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SHP2 plays a critical role in modulating tumor growth and PD-1-related signaling pathway, thereby serving as an attractive antitumor target. To date, no antitumor drugs targeting SHP2 have been approved, and hence, the search of SHP2 inhibitors with new chemical scaffolds is urgently needed. Herein, we developed a novel SHP2 allosteric inhibitor SDUY038 with a furanyl amide scaffold, demonstrating potent binding affinity (KD = 0.29 µM), enzymatic activity (IC50 = 1.2 µM) and similar binding interactions to SHP099. At the cellular level, SDUY038 exhibited pan-antitumor activity (IC50 = 7-24 µM) by suppressing pERK expression. Furthermore, SDUY038 significantly inhibited tumor growth in both xenograft and organoid models. Additionally, SDUY038 displayed acceptable bioavailability (F = 14%) and half-life time (t1/2 = 3.95 h). Conclusively, this study introduces the furanyl amide scaffold as a novel class of SHP2 allosteric inhibitors, offering promising lead compounds for further development of new antitumor therapies targeting SHP2.
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Amidas , Antineoplásicos , Desenho de Fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Animais , Regulação Alostérica/efeitos dos fármacos , Amidas/farmacologia , Amidas/química , Amidas/síntese química , Camundongos , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Furanos/farmacologia , Furanos/química , Furanos/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Proliferação de Células/efeitos dos fármacos , Camundongos NusRESUMO
The albino tea cultivar is one of the most important germplasms for key gene mining and high-quality tea producing. In order to elucidate the chlorophyll-deficient mechanism of albino cultivar 'Huangjinya' and its offspring, color difference, photosynthetic pigments and the relevant genes' expression of the tender shoots were comprehensively investigated in this study. Among the tested 16 offspring, 5 exhibited albino phenotype in spring and autumn, 3 showed albino phenotype in spring but normal green in autumn, while the rests were all normal green. The shoot of albino offspring had significantly higher lightness and/or yellowness than that of green ones, and possessed dramatically lower photosynthetic pigments and chlorophyll precursor protochlorophyllide (Pchlide), as well as higher chlorophyll a/chlorophyll b but lower chlorophylls/carotenoids in comparison with green ones. Among the tested genes involved in chlorophyll and carotenoid metabolism pathways, expression of the magnesium protoporphyrin IX monomethyl ester cyclase (CRD), 3,8-divinyl chlorophyllide 8-vinyl reductase (DVR), 5-aminolevulinate dehydratase 1 (HEMB1), 1-deoxy-D-xylulose 5-phosphate synthase 1 (DXS1) and 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (ISPH) was remarkably down-regulated in shoots of the albino offspring. Color difference indices of the offspring were significantly correlated with the levels of photosynthetic pigments and Pchlide, and low level of chlorophylls in shoot of albino offspring was mainly due to conversion obstacle from magnesium protoporphyrin â ¨ (Mg-Proto IX) to Pchlide which might be attributed to down-regulatory expression of CRD and DVR.
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Clorofila , Fenótipo , Protoclorifilida , Protoporfirinas , Clorofila/metabolismo , Protoclorifilida/metabolismo , Protoporfirinas/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , FotossínteseRESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive form of pulmonary fibrosis of unknown etiology. Despite ongoing research, there is currently no cure for this disease. Recent studies have highlighted the significance of competitive endogenous RNA (ceRNA) regulatory networks in IPF development. Therefore, this study investigated the ceRNA network associated with IPF pathogenesis. We obtained gene expression datasets (GSE32538, GSE32537, GSE47460, and GSE24206) from the Gene Expression Omnibus (GEO) database and analyzed them using bioinformatics tools to identify differentially expressed messenger RNAs (DEmRNAs), microRNAs (DEmiRNAs), and long non-coding RNAs (DElncRNA). For DEmRNAs, we conducted an enrichment analysis, constructed protein-protein interaction networks, and identified hub genes. Additionally, we predicted the target genes of differentially expressed mRNAs and their interacting long non-coding RNAs using various databases. Subsequently, we screened RNA molecules with ceRNA regulatory relations in the lncACTdb database based on the screening results. Furthermore, we performed disease and functional enrichment analyses and pathway prediction for miRNAs in the ceRNA network. We also validated the expression levels of candidate DEmRNAs through quantitative real-time reverse transcriptase polymerase chain reaction and analyzed the correlation between the expression of these candidate DEmRNAs and the percent predicted pre-bronchodilator forced vital capacity [%predicted FVC (pre-bd)]. We found that three ceRNA regulatory axes, specifically KCNQ1OT1/XIST/NEAT1-miR-20a-5p-ITGB8, XIST-miR-146b-5p/miR-31-5p- MMP16, and NEAT1-miR-31-5p-MMP16, have the potential to significantly affect IPF progression. Further examination of the underlying regulatory mechanisms within this network enhances our understanding of IPF pathogenesis and may aid in the identification of diagnostic biomarkers and therapeutic targets.
