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BACKGROUND: Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are involved in the occurrence and development of a variety of tumors. The aim of this study was to investigate the effects of circ_PPAPDC1A in Osimertinib resistance in NSCLC. METHODS: Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in Osimertinib-acquired resistance tissues of NSCLC. The effect of circ_PPAPDC1A on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_PPAPDC1A/miR-30a-3p/IGF1R axis. RESULTS: The results revealed that circ_PPAPDC1A was significantly upregulated in Osimertinib acquired resistance tissues of NSCLC. circ_PPAPDC1A reduced the sensitivity of PC9 and HCC827 cells to Osimertinib and promoted cell proliferation, invasion, migration, while inhibiting apoptosis in Osimertinib-resistant PC9/OR and HCC829/OR cells, both in vitro and in vivo. Silencing circ_PPAPDC1A partially reversed Osimertinib resistance. Additionally, circ_PPAPDC1A acted as a competing endogenous RNA (ceRNA) by targeting miR-30a-3p, and Insulin-like Growth Factor 1 Receptor (IGF1R) was identified as a functional gene for miR-30a-3p in NSCLC. Furthermore, the results confirmed that circ_PPAPDC1A/miR-30a-3p/IGF1R axis plays a role in activating the PI3K/AKT/mTOR signaling pathway in NSCLC with Osimertinib resistance. CONCLUSIONS: Therefore, for the first time we identified that circ_PPAPDC1A was significantly upregulated and exerts an oncogenic role in NSCLC with Osimertinib resistance by sponging miR-30a-3p to active IGF1R/PI3K/AKT/mTOR pathway. circ_PPAPDC1A may serve as a novel diagnostic biomarker and therapeutic target for NSCLC patients with Osimertinib resistance.
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Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , MicroRNAs , RNA Circular , Receptor IGF Tipo 1 , Transdução de Sinais , Humanos , MicroRNAs/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Acrilamidas/farmacologia , RNA Circular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Compostos de Anilina/farmacologia , Linhagem Celular Tumoral , Animais , Camundongos , Apoptose , Movimento Celular/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Masculino , Feminino , Indóis , PirimidinasRESUMO
Biochar may be potentially used as a rhizobial carrier due to its specific chemical compositions and surface properties, but the relationship between these properties and rhizobial survival rate is largely unknown. Here, we analysed the physicochemical characteristics and carrier potential of six types of biochars made from various feedstocks at 600 °C using slow pyrolysis method, and results were compared with conventional carrier material peat. Liquid suspension of Bradyrhziobium japonicum CB1809 was used to inoculate all the carrier materials. Shelf life and survival rate was determined via colony forming unit (CFU) method for up to 90 days under two storage temperature conditions (28 °C and 38 °C). The determined physicochemical characteristics of biochars were categorized into major elements, trace elements, relative ratios, surface morphology, functional groups, and key basic properties; and their interaction to shelf life was analysed using hypothesis-oriented structure equation modelling (path analysis). Results revealed that different types of biochars had different capacity to impact on shelf life due to their different physicochemical properties. Among all biochars pine wood BC was the most suitable carrier with the highest counts of 10.11 Log 10 CFU g-1 and 9.76 Log 10 CFU g-1 at the end of 90 days at 28 °C and 38 °C storage, respectively. Path analysis revealed that rhizobial shelf life was largely explained by total carbon (TC), manganese (Mn), specific surface area (SSA), pore size, CO (ketonic carbon), and O-CO (carboxyl carbon) functional groups, and all these indicators exhibited positive direct impact on shelf life. Pinewood BC showed the highest values of Mn, SSA, pore size and functional groups (CO and O-CO), contributing to its highest rhizobial shelf life and survival rate among other biochars and peat tested.
