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BACKGROUND: Neoadjuvant immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of early stage non-small cell lung cancer (NSCLC). However, little is known about which patients are likely to benefit most from neoadjuvant immunotherapy. In this study, we performed a multiplatform analysis on samples from resectable NSCLC treated with neoadjuvant immunotherapy to explore molecular characteristics related to immune responses. PATIENTS AND METHODS: A total of 17 patients with resectable stage IB-IIIA NSCLC treated with neoadjuvant immunotherapy were included. A multiplex cytokine assay, bulk TCR sequencing in peripheral blood, and multiplexed immunohistochemistry were performed. RESULTS: Low levels of stromal cell-derived factor (SDF)-1alpha at baseline were associated with unfavorable disease-free survival (DFS). Patients with major pathologic response (MPR) showed a decrease in HGF after one cycle of neoadjuvant immunotherapy. An increase in IDO and IP-10 was observed in patients who developed immune-related adverse events (irAEs) after neoadjuvant immunotherapy. There were no correlations between irAEs and MPR or DFS. The MPR group presented a significant decrease in white blood cells and neutrophil count after neoadjuvant immunotherapy. The high peripheral baseline TCR convergence was correlated with MPR and favorable DFS in lung squamous cell carcinoma (LUSC) receiving neoadjuvant immunotherapy. Neoadjuvant immunotherapy led to a significant increase in CD4+, CD8+, and CD8+CD39+ T-cell infiltration in tumor areas. CONCLUSIONS: This study suggests the potential roles of cytokines and TCR convergence for predicting ICIs response in resectable NSCLC and LUSC. CD8+CD39+T cells and CD4+ T cells could be involved in the action of neoadjuvant immunotherapy.
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BACKGROUND: The hypothesized link between low-density lipoprotein (LDL) and oncogenesis has garnered significant interest, yet its explicit impact on lung adenocarcinoma (LUAD) remains to be elucidated. This investigation aims to demystify the function of LDL-related genes (LRGs) within LUAD, endeavoring to shed light on the complex interplay between LDL and carcinogenesis. METHODS: Leveraging single-cell transcriptomics, we examined the role of LRGs within the tumor microenvironment (TME). The expression patterns of LRGs across diverse cellular phenotypes were delineated using an array of computational methodologies, including AUCell, UCell, singscore, ssGSEA, and AddModuleScore. CellChat facilitated the exploration of distinct cellular interactions within LDL_low and LDL_high groups. The findmarker utility, coupled with Pearson correlation analysis, facilitated the identification of pivotal genes correlated with LDL indices. An integrative approach to transcriptomic data analysis was adopted, utilizing a machine learning framework to devise an LDL-associated signature (LAS). This enabled the delineation of genomic disparities, pathway enrichments, immune cell dynamics, and pharmacological sensitivities between LAS stratifications. RESULTS: Enhanced cellular crosstalk was observed in the LDL_high group, with the CoxBoost+Ridge algorithm achieving the apex c-index for LAS formulation. Benchmarking against 144 extant LUAD models underscored the superior prognostic acuity of LAS. Elevated LAS indices were synonymous with adverse outcomes, diminished immune surveillance, and an upsurge in pathways conducive to neoplastic proliferation. Notably, a pronounced susceptibility to paclitaxel and gemcitabine was discerned within the high-LAS cohort, delineating prospective therapeutic corridors. CONCLUSION: This study elucidates the significance of LRGs within the TME and introduces an LAS for prognostication in LUAD patients. Our findings accentuate putative therapeutic targets and elucidate the clinical ramifications of LAS deployment.
