologia , Encéfalo/citologia , Encéfalo/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular , Doenças dos Peixes/patologia , Doenças dos Peixes/virologia , Genes MHC da Classe II/genética , Antígenos de Histocompatibilidade Classe II/biossíntese , Fator Regulador 1 de Interferon/metabolismo , Interferon gama/imunologia , Novirhabdovirus/metabolismo , Proteínas Nucleares/metabolismo , Percas/virologia , Transdução de Sinais/imunologia , Transativadores/metabolismo , Transcrição Gênica/genética , Ubiquitinação/fisiologiaRESUMO
Non-alcoholic fatty liver disease (NAFLD) is a complex pathogenic metabolic syndrome characterized by increased inflammation and endoplasmic reticulum stress. In recent years, natural polysaccharides derived from traditional Chinese medicine have shown significant anti-inflammatory effects, making them an attractive therapeutic option. However, little research has been conducted on the therapeutic potential of dried tangerine peel polysaccharide (DTPP) - one of the most important medicinal resources in China. The results of the present study showed that DTPP substantially reduced macrophage infiltration in vivo and suppressed the expression of pro-inflammatory factors and endoplasmic reticulum stress-related genes. Additionally, surface plasmon resonance analysis revealed that DTPP had a specific affinity to myeloid differentiation factor 2, which consequently suppressed lipopolysaccharide-induced inflammation via interaction with the toll-like receptor 4 signaling pathway. This study provides a potential molecular mechanism underlying the anti-inflammatory effects of DTPP on NAFLD and suggests DTPP as a promising therapeutic strategy for NAFLD treatment.
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Estresse do Retículo Endoplasmático , Inflamação , Polissacarídeos , Receptor 4 Toll-Like , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/antagonistas & inibidores , Polissacarídeos/farmacologia , Polissacarídeos/química , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Antígeno 96 de Linfócito/antagonistas & inibidores , Antígeno 96 de Linfócito/metabolismo , Carthamus tinctorius/química , Camundongos Endogâmicos C57BL , Estrutura Molecular , Relação Dose-Resposta a Droga , Relação Estrutura-Atividade , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Células RAW 264.7 , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/químicaRESUMO
An important risk factor for cardiovascular disease is dyslipidemia, especially abnormal cholesterol levels. The relation between probiotics and cholesterol-lowering capability has been extensively studied. Lactobacillus acidophilus plays a significant role in affecting host health, and produces multitudinous metabolites, which have prohibitory functions against pathogenic microorganisms. In this study, we identified a cholesterol-lowering strain AM13-1, isolated from a fecal sample obtained from a healthy adult male, and performed comprehensive function analysis by whole-genome analysis and in vitro experiments. Genome analyses of L. acidophilus AM13-1 revealed that carbohydrate and amino acid transport, metabolism, translation, ribosomal structure, and biogenesis are abundant categories of functional genes. No virulence factors or toxin genes with experimentally verified were found in the genome of strain AM13-1. Besides, plenty of probiotic-related genes were predicted from the L. acidophilus AM13-1 genome, such as cbh, atpA-D, and dltD, with functions related to cholesterol-lowering and acid resistance. And strain AM13-1 showed high-efficiency of bile salt hydrolase activity and the capacity for removing cholesterol with efficiency rates of 70%. These function properties indicate that strain AM13-1 can be considered as a probiotic candidate for use in food and health care products.
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Lactobacillus acidophilus , Probióticos , Humanos , Masculino , Lactobacillus acidophilus/genética , Lactobacillus acidophilus/metabolismo , Probióticos/metabolismo , Colesterol/metabolismo , FezesRESUMO
An efficient and operationally simple method for the synthesis of ß-keto sulfones through the BF3·OEt2-promoted reaction of alkynes and sodium sulfinates is developed. With its facile and selective access to the targets, it features good functional group compatibility, mild conditions, easily available starting materials, and good yields. Notably, the reaction does not require metal catalysts or chemical reagents with pungent odors.