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Rhizobium , Taxa de Sobrevida , Carvão Vegetal/química , Solo/química , Carbono/análise , Temperatura , Propriedades de SuperfícieRESUMO
South China has been experiencing very high rate of acid deposition and severe soil acidification in recent decades, which has been proposed to exacerbate the regional ecosystem phosphorus (P) limitation. We conducted a 10-year field experiment of simulated acid deposition to examine how acidification impacts seasonal changes of different soil P fractions in a tropical forest with highly acidic soils in south China. As expected, acid addition significantly increased occluded P pool but reduced the other more labile P pools in the dry season. In the wet season, however, acid addition did not change microbial P, soluble P and labile organic P pools. Acid addition significantly increased exchangeable Al3+ and Fe3+ and the activation of Fe oxides in both seasons. Different from the decline of microbial abundance in the dry season, acid addition increased ectomycorrhizal fungi and its ratio to arbuscular mycorrhiza fungi in the wet season, which significantly stimulated phosphomonoesterase activities and likely promoted the dissolution of occluded P. Our results suggest that, even in already highly acidic soils, the acidification-induced P limitation could be alleviated by stimulating ectomycorrhizal fungi and phosphomonoesterase activities. The differential responses and microbial controls of seasonal soil P transformation revealed here should be implemented into ecosystem biogeochemical model for predicting plant productivity under future acid deposition scenarios.
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Micorrizas , Fósforo , China , Ecossistema , Florestas , Fungos , Concentração de Íons de Hidrogênio , Micorrizas/fisiologia , Nitrogênio/farmacologia , Monoéster Fosfórico Hidrolases , Fósforo/análise , Solo , Microbiologia do SoloRESUMO
It is of great value to develop general, low-cost and even household methods for colorectal cancer detection. Here, a portable detection strategy based on a personal glucose meter (PGM) was designed for meeting this purpose. In this strategy, the anti-EpCAM coated magnet beads (MBs) were used as capture probes for enriching cancer cells and the aptamer modified and invertase loaded graphene oxides (GO) were used as report probes for producing glucose signal. This method is sensitive with detection limit as low as 560â¯cells, and demonstrates excellent detection specificity. Meanwhile, we succeeded in the specific detection of target cells in 20% human serum samples, indicating this method has great prospect in clinical diagnosis. Moreover, this method presents favourable universality for detecting different colorectal cancer cells by just using different recognition aptamers. Importantly, this method can be implemented for the target cell detection at room temperature without any expensive and large-scale instruments but a portable PGM. Therefore, this portable detection method possesses great potential in point-of-care detection of colorectal cancer cells.
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Técnicas Biossensoriais/métodos , Neoplasias do Colo/diagnóstico , Neoplasias Colorretais/diagnóstico , Aptâmeros de Nucleotídeos , Linhagem Celular , Humanos , Testes ImediatosRESUMO
The feasibility of using a polymerase chain reaction (PCR)-based label-free DNA sensor for the detection of Helicobacter pylori is investigated. In particular, H. pylori ureC gene, a specific H. pylori nucleic acid sequence, was selected as the target sequence. In the presence of ureC gene, the target DNA could be amplified to dsDNA with much higher detectable levels. After added the SYBR green I (SGI), the sensing system could show high fluorescence. Thus, the target DNA can be detected by monitoring the change of fluorescence intensity of sensing system. The clinical performance of this method was determined by comparing it with another conventional technique urea breath test (UBT). The result also showed good distinguishing ability between negative and positive patient, which was in good agreement with that obtained by the UBT. It suggests that the label-free fluorescence-based method is more suitable for infection confirmation test of H. pylori. This approach offers great potential for simple, sensitive and cost-effective identification of H. pylori infection.