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Torreya grandis (T. grandis) oil has been reported to alleviate symptoms of slow transit constipation (STC). However, the impact of sciadonic acid (SA), a distinctive fatty acid found in T. grandis oil, on the pathological progression of STC remains unclear. This study aimed to evaluate the effect of SA on STC and uncover the underlying mechanisms. The STC model was established by feeding Balb/c mice with loperamide. After 2 weeks of intervention, SA significantly improved weight loss and intestinal motility decline induced by STC, along with enhancing plasma indices and reducing colon pathological damage. SA effectively reversed the STC-induced decrease in the 5-HT4/cAMP/PKA/AQP4 signaling pathway genes and expression. Furthermore, 16S rRNA analysis demonstrated that SA mitigated the imbalance of the intestinal microbiota induced by STC, by reducing the ratio of Firmicutes to Bacteroidetes (F/B) and increasing the abundance of beneficial bacteria such as Akkermansia. In conclusion, SA intervention alleviated colonic dysfunction in STC mice. The activation of the SA-mediated 5-HT4/cAMP/PKA/AQP4 signaling pathway may serve as a potential target for STC treatment. These findings suggest that SA holds promise as a treatment option for STC and could potentially be extended to other related gut diseases for further investigation.
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Aquaporina 4 , Colo , Constipação Intestinal , Proteínas Quinases Dependentes de AMP Cíclico , AMP Cíclico , Camundongos Endogâmicos BALB C , Receptores 5-HT4 de Serotonina , Transdução de Sinais , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/metabolismo , Colo/metabolismo , Colo/efeitos dos fármacos , Receptores 5-HT4 de Serotonina/metabolismo , Receptores 5-HT4 de Serotonina/genética , Masculino , Camundongos , Aquaporina 4/metabolismo , Aquaporina 4/genética , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacosRESUMO
Alcoholrelated liver disease (ALD) is a major health concern worldwide. In recent years, there has been growing interest in natural products and functional foods for preventing and treating ALD due to their potential antioxidant and hepatoprotective properties. Rosa roxburghii Tratt, known for its rich content of bioactive compounds, has demonstrated promising health benefits, including antiinflammatory and antioxidant effects. Fermentation has been utilized as a strategy to enhance the bioavailability and efficacy of natural products. In the present study, using a mixture of Rosa roxburghii Tratt juice, lotus leaf extract and grape seed proanthocyanidins fermented by Lactobacillus plantarum HHLP56, a novel fermented Rosa roxburghii Tratt (FRRT) juice was discovered that can prevent and regulate ethanolinduced liver cell damage. Following fermentation, the pH was significantly decreased, and the content of VC and superoxide dismutase (SOD) were significantly increased, along with a noticeable enhancement in hydroxyl and 2,2diphenyl1picrylhydrazyl free radical scavenging abilities. Alpha Mouse liver 12 cells were exposed to ethanol for 24 h to establish an in vitro liver cell injury model. The present study evaluated the effects of FRRT on cell damage, lipid accumulation and oxidative stress markers. The results revealed that FRRT pretreatment (cells were pretreated with 2.5 and 5 mg/ml FRRT for 2 h) significantly reduced lipid accumulation and oxidative stress in liver cells. Mechanistically, FRRT regulated lipid metabolism by influencing key genes and proteins, such as AMPactivated protein kinase, sterol regulatory element binding transcription factor 1 and StearylCoA desaturase1. Furthermore, FRRT enhanced antioxidant activity by increasing SOD activity, glutathione and catalase levels, while reducing reactive oxygen species and malondialdehyde levels. It also reversed the expression changes of ethanolinduced oxidative stressrelated genes and proteins. In conclusion, a novel functional food ingredient may have been discovered with extensive potential applications. These findings indicated that FRRT has antioxidant properties and potential therapeutic benefits in addressing ethanolinduced liver cell damage through its effects on liver lipid metabolism and oxidative stress.
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Proteínas Quinases Ativadas por AMP , Etanol , Fermentação , Hepatócitos , Fator 2 Relacionado a NF-E2 , Extratos Vegetais , Rosa , Transdução de Sinais , Animais , Camundongos , Rosa/química , Transdução de Sinais/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Proteínas Quinases Ativadas por AMP/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Linhagem Celular , Antioxidantes/farmacologia , Sucos de Frutas e Vegetais , Substâncias Protetoras/farmacologiaRESUMO
Herein, we report a new "On-On" strategy based on the assembly and disassembly of fluorescein isothiocyanate nanoparticles (FITC-NPs) for sequential detections of glutathione (GSH) and caspase-3 (Casp3) with a multifunctional fluorescent probe 1. Theoretical investigations revealed the underlying mechanism that satisfactorily explained experimental results of such consecutive enhancements of fluorescence. Using this probe, we also successfully imaged the Casp3 activity in apoptotic cells.