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The inherent functional fractions (gelation and ice-affinitive fractions) of gelatin enable it as a promising cryoprotectant alternative. However, the composition-antifreeze property relationships of gelatin remain to be investigated. In this study, the HW-PSG and LW-PSG fractions of gelatin from fish scales were obtained, according to the critical gelation conditions and ice-binding measurements, respectively. Thermal hysteresis (THA) value, associated with ice nucleation, of LW-PSG was higher than that of HW-PSG. Besides, the relatively low-sized ice crystals (210-550 µm2) indicated that HW-PSG showed strong ice recrystallization inhibition (IRI) ability, compared to other groups. These results suggested that LW-PSG inhibited ice nucleation, while HW-PSG displayed the strong IRI ability. Furthermore, the antifreeze mechanisms were clarified through IRI measurements and molecular dynamics simulation. The minimum size of ice crystals was found for HW-PSG gels with dense microstructure, suggesting the HW-PSG retarded the growth of ice crystals by restricting the migration and phase transformation of water molecules. The hydrogen bond interactions between the ice crystal surface and ASN1294 and PRO1433 residues of LW-PSG, and hydrophobic interactions contributed to inhibiting the nucleation of ice crystals. This study provided some references to further enhance antifreeze performance of gelatin by modulating fragment composition.
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Gelatina , Simulação de Dinâmica Molecular , Gelatina/química , Animais , Gelo , Cristalização , Ligação de Hidrogênio , Crioprotetores/química , Crioprotetores/farmacologia , Interações Hidrofóbicas e Hidrofílicas , PeixesRESUMO
Rice protein peptides (RPP) are a potentially valuable source of high-quality calcium chelating properties. However, there is a lack of information regarding the calcium-absorption-promoting effect of RPP and its underlying mechanism. The present study adopted molecular docking methodologies to analyze the 10 most potent peptide segments from RPP. Results revealed that the peptide AHVGMSGEEPE (AHV) displayed optimal calcium binding properties (calcium-chelating capacity 55.69 ± 0.66 mg/g). Quantum chemistry analysis revealed that the AHV peptide effectively binds and forms stable complexes with calcium via the carbonyl oxygen atoms in valine at position 3 and the carbonyl of the C-terminal carboxyl group of glutamate at position 11. The spectral analysis results indicated that AHV may bind to calcium through carboxyl oxygen atoms, resulting in a transition from a smooth surface block-like structure to a dense granular structure. Furthermore, this study demonstrated that the 4 mmol/L AHV-Ca chelate (61.75 ± 13.23 µg/well) significantly increases calcium absorption compared to 1 mM CaCl2 (28.57 ± 8.59 µg/well) in the Caco-2 cell monolayer. In terms of mechanisms, the novel peptide-calcium chelate AHV-Ca derived from RPP exerts a cell-level effect by upregulating the expression of TRPV6 calcium-ion-channel-related genes and proteins (TRPV6 and Calbindin-D9k). This study provides a theoretical basis for developing functional foods with the AHV peptide as ingredients to improve calcium absorption.
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Cálcio , Oryza , Humanos , Cálcio/metabolismo , Células CACO-2 , Oryza/metabolismo , Simulação de Acoplamento Molecular , Cálcio da Dieta/metabolismo , Peptídeos/química , OxigênioRESUMO
With global climate change, the high-temperature environment has severely impacted the community structure and phenotype of marine diatoms. Phaeodactylum tricornutum, a model species of marine diatom, is sensitive to high temperature, which grow slowly under high temperature. However, the regulatory mechanism of P. tricornutum in response to high-temperature is still unclear. In this study, we found that the expression level of the HSP70A in the wild type (WT) increased 28 times when exposed to high temperature (26°C) for 1 h, indicating that HSP70A plays a role in high temperature in P. tricornutum. Furthermore, overexpression and interference of HSP70A have great impact on the exponential growth phase of P. tricornutum under 26°C. Moreover, the results of Co-immunoprecipitation (Co-IP) suggested that HSP70A potentially involved in the correct folding of the photosynthetic system-related proteins (D1/D2), preventing aggregation. The photosynthetic activity results demonstrated that overexpression of HSP70A improves non-photochemical quenching (NPQ) activity under high-temperature stress. These results reveal that HSP70A regulates the photosynthetic activity of P. tricornutum under high temperatures. This study not only helps us to understand the photosynthetic activity of marine diatoms to high temperature but also provides a molecular mechanism for HSP70A in P. tricornutum under high-temperature stress.