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New generation of nanomaterials with organelle-level precision provide significant promise for targeted attacks on mitochondria, exhibiting remarkable therapeutic potency. Here, we report a novel amphiphilic phenolic polymer (PF) for the mitochondria-targeted photodynamic therapy (PDT), which can trigger excessive mitochondrial DNA (mtDNA) damages by the synergistic action of oxidative stress and furan-mediated DNA cross-linking. Moreover, the phenolic units on PF enable further self-assembly with Mn2+ via metal-phenolic coordination to form metal-phenolic nanomaterial (PFM). We focus on the synergistic activation of the cGAS-STING pathway by Mn2+ and tumor-derived mtDNA in tumor-associated macrophages (TAMs), and subsequently repolarizing M2-like TAMs to M1 phenotype. We highlight that PFM facilitates the cGAS-STING-dependent immunity at the organelle level for potent antitumor efficacy.
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AIMS: Lactobacillus acidophilus has been extensively applied in plentiful probiotic products. Although several studies have been performed to investigate the beneficial characteristics and genome function of L. acidophilus, comparative genomic analysis remains scarce. In this study, we collected 74 L. acidophilus genomes from our gut bacterial genome collection and the public database and conducted a comprehensive comparative genomic analysis. METHODS AND RESULTS: This study revealed the potential correlation of the genomic diversity and niche adaptation of L. acidophilus from different perspectives. The pan-genome of L. acidophilus was found to be open, with metabolism, information storage, and processing genes mainly distributed in the core genome. Phage- and peptidase-associated genes were found in the genome of the specificity of animal-derived strains, which were related to the adaptation of the animal gut. SNP analysis showed the differences of the utilization of vitamin B12 in cellular of L. acidophilus strains from animal gut and others. CONCLUSIONS: This work provides new insights for the genomic diversity analysis of L. acidophilus and uncovers the ecological adaptation of the specific strains.
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Lactobacillus acidophilus , Probióticos , Animais , Lactobacillus acidophilus/genética , Genoma Bacteriano , GenômicaRESUMO
Tumor-derived exosome can suppress dendritic cells (DCs) and T cells functions. Excessive secretion of exosomal programmed death-ligand 1 (PD-L1) results in therapeutic resistance to PD-1/PD-L1 immunotherapy and clinical failure. Restored T cells by antiexosomal PD-L1 tactic can intensify ferroptosis of tumor cells and vice versa. Diminishing exosomal suppression and establishing a nexus of antiexosomal PD-L1 and ferroptosis may rescue the discouraging antitumor immunity. Here, we engineered phototheranostic metal-phenolic networks (PFG MPNs) by an assembly of semiconductor polymers encapsulating ferroptosis inducer (Fe3+) and exosome inhibitor (GW4869). The PFG MPNs elicited superior near-infrared II fluorescence/photoacoustic imaging tracking performance for a precise photothermal therapy (PTT). PTT-augmented immunogenic cell death relieved exosomal silencing on DC maturation. GW4869 mediated PD-L1 based exosomal inhibition revitalized T cells and enhanced the ferroptosis. This novel synergy of PTT with antiexosomal PD-L1 enhanced ferroptosis evoked potent antitumor immunity in B16F10 tumors and immunological memory against metastatic tumors in lymph nodes.
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Compostos de Anilina/química , Antígeno B7-H1/metabolismo , Compostos de Benzilideno/química , Compostos Férricos/química , Ferroptose , Estruturas Metalorgânicas/química , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Exossomos/metabolismo , Ferroptose/efeitos dos fármacos , Morte Celular Imunogênica/efeitos dos fármacos , Imunoterapia , Interferon gama/metabolismo , Melanoma Experimental/diagnóstico por imagem , Melanoma Experimental/terapia , Estruturas Metalorgânicas/farmacologia , Estruturas Metalorgânicas/uso terapêutico , Camundongos , Fenol/química , Técnicas Fotoacústicas , Polietilenoglicóis/química , Polímeros/química , Receptor de Morte Celular Programada 1/metabolismo , Nanomedicina TeranósticaRESUMO
Radiotherapy (RT) is hampered by the limited oxygen in tumors, which could be potentiated via reprogramming the oxygen metabolism and increasing the oxygen utilization efficiency. Herein, a metal-phenolic nanosensitizer (Hf-PSP-DTC@PLX) was integrated via an acid-sensitive hydrogen sulfide (H2 S) donor (polyethylene glycol-co-polydithiocarbamates, PEG-DTC) and a hafnium-chelated polyphenolic semiconducting polymer (Hf-PSP) in an amphiphilic polymer (poloxamer F127, PLX). Hf-PSP-DTC@PLX elicited a high imaging performance for precise RT and generated H2 S to reduce the cellular oxygen consumption rate via mitochondrial respiration inhibition, which reprogrammed the oxygen metabolism for improvement of the tumor oxygenation. Then, Hf-sensitization could fully utilize the well-preserved oxygen to intensify RT efficacy and activate immunogenicity. Such a synergistic strategy for improvement of oxygenation and oxygen utilization would have great potential in optimizing oxygen-dependent therapeutics.