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Genes Bacterianos , Infecções por Helicobacter/diagnóstico , Helicobacter pylori/genética , Espectrometria de Fluorescência/métodos , Benzotiazóis , Testes Respiratórios , DNA/análise , DNA/genética , Diaminas , Corantes Fluorescentes , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Humanos , Compostos Orgânicos , Reação em Cadeia da Polimerase , Quinolinas , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: This study seeks to investigate the impacts of Lactobacillus reuteri (L. reuteri) on hepatic ischemia-reperfusion (I/R) injury and uncover the mechanisms involved. METHODS: Mice in the I/R groups were orally administered low and high doses of L.reuteri (L.reuteri-low and L. reuteri-hi; 1 × 1010 CFU/d and 1 × 1011 CFU/d), for 4 weeks prior to surgery. Following this, mice in the model group were treated with an Nrf2 inhibitor (ML-385), palmitoylcarnitine, or a combination of both. RESULTS: After treatment with L. reuteri, mice exhibited reduced levels of serum aminotransferase (ALT), aspartate aminotransferase (AST), and myeloperoxidase (MPO) activity, as well as a lower Suzuki score and apoptosis rate. L. reuteri effectively reversed the I/R-induced decrease in Bcl2 expression, and the significant increases in the levels of Bax, cleaved-Caspase3, p-p65/p65, p-IκB/IκB, p-p38/p38, p-JNK/JNK, and p-ERK/ERK. Furthermore, the administration of L. reuteri markedly reduced the inflammatory response and oxidative stress triggered by I/R. This treatment also facilitated the activation of the Nrf2/HO-1 pathway. L. reuteri effectively counteracted the decrease in levels of beneficial gut microbiota species (such as Blautia, Lachnospiraceae NK4A136, and Muribaculum) and metabolites (including palmitoylcarnitine) induced by I/R. Likewise, the introduction of exogenous palmitoylcarnitine demonstrated a beneficial impact in mitigating hepatic injury induced by I/R. However, when ML-385 was administered prior to palmitoylcarnitine treatment, the previously observed effects were reversed. CONCLUSION: L. reuteri exerts protective effects against I/R-induced hepatic injury, and its mechanism may be related to the promotion of probiotic enrichment, differential metabolite homeostasis, and the Nrf2/HO-1 pathway, laying the foundation for future clinical applications.
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Microbioma Gastrointestinal , Limosilactobacillus reuteri , Traumatismo por Reperfusão , Camundongos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/uso terapêutico , Palmitoilcarnitina/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/tratamento farmacológico , IsquemiaRESUMO
Soft assembly of peptide and curcumin (Cur) molecules enables functional integration by finding dynamic equilibrium states through non-covalent interactions. Herein, we developed two soft assembly systems, curcumin-egg white peptides (Cur-EWP) aggregations (AGs) and Cur-EWP-casein-quaternary chitosan (Cur-EWP-CA-QC) nanoparticles (NPs) to comparatively investigate their therapeutic effects on ulcerative colitis in mice and elucidate their underlying mechanism. Results revealed that Cur-EWP AGs, despite gastrointestinal tract instability, exhibited a propensity for swift accumulation within the colorectal region, enriching mucus-associated and short-chain fatty acid (SCAF)-producing bacteria, restoring the intestinal barrier damage. Whereas, Cur-EWP-CA-QC NPs, benefiting from their remarkable stability and exceptional mucosal adsorption properties, not only enhanced permeability of Cur and EWP in the small intestine to activate the immune response and boost tight junction protein expression but also, in their unabsorbed state, regulated the intestinal flora, exerting potent anti-inflammatory activity. Soft assembly of peptides and hydrophobic nutraceuticals could synergize biological activities to modulate chronic diseases.
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Caseínas , Quitosana , Colite Ulcerativa , Curcumina , Curcumina/farmacologia , Curcumina/química , Quitosana/química , Quitosana/farmacologia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Animais , Camundongos , Caseínas/química , Caseínas/farmacologia , Nanopartículas/química , Peptídeos/farmacologia , Peptídeos/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Clara de Ovo/química , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacosRESUMO
Natural multicomponent peptides with abundant bioactivity, varied sizes, and tunable interaction potential are available for rational designing novel self-assembled delivery carriers. Herein, we exploited zein-hyaluronic acid nanoparticles (Z-HA NPs) with a predetermined ordered structure as precursor templates to induce the self-assembly of egg white-derived peptides (EWDP) to generate stable spherical architectures for the enhancement of curcumin (Cur). The resulting Z-EWDP-HA NPs encapsulated hydrophobic Cur through robust hydrogen bonding and hydrophobic interactions with high encapsulation efficiency (97.38% at pH 7.0). The NPs presented superior Cur aqueous solubility, redispersibility, and photothermal stability. More importantly, the self-assembled EWDP could exert synergistic antioxidant activity with Cur and enhance the bioaccessibility of Cur. Meanwhile, the favorable biocompatibility and membrane affinity of EWDP further prolonged residence and time-controlled release feature of Cur in the small intestine. Precursor template-induced multicomponent peptides' self-assembly provides an efficient and controllable strategy for co-enhanced bioactivity and self-assembly capacity of peptides, which could dramatically broaden the functionalization of multicomponent peptides hydrolyzed from natural food proteins.