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Diatomáceas , Proteínas de Choque Térmico HSP70 , Fotossíntese , Diatomáceas/metabolismo , Diatomáceas/fisiologia , Diatomáceas/genética , Temperatura Alta , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP70/genética , Fotossíntese/fisiologiaRESUMO
Introduction The global prevalence of diabetes is a pressing public health concern. Over 400 million individuals live with the effects of the disease, predominantly in low- and middle-income countries. In Aotearoa New Zealand (NZ), over 300 000 people have diabetes, resulting in a population rate of 43.1 per 1000. Enabling nurses to prescribe diabetes medications enhances accessibility and improves health outcomes for large sections of the population. Aim This rapid review was undertaken to investigate the influence of nurse prescribing on health care delivery for individuals with diabetes in NZ, Australia, the United Kingdom, and Canada, countries sharing comparable health care systems and multicultural backgrounds. Methods The review protocol was published on PROSPERO. In November 2022, a search was conducted across multiple databases to locate relevant literature and resources constrained to the last decade (from January 2012 to November 2022). Utilising the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework, data extraction was systematically structured, while rigorous appraisal processes upheld selection quality. Results Fifteen publications were identified as meeting predefined inclusion and exclusion criteria. The review of these articles revealed four main themes: the impact of nurse prescribing on clinical outcomes, levels of patient satisfaction, implications for health care service provisions, and identification of barriers and facilitators associated with nurse prescribing. Discussion This report identifies outcomes of nurse prescribing, concluding it provides a potential avenue for enhancing access to and alleviating the burden on health care systems.
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Diabetes Mellitus , Satisfação do Paciente , Humanos , Canadá , Austrália , Nova Zelândia , Diabetes Mellitus/tratamento farmacológicoRESUMO
tRNA-derived small RNAs (tsRNAs) constitute a subgroup of small noncoding RNAs (ncRNAs) originating from tRNA molecules. Their rich content, evolutionary conservatism, high stability, and widespread existence makes them significant in disease research. These characteristics have positioned tsRNAs as key players in various physiological and pathological processes. tsRNA actively participates in regulating many cellular processes, such as cell death, proliferation, and metabolism. tsRNAs could be promising diagnostic markers for cardiovascular diseases (CVDs). tsRNAs have been identified in serums, suggesting their utility as early indicators for the diagnosis of CVDs. Moreover, the regulatory roles of tsRNAs in CVDs make them promising targets for therapeutic intervention. This review provides a succinct overview of the characteristics, classification, and regulatory functions of tsRNAs in the context of CVDs. By shedding light on the intricate roles of tsRNAs, this knowledge could pave the way for the development of innovative diagnostic tools and therapeutic strategies for CVDs.
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Increasing ocean temperatures threaten the productivity and species composition of marine diatoms. High temperature response and regulation are important for the acclimation of marine diatoms to such environments. However, the molecular mechanisms behind their acclimation to high temperature are still largely unknown. In this study, the abundance of PtCPF1 homologs (a member of the cryptochrome-photolyase family in the model diatom Phaeodactylum tricornutum) transcripts in marine phytoplankton is shown to increase with rising temperature based on Tara Oceans datasets. Moreover, the expression of PtCPF1 in P. tricornutum at high temperature (26 °C) was much higher than that at optimum temperature (20 °C). Deletion of PtCPF1 in P. tricornutum disrupted the expression of genes encoding two phytotransferrins (ISIP2A and ISIP1) and two Na+/P co-transporters (PHATRDRAFT_47667 and PHATRDRAFT_40433) at 26 °C. This further impacted the uptake of Fe and P, and eventually caused the arrest of cell division. Gene expression, Fe and P uptake, and cell division were restored by rescue with the native PtCPF1 gene. Furthermore, PtCPF1 interacts with two putative transcription factors (BolA and TF IIA) that potentially regulate the expression of genes encoding phytotransferrins and Na+/P co-transporters. To the best of our knowledge, this is the first study to reveal PtCPF1 as an essential regulator in the acclimation of marine diatoms to high temperature through the coordination of Fe and P uptake. Therefore, these findings help elucidate how marine diatoms acclimate to high temperature.