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Técnicas Biossensoriais/métodos , Caspase 3/análise , Corantes Fluorescentes/química , Glutationa/análise , Nanopartículas/química , Linhagem Celular Tumoral , Fluoresceína-5-Isotiocianato/química , Humanos , Espectrometria de Fluorescência/métodosRESUMO
As a member of zinc-containing medium-chain alcohol dehydrogenase family, formaldehyde dehydrogenase (FDH) can oxidize toxic formaldehyde to less active formate with NAD(+) as a cofactor and exists in both prokaryotes and eukaryotes. Most FDHs are well known to be glutathione-dependent in the catalysis of formaldehyde oxidation, but the enzyme from Pseudomonas putida is an exception, which is independent of glutathione. To identify novel glutathione-independent FDHs from other bacterial strains and facilitate the corresponding structural and enzymatic studies, high-level soluble expression and efficient purification of these enzymes need to be achieved. Here, we present molecular cloning, expression, and purification of the FDH from Pseudomonas aeruginosa, which is a Gram-negative pathogenic bacterium causing opportunistic human infection. The FDH of P. aeruginosa shows high sequence identity (87.97%) with that of P. putida. Our results indicated that coexpression with molecular chaperones GroES, GroEL, and Tig has significantly attenuated inclusion body formation and improved the solubility of the recombinant FDH in Escherichiacoli cells. A purification protocol including three chromatographic steps was also established to isolate the recombinant FDH to homogeneity with a yield of â¼3.2 mg from 1L of cell culture. The recombinant P. aeruginosa FDH was properly folded and biologically functional, as demonstrated by the mass spectrometric, crystallographic, and enzymatic characterizations of the purified proteins.
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Aldeído Oxirredutases/metabolismo , Proteínas de Bactérias/metabolismo , Pseudomonas aeruginosa/enzimologia , Proteínas Recombinantes/metabolismo , Aldeído Oxirredutases/química , Aldeído Oxirredutases/genética , Aldeído Oxirredutases/isolamento & purificação , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Escherichia coli/genética , Escherichia coli/metabolismo , Chaperonas Moleculares , Pseudomonas aeruginosa/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Formaldehyde dehydrogenase (FDH) is a member of the zinc-containing medium-chain alcohol dehydrogenase family which oxidizes toxic formaldehyde to formate using NAD(+) as an electron carrier. Three-dimensional structures have been reported for FDHs from several different species. Most FDHs are dependent on glutathione for catalysis, but the enzyme from Pseudomonas putida is an exception. In this structural communication, the recombinant production, crystallization and X-ray structure determination at 2.7â Å resolution of FDH from P. aeruginosa are described. Both the tetrameric assembly and the NAD(+)-binding mode of P. aeruginosa FDH are similar to those of P. putida FDH, which is in good agreement with the high sequence identity (87.97%) between these two proteins. Preliminary enzymatic kinetics studies of P. aeruginosa FDH also revealed a conserved glutathione-independent `ping-pong' mechanism of formaldehyde oxidization.
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Aldeído Oxirredutases/química , Proteínas de Bactérias/química , Formaldeído/química , NAD/química , Pseudomonas aeruginosa/química , Aldeído Oxirredutases/genética , Aldeído Oxirredutases/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Domínio Catalítico , Sequência Conservada , Cristalografia por Raios X , Escherichia coli/genética , Formaldeído/metabolismo , Cinética , Modelos Moleculares , Dados de Sequência Molecular , NAD/metabolismo , Oxirredução , Ligação Proteica , Multimerização Proteica , Pseudomonas aeruginosa/enzimologia , Pseudomonas aeruginosa/genética , Pseudomonas putida/química , Pseudomonas putida/enzimologia , Pseudomonas putida/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homologia Estrutural de ProteínaRESUMO
Temperature has a large influence on insect abundances, thus under climate change, identifying major drivers affecting pest insect populations is critical to world food security and agricultural ecosystem health. Here, we conducted a meta-analysis with data obtained from 120 studies across China and Europe from 1970 to 2017 to reveal how climate and agricultural practices affect populations of wheat aphids. Here we showed that aphid loads on wheat had distinct patterns between these two regions, with a significant increase in China but a decrease in Europe over this time period. Although temperature increased over this period in both regions, we found no evidence showing climate warming affected aphid loads. Rather, differences in pesticide use, fertilization, land use, and natural enemies between China and Europe may be key factors accounting for differences in aphid pest populations. These long-term data suggest that agricultural practices impact wheat aphid loads more than climate warming.