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Curcumina , Disponibilidade Biológica , Clara de Ovo , Ligação de Hidrogênio , PeptídeosRESUMO
Fusarium head blight (FHB), is one of the destructive fugue diseases of wheat worldwide caused by the Fusarium verticillioides (F.v). In this study, a population consisting of 262 recombinant inbred lines (RILs) derived from Zhongmai 578 and Jimai 22 was used to map Quantitative Trait Locus (QTL) for FHB resistance, with the genotype data using the wheat 50 K single nucleotide polymorphism (SNP) array. The percentage of symptomatic spikelet (PSS) and the weighted average of PSS (PSSW) were collected for each RIL to represent their resistance to wheat head blight caused by F.v. In total, 22 QTL associated with FHB resistance were identified on chromosomes 1D, 2B, 3B, 4A, 5D, 7A, 7B, and 7D, respectively, from which 10 and 12 QTL were detected from PSS and PSSW respectively, explaining 3.82%-10.57% of the phenotypic variances using the inclusive composite interval mapping method. One novel QTL, Qfhb. haust-4A.1, was identified, explaining 10.56% of the phenotypic variation. One stable QTL, Qfhb. haust-1D.1 was detected on chromosome 1D across multiple environments explaining 4.39%-5.70% of the phenotypic variation. Forty-seven candidate genes related to disease resistance were found in the interval of Qfhb. haust-1D.1 and Qfhb. haust-4A.1. Genomic prediction accuracies were estimated from the five-fold cross-validation scheme ranging from 0.34 to 0.40 for PSS, and from 0.34 to 0.39 for PSSW in in-vivo inoculation treatment. This study provided new insight into the genetic analysis of resistance to wheat head blight caused by F.v, and genomic selection (GS) as a potential approach for improving the resistance of wheat head blight.
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The interindividual heterogeneity in response to the antihypertensive effect of irbesartan has received considerable attention because of gene polymorphism. In this study, we investigated the new combinational influences of AGTR1 and ABCB1 gene polymorphism on the therapeutic effect of irbesartan among Chinese hypertensive patients. A total of 353 samples including 168 normal people and 185 hypertensive patients were adopted, and genotypes comprise ABCB1 (CC, CT, and TT) and AGTR1 (AA and AC) in this study. The results of multiple linear regression models showed that no statistically significant differences were observed in blood pressure change following irbesartan administration in each genotype from either ABCB1 (CC, CT, and TT) or AGTR1 (AA and AC). However, spline smoothing analysis demonstrated that the blood pressure therapeutic responses of irbesartan presented a noticeable difference among different ABCB1 genotypes when irbesartan doses reached over 300 ng/mL. Eventually, we assumed that the different drug responses of irbesartan among various AGTR1 genotypes were due to the diversity of the irbesartan-conjugated protein, which is responsible for crossing-coupled intracellular G-protein-coupled receptors (GPCRs).
