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Background: Several studies have shown that bedside lung ultrasound findings in postanaesthesia care units (PACUs) and intensive care units (ICUs) correlate with postoperative pulmonary complications(PPCs) after noncardiac major surgery. However, it remains unclear whether lung ultrasound findings can be used as early predictors of PPCs in patients undergoing cardiac surgery. The main aim of our study was to evaluate the relationship between early postoperative point-of-care lung ultrasound findings and PPCs after cardiac surgery. Methods: Two board-certified physicians performed a point-of-care pulmonary ultrasound on cardiac surgery patients approximately 2 h after the patient was admitted to the ICU. Pulmonary complications occurring within 30 days postoperatively were recorded. Logistic regression modeling was used to analyze the relationship between lung ultrasound findings and PPCs. Results: PPCs occurred in 61 (30.9 %) of the 197 patients. Lung ultrasound scores(LUS), number of lung consolidation(NLC), and depth of pleural effusion(DPE) were more significant in patients who developed PPCs (P < 0.001). According to the multivariate analysis, NLC≥3(aOR 2.71,95%CI 1.14-6.44; p = 0.024)and DPE >0.95(aOR 3.79,95%CI 1.60-8.99; p = 0.002) were found to be independently associated with PPCs during this study. Conclusions: Our study demonstrated that DPE >0.95 and NLC ≥3 were associated with PPCs after cardiac surgery based on bedside lung ultrasound findings in the ICU. When these signs manifest perioperatively, the surgeon should be alerted and the necessary steps should be taken, especially if they present simultaneously.
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Thymocyte-expressed, positive selection-associated 1 (Tespa1) is a key molecule in T-cell development and has been linked to immune diseases. However, its role in antitumour CD8+T cell immunity remains unclear. Here, we demonstrated that Tespa1 plays an important role in antitumour CD8+T cell immunity. First, compared with wild-type (WT) mice, Lewis lung cancer cells grew faster in Tespa1 knockout (Tespa1-/-) mice, with reduced apoptosis, and decreased CD8+T cells in peripheral blood and tumor tissues. Second, the proportion of CD8+T and Th1 cells in the splenocytes of Tespa1-/- mice was lower than that in WT mice. Third, Tespa1-/- CD8+ tumor-infiltrating lymphocytes (TILs) showed weakened proliferation, invasion, cytotoxicity, and protein expression of IL-2 signalling pathway components compared to WT CD8+TILs. Furthermore, PD-1 expression in CD8+TILs was higher in Tespa1-/- than in WT mice. Lastly, CD8+TILs in WT mice improved the antitumour ability of Tespa1-/- mice. In conclusion, these findings suggest that Tespa1 plays a critical role in the tumor immune system by regulating CD8+T cells.
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Sustained activation of DNA damage response (DDR) signaling has been demonstrated to play vital role in chemotherapy failure in cancer. However, the mechanism underlying DDR sustaining in cancer cells remains unclear. In the current study, we found that the expression of the DDUP microprotein, encoded by the CTBP1-DT lncRNA, drastically increased in cisplatin-resistant ovarian cancer cells and was inversely correlated to cisplatin-based therapy response. Using a patient-derived human cancer cell model, we observed that DNA damage-induced DDUP foci sustained the RAD18/RAD51C and RAD18/PCNA complexes at the sites of DNA damage, consequently resulting in cisplatin resistance through dual RAD51C-mediated homologous recombination (HR) and proliferating cell nuclear antigen (PCNA)-mediated post-replication repair (PRR) mechanisms. Notably, treatment with an ATR inhibitor disrupted the DDUP/RAD18 interaction and abolished the effect of DDUP on prolonged DNA damage signaling, which resulted in the hypersensitivity of ovarian cancer cells to cisplatin-based therapy in vivo. Altogether, our study provides insights into DDUP-mediated aberrant DDR signaling in cisplatin resistance and describes a potential novel therapeutic approach for the management of platinum-resistant ovarian cancer.