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Afídeos , Agricultura , Animais , Mudança Climática , Ecossistema , TemperaturaRESUMO
Understanding how host plant chemistry affects invasive insects is crucial for determining the physiological mechanism of host use and predicting invasive insect outbreak and damage on hosts. Here, we examined the effects of plant nutrition and defensive chemicals on host preference and performance of adults and larvae of the invasive potato tuberworm, Phthorimaea operculella (Zeller; Lepidoptera: Gelechiidae), on four native (Solanum tuberosum, Nicotiana tabacum, Datura stramonium, and Solanum lycopersicum) and three new (Solanum melongena, Physalis alkekengi, and Lycium barbarum) host plants. We found that adults preferred to oviposit on S. tuberosum and N. tabacum leaves and the soil around these native host plants over other hosts. Larvae performed well on S. tuberosum and N. tabacum, reaching higher pupa weight and having better survival. Larvae performed poorly on S. melongena, S. lycopersicum, P. alkekengi, D. stramonium, and L. barbarum, with lower pupa weight and lower survival. Solanum tuberosum and N. tabacum had higher leaf soluble proteins than other plants and lower leaf total phenolics than S. lycopersicum, D. stramonium, and L. barbarum. Moreover, carbon content and soluble protein were positively associated with larval survival, while defensive traits (lignin and total phenolics) negatively affected larval survival. These findings provide insights into understanding of biochemical mechanisms of interactions between invasive insects and host plants, indicating the importance of considering plant chemistry when assessing invasive insect host use and damage.
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Conspecific aboveground and belowground herbivores can interact with each other, mediated by plant secondary chemicals; however, little attention has been paid to the interaction between leaf feeders and tuber-feeders. Here, we evaluated the effect of the foliar feeding of P. operculella larvae on the development of conspecific larvae feeding on harvested tubers by determining the nutrition and defense metabolites in the whole plant (leaf, root and tuber). We found that leaf feeding negatively affected tuber larval performance by increasing the female larval developmental time and reducing the male pupal weight. In addition, aboveground herbivory increased α-chaconine and glycoalkaloids in tubers and α-solanine in leaves, but decreased α-chaconine and glycoalkaloids in leaves. Aboveground herbivory also altered the levels of soluble sugar, soluble protein, starch, carbon (C), nitrogen (N), as well as the C:N ratio in both leaves and tubers. Aboveground P. operculella infestations could affect the performance of conspecific larvae feeding on harvested tubers by inducing glycoalkaloids in the host plant. Our findings indicate that field leaf herbivory should be considered when assessing the quality of potato tubers and their responses to pests during storage.
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A new dibenzylamine-quinoline derivative (DEEQ) was synthesized and investigated as a corrosion inhibitor for mild steel in 15% HCl solution in various ways, including via weight loss measurements, contact angle measurements, electrochemical measurements (EIS), scanning electron microscopy (SEM), scanning Kelvin probe (SKP) and theoretical calculations. The experimental results revealed that DEEQ is an effective corrosion inhibitor for oil and gas acidification. In an oil-water two-phase system, the wettability of mild steel can be changed by adsorption, while obeying the Langmuir adsorption isotherm. Finally, quantum chemical calculations and molecular dynamic simulation parameters further show a definite correlation between the theoretical and experimental results.
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In this paper, an embedded metal-wire nanograting was fabricated and used to construct a multifunctional optical device. The basic function of the nanograting is as a broadband polarizing beam splitter. On the top of the nanograting surface, a homogeneity cladding layer was deposited, and metal wires were deposited in the grating trench. This multifunctional optical device based on the artificial material is designed with a very simple structure, but with the functions of a variable optical attenuator, an optical switch, and a variable optical power splitter. The experimental result as a variable optical power splitter is presented.