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Diatomáceas , Simportadores , Diatomáceas/metabolismo , Ferro/metabolismo , Criptocromos/metabolismo , Temperatura , Fósforo/metabolismo , Aclimatação , Simportadores/metabolismoRESUMO
Tumor-associated macrophages (TAMs) are key regulators in tumor progression, but the precise role of bone marrow-derived monocytes (Mons) as TAM precursors and their dynamic phenotypes regulated by the tumor microenvironment (TME) remain unclear. Here, we developed an optimized microproteomics workflow to analyze low-cell-number mouse myeloid cells. We sorted TAMs and their corresponding Mons (1 × 105 per sample) from individual melanoma mouse models at both the early and late stages. We established the protein expression profiles for these cells by mass spectrometry. Subsequently, we analyzed the dynamics phenotypes of TAMs and identified a characteristic protein expression profile characterized by upregulated cholesterol metabolism and downregulated immune responses during tumor progression. Moreover, we found the downregulation of both STAT5 and PYCARD expression not only in late-stage TAMs but also in late-stage Mons, indicating a loss of the ability to induce inflammatory responses prior to Mons infiltration into TME. Taken together, our study provides valuable insights into the progression-dependent transitions between TAMs and their precursor cells, as well as the cross-organ communications of tumor and bone marrow.
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Macrófagos , Neoplasias , Camundongos , Animais , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia , Proteômica , Neoplasias/patologia , Fenótipo , Microambiente Tumoral/genéticaRESUMO
2-Aminobenzothiazoles are widely used in the fields of pharmaceuticals and pesticides. Herein, we report a metal-free protocol for the preparation of 2-aminobenzothiazoles by a covalent organic framework (COF) catalyzed tandem reaction. In the presence of catalytic amount of phenanthroline-decorated COF (Phen-COF), a variety of 2-aminobenzothiazoles are obtained in excellent yields by the cross-coupling of 2-iodoanilines with isothiocyanates at room temperature in water. In addition, the COF-catalyst is very stable and can be reused at least seven times without loss of its catalytic activity.
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BACKGROUND: The combination of the endocannabinoid system (ECS) and the type 2 cannabinoid receptor (CB2R) can activate various signal pathways, leading to distinct pathophysiological roles. This interaction has gained significant attention in recent research on fibrosis diseases. Focal adhesion kinase (FAK) plays a crucial role in regulating signals from growth factor receptors and Integrins. It is also involved in the transformation of fibroblasts into myofibroblasts. This study aims to investigate the impact of the CB2R agonist JWH133 on lung fibrosis and its potential to alleviate pulmonary fibrosis in mice through the FAK pathway. METHODS: The C57 mice were categorized into five groups: control, BLM, BLM + JWH133, BLM + JWH133 + NC, and BLM + JWH133 + FAK groups.JWH133 was administered to mice individually or in conjunction with the FAK vector. After 21 days, pathological changes in mouse lung tissues, inflammatory factor levels, hydroxyproline levels, and collagen contents were evaluated. Moreover, the levels of the FAK/ERK/S100A4 pathway-related proteins were measured. RESULTS: JWH133 treatment decreased inflammatory factor levels, attenuated pathological changes, and reduced extracellular matrix accumulation in the mouse model of bleomycin-induced pulmonary fibrosis; however, these effects were reversed by FAK. JWH133 attenuated fibrosis by regulating the FAK/ERK/S100A4 pathway. CONCLUSIONS: The results presented in this study show that JWH133 exerts a protective effect against pulmonary fibrosis by inhibiting the FAK/ERK/S100A4 pathway.Therefore, JWH133 holds promise as a potential therapeutic target for pulmonary fibrosis.