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Neoplasias Ovarianas , RNA Longo não Codificante , Feminino , Humanos , Cisplatino/uso terapêutico , Proteínas de Ligação a DNA/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Antígeno Nuclear de Célula em Proliferação , RNA Longo não Codificante/genética , Ubiquitina-Proteína Ligases , MicropeptídeosRESUMO
BACKGROUND: The relationship between preoperative frailty and pulmonary complications after cardiac surgery in elderly patients is unclear. This study was designed to evaluate the relationship between frailty and postoperative pulmonary complications (PPCs) in elderly patients undergoing cardiac surgery and to provide a basis for their prevention and treatment. AIMS: This study aimed to investigate the predictive value of preoperative frailty on pulmonary complications after cardiac surgery in elderly patients. METHODS: Frailty was assessed using the CAF. The diagnosis of PPCs was based on the criteria defined by Hulzebos et al., and patients were classified into a PPCs group and a non-PPCs group. Factors with clinical significance and P < 0.05 in univariate regression analysis were included in multivariate logistic regression analysis to determine the relationship between preoperative frailty and PPCs. The area under the receiver operating characteristic (ROC) curve (AUC) was used to compare the predictive effects of the CAF, EuroSCORE II, and ASA + age on the occurrence of PPCs. RESULTS: A total of 205 patients were enrolled in this study, 31.7% of whom developed PPCs. Univariate logistic regression analysis showed that frailty, ASA grade, EuroSCORE II, hemoglobin concentration, FVC, time of operation, and postoperative AKI were associated with the development of PPCs. However, after adjustments for all possible confounding factors, multivariate logistic regression results showed that frailty, prolonged operation time, and postoperative AKI were risk factors for PPCs, and the risk of postoperative PPCs in frail patients was approximately 4.37 times that in nonfrail patients (OR = 4.37, 95%CI: 1.6-11.94, P < 0.05). The predictive efficacy of the traditional perioperative risk assessment tools EuroSCORE II and ASA + age was lower than that of CAF. CONCLUSIONS: Frailty before surgery, prolonged operation time, and postoperative AKI were independent risk factors for pulmonary complications after heart surgery in elderly individuals, and CAF was more effective than the traditional risk predictors EuroSCORE II and ASA + age.
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Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Fragilidade , Humanos , Idoso , Fragilidade/epidemiologia , Estudos Prospectivos , Fatores de Risco , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Complicações Pós-Operatórias/etiologiaRESUMO
Both the absence of autophagy and excessive autophagy is double-edged sword in tumorigenesis. Due to the specificity of autophagy, its role in head and neck squamous cell carcinoma (HNSCC) is still unclear. In this study, we established five autophagy-related patterns in 1165 HNSCC patients with distinct cellular and molecular characteristics. Additionally, we developed a new scoring system (ATPscore) based on the differentially expressed genes (DEGs) among these five patterns, to represent the individual autophagy regulation pattern. ATPscore was shown to be significantly correlated with tumor immune microenvironment (TIME) infiltration, immune phenotypes, molecular subtypes, and genetic variations. We further found that ATPscore was both an independent prognostic factor and a potent predictor of clinical response to immune-checkpoint inhibitors (ICIs) based immunotherapy. We further verified the value of key gene SRPX in ATPscore in HNSCC cell lines with the in-depth research of ATPscore and found that it is closely related to immune subtypes, molecular subtypes, and immune activation-related markers. Our research could help us to understand the underlying mechanisms of tumor immunity and provide a solid foundation for combination of autophagy-targeted therapies with immunotherapies for clinical application in HNSCC.