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Sulfeto de Hidrogênio , Neoplasias , Háfnio , Humanos , Neoplasias/radioterapia , Oxigênio , PolímerosRESUMO
Autophagy is an evolutionarily conserved process in which the cell degrades its own components and recycles the biomolecules for survival and homeostasis. It is an important cellular process to eliminate pathogens or damaged organelles. Nucleophagy, also termed as nuclear autophagy, is a more recently described subtype of autophagy, in which nuclear components, such as nuclear lamina and DNA, are to be degraded. Nucleophagy plays a double-facet role in the development of cancer. On one hand, the clearance of damaged DNA or nuclear structures via autophagic pathway is crucial to maintain nuclear integrity and prevent tumorigenesis. On the other hand, in later stages of tumor growth, nucleophagy may facilitate cancer cell survival and metastasis in the nutrient-depleted microenvironment. In this review, we discuss the relationship between nucleophagy and cancer along with potential intervention methods to target cancer through manipulating nucleophagy. Given the known observations about nucleophagy, it could be promising to target different nuclear components during the processes of nucleophagy, especially nuclear lamina. Further research on investigating the role of nucleophagy in oncological context could focus on dissecting its remaining molecular pathways and their connection to known tumor suppressors.
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Autofagia , Neoplasias , Sobrevivência Celular , Dano ao DNA , Humanos , Neoplasias/metabolismo , Neoplasias/terapiaRESUMO
Engineering multifunctional nanoplatforms with high therapeutic benefits has become a promising strategy for intractable cancer treatment. A novel polyphenol-based nanocomplex was designed to evoke highly efficacious cancer immunosurveillance while localizing therapy on the primary tumor and to minimize systemic side effects. This nanocomplex is prepared via metal-polyphenol coordination by encapsulating a natural polyphenol, gossypol, and a newly synthesized polyphenol derivative, polyethylene glycol-Chlorin e6 (Ce6). The combination of gossypol from cotton and the photosensitizer Ce6 can induce chemotherapeutic/photodynamic immunogenic cancer cell death upon laser irradiation, which is supported by a rich maturation of dendritic cells, concentrated secretion of inflammatory cytokines, and significant inhibition of distant untreated tumors. Finally, an assistance of the programmed-cell-death ligand-1 checkpoint-blockade immunotherapy can enhance the anti-tumor immune stimulation of our nanoplatform to a higher level.