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Both crizotinib and sunitinib, novel orally-active multikinase inhibitors, exhibit antitumor activity and extend the survival of patients with a malignant tumor. However, some patients may suffer liver injury that can further limit the clinical use of these drugs, however the mechanisms underlying hepatotoxicity are still to be elucidated. Thus, our study was designed to use HepG2 cells in vitro and the ICR mice model in vivo to investigate the mechanisms of hepatotoxicity induced by crizotinib and sunitinib. Male ICR mice were treated orally with crizotinib (70 mg/kg/day) or sunitinib (7.5 mg/kg/day) for four weeks. The results demonstrated that crizotinib and sunitinib caused cytotoxicity in HepG2 cells and chronic liver injury in mice, which were associated with oxidative stress, apoptosis and/or necrosis. Crizotinib- and sunitinib-induced oxidative stress was accompanied by increasing reactive oxygen species and malondialdehyde levels and decreasing the activity of superoxide dismutase and glutathione peroxidase. Notably, the activation of the Kelch-like ECH-associated protein-1/Nuclear factor erythroid-2 related factor 2 signaling pathway was involved in the process of oxidative stress, and partially protected against oxidative stress. Crizotinib and sunitinib induced apoptosis via the mitochondrial pathway, which was characterized by decreasing Bcl2/Bax ratio to dissipate the mitochondrial membrane potential, and increasing apoptotic markers levels. Moreover, the pan-caspase inhibitor Z-VAD-FMK improved the cell viability and alleviated liver damage, which further indicated the presence of apoptosis. Taken together, this study demonstrated that crizotinib- and sunitinib-caused oxidative stress and apoptosis finally impaired hepatic function, which was strongly supported by the histopathological lesions and markedly increased levels of serum alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase.
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To better understand the responses of vegetable yields in a greenhouse system to organic fertilizer through a quantitative evaluation based on peer-reviewed journal articles and in consideration of environmental managerial factors. We conducted a meta-analysis of 453 paired observations from 68 peer-reviewed journal articles to assess the response of vegetable yields in greenhouse vegetable systems in China to organic fertilization. Compared with the control (no organic fertilizer), organic fertilization significantly increased the yields of vegetables by 44.11% on average. The response of vegetable yields to organic fertilizer tended to increase with the increasing experimental duration. Organic fertilizer application had the greatest potential for leafy vegetables (+76.44%), in loamy soils (+53.94%), at moderate organic fertilizer carbon input levels (+54.13%), and in soils with moderate initial soil total nitrogen levels (+50.89%). Aggregated boosted tree analysis indicated that organic fertilizer carbon inputs, vegetable type and experimental duration were the predominant factors that manipulated the response of vegetable yields to organic fertilizer application. The rational application of farmyard manure would be a promising strategy for increasing vegetable yields in greenhouse vegetable systems in China. Factoring in vegetable type, carbon and nitrogen inputs of organic fertilizer, and soil texture would benefit vegetable yields with the application of organic fertilizer.
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Orchard grass coverage has been widely adopted to increase fruit yield by improving soil fertility. However, the impact of the environment on the changes in soil organic carbon (SOC) stocks consecutive to orchard grass coverage remain poorly quantified at a large scale. The present study aimed to examine the responses of SOC stocks to grass coverage at a soil depth of 0-30 cm in orchards compared to clean tillage. A total of 342 observations across China from 139 peer-reviewed publications were subjected to meta-analysis. Aggregated boosted tree analysis was performed, evaluating the determinants of SOC stocks, such as plant traits (e.g., fruit tree type, grass type, orchard age, and grass age), edaphic variables (e.g., initial SOC and nitrogen concentration, soil pH, and soil clay content), climatic factors (e.g., mean annual precipitation (MAP) and mean annual temperature (MAT)), and management practices (e.g., grass source, grass growing mode, fertilization, grass mowing, placement of mowed residues, and irrigation). On average, orchard grass coverage significantly enhanced SOC stocks by 21.47% (percentage change) compared to clean tillage. Biotic and abiotic factors influenced this increase in SOC stocks following grass coverage in orchards to different extents. Grass age and soil clay content were the main determinants driving the variation in the SOC stocks following grass coverage in orchards. Thus, we propose an efficient way to optimize C sequestration in grass covered orchards, regarding plant traits, climatic factors, edaphic variables, and management practices. Longer than 12 months of surface grass coverage with cultivated grass species in mature deciduous fruit orchards (≥5 years) efficiently increased SOC stocks. This is particularly the case for acidic (pH < 6.5) soils with low C content (SOM < 15 g kg-1) in areas with suitable rainfall and temperature conditions (MAP ≥ 400 mm, MAT ≥ 10 °C). Collectively, this meta-analysis identified orchard grass coverage as a promising practice for significantly increasing SOC stocks at 0-30 cm across large geospatial locations in China.