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Autofagia , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Imunoterapia , Fenótipo , Microambiente TumoralRESUMO
The newly harvested Jidan 66 (JD66) and Liangyu 99 (LY99) varieties of corns were stored for 56 days at constant temperature of 15 and 25 °C with relative humidity of 55%. The postharvest ripening resulted in more disordered secondary structure and less compact tertiary conformation of zein. The emulsifying activity and foaming stability reached maximum after storage of corns at 15 and 25 °C for 14 days, while the emulsifying stability and foaming capacity were the highest at two temperatures of storage for 7 days and 28 days, respectively. Furthermore, zein had the highest viscoelasticity as well as the strongest antioxidant activities after the storage of JD66 at two temperatures for 28 days and the storage of LY99 at 15 °C for 42 days and at 25 °C for 28 days. Therefore, appropriate postharvest ripening of corns changed the structure of zein, improving its antioxidant activities and physicochemical properties.
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This study aimed to identify novel pancreatic lipase (PL) inhibitors using affinity ultrafiltration combined with spectroscopy and molecular docking. Cyanidin-3-O-glucoside (C3G; IC50: 0.268 mg/mL) and catechin (IC50: 0.280 mg/mL) were shown to be potent PL inhibitors extracted from black rice and adzuki bean coat extracts. Isobologram analysis revealed that the combined use of C3G and catechin at a ratio of 2:3 had a remarkable synergistic effect (IC50 of the mixture: 0.201 mg/mL). The inhibitory mechanism of C3G-catechin mixture was of mixed type. The C3G-catechin mixture had a great impact on PL secondary structures. Molecular docking analysis further demonstrated that these polyphenols formed hydrophobic interactions and hydrogen bonds with amino acid residues in the binding pocket of PL. Collectively, C3G and catechin were shown to inhibit PL in a synergistic manner and can be potentially used for the development of food supplements for obesity prevention.
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Catequina , Catequina/farmacologia , Catequina/química , Lipase , Simulação de Acoplamento Molecular , Glucosídeos/química , Antocianinas/químicaRESUMO
Cancer stem cells (CSCs) drive tumor relapse, which is a major clinical challenge in colon cancer. Targeting CSCs presents a great opportunity in eradicating cancer cells and thus treatment of patients with cancer. However, the epigenetic control of the CSC signature and key molecules involved in colon cancer remains undefined. In this study, we demonstrated that alpha-1,3-glucosyltransferase (ALG8) is upregulated in colon cancer tissues compared with normal tissues. Overexpression of the ALG8 gene predicted poor overall survival and disease-free survival in colon cancer patients. Silencing of the ALG8 gene repressed the stemness of colon tumor cells. Xenograft mice transplanted with ALG8-deficient tumor cells significantly alleviated tumor burden and prolonged survival in comparison with control mice. Further analysis showed that ALG8 gene promoted cancer stemness through inducing glycosylation of LRP6, which activates the WNT/beta-catenin signaling pathway. Importantly, attenuation of the glycosylation using tunicamycin abrogated the effect of ALG8 gene on cancer stemness. Taken together, our findings demonstrated that ALG8 enhances colon tumorigenesis by activating the WNT/beta-catenin signaling pathway. Therefore, ALG8 gene is a potential therapeutic target in colon cancer.
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Neoplasias do Colo , Via de Sinalização Wnt , Humanos , Camundongos , Animais , Via de Sinalização Wnt/genética , Glicosilação , Recidiva Local de Neoplasia/genética , Células-Tronco Neoplásicas , Neoplasias do Colo/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Glucosiltransferases/genéticaRESUMO
CCT3 played a key role in many cancers. This study aimed to further explore the characteristics of CCT3 from a pan-cancer perspective and reveal the driving forces for CCT3. By bioinformatic analysis, we found that the mRNA and protein levels of CCT3 were abnormally elevated in most tumor types and were correlated with poor prognosis. Single-cell sequencing data indicated an abnormal increase of CCT3 expression in both malignant cells and multiple immune cells. In the tumor microenvironment, CCT3 expression was negatively relevant with immune cell infiltration and immune checkpoint genes expression. In colon cancer, knockdown of CCT3 inhibited cell proliferation. Gene set enrichment analysis showed that CCT3 may be oncogenic by regulating amino acid metabolism. Furthermore, we predicted sensitive drugs for CCT3 by virtual screening and sensitivity analysis. Many driver genes such as TP53 and KRAS were essential for CCT3 overexpression. Epigenetic factors, enhancers in particular, were also critical for CCT3 expression. Additionally, we constructed the lncRNA/circRNA-miRNA-CCT3 regulatory network. Collectively, CCT3 had the potential to be a diagnostic and prognostic biomarker for multiple tumor types. CCT3 expression was relevant with an immunosuppressive tumor microenvironment. CCT3 could be a new molecular target for colon cancer. Both genetic and epigenetic factors were responsible for CCT3 expression in tumors.