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Agonistas de Receptores de Canabinoides , Fibrose Pulmonar , Transdução de Sinais , Animais , Camundongos , Bleomicina , Agonistas de Receptores de Canabinoides/farmacologia , Fibrose , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Pulmão/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacosRESUMO
Their unique layered structure, large specific surface area, good stability, high negative charge density between layers, and customizable composition give layered double hydroxides (LDHs) excellent adsorption and detection performance for heavy metal ions (HMIs). However, their easy aggregation and low electrical conductivity limit the practical application of untreated LDHs. In this work, a ternary MgZnFe-LDHs engineered porous biochar (MgZnFe-LDHs/PBC) heterojunction was proposed as a sensing and adsorption material for the effective detection and removal of Cd2+ from wastewater. The growth of MgZnFe-LDHs in the PBC pores not only reduces the accumulation of MgZnFe-LDHs, but also improves the electrical conductivity of the composite. The synergistic effect between MgZnFe-LDHs and PBC enables the composite to achieve a maximum adsorption capacity of up to 293.4 mg/g for Cd2+ in wastewater. Meanwhile, the MgZnFe-LDHs/PBC-based electrochemical sensor shows excellent detection performance for Cd2+, presenting a wide linear range (0.01 ng/L-1 mg/L), low detection limit (3.0 pg/L), good selectivity, and stability. The results indicate that MgZnFe-LDHs/PBC would be a potential material for detecting and removing Cd2+ from wastewater.
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Cádmio , Poluentes Químicos da Água , Cádmio/química , Águas Residuárias , Adsorção , Porosidade , Poluentes Químicos da Água/química , Hidróxidos/químicaRESUMO
Antimony (Sb) is a serious toxic and non-essential metalloid for animals, humans, and plants. The rapid increase in anthropogenic inputs from mining and industrial activities, vehicle emissions, and shoot activity increased the Sb concentration in the environment, which has become a serious concern across the globe. Hence, remediation of Sb-contaminated soils needs serious attention to provide safe and healthy foods to humans. Different techniques, including biochar (BC), compost, manures, plant additives, phyto-hormones, nano-particles (NPs), organic acids (OA), silicon (Si), microbial remediation techniques, and phytoremediation are being used globally to remediate the Sb polluted soils. In the present review, we described sources of soil Sb pollution, the environmental impact of antimony pollution, the multi-faceted nature of antimony pollution, recent progress in remediation techniques, and recommendations for the remediation of soil Sb-pollution. We also discussed the success stories and potential of different practices to remediate Sb-polluted soils. In particular, we discussed the various mechanisms, including bio-sorption, bio-accumulation, complexation, and electrostatic attraction, that can reduce the toxicity of Sb by converting Sb-V into Sb-III. Additionally, we also identified the research gaps that need to be filled in future studies. Therefore, the current review will help to develop appropriate and innovative strategies to limit Sb bioavailability and toxicity and sustainably manage Sb polluted soils hence reducing the toxic effects of Sb on the environment and human health.
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Antimônio , Poluentes do Solo , Humanos , Antimônio/toxicidade , Solo , Poluentes do Solo/análise , Biodegradação Ambiental , MineraçãoRESUMO
Purpose: The risk of cardiovascular disease (CVD) mortality in patients with localized prostate cancer (PCa) by risk stratification remains unclear. The aim of this study was to determine the risk of CVD death in patients with localized PCa by risk stratification. Patients and methods: Population-based study of 340,806 cases in the Surveillance, Epidemiology, and End Results (SEER) database diagnosed with localized PCa between 2004 and 2016. The proportion of deaths identifies the primary cause of death, the competing risk model identifies the interaction between CVD and PCa, and the standardized mortality rate (SMR) quantifies the risk of CVD death in patients with PCa. Results: CVD-related death was the leading cause of death in patients with localized PCa, and cumulative CVD-related death also surpassed PCa almost as soon as PCa was diagnosed in the low- and intermediate-risk groups. However, in the high-risk group, CVD surpassed PCa approximately 90 months later. Patients with localized PCa have a higher risk of CVD-related death compared to the general population and the risk increases steadily with survival (SMR = 4.8, 95% CI 4.6-5.1 to SMR = 13.6, 95% CI 12.8-14.5). Conclusions: CVD-related death is a major competing risk in patients with localized PCa, and cumulative CVD mortality increases steadily with survival time and exceeds PCa in all three stratifications (low, intermediate, and high risk). Patients with localized PCa have a higher CVD-related death than the general population. Management of patients with localized PCa requires attention to both the primary cancer and CVD.