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Carbono , Solo , China , Argila , FrutasRESUMO
Forests play an essential role in mitigating climate change by sequestering carbon dioxide from the atmosphere. The establishment of mixed plantations is a promising way to store carbon (C) in soil compared with monocultures. However, monoculture forests largely dominate the rapid increase in forest areas in China. To optimize afforestation strategies and maximize the subsequent potential of C sequestration, we conducted a meta-analysis with 427 observations across 176 study sites in China. The goal was to quantify changes in the stocks of soil organic carbon (SOC) in mixed plantations compared with monocultures and to identify the predominant drivers for the stocks of SOC, including geological location, climatic factors, land use history, edaphic properties, plantation age, the inclusion of nitrogen-fixing trees, mixing proportion, and mixed plant types. The results showed that mixed plantations significantly increased the SOC stocks by 12% compared with monocultures, and the mixing proportion should not exceed 55% to produce higher SOC stocks in mixed plantations compared with monoculture. Additionally, mixed plantations in barren land are the most likely to increase the SOC stocks with limited water or low temperatures for growth. Additional measures instead of mixed plantations should be explored to increase SOC stocks in north, central, and northwest China. The data from this study demonstrated the spatiotemporal variability on the storage of SOC driven by mixed trees and has valuable implications for the establishment and management of afforestation.
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Sequestro de Carbono , Carbono , Florestas , Solo , Biodiversidade , Carbono/análise , China , Ecossistema , Recuperação e Remediação Ambiental , Compostos Orgânicos/análise , Solo/químicaRESUMO
BACKGROUND: Colorectal cancer (CRC) is the most common type of gastrointestinal malignant tumour. Colorectal adenocarcinoma (COAD) - the most common type of CRC - is particularly dangerous. The role of the immune system in the development of tumour-associated inflammation and cancer has received increasing attention recently. METHODS: In the present study, we compiled the expression profiles of 262 patients with complete follow-up data from The Cancer Genome Atlas (TCGA) database as an experimental group and selected 65 samples from the Gene Expression Omnibus (GEO) dataset (of which 46 samples were with M0) as a verification group. First, we screened the immune T helper 17 (Th17) cells related to the prognosis of COAD. Subsequently, we identified Th17 cells-related hub genes by utilising Weighted Gene Co-expression Network Analysis (WGCNA) and Least Absolute Shrinkage and Selector Operation (LASSO) regression analysis. Six genes associated with the prognosis in patients with COAD were identified, including: KRT23, ULBP2, ASRGL1, SERPINA1, SCIN, and SLC28A2. We constructed a clinical prediction model and analysed its predictive power. RESULTS: The identified hub genes are involved in developing many diseases and closely linked to digestive disorders. Our results suggested that the hub genes could influence the prognosis of COAD by regulating Th17 cells' infiltration. CONCLUSIONS: These newly discovered hub genes contribute to clarifying the mechanisms of COAD development and metastasis. Given that they promote COAD development, they may become new therapeutic targets and biomarkers of COAD.