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This study investigated the effects of ultrasonic, freeze-thaw, and combined pretreatments on corn starch oil absorption. Low-field nuclear magnetic resonance (LF NMR) was used to study the oil absorption changes after frying of corn starch (CS) subjected to different treatments. The structural characteristics of samples were evaluated using various techniques. Scanning electron microscopy, contact angle, and particle size analysis showed that corn starch subjected to combined ultrasonic and freeze-thaw treatment generated larger, coarser particles with a denser structure. Furthermore, X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry showed that combined treatment improved the order and thermal stability of CS molecules, thereby inhibiting oil absorption during frying. The results showed that combined ultrasonic and freeze-thaw pretreatment significantly reduced the oil absorption of corn starch before and after frying.
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Although aberrant LINC00857 expression may play a key role in oncogenesis, no research has analyzed the pan-cancer oncogenic roles of LINC00857, particularly in tumor immunology. Here, we integrated data from several databases to analyze the characteristics of LINC00857 in pan-cancer. We found that LINC00857 was overexpressed and correlated with a poor prognosis in a variety of cancers. Furthermore, high-expression of LINC00857 was negatively associated with immune cell infiltration and immune checkpoint gene expression. Notably, LINC00857 expression was negatively related to microsatellite instability and tumor mutation burden in colorectal cancer, implying poor reaction to immunotherapy when LINC00857 was highly expressed. Targeting LINC00857 could dramatically impair the proliferative ability of colorectal cancer cells. After RNA-sequencing in HCT116 cells, gene set enrichment analysis showed that LINC00857 may accelerate cancer progression by inhibiting the ferroptosis pathway and promoting glycolipid metabolism in colorectal cancer. Screening by weighted gene co-expression network analysis determined PIWIL4 as a target of LINC00857, which also performed an immunosuppressive role in colorectal cancer. Based on the structure of PIWIL4, a number of small molecule drugs were screened out by virtual screening and sensitivity analysis. In summary, LINC00857 expression was closely correlated with an immunosuppressive microenvironment and may be a novel diagnostic and prognostic biomarker for diverse cancers. The LINC00857/PIWIL4 axis may be predictive biomarkers for immunotherapy and valuable molecular targets for malignant tumors.
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Super enhancers are critical for the gene transcription responsible for cell fate by interacting with transcription factors. However, the relevance of HSF1 to super enhancers in tumors remains obscure. We profiled H3K27ac enrichment by chromatin immunoprecipitation sequencing. HSF1-mediated lncRNAs were identified by lncRNA microarray. The characteristics of LINC00857 were explored by in vitro and in vivo assays. The mechanism was studied via chromatin immunoprecipitation, RNA immunoprecipitation, and HSF1/ANXA11 knockout mice. We found that super enhancers occupied multiple gene loci in colorectal cancer. We screened out an HSF1-mediated super enhancer, lncRNA-LINC00857, which exerts its characteristics in promoting cell growth via regulating glutamine metabolism. Notably, HSF1 could stimulate the super-enhancer activity of LINC00857 by the enrichment of acetyltransferase P300 to its gene loci, contributing to LINC00857 transcription. In turn, nuclear LINC00857 cooperated with HSF1 to promote ANXA11 transcription, which modulated SLC1A5/ASCT2 protein expression by binding competitively to miR-122-5p. The knockout of ANXA11 attenuated colorectal cancer formation in vivo. Collectively, we shed light on a closely cooperative machinery between HSF1 and super enhancers. HSF1 could stimulate acetyltransferase P300-mediated super-enhancer activity to facilitate LINC00857 expression, contributing to SLC1A5-mediated glutamine transport. Targeting the HSF1/LINC00857/ANXA11 axis may provide a valuable therapeutic strategy against colorectal cancer.