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This study investigates the potential role of Glycosyltransferases (GTs) in the glycosylation process and their association with malignant tumors. Specifically, the study focuses on PARP14, a member of GTs, and its potential as a target for tumors in the diagnosis and treatment of cervical cancer. To gather data, the study used somatic mutation data, gene expression data and clinical information from TCGA-CESE dataset as well as tissue samples from cervical cancer patients. Further verification was conducted through RT-qPCR and immunohistochemistry staining on cervical cancer tissues to confirm the expression of PARP14. The study utilized Kaplan-Meier for survival analysis of cervical cancer patient and found significant mutational abnormalities in GTs. The high frequency mutated gene was identified as PARP14. RT-qPCR revealed significantly higher mRNA expression of PARP14 compared to precancerous tissue. Using IHC combined with Kaplan-Meier,patients in the PARP14 high expression group had a better prognosis than the low expression group. The study identified PARP14 as a frequently mutated gene in cervical cancer and proposed its potential role in diagnosis and treatment.
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Poli(ADP-Ribose) Polimerases , Neoplasias do Colo do Útero , Feminino , Humanos , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/genética , Glicosiltransferases/genética , Prognóstico , MutaçãoRESUMO
In acute lung injury, two subsets of lung macrophages exist in the alveoli: tissue-resident alveolar macrophages (AMs) and monocyte-derived alveolar macrophages (MDMs). However, it is unclear whether these 2 subsets of macrophages have different functions and characteristics during the recovery phase. RNA-sequencing of AMs and MDMs from the recovery period of LPS-induced lung injury mice revealed their differences in proliferation, cell death, phagocytosis, inflammation and tissue repair. Using flow cytometry, we found that AMs showed a higher ability to proliferate, whereas MDMs expressed a larger amount of cell death. We also compared the ability of phagocytosing apoptotic cells and activating adaptive immunity and found that AMs have a stronger ability to phagocytose, while MDMs are the cells that activate lymphocytes during the resolving phase. By testing surface markers, we found that MDMs were more prone to the M1 phenotype, but expressed a higher level of pro-repairing genes. Finally, analysis of a publicly available set of single-cell RNA-sequencing data on bronchoalveolar lavage cells from patients with SARS-CoV-2 infection validated the double-sided role of MDMs. Blockade of inflammatory MDM recruitment using CCR2-/- mice effectively attenuates lung injury. Therefore, AMs and MDMs exhibited large differences during recovery. AMs are long-lived M2-like tissue-resident macrophages that have a strong ability to proliferate and phagocytose. MDMs are a paradoxical group of macrophages that promote the repair of tissue damage despite being strongly pro-inflammatory early in infection, and they may undergo cell death as inflammation fades. Preventing the massive recruitment of inflammatory MDMs or promoting their transition to pro-repairing phenotype may be a new direction for the treatment of acute lung injury.
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Amifostine is a normal cell protection agent, not only used in the adjuvant therapy of lung cancer, ovarian cancer, breast cancer, nasopharyngeal cancer, bone tumor, digestive tract tumor, blood system tumor and other cancers in order to reduce the toxicity of chemotherapy drugs, and recent studies have reported that the drug can also reduce lung tissue damage in patients with pulmonary fibrosis, but its mechanism of action is not yet fully understood. In this study, we explored the potential therapeutic effects and molecular mechanisms of AMI on bleomycin (BLM)-induced pulmonary fibrosis in mice. A mouse model of pulmonary fibrosis was established using BLM. We then assessed histopathological changes, inflammatory factors, oxidative indicators, apoptosis, epithelial-mesenchymal transition, extracellular matrix changes, and levels of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway-related proteins in the BLM-treated mice to determine the effect of AMI treatment on these factors. BLM-treated mice had substantial lung inflammation and abnormal extracellular matrix deposition. Overall, treatment with AMI significantly improved BLM-induced lung injury and pulmonary fibrosis. More specifically, AMI alleviated BLM-induced oxidative stress, inflammation, alveolar cell apoptosis, epithelial-mesenchymal transition, and extracellular matrix deposition by regulating the PI3K/Akt/mTOR signaling pathway. This finding that AMI can alleviate pulmonary fibrosis in a mouse model by inhibiting activation of the PI3K/Akt/mTOR signaling pathway lays a foundation for potential future clinical application of this agent in patients with pulmonary fibrosis.