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Nanomedicina , Neoplasias/terapia , Polifenóis/química , Antineoplásicos/uso terapêutico , Antígeno B7-H1/imunologia , Morte Celular/efeitos dos fármacos , Terapia Combinada , Humanos , Imunoterapia , Nanopartículas/uso terapêutico , Neoplasias/imunologia , Neoplasias/patologia , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
Manure amendment generally bolsters soil organisms but not all bacteria equally. To understand why different taxa respond differently, we used shotgun metagenomic approaches to profile functional potentials and correlate them with taxon abundances. A soil originally unproductive was reclaimed using commercial manure and finally became productive. The abundance of Firmicutes in the soil decreased, whereas that of Bacteroidetes and Proteobacteria increased after manure addition. Thirty-nine KEGG modules were significantly different across fertilizer treatments. These modules were mainly associated with the phosphoenolpyruvate-dependent phosphotransferase system (PTS), ATP-binding cassette (ABC) transporters, and two-component signal transduction systems. The Proteobacteria and Firmicutes mainly contributed to these modules. Correlation between the abundances of phyla and orthologs showed two distinctive patterns. One linked the Firmicutes to cell wall biosynthesis, PTS, and ABC transporters, and the other linked the Betaproteobacteria, Bacteroidetes, and Verrucomicrobia to lipopolysaccharide biosynthesis, bacterial motility, and carbon metabolism. Correlation between the abundances of phyla and Carbohydrate-Active Enzyme Database families also showed two distinctive patterns, one of them linking the Betaproteobacteria, Bacteroidetes, and Verrucomicrobia to very high abundances of glycosyltransferases and glycoside hydrolases. Overall, the Proteobacteria and Firmicutes were main drivers of functional potential differences across fertilizer treatments. The Firmicutes were enriched with genes associated with cell wall biosynthesis and membrane transports, while Proteobacteria with lipopolysaccharide biosynthesis and carbohydrate metabolism, which supports our hypothesis that the Firmicutes have a lower potential for utilizing manure-derived carbohydrates, while Proteobacteria have a higher potential. This explains why the Proteobacteria and Firmicutes responded to manure differently.
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Firmicutes/genética , Esterco/microbiologia , Metagenoma , Proteobactérias/genética , Microbiologia do Solo , Carbono/metabolismo , Fertilizantes/análiseRESUMO
There is paucity of long-term data on adult survivors after biventricular repair of pulmonary atresia with intact ventricular septum (PAIVS) and pulmonary stenosis (PS). This study aimed to determine the cardiac and non-cardiac outcomes of adult survivors after biventricular repair of PAIVS and PS. The cardiac, neurodevelopmental and liver problems of 111 adults, 40 with PAIVS and 71 with PS, were reviewed. The median follow-up duration of our patients was 26.5 years (range 14.8-55 years). The freedom from reintervention at 30 years was 17.4% and 73.3% for PAIVS and PS patients (p < 0.001), respectively. Compared with PS patients, PAIVS patients had significantly greater prevalence of right atrial and right ventricular (RV) dilatation, and moderate to severe tricuspid and pulmonary regurgitation (all p < 0.05), and cardiac arrhythmias (22.5% vs. 8.5%, p = 0.047). The freedom from development of cardiac arrhythmias at 30 years of 68.4% and 91.6%, respectively, in PAIVS and PS patients (p = 0.03). Cox proportional hazards model identified PAIVS as an independent risk factor for reintervention (HR 4.0, 95% CI 2.1-7.6, p < 0.001) and development of arrhythmias (HR 4.1, 95% CI 1.1-14.4, p = 0.03). Neurodevelopmental problems were found in 17.5% of PAIVS patients and 7.0% of PS patients (p = 0.11). Liver problems occurred in 2 (5%) PAIVS patients, both of whom required conversion to 1.5 ventricular repair. In conclusion, long-term problems, including the need for reinterventions, cardiac arrhythmias, RV dilation, pulmonary regurgitation, and neurodevelopmental and liver issues are more prevalent in adult PAIVS than PS survivors.