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BACKGROUND: The extravasation capability of hepatocellular carcinoma (HCC) cells plays a vital role in distant metastasis. However, the underlying mechanism of extravasation in HCC lung metastasis remains largely unclear. METHODS: The expression of ARHGEF37 in human HCC specimens and HCC cell lines was examined by quantitative RT-PCR, western blot, and immunohistochemistry (IHC) analyses. The biological roles and mechanisms of ARHGEF37/Cdc42 in promoting lung metastasis were investigated in vitro and in vivo using cell lines, patient samples, xenograft models. RESULTS: In the current study, we found that Rho guanine nucleotide exchange factor 37 (ARHGEF37) was upregulated in human HCC samples and was associated with tumor invasiveness, pulmonary metastasis and poor prognosis. Overexpressing ARHGEF37 significantly enhanced the extravasation and metastatic capability of HCC cells via facilitating tumor cell adhesion to endothelial cells and trans-endothelial migration. Mechanistically, ARHGEF37 directly interacted with and activated Cdc42 to promote the invadopodia formation in HCC cells, which consequently disrupted the interaction between endothelial cells and pericytes. Importantly, treatment with ZCL278, a specific inhibitor of Cdc42, dramatically inhibited the attachment of ARHGEF37-overexpressing HCC cells to endothelial cells, and the adherence and extravasation in the lung alveoli, resulting in suppression of lung metastasis in mice. CONCLUSION: Our findings provide a new insight into the underlying mechanisms on the ARHGEF37 overexpression-mediated extravasation and pulmonary metastasis of HCC cells, and provided a potential therapeutic target for the prevention and treatment of HCC pulmonary metastasis.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Pulmonares , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/patologia , Camundongos , Metástase Neoplásica/patologiaRESUMO
The differentiation of innate lymphoid cells (ILCs) from hematopoietic stem cells needs to go through several multipotent progenitor stages. However, it remains unclear whether the fates of multipotent progenitors are predefined by epigenetic states. Here, we report the identification of distinct accessible chromatin regions in all lymphoid progenitors (ALPs), EILPs, and ILC precursors (ILCPs). Single-cell MNase-seq analyses revealed that EILPs contained distinct subpopulations epigenetically primed toward either dendritic cell lineages or ILC lineages. We found that TCF-1 and GATA3 co-bound to the lineage-defining sites for ILCs (LDS-Is), whereas PU.1 binding was enriched in the LDSs for alternative dendritic cells (LDS-As). TCF-1 and GATA3 were indispensable for the epigenetic priming of LDSs at the EILP stage. Our results suggest that the multipotency of progenitor cells is defined by the existence of a heterogeneous population of cells epigenetically primed for distinct downstream lineages, which are regulated by key transcription factors.
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Imunidade Inata , Linfócitos , Diferenciação Celular , Linhagem da Célula , Epigênese Genética , Células-Tronco HematopoéticasRESUMO
This study first used adzuki bean seed coat polyphenol (ABSCP) to modify zein and form covalent nanoparticles (ZAP) and used ZAP as an emulsifier to stabilize Pickering emulsion (ZAE). The results showed that the ratio of zein-ABSCP controlled the physicochemical properties of the two compounds. ZAP could be absorbed on the water-oil surface and stabilized ZAE, which presented as a non-Newtonian fluid state with good rheological properties. The addition of ABSCP inhibited lipid oxidation in a dose-dependent manner, as verified through the analysis of accelerated oxidation experiments (50 °C, 20 days). In in vitro gastrointestinal digestion of ZAE showed that free fatty acids (FFA) release gradually decreased with ABSCP concentration increasing. Moreover, ABSCP gave ZAE a strong red-yellow color, which allowed ZAE to be used for specific applications (e.g., natural pigments). Our findings make it feasible to develope functional food and food-grade delivery systems made of protein-plant polyphenols nanoparticles.