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Amifostina , Neoplasias Nasofaríngeas , Fibrose Pulmonar , Animais , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fosfatidilinositol 3-Quinase , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Bleomicina/toxicidade , Modelos Animais de Doenças , Transdução de Sinais , Serina-Treonina Quinases TOR , MamíferosRESUMO
Blepharoglossum is a rare orchid genus of the Malaxidinae primarily distributed in tropical Pacific islands, with several species occurring in the Taiwan and Hainan Islands of China. Currently, the monophyletic status of Blepharoglossum has been challenged, and the phylogenetic relationships among its allied groups have remained unresolved with traditional DNA markers. In this study, we initially sequenced and annotated the chloroplast (cp) genomes of two Blepharoglossum species, Blepharoglossum elegans (Lindl.) L. Li and Blepharoglossum grossum (Rchb.f.) L. Li. These cp genomes of Blepharoglossum share the typical quadripartite and circular structure. Each of the genomes encodes a total of 133 functional genes, including 87 protein-coding genes (CDS), 38 tRNA genes and 8 rRNA genes. By comparing the sequence differences between these two cp genomes, it was found that they are relatively conserved in terms of overall gene content and gene arrangement. However, a total of 684 SNPs and 2664 indels were still identified, with ycf1, clpP, and trnK-UUU protein-coding genes having the highest number of SNPs and indels. In further comparative analyses among the six cp genomes in Malaxidinae, significant sequence divergences were identified in the intergenic regions, namely rps16-trnQ-UUG, trnS-GCU-trnG-GCC, rpoB-trnC-GCA, trnE-UUC-trnT-GGU, trnF-GAA-trnV-UAC, atpB-rbcL, petA-psbJ, psbE-petL, psbB-psbT, trnN-GUU-rpl32, trnV-GAC-rps7, and rps7-trnL-CAA, and five coding regions, including matK, and rpoC2, ycf1, and two ycf2 genes. Phylogenetic analysis indicated that Blepharoglossum and Oberonia form a highly supported sister group relationship. Our results are consistent with previous studies and present increased resolution among major clades.
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Genoma de Cloroplastos , Orchidaceae , Orchidaceae/genética , Filogenia , Mutação INDEL , Marcadores GenéticosRESUMO
Idiopathic pulmonary fibrosis (IPF) seriously threatens human life and health, and no curative therapy is available at present. Nintedanib is the first agent approved by the US Food and Drug Administration (FDA) in order to treat IPF; however, its mechanism of inhibition of IPF is still elusive. According to recent studies, nintedanib is a potent inhibitor. It can antagonize platelet-derived growth factor (PDGF), basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), etc., to inhibit pulmonary fibrosis. Whether there are other signaling pathways involved in IPF remains unknown. This study focused on investigating the therapeutic efficacy of nintedanib in bleomycin-mediated pulmonary fibrosis (PF) mice through PI3K/Akt/mTOR pathway. Following the induction of pulmonary fibrosis in C57 mice through bleomycin (BLM) administration, the mice were randomized into five groups: (1) the normal control group, (2) the BLM model control group, (3) the low-dose Nintedanib administration model group, (4) the medium-dose nintedanib administration model group, and (5) the high-dose nintedanib administration model group. For lung tissues, morphological changes were found by HE staining and Masson staining, ELISA method was used to detect inflammatory factors, alkaline water method to estimate collagen content, and western blotting for protein levels. TUNEL staining and immunofluorescence methods were used to analyze the effect of nintedanib on lung tissue and the impacts and underlying mechanisms of bleomycin-induced pulmonary fibrosis. After 28 days, bleomycin-treated mice developed significant pulmonary fibrosis. Relative to bleomycin-treated mice, nintedanib-treated mice had markedly reduced degrees of PF. In addition, nintedanib showed lung-protective effects by up-regulating antioxidant levels, down-regulating inflammatory protein expression, and reducing collagen accumulation. We demonstrated that nintedanib ameliorated bleomycin-induced lung injury by inhibiting the P13K/Akt/mTOR pathway as well as apoptosis. In addition, significant improvement in pulmonary fibrosis was seen after nintedanib (30/60/120 mg/kg body weight/day) treatment through a dose-dependent way. Histopathological results further corroborated the effect of nintedanib treatment on remarkably attenuating bleomycin-mediated mouse lung injury. According to our findings, nintedanib restores the antioxidant system, suppresses pro-inflammatory factors, and inhibits apoptosis. Nintedanib can reduce bleomycin-induced inflammation by downregulating PI3K/Akt/mTOR pathway, PF, and oxidative stress (OS).