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Procedimentos Cirúrgicos Cardíacos/métodos , Cardiopatias Congênitas/cirurgia , Atresia Pulmonar/cirurgia , Estenose da Valva Pulmonar/cirurgia , Adulto , Arritmias Cardíacas/etiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ecocardiografia/métodos , Feminino , Seguimentos , Cardiopatias Congênitas/complicações , Ventrículos do Coração/cirurgia , Humanos , Masculino , Atresia Pulmonar/complicações , Estenose da Valva Pulmonar/complicações , Reoperação/estatística & dados numéricos , Fatores de Risco , Sobreviventes , Resultado do TratamentoRESUMO
BACKGROUND We aimed to identify pivotal genes and pathways involved in pancreatic ductal adenocarcinoma (PDAC), and explore possible molecular markers for the early diagnosis of the disease. MATERIAL AND METHODS The array data of GSE74629, including 34 PDAC samples and 16 healthy samples, was downloaded from GEO (Gene Expression Omnibus) database. Then, the DEGs (differentially expressed genes) in PDAC samples were compared with healthy samples using limma (linear models for microarray). Gene functional interaction networks were analyzed with Cytoscape and ReactomeFIViz. PPI networks were constructed with Cytoscape software. In addition, PPI (protein-protein interaction) network clustering modules were analyzed with ClusterONE, and the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analyses for modules were performed. RESULTS A total of 630 upregulated and 1,002 downregulated DEGs were identified in PDAC samples compared with healthy samples. Some ribosomal protein genes with higher average correlation in module 0 were enriched in the ribosome pathway. NUP107 (nucleoporin 107 kDa) and NUP160 (nucleoporin 160 kDa) were enriched in module 3. HNRNPU (heterogeneous nuclear ribonucleoprotein U) with higher average correlation in module 8 was enriched in the spliceosome pathway. The ribosome pathway and the spliceosome pathway were significantly enriched in cluster 1 and cluster 2, respectively. CONCLUSIONS Ribosomal protein genes Nup170, Nup160, and HNRNPU, and the ribosome pathway as well as the spliceosome pathway may play important roles in PDAC progression. In addition, ribosomal protein genes Nup170, Nup160, and HNRNPU may be used as possible molecular markers for the early diagnosis of the disease.
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Biomarcadores Tumorais/análise , Carcinoma Ductal Pancreático/diagnóstico , Perfilação da Expressão Gênica/métodos , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Biologia Computacional/métodos , Redes de Comunicação de Computadores , Bases de Dados Genéticas , Regulação para Baixo , Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Mapas de Interação de Proteínas , Transdução de Sinais/genética , Software , Regulação para CimaRESUMO
In this study, a new method for the simultaneous quantitative determination of triclopyr and aminopyralid in forage grass, hay, and soil was developed and validated using gas chromatography coupled with electron capture detector (GC-ECD). In this method, a simple and maneuverable esterification reaction was applied to convert the two acidic herbicides into their ester form with methanol. The target compounds were extracted with 1% hydrochloric acid-acetonitrile, esterified, purified by florisil solid-phase extraction cartridge, and detected in a single run by the GC-ECD. The average recoveries using this method, at different fortified levels, ranged from 80% to 104% with intra-day and inter-day RSDs in the range of 1.2-10.8% and 3.3-10.3% for both the herbicides, respectively. The LODs were below 0.02â¯mg/kg while the LOQs were below 0.05â¯mg/kg, both of which were much lower than the maximum residue limits (MRLs) of 25-700â¯mg/kg in pastures, as established by the USA (the code of federal regulations). The open field dissipation and residual analysis in pastures and soil were conducted with the commercial formulation at two locations. With time, both triclopyr and aminopyralid dissipated via first-order kinetics. In forage grass, both compounds degraded rapidly over the first 14- or 21-d period and at a slow rate over the remainder of experimental days. In soil, they degraded at a relatively slow rate, and dissipated steadily to below or close to the LOQ by 60-d post application. The half-lives of triclopyr were 1.4-1.8 d and 6.2-9.0 d and aminopyralid were 1.7-2.1 d and 8.2-10.6 d in terms of forage grass and soil, respectively. The terminal residue results indicated that on 7 d after the treatment, the residues of aminopyralid and triclopyr in forage grass and hay were lower than the MRLs set by the USA. This work can provide guidance on the reasonable use of these herbicides and also provide an analytical method for the determination of triclopyr and aminopyralid in pasture and soil.
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Ácidos Carboxílicos/análise , Cromatografia Gasosa/métodos , Glicolatos/análise , Herbicidas/análise , Piridinas/análise , Poluentes do Solo/análise , Ácidos Carboxílicos/isolamento & purificação , Elétrons , Glicolatos/isolamento & purificação , Herbicidas/isolamento & purificação , Resíduos de Praguicidas/análise , Resíduos de Praguicidas/isolamento & purificação , Piridinas/isolamento & purificação , Solo/química , Poluentes do Solo/isolamento & purificação , Extração em Fase SólidaRESUMO
This paper describes the ultrasound-assisted extraction (UAE) of pristimerin from Celastrus orbiculatus. Methanol was the most effective for pristimerin extraction, followed by ethanol, ethyl acetate, n-butanol, and water. To optimize the conditions, the Box-Behnken design, a widely used form of response surface methodology, was used to investigate the effects of parameters on UAE. Several variables, such as extraction time, ultrasonic power, extraction temperature, and solvent-to-solid (S/S) ratio were investigated. The highest extraction yield of 1.843 mg/g was obtained using methanol under optimal conditions with an extraction time of 40 min, ultrasonic power of 105 W, an S/S ratio of 40 mL/g, and an extraction temperature of 52°C. The experimental values under optimal conditions agreed well with the predicted values, suggesting that UAE has good potential as an extraction method for pristimerin from C. orbiculatus.