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Nanopartículas , Vigna , Zeína , Digestão , Emulsões/química , Lipídeos , Nanopartículas/química , Tamanho da Partícula , Polifenóis , Sementes , Zeína/químicaRESUMO
Parkinson's disease (PD) is a devastating disease of the central nervous system that occurs mainly in the elderly age group, affecting their quality of life. The PD pathogenesis is not yet fully understood and lacks the disease-modifying treatment strategies. Sanghuangprous vaninii (S. vaninii) is a perennial fungus with a plethora of pharmacological activities including anti-cancer and antioxidant activity and so on. However, no study till date has reported its neuroprotective effect against symptoms that are similar to PD in pre-clinical investigation. In the current study, we investigated anti-PD-like effects of S. vaninii mycelium extracts (SvMEs) on MPTP-induced PD in zebrafish. We observed that the loss of dopaminergic neurons and neurovascular reduction were reversed by using SvMEs in the zebrafish brain in a concentration-independent manner. Moreover, it also relieved locomotor impairments in MPTP-induced PD zebrafish. In addition, SvMEs exerted significant antioxidant activity in vitro, which was also demonstrated in vivo on ktr4:NTR-hKikGR zebrafish. Upon investigating the underlying mechanism, we found that SvMEs may alleviate oxidant stress and accelerate α-synuclein degradation and then alleviate PD-like symptoms. Antioxidant-related genes (sod1, gss, gpx4a, gclm, and cat) implied that the SvMEs exhibited anti-PD activity due to the antioxidation mechanism. Finally, upon analysis of chemical composition of SvMEs by liquid chromatography-mass spectrometry, we identified 10 compounds that are plausibly responsible for the anti-PD-like effect of SvMEs. On the limiting part, the finding of the study would have been more robust had we investigated the protein expression of genes related to PD and oxidative stress and compared the effects of SvMEs with any standard anti-PD therapy. Despite this, our results indicated that SvMEs possess anti-PD effects, indicating SvMEs as a potential candidate that is worth exploring further in this avenue.
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Basidiomycota , Intoxicação por MPTP , Fármacos Neuroprotetores , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Intoxicação por MPTP/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Qualidade de Vida , Peixe-ZebraRESUMO
RAB42 is a member of the RAS family. However, the roles and driving forces for RAB42 in tumors remain elusive. In this study, we performed a comprehensive pan-cancer analysis of the roles and regulatory mechanisms of RAB42 using bioinformatics and experiments. Online databases such as Sanger Box, ACLBI and TIDE were used to search for the expression levels, prognostic value and immune features of RAB42. We observed that RAB42 expression was upregulated in most tumors and was closely associated with poor prognosis. Enrichment analysis indicated that RAB42 was related to multiple biological functions, especially the immune process. RAB42 expression had a positive correlation with immune cell infiltration and immune checkpoint gene expression. RAB42 had a high predictive value for immunotherapy efficiency. Our study screened out susceptible drugs for the RAB42 protein by sensitivity analysis and virtual screening. Many key driver genes such as TP53 contributed to RAB42 expression. DNA methylation, super-enhancer and non-coding RNAs were the epigenetic factors responsible for RAB42 expression. In brief, RAB42 could serve as a diagnostic and prognostic biomarker in many tumor types. RAB42 might be a predictive biomarker and a new target for immunotherapy. Genetic and epigenetic factors were essential for RAB42 overexpression in tumors.