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BACKGROUND: Annoying snore is the principle symptom and problem in obstructive sleep apnea syndrome (OSAS). However, investigation has been hampered by the complex snoring sound analyses. OBJECTIVE: This study was aimed to investigate the energy types of the full-night snoring sounds in patients with OSAS. PATIENTS AND METHOD: Twenty male OSAS patients underwent snoring sound recording throughout 6 hours of in-lab overnight polysomnogragphy. Snoring sounds were processed and analyzed by a new sound analytic program, named as Snore Map®. We transformed the 6-hour snoring sound power spectra into the energy spectrum and classified it as snore map type 1 (monosyllabic low-frequency snore), type 2 (duplex low-&mid-frequency snore), type 3 (duplex low- & high-frequency snore), and type 4 (triplex low-, mid-, & high-frequency snore). The interrator and test-retest reliabilities of snore map typing were assessed. The snore map types and their associations among demographic data, subjective snoring questionnaires, and polysomnographic parameters were explored. RESULTS: The interrator reliability of snore map typing were almost perfect (κ = 0.87) and the test-retest reliability was high (r = 0.71). The snore map type was proportional to the body mass index (r = 0.63, P = 0.003) and neck circumference (r = 0.52, P = 0.018). Snore map types were unrelated to subjective snoring questionnaire scores (All P>0.05). After adjustment for body mass index and neck circumference, snore map type 3-4 was significantly associated with severity of OSAS (r = 0.52, P = 0.026). CONCLUSIONS: Snore map typing of a full-night energy spectrum is feasible and reliable. The presence of a higher snore map type is a warning sign of severe OSAS and indicated priority OSAS management. Future studies are warranted to evaluate whether snore map type can be used to discriminate OSAS from primary snoring and whether it is affected by OSAS management.
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Apneia Obstrutiva do Sono/fisiopatologia , Ronco/fisiopatologia , Adulto , Índice de Massa Corporal , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Espectrografia do Som , Inquéritos e QuestionáriosRESUMO
An ultra-high pressure liquid chromatography-tandem mass spectrometry method has been developed and validated for identification and quantification of five major bioactive components in rat plasma after oral administration of Qihuotongqiao tablets. The analysis was performed on an Acquity UPLC HSS T3 column (100 mm x 2.1mm, 1.8 microm; Waters, USA) utilizing a gradient elution profile and a mobile phase consisting of (A) water containing 0.5 mM ammonium chloride and (B) acetonitrile. Electrospray ionization (ESI) tandem interface was employed prior to mass spectrometric detection. The calibration curve was linear over the range of 4.2-416.0 ng/mL for notoginsenoside R1, 38.4-3840.0 ng/mL for ginsenoside Rg(1), 3.7-368.0 ng/mL for ginsenoside Re, 37.6-5640.0 ng/mL ginsenoside Rb(1) and 4.5-448.0 ng/mL for icariin, respectively. The average accuracies ranged from 87.2 to 109.3% with RSD< or =13.7%. The results indicated that ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) provided improved chromatographic parameters resulting in significantly increased sample throughput including lower solvent consumption and lower limits of quantitation (LLOQ) for most of target analytes compared to previous method employing conventional high-performance liquid chromatography (HPLC) separation. So, the established method was validated, sensitive and reliable for the determination of five major bioactive components in rat plasma.
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Cromatografia Líquida de Alta Pressão/métodos , Ginsenosídeos/sangue , Panax notoginseng/química , Espectrometria de Massas em Tandem/métodos , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Ginsenosídeos/administração & dosagem , Ginsenosídeos/química , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
What we believe to be a new type of embedded metal-wire nanograting is fabricated, in which the metal wires are embedded under the trenches of the substrate, and a cladding layer is deposited on the surface of the trenches to protect the metal-wire grating. The substrate of the nanograting is antireflectively coated to further increase the performance of the device. This novel embedded nanograting has a high extinction ratio, low insertion loss for optical communication wavelengths, and good wearability for practical applications. This kind of metal-wire nanograting is attractive as a polarizing beam splitter or combiner to construct various optical devices. By using this newly developed kind of nanograting, a polarization beam splitter/combiner with good performance is fabricated.