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Celastrus/química , Triterpenos/química , Ultrassom/métodos , Estrutura Molecular , Triterpenos Pentacíclicos , Folhas de Planta/química , SolventesRESUMO
BACKGROUND: Biomass smoke is associated with the risk of chronic obstructive pulmonary disease (COPD), but few studies have elaborated approaches to reduce the risk of COPD from biomass burning. The purpose of this study was to determine whether improved cooking fuels and ventilation have effects on pulmonary function and the incidence of COPD. METHODS AND FINDINGS: A 9-y prospective cohort study was conducted among 996 eligible participants aged at least 40 y from November 1, 2002, through November 30, 2011, in 12 villages in southern China. Interventions were implemented starting in 2002 to improve kitchen ventilation (by providing support and instruction for improving biomass stoves or installing exhaust fans) and to promote the use of clean fuels (i.e., biogas) instead of biomass for cooking (by providing support and instruction for installing household biogas digesters); questionnaire interviews and spirometry tests were performed in 2005, 2008, and 2011. That the interventions improved air quality was confirmed via measurements of indoor air pollutants (i.e., SO2, CO, CO2, NO2, and particulate matter with an aerodynamic diameter of 10 µm or less) in a randomly selected subset of the participants' homes. Annual declines in lung function and COPD incidence were compared between those who took up one, both, or neither of the interventions. Use of clean fuels and improved ventilation were associated with a reduced decline in forced expiratory volume in 1 s (FEV1): decline in FEV1 was reduced by 12 ml/y (95% CI, 4 to 20 ml/y) and 13 ml/y (95% CI, 4 to 23 ml/y) in those who used clean fuels and improved ventilation, respectively, compared to those who took up neither intervention, after adjustment for confounders. The combined improvements of use of clean fuels and improved ventilation had the greatest favorable effects on the decline in FEV1, with a slowing of 16 ml/y (95% CI, 9 to 23 ml/y). The longer the duration of improved fuel use and ventilation, the greater the benefits in slowing the decline of FEV1 (p<0.05). The reduction in the risk of COPD was unequivocal after the fuel and ventilation improvements, with an odds ratio of 0.28 (95% CI, 0.11 to 0.73) for both improvements. CONCLUSIONS: Replacing biomass with biogas for cooking and improving kitchen ventilation are associated with a reduced decline in FEV1 and risk of COPD. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR-OCH-12002398.
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Poluentes Atmosféricos/efeitos adversos , Poluição do Ar em Ambientes Fechados/efeitos adversos , Culinária , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Ventilação/normas , Adulto , Idoso , China/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Material Particulado/efeitos adversos , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Testes de Função RespiratóriaRESUMO
OBJECTIVE: To observe the detrimental effects of wood smoke condensate (WSC) exposure on human bronchial epithelial cells (HBEC), and to explore the expression of epithelial-mesenchymal transition (EMT) markers in HBEC exposed to WSC. METHODS: HBEC were exposed respectively to 5, 10, 20, 40 and 50 mg/L of WSC /CSC for 7 days, with control groups only in cell culture medium at the same time, then the total cytoactivity was detected by cell counting kit-8. After observing the cellular morphology of WSC-stimulated HBEC. Western blot and immunofluorescence method were used to evaluate the expression levels of type I collagen, vimentin, E-cad and MMP-9 in HBEC exposed to WSC (10 mg/L) and cigarette smoke condensate (CSC) (10 mg/L) for 7 days. Statistical evaluation of the continuous data was performed by ANOVA. Independent-Samples t-test for between-group comparisons. RESULTS: After 7 days of exposure to WSC, HBEC manifested a morphological characteristic of loss of cell-cell contact and elongated shape. The level of E-cad was decreased in WSC exposure groups (Western blot: 0.30 ± 0.05, F = 22.07, P < 0.05) compared with the groups without WSC exposure (Western blot: 0.59 ± 0.08, F = 22.07, P < 0.05). In contrast, an upregulation in expression of type I collagen (Western blot: 0.58 ± 0.04 vs 0.26 ± 0.02, F = 119.72, P < 0.05) and MMP-9 (0.56 ± 0.08 vs 0.19 ± 0.03, F = 21.79, P < 0.05) was observed in the presence of WSC, compared with the control groups. Immunofluorescence analysis showed that after a 7-day exposure to WSC in these cells, the E-cad protein was lost whereas type I collagen, vimentin and MMP-9 were acquired. Both Western blot and immunofluorescence analysis showed no difference in expression levels of E-cad, type I collagen, vimentin and MMP-9 between WSC and CSC exposure groups. CONCLUSION: WSC exposure could induce EMT-like process in human airway epithelial cells.