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Neoplasias , Humanos , Neoplasias/genética , Biologia Computacional , Metilação de DNA , Bases de Dados Factuais , EpigenômicaRESUMO
CD8+ T cells belonging to the adaptive immune system play key roles in defending against viral infections and cancers. The current CD8+ T cell-based immunotherapy has emerged as a superior therapeutic avenue for the eradication of tumor cells and long-term prevention of their recurrence in hematologic malignancies. It is believed that an effective adaptive immune response critically relies on the help of the innate compartment. Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that have been considered some of the first cells to respond to infections and can secrete a large amount of diverse cytokines and chemokines to widely modulate the innate and adaptive immune responders. Like CD8+ T cells, iNKT cells also play an important role in defense against intracellular pathogenic infections and cancers. In this review, we will discuss the CD8+ T-cell immunity contributed by iNKT cells, including iNKT cell-mediated cross-priming and memory formation, and discuss recent advances in our understanding of the mechanisms underlying memory CD8+ T-cell differentiation, as well as aging-induced impairment of T-cell immunity.
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Células T Matadoras Naturais , Neoplasias , Humanos , Linfócitos T CD8-Positivos , Ativação Linfocitária , CitocinasRESUMO
Insulin resistance (IR) is one of the pathological reasons for type II diabetes mellitus (T2DM). Therefore, it is important to prevent the body from developing T2DM by improving IR and maintaining glucose homeostasis. Anthocyanins (ACNs) are water-soluble pigments and are widely distributed in natural products. This article summarizes research on the bioavailability and metabolism of ACNs. Moreover, we further elaborate on how ACNs reduce IR and hyperglycemia during the development of T2DM based on studies over the past 20 years. Many studies have demonstrated that ACNs are small molecules that target the pancreatic, liver, muscle, and adipose tissues, preventing IR and hyperglycemia. However, the molecular mechanisms are still unclear. Therefore, we envision whether the molecular mechanism of reducing T2DM by ACNs could be more deeply investigated.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Antocianinas , Antioxidantes/farmacologia , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta , Humanos , InsulinaRESUMO
Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a target for disease prevention. However, the relationship between ACE2 expression and its clinical implications in SARS-CoV-2 pathogenesis remains unknown. Here, we explored the location and expression of ACE2, and its correlation with gender, age, and cigarette smoke (CS), in a CS-exposed mouse model and 224 non-malignant lung tissues (125 non-smokers, 81 current smokers, and 18 ex-smokers) by immunohistochemistry. Moreover, the correlations of ACE2 with CS-induced oxidative stress-related markers, hypoxia-inducible factor-1α (HIF-1α), inducible nitric oxide synthase (iNOS), and 4-hydroxynonenal (4-HNE) were investigated. Chromatin immunoprecipitation and luciferase reporter assays identified the cause of ACE2 overexpression in human primary lung epithelial cells. We demonstrated that ACE2 was predominantly overexpressed on the apical surface of bronchial epithelium, while reduced in alveolar epithelium, owing to the dramatically decreased abundance of alveolar type II pneumocytes in CS-exposed mouse lungs. Consistent with this, ACE2 was primarily significantly overexpressed in human bronchial and alveolar epithelial cells in smokers regardless of age or gender. Decreased ACE2 expression was observed in bronchial epithelial cells from ex-smokers compared with current smokers, especially in those who had ceased smoking for more than 10 years. Moreover, ACE2 expression was positively correlated with the levels of HIF-1α, iNOS, and 4-HNE in both mouse and human bronchioles. The results were further validated using a publicly available dataset from The Cancer Genome Atlas (TCGA) and our previous integrated data from Affymetrix U133 Plus 2.0 microarray (AE-meta). Finally, our results showed that HIF-1α transcriptionally upregulates ACE2 expression. Our results indicate that smoking-induced ACE2 overexpression in the apical surface of bronchial epithelial cells provides a route by which SARS-CoV-2 enters host cells, which supports clinical relevance in attenuating the potential transmission risk of COVID-19 in smoking populations by smoking cessation. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.