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Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Células Th17/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Asparaginase/genética , Asparaginase/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismo , Biomarcadores Tumorais/imunologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Biologia Computacional , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Gelsolina/genética , Gelsolina/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Queratinas Tipo I/genética , Queratinas Tipo I/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismoRESUMO
Considerable attention has been raised on crizotinib- and sunitinib-induced hepatotoxicity, but the underlying mechanisms need further examination. In addition, limited therapeutic strategies exist to reduce the liver damage caused by crizotinib and sunitinib. This study investigated the mechanisms of crizotinib- and sunitinib-induced hepatotoxicity and the potential mitigation through ROS and Nrf2 signaling. Firstly, crizotinib and sunitinib reduced cell viability in human liver cells (L02 cells) and triggered dramatic liver injury in mice. Subsequently, we found that crizotinib and sunitinib activated the oxidative stress response (decreased level of GPx and SOD, and increased MDA content) in vivo. Crizotinib and sunitinib also stimulated hepatocyte mitochondrial apoptosis and necrosis in L02 cells in a dose-dependent manner. In vivo studies further confirmed that crizotinib and sunitinib decreased mitochondrial membrane potential and activated apoptosis-associated proteins (cleaved-PARP, cleaved caspase3, cytochrome c, Bcl2 and Bax). Furthermore, mechanistic investigations demonstrated that crizotinib and sunitinib accumulated ROS and inhibited Nrf2 signaling, and that ROS scavenger NAC and Nrf2 agonist tBHQ alleviated the extent of cell damage and the mitochondrial apoptosis during crizotinib- and sunitinib-induced hepatotoxicity in L02 cells. Collectively, these findings indicated that NAC and tBHQ play the crucial roles in crizotinib- and sunitinib-induced mitochondrial apoptosis via the regulation of oxidative stress.
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Nano-antibacterial agents can play a critical role in chronic wound management. However, the design of an intelligent nanosystem that can provide both a visual warning of infection and precise sterilization remains a hurdle. Herein, a rod-like porphyrin-based metal-organic framework theranostic nanosystem (Zn-TCPP nanorods) is fabricated via coordination chelation between tetrakis(4-carboxylphenyl)porphyrin and zinc ions. This system can show significant fluorescence activation in response to the local elevated pH shown by chronic wounds, a main indicator of wound infection. Meanwhile, under the guidance of fluorescence imaging, the highly spatiotemporally precise photodynamic inactivation of microorganisms can be carried out without the destruction of surrounding normal cells and nascent cells. The results demonstrated that the Zn-TCPP nanorods were a highly sensitive and reversible probe for sensing alkaline pH levels. Alterations in the fluorescence of the Zn-TCPP nanorods can accurately indicate the infection status and heterogeneity of infection within the wound bed. Under specific light irradiation, the Zn-TCPP nanorods can exterminate 97% of Staphylococcus aureus via the generation of reactive oxygen species (ROS). Assays of extensive wounds demonstrate that the precise fluorescence-imaging-guided suppression of bacterial infection can significantly reduce the mouse mortality rate and accelerate wound healing. This system provides the opportunity for "precision medicine" relating to chronic wounds and some large-area wounds.
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Materiais Biocompatíveis/química , Estruturas Metalorgânicas/química , Metaloporfirinas/química , Nanotubos/química , Animais , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/patologia , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/uso terapêutico , Diabetes Mellitus Experimental/patologia , Concentração de Íons de Hidrogênio , Luz , Camundongos , Camundongos Transgênicos , Imagem Óptica , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismo , Cicatrização/efeitos dos fármacosRESUMO
Aim: Our study aimed at investigating how LINC01133 functions in gastric cancer (GC) progression. Materials & methods: Gain-of-function and loss-of-function approaches were applied to analyze the effects of LINC01133, microRNA-576-5p (miR-576-5p) and somatostatin (SST) on the biological behaviors of GC cells and in tumor-bearing nude mice. Results: GC tissues and cells showed low expression of LINC01133, and LINC01133 overexpression decreased malignant phenotypes of GC cells. Moreover, LINC01133 upregulated SST through binding to miR-576-5p. Overexpressing miR-576-5p or suppressing SST reversed the functions of LINC01133 in biological potentials of GC cells and tumor growth. Conclusion: LINC01133 overexpression may inhibit GC development by downregulation of miR-576-5p and upregulation of SST, which suggests new therapeutic targets for GC.