Assuntos
Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fumaça/efeitos adversos , Madeira , Western Blotting , Brônquios/citologia , Brônquios/metabolismo , Proliferação de Células , Células Cultivadas , Colágeno Tipo I/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Doença Pulmonar Obstrutiva Crônica/etiologia , Nicotiana/toxicidade , Vimentina/metabolismoRESUMO
Recent years have witnessed the incredible performance boost of data-driven deep visual object trackers. Despite the success, these trackers require millions of sequential manual labels on videos for supervised training, implying the heavy burden of human annotating. This raises a crucial question: how to train a powerful tracker from abundant videos using limited manual annotations? In this paper, we challenge the conventional belief that frame-by-frame labeling is indispensable, and show that providing a small number of annotated bounding boxes in each video is sufficient for training a strong tracker. To facilitate that, we design a novel SParsely-supervised Object Tracking (SPOT) framework. It regards the sparsely annotated boxes as anchors and progressively explores in the temporal span to discover unlabeled target snapshots. Under the teacher-student paradigm, SPOT leverages the unique transitive consistency inherent in the tracking task as supervision, extracting knowledge from both anchor snapshots and unlabeled target snapshots. We also utilize several effective training strategies, i.e., IoU filtering, asymmetric augmentation, and temporal calibration to further improve the training robustness of SPOT. The experimental results demonstrate that, given less than 5 labels for each video, trackers trained via SPOT perform on par with their fully-supervised counterparts. Moreover, our SPOT exhibits two desirable properties: 1) SPOT enables us to fully exploit large-scale video datasets by efficiently allocating sparse labels to more videos even under a limited labeling budget; 2) when equipped with a target discovery module, SPOT can even learn from purely unlabeled videos for performance gain. We hope this work could inspire the community to rethink the current annotation principles and make a step towards practical label-efficient deep tracking.
RESUMO
Malignant melanoma is an aggressive skin cancer with a high metastatic and mortality rate. Owing to genetic alterations, melanoma cells are resistant to apoptosis induction, which reduces the efficacy of most adjuvant systemic anticancer treatments in clinical. Here, a noninvasive strategy for anti-melanoma immunotherapy based on a manganese-coordinated nanomedicine is provided. Supplemented with photoirradiation, photon-mediated reactive oxygen species generation by photosensitizer chlorin e6 initiates photon-controlled pyroptosis activation (PhotoPyro) and promotes antitumor immunity. Simultaneously, photoirradiation-triggered double-stranded DNA generation in the cytosol would activate the Mn2+ -sensitized cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which further augment the PhotoPyro-induced immune response. The syngeneic effect of these immunostimulatory pathways significantly benefits dendritic cell maturation by damage-associated molecular patterns and proinflammatory cytokines secretion, thereby activating T cells and remarkably eliciting a systemic antitumor immune response to inhibiting both primary and distant tumor growth. Collaboratively, the photoirradiation-triggered PhotoPyro and cGAS-STING pathway activation by nanomedicine administration could enhance the antitumor capacity of immunotherapy and serve as a promising strategy for melanoma treatment.