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MicroRNAs/genética , Interferência de RNA , RNA Longo não Codificante/genética , Somatostatina/biossíntese , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Animais , Linhagem Celular Tumoral , Bases de Dados Genéticas , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Modelos Biológicos , Somatostatina/genética , Neoplasias Gástricas/patologia , TranscriptomaRESUMO
Tumour protein translationally controlled 1 (TPT1) antisense RNA 1 (TPT1-AS1) is known to be involved in the development and metastasis of cervical and ovarian cancers; however, its biological role in colorectal cancer (CRC) remains unknown. This study aimed to determine the function and mechanism of action of TPT1-AS1 in the progression and metastasis of CRC. Elevated TPT1-AS1 levels were observed in CRC tissues. Furthermore, the high expression levels were found to be correlated with unfavourable clinicopathological characteristics in CRC. Cell function experiments demonstrated that TPT1-AS1 depletion impeded cell proliferation, migration and invasion and enhanced cell adhesion; it also attenuated tumorigenesis and metastasis in vivo. Additionally, TPT1-AS1 was predominately located in the nuclei of the cells and could upregulate the expression of TPT1 by recruiting mixed lineage leukaemia protein-1 (MLL1), which increased the trimethylation of H3K4 me3 in the TPT1 promoter region and subsequently activated FAK and JAK-STAT3 signalling cascades. The inhibition of FAK activation by PF573228 significantly attenuated the oncogenic effect of TPT1-AS1. These findings indicated that TPT1-AS1 promoted tumour progression and metastasis in CRC by upregulating TPT1 levels and activating the FAK and JAK-STAT3 signalling pathways. Thus, TPT1-AS1 may be considered as a potential therapeutic target for CRC.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , RNA Antissenso/genética , RNA Longo não Codificante/genética , Animais , Carcinoma/patologia , Carcinoma/secundário , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Quinase 1 de Adesão Focal/genética , Células HCT116 , Células HT29 , Humanos , Janus Quinases/genética , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Transplante de Neoplasias , Fator de Transcrição STAT3/genética , Transdução de Sinais , Carga Tumoral , Proteína Tumoral 1 Controlada por Tradução , Regulação para CimaRESUMO
Circular RNA (circRNA) abnormal expression and regulation are involved in the occurrence and development of a variety of tumors. However, the role of circRNAs still remains unknown in gastrointestinal stromal tumors (GISTs). In the present study, the differential circRNA expression profile of GISTs was screened by human circRNAs chip and verified by qRT-PCR. The circRNA-miRNA-mRNA regulatory network was constructed using the cytoHubba plugin based on the Cytoscape software. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore circRNA functions. Six significantly differential circRNAs were also verified in 20 pairs of GISTs and adjacent tissues by qRT-PCR. The result showed that a total of 543 differentially expressed circRNAs were identified in GISTs, of which 242 were up-regulated and 301 were down-regulated. Additionally, the circRNA-miRNA-mRNA network contained six circRNAs, 30 miRNAs, and 308 mRNAs, and the targeted mRNAs were associated with "regulation of biological process," "intracellular organelle," "protein binding," and enriched in Wnt signaling pathway. Furthermore, qRT-PCR demonstrated that hsa_circRNA_061346, hsa_circRNA_103114, and hsa_circRNA_103870 were significantly up-regulated in GISTs (n = 20), and hsa_ circRNA_405324, hsa_circRNA_406821, and hsa_circRNA_000361 were dramatically down-regulated in GISTs (n = 20). In addition, all of these circRNAs were shown to have high diagnostic values, and most of them were significantly associated with tumor size, mitotic figure, and malignant degrees in GISTs (P < 0.05). Therefore, we concluded that circRNAs were abnormally expressed in GISTs, and the circRNA-miRNA-mRNA regulatory network plays an important role in the occurrence and development of GISTs. Also, the identified six candidate circRNAs might be critical circRNAs and may present as potential diagnostic biomarkers for GISTs.